SECTION 14 Medical disorders in pregnancy

14.1 Physiological changes of normal pregnancy 256

14.1 Physiological changes of normal pregnancy 2563

ESSENTIALS Almost every maternal organ system makes a physiological adapta- tion to pregnancy for optimal pregnancy outcome. An understanding of these adaptations brings insight into the aetiology of gestational syndromes and helps the clinician to manage pregnant women with pre-​existing chronic illness. Physiological adaptations in pregnancy include:  (1) cardiovas- cular—​cardiac output increases by 30–​40%; (2) respiratory—​oxygen consumption increases 20%; and (3) renal—​glomerular filtration rate increases 55%. Biochemical and endocrine changes in pregnancy include: altered normal ranges for many important metabolic and endocrine labora- tory tests, such as (1) serum creatinine and urea—​both decreased; (2)  cholesterol and triglycerides—​both increased; (3)  liver blood tests—​alkaline phosphatase increased up to fourfold; and (4) thy- roid function tests—​free thyroxine and tri-​iodothyronine levels fall, thyroid-​stimulating hormone levels fall then rise. Awareness of these changes is essential, both for recognition of disease in pregnancy and to prevent inappropriate pursuit of test results that are normal in pregnancy. Long-​term implications of pregnancy syndromes: pre-​eclampsia and gestational diabetes mellitus for example, can be considered ex- aggerated responses to pregnancy that resolve after childbirth, but herald hypertension and diabetes mellitus in later life. Introduction Pregnancy makes extra physiological demands on almost all ma- ternal organs. Women with pre-​pregnancy disease may be unable to meet these gestational demands, which puts their own health at risk and compromises pregnancy outcome. In some women, the physio- logical changes of pregnancy unmask a subclinical predisposition to future disease through the transient development of gestational syndromes, such as pre-​eclampsia and gestational diabetes mellitus. In this respect pregnancy acts as a maternal ‘stress test’ that identifies a woman’s vulnerability to future disease. An understanding of the normal physiological demands of pregnancy not only brings insight into the aetiology and management of gestational syndromes, but also helps the clinician advise women with pre-​existing chronic illness about the risks and consequences of pregnancy. Preparing for pregnancy The female body prepares for pregnancy during every menstrual cycle. It is not only the endometrium that anticipates implantation of a fertilized ovum, but the whole cardiovascular system. During the postovulatory or luteal phase of each menstrual cycle there is a de- crease in systemic vascular resistance by approximately 20%, leading to a 10% fall in mean arterial pressure compared with the follicular phase. Cardiac output increases by almost 20%, and renal vasodila- tation increases both renal blood flow and glomerular filtration by approximately 10%. All of these changes resolve with involution of the corpus luteum and onset of menses. Cardiovascular changes in pregnancy If fertilization is successful, the haemodynamic changes established in the menstrual cycle progress further. Systemic vascular resistance (SVR) falls by almost 40% and causes a maximal decrease in mean arterial pressure by mid-​pregnancy. Both systolic and diastolic blood pressure fall significantly by week 5–​6 of healthy pregnancy, then rise to non​pregnancy levels at term. In normal weight, nulliparous women having a normal pregnancy, the mean blood pressure (95% reference range) at 12 weeks is 112/​65 (89–​136/​49–​82) mm Hg and at 37 weeks 116/​70 (92–​140/​52–​88) mm Hg. Heart rate increases by approximately 20%, from a pre-​pregnancy average 72 beats/​min (range 60–​100 bpm) to 85 beats/​min at term (range 72–​120). The rise in stroke volume and fall in SVR results in a 30–​40% increase in cardiac output by 24 weeks, which is sustained until the final weeks of pregnancy. During the third trimester, cardiac output falls in the supine position when the gravid uterus compresses the inferior vena cava. Throughout pregnancy, left ventricular wall thickness and left ventricular mass increase by up to 30% and 50%, respectively. Cardiac output returns almost completely to pre-​pregnancy levels within two weeks of delivery. 14.1 Physiological changes of normal pregnancy David J. Williams

Section 14  Medical disorders in pregnancy 2564 Distribution of increased cardiac output Although it is technically difficult to measure blood flow to par- ticular maternal viscera during pregnancy, it is clear that the timing and extent of changes to blood flow varies between organs. This is summarized in Fig. 14.1.1. Mammary artery blood flow increases early in pregnancy and causes breast tenderness and swelling. Mechanism of gestational cardiovascular change As blood flow to maternal visceral organs increases during the menstrual cycle, maternal rather than fetoplacental factors are implicated in the early cardiovascular adaptations to pregnancy. Oestrogen, mainly in the form of 17β-​oestradiol and the 6 KDa hormone relaxin, are potent vasodilators. Both are produced by the corpus luteum during the luteal phase of each menstrual cycle and for the first 10 weeks of pregnancy. After 10 weeks, the pla- centa secretes its own 17β-​oestradiol, so that by 37 weeks’ gestation maternal oestradiol levels are approximately 250-​fold higher than those found during the menstrual cycle. 17β-​Oestradiol relaxes vascular smooth muscle through both endothelium-​dependent and independent mechanisms, and all of the endothelium-​derived vasodilators—​nitric oxide, prostacyclin, and endothelial-​derived hyperpolarizing factor—​have been implicated in the gestational fall of systemic vascular resistance. Relaxin has both rapid and sus- tained vasodilatory effects that work through activation of endo- thelial nitric oxide synthase, and vascular endothelial and placental growth factors, respectively. Much less is known about the vascular effects of progesterone, whose circulating levels increase by a similar amount to 17β-​ oestradiol and may play a role in reducing pressor responsiveness to angiotensin II. Although the precise mechanism of maternal vasodilatation is likely to be different in different vascular beds, a healthy endothe- lium is essential for normal cardiovascular adaptation to pregnancy. Fluid balance during pregnancy Arterial dilatation creates a relatively underfilled state, which stimu- lates the renin–​angiotensin–​aldosterone system. As a result, sodium and water retention throughout pregnancy leads to a 6–​8 litre rise Fig. 14.1.1  Changes in maternal organ blood flow during healthy pregnancy. DBP, diastolic blood pressure; ERPF, estimated renal plasma flow; GFR, glomerular filtration rate; SBP, systolic blood pressure.

14.1  Physiological changes of normal pregnancy 2565 in total extracellular fluid volume. Plasma volume increases steadily until week 32, when it is 40% (or c.1.2 litres) above non​pregnant levels. This is partly mediated by a fall in the osmotic threshold for thirst, with a concomitant fall in the threshold for secretion of anti- diuretic hormone (AVP) preventing a water diuresis and sustaining a lower plasma osmolality by 10 mosmol/​kg until term. During the second half of pregnancy, placental production of vasopressinase in- creases maternal AVP degradation, but plasma AVP levels remain stable as pituitary secretion of AVP normally increases fourfold. A  failure of increased maternal AVP secretion leads to transient diabetes insipidus of pregnancy. Plasma atrial natriuretic pep- tide levels are normal until the second trimester, when they rise by approximately 40%. Immunological changes during pregnancy It is often presumed that pregnant women are immunosuppressed in order not to reject the fetal semi-​allograft. This is not true. Certain aspects of maternal immunity are modulated, but it is the placenta that deserves most credit for eluding maternal immunity. Much harm is prevented by the physical separation of maternal and fetal blood. For instance, when this placental barrier is breached a rhesus-​ negative mother can be exposed to rhesus-​positive fetal blood and then develop alloantibodies that will haemolyse red cells of future rhesus-​positive offspring. In normal pregnancy the placenta must invade uterine tissue, the decidua. To avoid a hostile immune response the surface layers of placenta, extravillous trophoblast, express both a unique non-​ polymorphic HLA G and a classical polymorphic histocompati- bility antigen, HLA C. The unique interaction between placental HLA C subgroup and maternal decidual natural killer (NK) cell immunoglobulin receptor appears to dictate the level of placental invasion and consequent pregnancy success. The placenta also ex- presses a plethora of complement control systems to protect itself from the gestational rise in serum levels of maternal complement factors C3 and C4. Innate immunity is modulated in pregnancy so that maternal NK cell activity at the uteroplacental interface promotes placental in- vasion, but intercurrent infection can activate latent NK cytolytic activity to harm fetal and maternal tissues. Fetal survival is also enhanced by a shift away from maternal T-​helper 1 cytokine re- sponses, which promote cell-​mediated immunity towards a stronger T-​helper 2 cytokine response that promotes antibody production. In consequence, pregnant women are more prone to severe infec- tions with intracellular pathogens such as malaria, tuberculosis, listeria, and Salmonella typhimurium, and they are also more likely to suffer reactivation of viruses such as Epstein–​Barr. However, T regulatory cells are elevated in healthy pregnancy and may also reduce autoimmune and alloimmune responses to maternal self and fetoplacental antigens. Circulating levels of maternal immunoglobulin increase and im- munoglobulin heavy chain (IgG) transferred across the placenta provides passive immunity to the fetus. Neutrophils increase in number and develop a proinflammatory phenotype. Mean total white cell count increases to 9.0 × 109/​litre and can rise as high as 40.0 × 109/​litre during labour, returning to normal within six days. Erythrocyte sedimentation rate (ESR) rises as a consequence of in- creased fibrinogen and globulin: an ESR over 30 mm/​h is usual, and up to 70 mm/​h is within normal limits. Circulating levels of C-​reactive protein do not change during healthy pregnancy and remain a good marker of incidental inflammation. Anatomical changes to the maternal immune system include involution of the thymus and enlargement of the spleen. Understanding gestational immune modulation and how it fails in pathological pregnancies will facilitate measures to improve preg- nancy outcome. Ventilatory changes during pregnancy The increased metabolic demands of pregnancy lead to a pro- gressive increase in oxygen consumption of up to almost 20% by term. Pregnant women breathe more deeply, but not more quickly, to achieve this. Tidal volume increases from approximately 500 to 700 ml, and effective alveolar ventilation actually surpasses the body’s demand for oxygen, creating a respiratory alkalosis with Pco2 falling from 5.0 to 4.0 kPa. Progesterone stimulates deeper breathing by a direct effect on the respiratory centre, particularly increasing sensitivity to CO2. Renal changes during pregnancy By 16 weeks gestation, renal blood flow has increased by 80% (Fig. 14.1.1) and glomerular filtration rate by 55%. The rise in renal blood flow causes the kidneys to swell so that they appear approximately 1 cm longer on ultrasonography. The renal pelvis and ureters dilate, sometimes appearing obstructed to those un- aware of these changes. Serum levels of creatinine and urea fall, so that levels considered normal outside pregnancy may reflect renal impairment during pregnancy. Proteinuria increases during pregnancy, but levels above 300 mg/​24 h, or a protein:creatinine ratio greater than 30 mg/​mmol should be considered abnormal. Gestational glycosuria reflects re- duced tubular glucose reabsorption and does not necessarily indi- cate hyperglycaemia. Furthermore, reduced tubular absorption of bicarbonate creates a metabolic acidosis that compensates for the respiratory alkalosis, keeping maternal pH at 7.4. The renal production of erythropoietin, active vitamin D, and renin increases during healthy pregnancy, but their effects are masked by other physiological changes. In early pregnancy, per- ipheral vasodilatation exceeds the renin–​aldosterone mediated plasma volume expansion, hence mean arterial pressure falls until the third trimester. The 40% expansion of plasma volume exceeds the effect of a two to fourfold increase in maternal serum erythro- poietin levels, which stimulates only a 25% rise in red cell mass. This creates a ‘physiological anaemia’, which should not normally cause haemoglobin concentration to fall to less than 98 g/litre (see Chapter 14.17). Similarly, active vitamin D circulates at twice non​gravid levels, but concomitant halving of parathyroid hormone levels, as well as hypercalciuria and increased fetal requirements, keeps plasma ionized calcium levels unchanged.

Section 14  Medical disorders in pregnancy 2566 Liver metabolism during pregnancy Hepatic artery and portal vein blood flow increase during the third trimester of healthy pregnancy (Fig. 14.1.1). Hepatic syn- thetic function and metabolism lead to an increase in serum concentrations of fibrinogen, ceruloplasmin, transferrin, and binding proteins such as thyroid-​binding globulin, but a fall in serum albumin levels by approximately 25%. At term, serum cholesterol is raised by 50% and triglycerides by up to 300%. Increasing demands for maternal energy production are met through increased activity of the tricarboxylic acid cycle and ketogenesis during the third trimester. The normal ranges for aspartate transaminase, alanine transaminase, γ-​glutamyl trans- ferase, and bilirubin decrease by as much as 20% from the first trimester until term. Maternal serum bile acid levels remain un- changed throughout healthy pregnancy (third trimester mean and 95% CI; 3.9 µmol/​litre (1.8–​8.2 µmol/​litre)). After 20 weeks’ gestation, placental production of alkaline phosphatase increases maternal plasma levels by up to fourfold. Telangiectasia and palmar erythema are common signs of healthy pregnancy that resolve postpartum. The gastrointestinal system in pregnancy Nausea and vomiting affect about 60% of women during the first trimester. The rise and fall of hCG levels correlate temporally with the onset and improvement of these symptoms, but the underlying cause is undoubtedly multifactorial. Relaxation of intestinal smooth muscle by progesterone and relaxin creates many of the other pregnancy-​induced gastrointestinal changes: gastric motility and small-​bowel transit are slowed, especially during labour; the gallbladder enlarges and empties slowly in response to meals; a de- crease in lower oesophageal pressure leads to gastro-​oesophageal re- flux in many women. Endocrine changes in pregnancy Thyroid function The thyroid faces three challenges during pregnancy. First, increased renal clearance of iodide and losses to the fetus create a state of rela- tive iodine deficiency. Pregnancy therefore stimulates growth of thy- roid goitres, particularly when dietary iodine intake is low. Secondly, high oestrogen levels induce hepatic synthesis of thyroid-​binding globulin, but free thyroxine (T4) and tri-​iodothyronine (T3) levels fall progressively during pregnancy to levels below the normal range for non​pregnant women (Table 14.1.1). Thirdly, placental hCG shares structural similarities with thyroid-​stimulating hormone (TSH) and has weak TSH-​like activity. For this reason, TSH levels fall in the first trimester, but rise back towards non​pregnancy levels in the third ­trimester (Table 14.1.1). Although hCG rarely stimu- lates free T4 levels into the thyrotoxic range, trophoblastic disease and hyperemesis gravidarum associated with high hCG levels can lead to biochemical hyperthyroxinaemia and suppression of TSH suggestive of thyrotoxicosis. Importantly, under these circum- stances the mother remains clinically euthyroid and her thyroid bio- chemistry will resolve with resolution of hyperemesis. Pituitary function The maternal pituitary makes only a small contribution to a suc- cessful pregnancy once ovulation has occurred and the uterus is prepared for implantation. The only pituitary hormone to in- crease significantly during pregnancy (by c.10-​fold) is prolactin, which is responsible for breast development and subsequent milk production. Pituitary secretion of growth hormone (GH) is mildly suppressed during the second half of pregnancy by placental production of a GH variant, the role of which is unclear, but it may contribute to ges- tational insulin resistance. Placental production of adrenocorticotropic hormone (ACTH) leads to an increase in maternal ACTH levels, but not beyond the normal range for non​pregnant subjects. Free cortisol levels double, and in the second half of pregnancy may contribute to insulin resist- ance and striae gravidarum. High oestrogen levels during pregnancy stimulate lactotroph hyperplasia and result in pituitary enlargement. These high levels, together with those of progesterone, suppress luteinizing hormone (LH) and follicular stimulating hormone (FSH). Plasma follicular stimulating hormone levels recover within two weeks of child- birth, but pulsatile luteinizing hormone release is generally not Table 14.1.1  Important gestational changes during pregnancy Non​pregnant First trimester Second trimester Third trimester Haemoglobin
(g/​dl) 109–​151 110–​143 100–​137 98–​137 Platelets
(×109/​litre) 168–​433 174–​391 171–​409 155–​429 White cell count (×109/​litre) 4.3–​12.4 5.7–​13.6 6.2–​14.8 5.9–​16.9 Alanine transaminase
(IU/​litre) 0–​40 6–​32 6–​32 6–​32 Serum creatinine (μmol/​litre) 73 ± 10 60 ± 8 54 ± 10 64 ± 9 Plasma urea (mmol/​litre) 4.3 ± 0.8 3.5 ± 0.7 3.3 ± 0.8 3.1 ± 0.7 Plasma urea
(μmol/​litre) 246 ± 59 189 ± 48 214 ± 71 269 ± 56 Thyroid function free T4 (pmol/​litre) TSH (mlU/​litre) 12.0–​22 0.25–​4.2 11.1–​18.5 0.02–​3.12 9.8–​16.3 0.34–​2.99 8.6–​14.6 0.38–​5.43 Fasting cholesterol (mmol/​litre) 5.0 ± 0.3 5.5 ± 0.4 6.9 ± 0.4 7.8 ± 0.4

14.1  Physiological changes of normal pregnancy 2567 resumed until after breastfeeding. Elevated prolactin levels inhibit gonadotropin-​releasing hormone (GnRH) and hence luteinizing hormone in breastfeeding mothers. Carbohydrate metabolism Women develop insulin sensitivity during the first half of preg- nancy, but insulin resistance after 20 weeks’ gestation. In the second half of pregnancy a glucose load will stimulate greater maternal insulin release, but with less effect. Obese women who are already insulin resistant are more likely to develop gestational diabetes mellitus. Hormones that might mediate this insulin re- sistance include cortisol, progesterone, oestrogen, and human placental lactogen. Placental production of human placental lactogen, a GH-​like protein, coincides temporally with insulin resistance. Coagulation In anticipation of haemorrhage at childbirth, normal pregnancy is characterized by low-​grade, chronic intravascular coagulation within both the maternal and uteroplacental circulation. During pregnancy maternal levels of clotting factors V, VIII, and X increase, while anticoagulant factors decrease; particularly protein S levels and fibrinolytic activity. These changes lead to an acquired protein C resistance in nearly half of all pregnant women. However, physio- logical contraction of the uterus by oxytocin at childbirth is the most effective way to prevent peripartum haemorrhage. Skin and hair during pregnancy Hyperpigmentation affects up to 90% of pregnant women. Areas that are normally hyperpigmented, such as the areolae and vulva, become darker. This may be mediated by oestrogen and progesterone, which are powerful melanogenic stimulants. Hair growth increases during pregnancy and hair loss is accelerated postpartum. The gestational rise in corticosteroids and ovarian androgens contributes to the number of hairs in the growing phase (anagen). The levels of these hormones fall postpartum and hair growth moves back into the resting phase (telogen). FURTHER READING Chapman AB, et al. (1998). Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Internat, 54, 2056–​63. Conrad KP (2011). Maternal vasodilatation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol, 301, R267–​75. Kenyon A, Adamason AP, Williams DJ (2010). Physiology. In: Bennett P, Williamson C (eds) Basic science in obstetrics and gynaecology, 4th edition, Chapter 10. Churchill Livingston, London. Macdonald-​Wallis C, et al. (2015). Gestational-​age-​specific reference ranges for blood pressure in pregnancy: findings from a prospective cohort. J Hypertens, 33, 96–​105. McNeil AR, Stanford PE (2015). Reporting thyroid function tests in pregnancy. Clin Biochem Rev, 36, 109–​26. Poppas A, et al. (1997). Serial assessment of the cardiovascular system in normal pregnancy. Circulation, 95, 2407–​15. Williams DJ (ed) (2015). Maternal medicine. Preface: issue 29.5. Best Pract Res Clin Obstet Gynaecol, 29, 577–​8.

14.10 Diabetes in pregnancy 2627

14.10 Diabetes in pregnancy 2627

ESSENTIALS Diabetes in pregnancy is predominantly either pre-​existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter defined as diabetes or glucose intolerance first diagnosed during the preg- nancy. Gestational diabetes usually arises in the late second trimester and is common, affecting from 2–​6% to 15–​20% of pregnant women depending on diagnostic criteria and country of origin. Gestational diabetes is most commonly diagnosed on the basis of an oral glucose tolerance test performed at 24–​28 weeks’ gesta- tion by a plasma glucose at 0 minutes of more than 5.1 (or >5.6, depending on the authority) mmol/​litre, or at 120 minutes of more than 8.5 (or >7.8) mmol/​litre. Diabetes affects fertilization, implantation, embryogenesis, or- ganogenesis, fetal growth and development, and neonatal and perinatal morbidity and mortality. Preconception counselling is associated with improved pregnancy outcomes. Key aspects of periconceptional and pregnancy management include optimization of glycaemic control, stopping of medications contra-​indicated in pregnancy, avoidance of hypoglycaemia and diabetic ketoacidosis, and screening and management of diabetic complications. Risks to the fetus of maternal diabetes include congenital malfor- mations, fetal macrosomia, intrauterine growth restriction, and those from the increased incidence of maternal pre-​eclampsia. Long-​term adverse effects such as increased susceptibility to metabolic disease later in life are also recognized. Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy for manage- ment by a hospital-​based multidisciplinary team. Optimal blood glu- cose targets are a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8 mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. In some women with gestational diabetes this may be achieved with diet and exercise, but oral hypo- glycaemic agents (typically metformin or glibenclamide) and/​or in- sulin are often required. Women with diabetes should give birth in hospitals where 24 hour-​a-​day advanced neonatal resuscitation skills are available. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then because of the increased risk of stillbirth. The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose. Introduction Diabetes mellitus (DM), whether pre-​existing, or new onset in preg- nancy has major long-​term implications for both maternal and fetal health. The overall incidence of diabetes in women of child- bearing age has increased over the last decade and is anticipated to continue to rise. One of the underlying causes of this is the rising prevalence of obesity, and this is impacting on the type of diabetes as well as the demographic factors of pregnant women with diabetes. Understanding the type of diabetes a woman has and the associated risk factors is key to the management of diabetes in pregnancy, as well as the implication for success or failure of potential interven- tion strategies. In addition, as the number of pregnant women with diabetes rises, there is a substantial impact on healthcare costs and resource utilization, emphasizing the need for the implementation of the best evidence-​based cost-​efficient treatment strategies. The physiology of glucose homeostasis during pregnancy In normal early pregnancy there is an increase in insulin sensitivity and a fall in fasting plasma glucose in non​obese women. This increase in insulin sensitivity accounts for the fall in insulin requirements seen in women with type 1 DM and their susceptibility to hypogly- caemia during the first trimester. Insulin sensitivity continues to in- crease at the beginning of the second trimester, after which there is a progressive reduction in insulin sensitivity until term, and by late pregnancy insulin sensitivity will have fallen by 40–​60%. The underlying mechanisms for these changes are complex and due in part to maternal and placental adipokines and cytokines, as well as to the upregulation of the growth hormone/​insulin-​like growth factor axis by high circulating concentration of placental 14.10 Diabetes in pregnancy Bryony Jones and Anne Dornhorst

Section 14  Medical disorders in pregnancy 2628 growth hormone. The contributions of the early increase in corpus luteal and then placental progesterone and 17β-​oestrogen by 10-​ and 30-​fold, respectively, on insulin resistance is unclear. The physiological reduction in insulin sensitivity in later preg- nancy facilitates the maternal-​fetal transfer of glucose and other nutrients across the placenta. Decreased insulin sensitivity de- creases the glucose uptake in maternal muscle, the principal site of whole-​body glucose disposal, thereby redirecting glucose to the fetus where it is the principal fetal substrate. This transfer of glu- cose is facilitated by GLUT-​1, a specific placental glucose trans- porter protein, and by the maternal-​fetal glucose concentration gradient. By late pregnancy the degree of maternal hepatic and peripheral insulin resistance results in an increased hepatic glu- cose output and free fatty acid release from maternal adipose stores that increase during early pregnancy due to the relative insulin resistance. This normal physiological fall in insulin sensitivity in pregnancy is greater in obese women and those with gestational diabetes mellitus (GDM). Maternal insulin secretion increases in response to the fall in insulin sensitivity, such that post-​prandial insulin secretion is in- creased 200–​250% from baseline levels by late pregnancy. This is ac- companied by an adaptive increase in the numbers of β cells in small islets, implying β-​cell neogenesis rather than duplication of β cells in existing islets. The increase in maternal insulin secretion helps promote maternal lipogenesis in early pregnancy and the deposition of adipose stores. If the maternal insulin response to pregnancy is inadequate, ma- ternal hyperglycaemia will develop, leading to the development of gestational diabetes mellitus. While most women who become hyperglycaemic are at risk of future type 2 DM, and start pregnancy with increased insulin resistance such that their insulin demands to maintain euglycaemia in pregnancy are extremely high, a smaller proportion of women are in the early preclinical phases of type 1 DM. The increased insulin demands of pregnancy account for the observation that there is a threefold increase in the new presentation of type 1 DM in pregnancy. Identifying this small group of women is important as early insulin treatment and close antenatal surveillance is important. Epidemiology and classification Diabetes in pregnancy is predominantly either pre-​existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter de- fined as diabetes or glucose intolerance first diagnosed during the pregnancy. There are other rarer forms of pre-​existing diabetes, including monogenetic diabetes, recognition of which in preg- nancy will increase as awareness and the ability to diagnose them increases. While the overall incidence of women with diabetes of any type is increasing, the largest proportional rise is seen in women with pre-​existing type 2 diabetes mellitus and gestational diabetes. In 2012, overall prevalence of gestational diabetes across Europe was reported as between 2 to 6%, but this is dependent on the diag- nostic criteria used and the ethnic and demographic mix of the antenatal population, and higher values will be reported as more universal screening and testing for gestational diabetes is intro- duced (see later). Maternal gestational diabetes and obesity are both independently associated with adverse pregnancy outcomes, and their combination has a greater impact than either one alone. Obesity and gestational diabetes are also associated with adverse long-​term cardiovascular health in both the mother and the child in later life. In 2015 it was es- timated that in England and Wales around 35 000 pregnant women annually would have either pre-​existing diabetes (20%) or gesta- tional diabetes mellitus (80%). Gestational diabetes usually arises in the late second trimester as a consequence of the pregnancy-​induced changes in maternal carbo- hydrate metabolism. However, undiagnosed type 2 diabetes mellitus is increasingly seen, and it is essential to identify these women as their clinical management needs to be similar to those with pre-​ existing recognized type 2 and optimized as early in pregnancy as possible. The diagnosis of diabetes and type of diabetes in pregnancy The criteria for the diagnosis of diabetes outside of pregnancy can be made by any of the following; • a fasting plasma glucose of 7.0 mmol/​litre or above; • a two-​hour plasma glucose of 11.1 mmol/​litre or above during a 75 g oral glucose tolerance test taken as anhydrous glucose dis- solved in water; • a glycosylated haemoglobin (HbA1c) of 6.5% (48  mmol/​mol) or above; • a random plasma glucose of 11.1 mmol/​litre or above in the pres- ence of hyperglycaemic symptoms. The distinction between type 1 and type 2 diabetes mellitus can usually be made on the basis of clinical risk factors. Both types 1 and 2 are heterogeneous diseases in which the clinical presenta- tion and disease progression in adults may vary considerably and can appear to overlap. The diagnosis of type 1 diabetes mellitus, an autoimmune disease characterized by β-​cell destruction, can if necessary usually be confirmed by the presence of islet specific autoantibodies and low circulating or undetectable concentration of serum C-​peptide, a measure of endogenous insulin secretion. These islet cell autoantibodies include those directed against in- sulin, glutamic acid decarboxylase (GAD) (GAD65), the tyro- sine phosphatases IA-​2 and IA-​2b, and ZnT8. The diagnosis of type 2 diabetes mellitus remains a clinical diagnosis. Other than hyperglycaemia, including elevated HbA1c levels, there are no specific clinical diagnostic tests for type 2 diabetes mellitus. The lack of β-​cell autoimmunity, other autoimmune diseases, or other known causes for hyperglycaemia all favour a diagnosis of type 2. Most, but not all, patients with type 2 are overweight or obese, and many will have a family history of type 2 diabetes mellitus or other metabolic risk factors. See Chapter  13.9.1 for further discussion. In pregnancy, if the diagnosis of pre-​existing type 1 diabetes mellitus is uncertain, the presence of GAD antibodies would be ex- pected to confirm the diagnosis in around 80% of cases, and the de- cision to undertake further testing for antibodies will depend on risk assessment (Fig. 14.10.1).

14.10  Diabetes in pregnancy 2629 Gestational diabetes mellitus Definition and diagnosis Gestational diabetes mellitus is defined as a new diagnosis of dia- betes during pregnancy. There remains some controversy as how best to diagnose it. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was designed to establish internationally agreed diagnostic criteria. In this landmark observational study more than 25 000 non​diabetic pregnant women were recruited between 2000 and 2006 from nine different countries. All women underwent a 75 gram, two-​hour OGTT between 24 and 32 weeks’ gestation, with healthcare providers blinded to the results unless sug- gestive of overt diabetes (fasting plasma glucose above 5.8 mmol/​l (105 mg/​dl), or the 2-​hour value above 11.1 mmol/​l (200 mg/​dl), or a random plasma glucose at 34–​37 weeks above 8.9 mmol/​l (160 mg/​ dl)). The fasting, 1-​ and 2-​hour plasma glucose results of the OGTT were analysed from 23 316 mother-​newborn pairs for their asso- ciation with four primary outcomes: macrosomia (corrected birth weight >90th centile), primary caesarean delivery, clinical neonatal hypoglycaemia, and hyperinsulinemia (as assessed by cord serum c-​peptide >90th centile for the study group as a whole). The analysis of the data showed the associations between the OGTT results at dif- ferent time points and the four primary outcomes were continuous, with no clear inflection points. The results of the HAPO analysis formed the basis of the International Association of the Diabetes and Pregnancy Study Groups (IAPDSG) 2014 criteria for gestational diabetes. The new criteria for gestational diabetes were based on the threshold of glu- cose value at each time point that gave a 1.75 likelihood of an adverse outcome when compared with the mean reference value at the three separate time points. The American Diabetes Association (ADA), World Health Organization, and International Diabetes Federation all subsequently endorsed the IAPDSG diagnostic criteria for gesta- tional diabetes, which included a 75 gm OGTT performed between 24 to 28 weeks. In contrast to the HAPO-​derived criteria, following a cost-​ effectiveness analysis of published intervention studies the National Institute for Health and Care Excellence (NICE) 2015 Diabetes and Pregnancy update proposed a higher fasting value and a lower two-​ hour oral glucose tolerance test value, with no one-​hour value for the diagnosis of gestational diabetes (Table 14.10.1). The NICE criteria also advocate the use of universal screening of five risk factors iden- tified at the initial antenatal visit, with a 75 gm OGTT between 26 to 28 weeks performed on only those women with one or more risk fac- tors, these being a body mass index (BMI) above 30 kg/​m2, a previous macrosomic baby weighing 4.5 kg or above, previous gestational dia- betes, a first-​degree relative with diabetes, and belonging to an ethnic family origin with a high background prevalence of diabetes. An earlier diagnostic OGTT (at 16 weeks) is recommended for women with a history of previous gestational diabetes, with repeat at 24–​28 weeks if the first test was normal. The five risk factors recom- mended by NICE is not exhaustive and leaves out other recognized risk factors, including increasing age and a history of polycystic ovary syndrome. The NICE-​recommended screening at booking potentially may miss up to 25% of women with gestational diabetes. Applying the new IAPDSG criteria to the original HAPO cohort diagnosed between 15 to 20% of parturients as having gestational diabetes, depending on country of origin. Gestational diabetes mellitus in early pregnancy There is currently no agreed strategy for identifying women not known to have diabetes who have significant hyperglycaemia in early pregnancy. Glycosylated haemoglobin (HbA1c) is less reliable No need to test for type 1 DM Test for Type 1 DM using GAD* antibodies Autoimmune thyroid disease, coeliac disease, Addison’s vitiligo, myasthenia gravis, pernicious anaemia. autoimmune hepatitis, Two or more risk factors for type 2 DM- BMI > 27kg/m2, family history of type 2 DM, age > 40 yrs., nonwhite, previous GDM 1st or 2nd degree relative with type 1 DM or other autoimmune diseases No risk factors for type 2 DM Strong family history of type 2 DM Fig. 14.10.1  Factors affecting the decision to test for GAD antibodies in a patient with diabetes in pregnancy.

Section 14  Medical disorders in pregnancy 2630 in pregnancy due to the higher turnover of erythrocytes, and fasting blood glucose falls in early pregnancy. However, an HbA1c meas- urement of ≥5.9% (≥41 mmol/​mol) at the initial antenatal clinic ap- pears to be a good discriminator for women who have significant glucose intolerance on a subsequent OGTT performed at around 20 weeks’ gestation, and with an increased risk of adverse pregnancy outcomes. This HbA1c value is lower than the diagnostic value for diabetes outside pregnancy (HbA1c 6.5% (48 mmol/​mol). Aetiology As described, pregnancy induces a state of relative decreased insulin sensitivity due to both maternal and placental factors. High circu- lating levels of maternal free fatty acids, adipokines, and cytokines may be factors contributing to this. Women who are obese and those who have gestational diabetes have increased levels of many of the adipokines and inflammatory cytokines associated with de- creased insulin sensitivity, including leptin, tumour necrosis factor-​α (TNF​α) and interleukin-​6, while the insulin sensitizing adipocyte cytokine adiponectin is reduced. The placenta is a major source of these cytokines, hormones, and inflammatory mediators, as well as of human placental lactogen and placental growth hormone. Pregnancy is a physiologically leptin-​resistant state and results in a significant upregulation of leptin, which in turn leads to hyperglycaemia. The human growth hormone (GH) gene cluster contains a single gene expressed solely in the anterior pituitary (GH1), plus four genes expressed in the placenta (SHL1, CSH1, GH2, CSH2). GH1 encodes solely pituitary GH, which is also a ligand for the maternal GH re- ceptor and stimulates the insulin-​like growth factor (IGF)-​1 axis. In pregnancy the 6–​8-​fold increase in placental growth hormone in- creases and replaces normal circulating pituitary growth hormone by 20 weeks’ gestation, and this is thought to decrease insulin sensitivity by inhibiting key components of the insulin-​signalling pathway. The other members of the GH gene cluster, CSH1 and CSH2, en- code for human placental lactogen which is a ligand for the maternal prolactin receptors. This can be detected in the maternal circulation by six weeks’ gestation and has been implemented in augmenting maternal insulin resistance and promoting the supply of fatty acids and glucose to the placenta. Changes in the placental microcirculation and placental dysfunc- tion leading to increased fetal complications have been attributed to the adverse diabetic metabolic milieu resulting from hypergly- caemia, hyperinsulinism, dyslipidaemia, and secretion of adipokines and inflammatory cytokines, causing increased oxidative stress and protein glycosylation. Rarer forms of diabetes Monogenic β-​cell diabetes is thought to be responsible for approxi- mately 2% of all diabetes diagnosed before the age of 45 years, about 80% of such patients being misdiagnosed as either type 1 or type 2 diabetes, reflecting lack of clinical awareness and limited clinical access to genetic testing. Clues to the diagnosis of monogenic forms of diabetes include lack of typical characteristics of type 1 diabetes (no islet cell auto- antibodies, low or no insulin requirement five years after diagnosis, persistence of measurable stimulated C-​peptide, absence of dia- betic ketoacidosis), or type 2 diabetes (lack of obesity, hypertension, dyslipidaemia), in the presence of a strong family history of diabetes. An autosomal dominant family history of diabetes may be caused by monogenic disruption of glucokinase (GCK), hepatic nuclear factor (HNF)-​1A, HNF-​4A, or HNF-​1B gene expression. The mo- lecular diagnosis of such forms of diabetes is important because it enables genetic counselling, predictive genetic testing in affected families, personalized tailoring of medication, and provides patient information regarding prognosis. GCK-​related diabetes Making the diagnosis of GCK-​related diabetes is important as it al- lows patients to be reassured that they have an inherited tendency to mild hyperglycaemia, which requires no specific glucose-​lowering treatment or self-​monitoring of blood glucose (outside of preg- nancy), because the condition is not associated with microvascular or macrovascular complications. It also has important implications for management of pregnancy, because in parturients with GCK-​ related diabetes the risk of fetal macrosomia depends upon the fetal GCK genotype. If the fetus has not inherited the GCK mutation it will respond to maternal hyperglycaemia with increased insulin produc- tion, leading to excess fetal growth (adding an additional approxi- mately 550–​700 g by term). Alternatively, if the fetus does inherit the GCK abnormality, it will sense the maternal hyperglycaemia as normal, produce normal amounts of insulin and have normal growth, and in this context the aggressive lowering of maternal glu- cose into the normal range may adversely affect fetal growth. As it is not currently possible to determine the fetal genotype non​invasively during pregnancy, the decision on whether to treat maternal hyperglycaemia in parturients with GCK-​related diabetes is made on the basis of monitoring fetal abdominal circumference, with a reading above the 75th percentile being the recommended threshold to start insulin and normalize maternal glycaemia. In the future, fetal genotyping using cell-​free fetal DNA from maternal plasma sampling during early pregnancy may assist in this context. Table 14.10.1  Recommendations for screening and oral glucose tolerance testing in pregnancy IAPDSG criteria NICE 2015 criteria Screening None Risk factors at 1st antenatal clinic

  1. BMI >30 kg/​m2
  2. Previous history of GDM
  3. Previous macrosomic birth, ≥ 4.5 kg
  4. Family history
  5. Minority ethnic family origin with a high prevalence of diabetes 75 gm OGTT Universal at
    24–​28 weeks Selective testing 26–​28 weeks Based on the presence of risk factors Plasma glucose IAPDSG criteria one or more of the following thresholds
    be met or exceeded: NICE 2015 criteria one or more of the following thresholds be met or exceeded 0 minute 5.1 mmol/​litre (92 mg/​dl) 5.6 mmol/litre (100 mg/​dl) 60 minute 10 mmol/​litre (180 mg/​dl) 120 minute 8.5 mmol/​litre (153 mg/​dl) 7.8 mmol/​litre (140 mg/​dl) GDM, gestational diabetes mellitus.

14.10  Diabetes in pregnancy 2631 The impact of diabetes on the mother and fetus during pregnancy Diabetes affects all aspects of a woman’s reproductive life, including pregnancy. Diabetes, specifically maternal hypergly- caemia, affects fertilization, implantation, embryogenesis, or- ganogenesis, fetal growth, and development and neonatal and perinatal morbidity and mortality. Women with pre-​existing diabetes or those who develop diabetes during the pregnancy are at added risk of maternal and fetal complications during preg- nancy. Maternal diabetes and obesity also influence the risk of future obesity and diabetes in the child, through epigenetic fac- tors and fetal programming in utero. Preconception planning, surveillance, and screening throughout pregnancy by a multi- disciplinary specialist team can lessen the risks for both mother and fetus. Preconception counselling for women with diabetes Preconception counselling is associated with improved pregnancy outcomes. Uptake is highly dependent on sociodemographic fac- tors, and women with the greatest social deprivation scores, those with type 2 diabetes mellitus, and those from ethnic minority groups are less likely to access these services. As half of all pregnancies are unplanned, counselling women about pregnancy should form part of the ongoing care pathway for all women of childbearing age with diabetes. When any potentially teratogenic medication is prescribed as part of a woman’s routine diabetes care (such as an angiotensin converting enzyme (ACE)-​ inhibitor or a statin (HMG-​CoA reductase inhibitor)) women need to be counselled on the need to stop this prior to or as soon as preg- nancy is confirmed in an unplanned pregnancy. In addition, ad- vice should be given on the need to take high dose folic acid (5 mg daily) three months prior to pregnancy and continued for the first 12 weeks in pregnancy to reduce the risk of fetal neural tube defects. The key elements of preconception counselling and assessment are shown in Table 14.10.2. Management of diabetes peri-​conceptionally
and in pregnancy Optimizing glycaemic control Women need to be supported to achieve optimal glycaemic control peri-​conceptionally and throughout pregnancy to reduce the risk of miscarriage, congenital malformation, stillbirth, and neonatal death. Improved control prior to pregnancy also reduces the risk of deterioration of diabetic retinopathy and nephropathy during the pregnancy. Providing women with structured education around in- sulin management and dose adjustment of their rapid acting insulin to match their carbohydrate intake improves glycaemic control and lessens the risk of hypoglycaemia. Meta-​analysis of large data sets shows that congenital malfor- mations, preterm delivery and maternal hyperglycaemia in the first trimester of pregnancy are all reduced in women who receive preconception counselling. There is a strong positive association of fasting glucose or glycated haemoglobin in women with type 1 diabetes mellitus and type 2 diabetes mellitus and major fetal anom- alies, with multiple organ anomalies associated with the poorest glycaemic control. This association is so strong that 2015 NICE guidance is that women with an HbA1c above 86 mmol/​mol (10%) be strongly advised not to get pregnant. 2015 NICE guidance is to aim for an HbA1c below 48 mmol/​mol (6.5%) if this is achievable without causing problematic hypogly- caemia. Plasma glucose targets are fasting levels of 5–​7 mmol/​l on waking for women with type 1 diabetes mellitus and a plasma glu- cose level of 4–​7 mmol/​l before meals at other times of the day. To achieve this level of glycaemic control women with type 1 diabetes mellitus will require the use of a multiple dose insulin regime con- sisting of 4 or 5 insulin injections a day given as 1 or 2 basal insulin injections and 3 bolus rapid acting insulin injections to cover the main meals, or a continuous subcutaneous insulin infusion (CSII) pump. Recent technological advances around insulin pumps, con- tinuous glucose monitoring, and automated bolus insulin calcula- tors that help calculate pre-​meal insulin dosing depending on the amount of carbohydrate eaten, are all available to help women to achieve these targets. In the future, closed-​loop insulin delivery technologies, combining real-​time continuous glucose monitoring with CSII using a computer algorithm, will also be available, and early work in this field holds great promise that lower HbA1c levels will be achievable with less risk of hypoglycaemia. For women with type 2 diabetes mellitus, achieving an HbA1c below 48 mmol/​mol (6.5%) prior to pregnancy is easier, as these women will be at less risk of hypoglycaemia due to their relatively short history of diabetes and less dependency on insulin therapies. However, many such women will need to be started on an insulin prior to a planned pregnancy as all oral agents other than metformin will need to be stopped. Medication review Some antihypertensive and lipid lowering agents routinely used in the management of diabetes have been associated with an increased risk of congenital malformations when used in the first trimester. These include ACE-​inhibitors, angiotensin II receptor blockers, and the HMG-​CoA reductase inhibitors known collectively as statins. NICE guidance cautions against the use of thiazides and related Table 14.10.2  Key elements of preconception counselling Optimizing glycaemic control Medication review Screening and management of diabetes complications Advice regarding diet and weight Information on pregnancy risk to the mother, including particular risks of hypoglycaemia and DKA Increased risk of hypertensive disease in pregnancy Information on pregnancy risk to the baby—​risk of congenital abnormalities, preterm birth, and risk of macrosomia and growth restriction Importance of pregnancy planning and accessing multidisciplinary care in early pregnancy DKA, diabetic ketoacidosis.

Section 14  Medical disorders in pregnancy 2632 diuretics in pregnancy. Daily 5 mg of folic acid is recommended three months prior to any planned pregnancy. Screening and management of diabetic complications During preconception counselling women need to be informed of how a pregnancy may affect their own health, including the impact on pre-​existing micro and macrovascular disease. It is important to ensure that a retinal and renal assessment has been performed within the previous year, and to seek information on symptoms of peripheral and autonomic neuropathy, and all cardiovascular risk factors including hypertension and hypercholesterolaemia. Retinopathy Pregnancy can lead to new onset diabetic retinopathy or worsening of pre-​existing disease. Sight-​threatening diabetic retinopathy in pregnancy is rare, but proliferative diabetic retinopathy which accel- erates during pregnancy may not regress post-​partum. Screening for retinopathy is therefore recommended prior to pregnancy, during early pregnancy, and again at 28 weeks’ gestation. Any retinopathy detected requires treatment as it may deteriorate during pregnancy, and ongoing follow-​up during pregnancy and postnatally will be re- quired. Diabetic retinopathy is not a contraindication to rapid opti- mization of blood glucose control in women who present with a high HbA1c, nor is it a contraindication to pregnancy or vaginal birth. Renal function Physiological changes occur in renal function in pregnancy. Glomerular filtration rate, creatinine clearance, and protein excre- tion all increase. Renal function is usually preserved in women with diabetes who start pregnancy with normal renal function. Women with diabetic nephropathy (serum creatinine >1.5  mg/​dl or pro- teinuria of more than 3 g protein/​24 hours) have an increased risk of preeclampsia, preterm delivery, fetal growth restriction, peri- natal death, and a permanent deterioration in renal function (see Chapter 14.5). Assessment of renal function at the outset of preg- nancy is important as optimization of blood glucose as well as blood pressure before pregnancy may improve maternal and fetal out- comes. Furthermore, knowing baseline renal function (serum cre- atinine and urinary microalbumin excretion or urinary albumin/​ protein creatinine ratio) is essential for later comparison in case preeclampsia is suspected. Autonomic neuropathy Pre-​existing autonomic neuropathy is an important risk factor for poor glucose control, increased glucose variability and hypogly- caemia. It is also associated with gastroparesis. Although pregnancy does not worsen autonomic neuropathy, it can worsen the symp- toms of gastroparesis due to the hormonal and mechanical effects of pregnancy that independently slow intestinal motility. Patients with gastroparesis may develop severe nausea and vomiting, as well as malabsorption, that complicate the timing of insulin administration and contribute to high levels of glucose variability and post-​prandial hypoglycaemia. Women with autonomic neuropathy should have an anaesthetic assessment in the third trimester of pregnancy due to the associated increased anaesthetic risk. Maternal complications of diabetes in pregnancy Hypoglycaemia Hypoglycaemia in pregnancy is a significant problem, affecting up to 70% of women with pre-​existing diabetes and associated with ex- cess mortality. Undoubtedly the strict glycaemic targets women are expected to achieve before and during pregnancy are an important factor. Awareness of hypoglycaemic symptoms is reduced in preg- nancy and women require assessment and education around hypo- glycaemia avoidance. This is particularly important for those with initial poor glycaemic control who undergo rapid intensification of their insulin management. Hypoglycaemia is particularly prevalent in the first half of preg- nancy, when insulin requirements actually fall, and the first few weeks post-​partum (Fig. 14.10.2). Women who have frequent 16 14 12 10 8 6 4 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Gestational week Number of events Fig. 14.10.2  Hypoglycaemic episodes during pregnancy in women with type 1 diabetes. Reproduced from Nielsen LR et al. (2008). Hypoglycemia in pregnant women with type I diabetes. Diabetes Care, 31(1), 9–​14. Copyright © 2008, American Diabetes Association.

14.10  Diabetes in pregnancy 2633 hypoglycaemic events may benefit from “smart” diabetes tech- nologies, including insulin pumps with continuous glucose moni- toring that allows the glucose monitor to temporarily switch off
the insulin pump. Diabetic ketoacidosis Diabetic ketoacidosis is a rare but serious complication in preg- nancy and has an associated fetal mortality of up to 10%. All women with type 1 diabetes mellitus should be provided with blood ketone testing strips and a meter, instructed on their use, and advised to test for ketonaemia if they become hyperglycaemic or unwell, and be aware of the indications to seek urgent medical advice. Diabetic ketoacidosis can occur at near normal blood glucose levels during pregnancy, hence it should be excluded in any preg- nant woman with pre-​gestational diabetes and persistent nausea and vomiting. The risk of diabetic ketoacidosis increases in late preg- nancy due to increased insulin demands and enhanced lipolysis. The treatment of diabetic ketoacidosis in pregnancy is the same as for non​pregnant patients. Fetal assessment should occur following ma- ternal stabilization, noting that fetal heart rate abnormalities usu- ally correct with maternal treatment. Pre-​existing diabetic complications Pre-​existing complications differ in women with type 1 or type 2 diabetes mellitus, or gestational diabetes. Women with type 1 dia- betes mellitus are likely to have had diabetes for longer than those with type 2 diabetes mellitus, and established diabetic microvascular disease increases with diabetes duration. Retinopathy, nephropathy, and neuropathy, both peripheral and autonomic, are all more common in women with type 1 diabetes mellitus. Women with type 2 diabetes mellitus are more likely to have a duration of diabetes of less than 10 years and usually less than 5 years, but this may change in the future due to the increasing prevalence of type 2 diabetes mellitus among younger women. All women with diabetes, particularly those with longstanding type 1diabetes mellitus and older obese women with type 2 diabetes mellitus and gestational diabetes, are at an increased risk of diabetic macrovascular disease, including coronary heart disease. Diabetic macrovascular disease remains uncommon in pregnancy, but when it precedes or occurs for the first time in pregnancy, both maternal and fetal outcomes are poor. As the prevalence of macrovascular complications increases with duration of diabetes mellitus, and the numbers of women choosing to delay childbirth into their thirties and forties increases, the prevalence of macrovascular complica- tions in the pregnant population are likely to increase. Other maternal complications The potential maternal complications from conception to the post-​ partum period are listed in Table 14.10.3. Risks to the fetus Although maternal glucose crosses the placental barrier, insulin does not and, consequently, increases in maternal glucose stimulate fetal insulin production and result in hyperplasia of fetal insulin Table 14.10.3  Maternal complications of diabetes from conception to the post-​partum period Time Issue Type 1 DM Type 2 DM GDM Conception Fertility Subfertility due to poor control Delayed menarche Early menopause Autoimmune ovarian failure Increased prevalence of weight related amenorrhoea (anorexia) Subfertility if associated with polycystic ovarian syndrome 1st trimester 0–​12 wks Miscarriage Increased Poor glycaemic control Increased if due to PCO Hypoglycaemia High risk of severe recurrent hypoglycaemia Loss of hypoglycaemic awareness 2nd trimester 13–​28 wks Retinopathy Worsening retinopathy Hypoglycaemia High risk of severe recurrent hypoglycaemia Autonomic neuropathy Gastroparesis Nephropathy Worsening renal function Increased proteinuria 3rd trimester 29–​40 wks Preeclampsia Pregnancy-​induced hypertension Operative birth Birth trauma Failed induction of labour Operative birth including caesarean section Birth trauma Post-​partum Post-​partum haemorrhage Increased risk Long term, 1–​10 years Expected improvement of any pregnancy related deterioration in retinopathy and nephropathy Long-​term risk of coronary vascular disease, and diabetic microvascular complications Recurrent GDM Future type 2 DM Increased risk of CVD CVD, cardiovascular disease; DM, diabetes mellitus; GDM, gestational diabetes mellitus.

Section 14  Medical disorders in pregnancy 2634 sensitive tissues. Maternal hyperglycaemia also enhances produc- tion of hPG, fetal IGF, and TNF​α. Like insulin, these act as fetal growth factors and result in accelerated fetal growth, macrosomia, and enlargement of the heart and liver. Congenital malformations As previously discussed, diabetes mellitus is also associated with an increased risk of congenital malformation which is dependent upon glycaemic control (Fig. 14.10.3). When women with diabetes have a normal HbA1c in early pregnancy, congenital malformation rates approach that of the background population (risk of around 2%), but as HbA1c values increase from two to eight standard deviations above the normal range the malformation risk rises from 3 to 10% respectively. Diabetes mellitus is associated with a wide variety of malformations involving the cardiovascular system (e.g. transposition of the great vessels, ventricular septal defect), the central nervous system (e.g. anencephaly, spina bifida, hydrocephaly and holoprosencephaly), the genitourinary system, and the skeleton. The exact mechanism of the embryopathy remains uncertain, but there is evidence for contri- butions from increased oxidative stress due to elevated superoxide dismutase activity, reduced levels of myoinositol and arachidonic acid, and inhibition of the pentose phosphate shunt pathway. Fetal macrosomia Maternal weight gain, even without diabetes, predisposes to fetal macrosomia, hence obese pregnant women are advised to avoid un- necessary weight gain during pregnancy. The causes of macrosomia are not fully understood. The Freinkel hypothesis attributes excessive fetal insulin to increased transport of maternal fuel to the conceptus as the predominant cause of fetal macrosomia. However, fetal growth is complex and influenced by maternal, paternal, and fetal genes and factors, uterine environment, and maternal and fetal hormonal status. Infants of diabetic mothers have an additional influence of maternal fluctuations in glycaemia, as a hyperinsulinized fetus can cause a glu- cose steal phenomenon in late pregnancy, reducing maternal insulin requirements and precipitating maternal hypoglycaemia. Macrosomia is associated with risks for birth for both the fetus and the mother. It is a risk factor for shoulder dystocia which can be difficult to predict but may occur more commonly in fetuses of diabetic mothers with an estimated weight of more than 4 kg, and up to 50% in fetuses weighing 4.5 kg or more. Operative delivery and caesarean section are increased in both preexisting and gesta- tional diabetes, independent of the effect of birth weight, potentially related to placental dysfunction leading to fetal distress in labour. Intrauterine growth restriction Pre-​existing diabetes is also associated with intrauterine growth re- striction (IUGR), which is diagnosed when ultrasound-​estimated fetal weight is below the 10th percentile for gestational age, implying a possible pathological process causing the low fetal weight. IUGR in pregnancy complicated by pre-​existing diabetes is usually caused by placental dysfunction related to maternal vasculopathy. Prevention of IUGR should ideally start before pregnancy. Strict gly- caemic control and intensive treatment of nephropathy and hyper- tension are essential. Low-​dose aspirin initiated before 16 gestational weeks may also reduce IUGR risk in women with vasculopathy. Umbilical and other fetal Doppler studies can guide diagnosis and surveillance of fetuses with IUGR as these may reflect placental re- sistance and function. Pre-​eclampsia There is an increased risk of pre-​eclampsia in women with pre-​ existing diabetes, especially in those with diabetic nephropathy. Preterm delivery may be required, balancing the risks of delivery and neonatal short term and long-​term effects of prematurity. Delivery management and the timing of delivery is made according to maternal well-​being, the degree of glycaemic control, the pres- ence of diabetic complications, growth of the fetus, evidence of uteroplacental insufficiency, and the results of fetal surveillance. Perinatal mortality remains high among infants of mothers with type 1 and type 2 diabetes mellitus. Although high glucose levels have been implicated, the exact mechanism remains unclear. Neonatal and longer-​term effects The impact of maternal hyperglycaemia persists into the neonatal period with an increased risk of neonatal hypoglycaemia, respiratory distress, polycythaemia, hypocalcaemia, and hyperbilirubinaemia. The severity of these fetal metabolic problems correlates with levels of C-​peptide, insulin, and erthyropoietin in amniotic fluid and fetal cord blood, but these are not measured routinely. There is also a growing body of evidence suggesting a longer-​term effect of poor glycaemic control on neonatal outcome. Fetal pancreatic islet cells subjected to hyperglycaemia in utero appear to contribute to an increased susceptibility to metabolic disease later in life, such as obesity, type 2 diabetes mellitus, and the metabolic syndrome. The risks of developing type 2 diabetes mellitus are complex and poorly understood, but infants with both decreased and increased birth weight are at increased risk of developing type 2 diabetes mellitus when compared to those born with a normal birth weight. Management of diabetes in pregnancy Pre-​existing diabetes Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy with an early dating scan at 11–13 weeks. Multidisciplinary, consultant-​led, 30 25 20 15 10 5 0 Women without diabetes 6.1–7.7 7.8–10.0

10.0 HbA1c (%) Congenital malformation (%) Fig. 14.10.3  Risk of congenital malformation dependent upon glycaemic control. Reproduced from BMJ, Taylor and Davison, 334: 742–​745, copyright © 2007, with permission from BMJ Publishing Group Ltd.

14.10  Diabetes in pregnancy 2635 hospital-​based care is usually the most appropriate level of care, with the multidisciplinary team (MDT) comprising of endocrinologists, diabetes nurses, dieticians, specialist midwives, and obstetricians. In addition to routine antenatal care and screening tests, regular sur- veillance (usually every two weeks) is suggested to assess blood glu- cose levels, screen for fetal anomaly, and assess fetal growth (Table 14.10.4). All women should have contact details and telephone ac- cess between clinic visits with a member of the MDT team. The optimal blood glucose targets remain the same throughout pregnancy and are similar regardless of the type of diabetes, namely a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8 mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. However, these targets may need to be individual- ized and increased for women at risk of hypoglycaemia. Women with type 1, type 2, or gestational diabetes on multiple dose insulin regimen or pump therapy are advised to perform home glucose monitoring fasting, one hour pre-​meals, one to two hours post-​meal, and before bed. Women with gestational diabetes man- aged with diet and exercise alone, or oral therapy, only need to test fasting and one to two hours post-​meals. Gestational diabetes Women with gestational diabetes should be taught home glu- cose monitoring to ensure that their glycaemic targets are met throughout the duration of pregnancy. The aim of treatment is to achieve euglycaemia (while avoiding hypoglycaemia), as this has been shown to benefit both maternal and fetal outcomes. The primary intervention for women diagnosed with gesta- tional diabetes but with a fasting blood glucose below 6 mmol/​l is dietary counselling in combination with physical activity and self-​ monitoring of blood glucose. In women who have a fasting blood glucose on OGTT above 7.0 mmol/​l, diet and exercise alone would not be expected to lower this value to 5.3 mmol/​litre within an ac- ceptable time period, and therefore the prompt initiation of insulin therapy, with or without metformin, is advised. For women with a fasting blood glucose on OGTT between 6.0 to 7.0 mmol/​l, imme- diate treatment with insulin therapy, with or without metformin, should be considered if there is clinical evidence of macrosomia or polyhydramnios. Dietary advice All patients with gestational diabetes should be referred to specialist dieticians, the key elements of dietary advice being to substitute complex for simple carbohydrates and increase dietary fibre. The need for pharmacological therapy for gestational diabetes depends entirely on the severity of the glucose intolerance, in addition to fetal growth as assessed on prenatal ultrasound. Diet alone will maintain the fasting and postprandial blood glucose values within the target range in approximately half of women with gestational diabetes. Exercise The role of exercise in gestational diabetes may be even more im- portant than in women with pre-​existing diabetes, given that ex- ercise in some women may lessen the need for medical therapy. Moderate exercise in women with gestational diabetes is well tol- erated and has been shown to lower maternal glucose levels. Using exercise after a meal in the form of a brisk walk may blunt the post- prandial glucose excursions sufficiently to avoid the need of medical therapy. Establishing a regular routine of modest exercise during pregnancy may also have long-​lasting benefits for women with ges- tational diabetes due to their appreciable risk of developing type 2 diabetes in the future. Pharmacological treatments If diet and exercise are insufficient, oral hypoglycaemic agents and/​ or insulin will be required. Insulin does not cross the placenta, but is more difficult to administer, and the risk of hypoglycaemia and weight gain is greater than with oral hypoglycaemic agents. Oral hypoglycaemics, particularly metformin and glibenclamide, have been demonstrated to be safe and efficacious in pregnancy. The advantages of metformin include ease of use, low risk of hypo- glycaemia, and limitation of maternal weight gain and weight re- tention post-​partum. Although there is a theoretical concern that metformin crosses the placenta, recent evidence has demonstrated acceptable short-​term outcomes, with longer term outcomes yet to be clearly defined. Use of metformin was recommended by NICE in 2015, but it does not currently have a UK licence for use in diabetes in pregnancy. Glibenclamide is the only sulfonylurea that has been studied in a large randomized control trial performed in women with gestational diabetes. Maternal glycaemic control, macrosomia, neonatal hypoglycaemia, and neonatal outcomes were not different between women managed with glibenclamide or insulin. There is either very limited or no safety or outcome data on women with gestational diabetes being treated with other oral agents, including pioglitazone, metglitinides, acarbose, and incretins. If blood glucose control remains above target following treatment with the oral agents, then a recombinant human insulin should be considered. It is common to add a short and medium duration acting insulin to achieve better 24-​hour control while continuing the Table 14.10.4  Management plan for diabetes in pregnancy Early pregnancy 8–​9 weeks Booking visit Dating scan at 11–13 weeks HbA1C, renal profile, assessment of proteinuria Baseline BP Referral for retinopathy screen 12 weeks Diabetes review First trimester ultrasound scan 14–​16 weeks Routine antenatal care 18–​20 weeks Anomaly scan including fetal echocardiography 22 weeks Diabetes review 24 weeks Ultrasound fetal growth 26 weeks 28 weeks Ultrasound fetal growth 30 weeks 32 weeks Ultrasound fetal growth 34 weeks 36 weeks Ultrasound fetal growth 37 weeks 38 weeks Aim for delivery of women with pre-​existing diabetes Consider delivery of women with complex gestational diabetes 40 weeks Offer induction of labour in women with gestational diabetes

Section 14  Medical disorders in pregnancy 2636 metformin therapy. Glibenclamide is usually discontinued once in- sulin is required. There is evidence suggesting an association between vitamin D deficiency/​insufficiency and gestational diabetes, although the mo- lecular or cellular mechanisms for this association is unclear. It is currently not known whether vitamin D supplementation can re- duce the risk of developing gestational diabetes and/​or improve glycaemic control in diabetic pregnant women with vitamin D defi- ciency/​insufficiency. Obstetric matters Timing, mode, and place of birth Women with diabetes should give birth in hospitals where 24 hours-​ a-​day advanced neonatal resuscitation skills are available. Women with type 1 or type 2 diabetes mellitus and no other complications should be advised that birth between 37 + 0 weeks and 38 + 6 weeks of pregnancy lessens their heightened risk of stillbirth. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then. Birth before 37 + 0 weeks may be advisable if there are metabolic or maternal or fetal indications. Antenatal steroids for fetal lung maturation can be used if a preterm delivery is anticipated, but close glycaemic monitoring is required alongside careful insulin titration. Management of diabetes in labour During labour and delivery, most women with pre-​existing diabetes should be managed with a sliding scale of intravenous insulin and dextrose infusion to maintain capillary plasma glucose between 4 and 7 mmol/​litre to lessen the risk of neonatal hypoglycaemia. Hourly capillary plasma glucose should be performed. Women with gestational diabetes using diet, oral hypoglycaemic agents, or small doses of insulin can cease the medications in labour, with continued regular assessment of maternal capillary glucose. Women with gestational diabetes requiring large doses of insulin may require an insulin sliding scale in labour. Post-​partum care The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose. It is important for women and healthcare staff to be prepared for the potential increased risk of hypoglycaemia in the immediate post-​partum period. Breastfeeding, lack of sleep, and the need for maternal adjustment to not requiring ‘tight glycaemic’ control as during the pregnancy, all contribute to this increased risk, which can be reduced if post-​partum women take 25–​30% less than their pre-​pregnancy insulin dose. Women taking insulin who breastfeed should test their blood glucose before and after breastfeeding and be encouraged to have a snack before and have one available when feeding. Due to the heightened risk of hypoglycaemia when breastfeeding, women need to be warned of the potential dangers to the newborn when breast- feeding in bed. Healthcare staff and patients should be trained to monitor for both neonatal and maternal hypoglycaemia. Women with type 2 diabetes mellitus on metformin prior to and during pregnancy can safely continue this post-​partum and during breastfeeding. The concentration of metformin in breast milk is low, and infant exposure to metformin has been reported to range be- tween 0.3 to 1.1% of the weight-​normalized maternal dose. Breastfeeding appears to confer an advantage to all women, redu- cing incidence of developing type 2 diabetes mellitus in those with and those without gestational diabetes. Breastfeeding has also been linked to a decreased risk of the infant developing obesity and im- paired glucose tolerance in later life. Women with gestational diabetes can usually cease all diabetes medication post-​partum, with most reverting to normal glucose levels soon after birth, although 5–​10% will fulfil the criteria for type 2 diabetes. Although screening women with prior gestational dia- betes for subsequent type 2 is accepted, there is a lack of consensus as to how and when this should be done. The ADA recommends using a 75 gm OGTT to screen for persistent diabetes 6–​12 weeks’ post-​partum, and lifelong screening for development of diabetes or pre-​diabetes at least every three years. In the United Kingdom, the 2015 NICE guidelines recommend a laboratory glucose prior to dis- charge, and a fasting glucose 6–​13 weeks post-​partum or a HbA1C after 13 weeks, with an annual fasting plasma glucose or HbA1C thereafter. All women with prior gestational diabetes remain at risk of diabetes in the future, with up to half developing type 2 diabetes mellitus within 10 years. A programme of diet and exercise can im- prove this risk, hence dietary and lifestyle modifications, including regular exercise, should be advocated in the long term. Post-​partum care should include advise on family planning and the need for contraception that allows women time to optimize their health prior to any future pregnancy. Areas of uncertainty, controversy, and future developments The maternal and neonatal obstetric outcomes in women with pre-​ existing diabetes have the potential to improve with continuing advances in diabetes management, fetal surveillance, and neonatal care. However, a significant improvement in pregnancy outcomes will require more women with pre-​existing diabetes to plan their pregnancy and participate in preconception counselling to optimize their glycaemic control and identify and manage proactively any dia- betic complications prior to pregnancy. Preconception counselling improves both maternal and fetal short-​ and long-​term outcomes. It will become increasingly important to identify women with gestational diabetes, not only to minimize the impact of gesta- tional diabetes on the pregnancy, but also for the future health of the child. Women with gestational diabetes represent the future population of parous women with diabetes, mostly type 2. This po- tential provides an opportunity for targeted prevention strategies to curb the current rise in obesity and type 2 diabetes. The association

14.10  Diabetes in pregnancy 2637 of obesity and glucose intolerance in the offspring of women with pre-​existing diabetes mellitus or gestational diabetes provides an opportunity for intergenerational risk prevention for future obesity and diabetes. FURTHER READING Bellamy L, et al. (2009). Type 2 diabetes mellitus after gestational dia- betes: a systematic review and meta-​analysis. Lancet, 373, 1773–​9. Confidential Enquiry into Maternal and Child Health (2005). Pregnancy in women with type 1 and type 2 diabetes in 2002–​03, England, Wales and Northern Ireland. London, CEMACH. Crowther CA, et al. (2005). Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med, 352, 2477–​86. Garcia-​Patterson A, et  al. (2010). Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia, 53, 446–​51. Guerin A, Nisenbaum R, Ray JG (2007). Use of maternal GHb concen- tration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care, 30, 1920–​5. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Group (2008). Hyperglycemia and adverse pregnancy outcomes.
N Engl J Med, 358, 1991–​2002. International association of diabetes and pregnancy study groups (2010). International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care, 33, 676–​82. Macintosh MC, et  al. (2006). Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland:  population-​based study. BMJ, 333, 177. National Institute for Health and Care Excellence (NICE) (2015). Diabetes in Pregnancy:  Management from Preconception to the Postnatal Period. https://​www.nice.org.uk/​guidance/​ng3 Rowan JA, et al. (2008). Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med, 358, 2003–​15. Secher AL, et al. (2013). The effect of real-​time continuous glucose monitoring in pregnant women with diabetes: a randomized con- trolled trial. Diabetes Care, 36, 1877–​83. Stewart ZA, et al. (2016). Closed-​loop insulin delivery during preg- nancy in women with type 1 diabetes. N Engl J Med, 375, 644–​54. Tennant PW, et  al. (2014). Pre-​existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-​ based study. Diabetologia, 57, 285–​94. Tripathi, A., et al. (2010). Preconception counseling in women with diabetes: a population-​based study in the north of England. Diabetes Care, 33, 586–​8. Zhao P, et  al. (2016). Maternal gestational diabetes and childhood obesity at age 9–​11: results of a multinational study. Diabetologia, 59, 2339–​48.

14.11 Endocrine disease in pregnancy 2638

14.11 Endocrine disease in pregnancy 2638

ESSENTIALS Thyroid Many pregnant women will develop goitre. Gestational thyrotoxi- cosis needs to be differentiated from Graves’ disease, which requires treatment with propylthiouracil in early pregnancy and carbimazole in later pregnancy. Overt hypothyroidism is associated with ad- verse maternal and fetal outcomes and should be treated to main- tain thyroid-​stimulating hormone within the trimester-​specific reference range. Adrenal The diagnosis of both Addison’s disease and Cushing’s syndrome can be challenging in pregnancy. Patients with adrenal insufficiency may require higher replacement steroid doses, particularly in the third trimester. Pituitary Prolactinomas are commonly encountered in pregnancy. Women with macroprolactinomas should have visual field monitoring throughout pregnancy. Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period. Thyroid disease Thyroid physiology in pregnancy Pregnancy has a significant impact on thyroid physiology. The fetal thyroid does not secrete active thyroid hormone until 18–​20 weeks of gestation, hence maternal thyroid hormone production must in- crease by up to 50% in order to provide enough thyroid hormone for the developing fetus. As a result, many pregnant women, particu- larly in iodine deficient areas, will develop goitre. Interpretation of thyroid tests is also affected by pregnancy. Thyroid-​stimulating hormone (TSH) closely resembles β-​HCG at a molecular level, and due to cross-​reactivity in pregnancy normal TSH ranges are lower. Trimester-​specific reference ranges for use in pregnancy have been developed in many laboratories: these should be used wherever possible, since TSH ranges will depend upon the population and ethnicity of the women studied. Gestational thyrotoxicosis In early pregnancy, particularly in those with excessive vomiting or with twin pregnancies, excessively high β-​HCG levels can lead to apparent thyrotoxicosis. Most women with gestational thyrotoxi- cosis can be managed conservatively with fluids and antiemetics, although it is important to differentiate from Graves’ disease pre- senting in pregnancy: several clinical features can help to discrim- inate (Table 14.11.1). Treatment of Graves’ disease in pregnancy Graves’ disease affects around 0.2% of pregnancies. Carbimazole (methimazole) is the most commonly used drug for thyrotoxicosis. Case reports (although not larger studies) have associated this drug with rare congenital malformations including aplasia cutis and oesophageal atresia, and so propylthiouracil has traditionally been recommended for use pre-​pregnancy. Propylthiouracil, how- ever, has been associated with hepatotoxicity in late pregnancy, so a balance between the small risks associated with these two medi- cations is required. Treatment, which can usually be down-​titrated, should be continued throughout pregnancy and into the early post-​ partum period to reduce the risk of early recurrence post-​partum (see Box 14.11.1). Block and replace regimes should be avoided in pregnancy. If antithyroid medications are ineffective or not tolerated, then surgical treatment should be considered; the use of radioactive iodine is contra-​indicated in pregnancy and while breastfeeding. 14.11 Endocrine disease in pregnancy David Carty Table 14.11.1  Differentiation of Graves’ disease from gestational thyrotoxicosis Graves’ disease Gestational thyrotoxicosis Goitre √ X Thyroid receptor antibodies √ X Symptoms prior to pregnancy √ X Eye signs √ X

14.11  Endocrine disease in pregnancy 2639 Women are at risk of recurrence of Graves’ disease in the post-​ partum period, and thyroid function tests should be monitored regularly after delivery. Loss of ability to breast-​feed can be an early sign of recurrence. Both carbimazole and propylthiouracil are de- tectable in breast milk, although there is no evidence of harm to the baby: in general, if further pregnancy is desired then propylthiouracil is preferable. Hypothyroidism in pregnancy Overt hypothyroidism is associated with several adverse maternal and fetal outcomes, including pre-​eclampsia, intrauterine growth restriction, preterm delivery, and reduced intelligence quotient (IQ) in the offspring. Treatment of overt hypothyroidism leads to an improvement in these outcomes and for this reason many clinicians advocate the universal screening of thyroid function in pregnant women. The aim in pregnancy is to maintain TSH within the trimester-​specific reference range. Some women with hypothyroidism will require an increase in daily dose of thyroxine of 25–​50 mcg to attain this: those with no thyroid gland because of previous radio iodine or surgical treatment are more likely to need a dose increase than those with autoimmune hypothyroidism. T3 does not cross the placenta, and its use should be avoided in pregnancy. Subclinical hypothyroidism describes TSH above the trimester-​ specific reference range, but with a normal fT4. Depending on the population studied, rates of this condition are reported to be up to 15%. Although associated with adverse fetal and maternal outcomes in some studies, evidence that thyroxine treatment leads to an improvement in these outcomes is limited and con- flicting. Recent guidelines from US and European Societies advo- cate treatment with thyroxine of women found to have subclinical hypothyroidism, although definitions differ between guidelines. Fetal and neonatal thyroid dysfunction In women with uncontrolled thyrotoxicosis or high thyroid re- ceptor antibody (TRAB) titres, additional fetal ultrasound moni- toring of fetal heart rate, growth, amniotic fluid volume, and assessment for fetal goitre should be undertaken. The diagnosis of fetal thyrotoxicosis can be confirmed if necessary by fetal blood sampling. Treatment is by maternal administration of high-​dose propylthiouracil (300–​450 mg/​day) together with thyroxine during gestation to prevent maternal hypothyroidism. Involvement of fetal medicine specialists is required. Neonatal hypothyroidism may very rarely occur at birth due to maternal TSH receptor blocking anti- bodies, maternal antithyroid drug administration, iodine deficiency, and maternal goitrogen ingestion. All these conditions are transient, and the mother can be reassured. Post-​partum thyroid dysfunction Up to 15% of women in the general population have positive thyroid peroxidase antibodies; of these 50% will develop a degree of post-​ partum thyroid dysfunction. The condition is thought to be caused by autoimmune-​associated release of preformed hormone from the thyroid. In general, the disease is characterized by transient thyro- toxicosis, followed by hypothyroidism, and then a return to normal (Fig. 14.11.1) The thyrotoxic phase is usually asymptomatic; in contrast the hypothyroid phase will often be associated with symptoms and re- quire thyroxine treatment. There is a high risk of recurrence in fu- ture pregnancies, and up to 65% of women will develop permanent hypothyroidism during long-​term follow-​up. TSH should be meas- ured annually in affected women. Thyroid nodules in pregnancy Thyroid nodules occur in up to 10% of pregnant women, and in general these should be dealt with in a similar manner to outwith Box 14.11.1  Management of Graves’ disease in pregnancy • Confirm diagnosis • Treat with propylthiouracil if diagnosed prior to planned pregnancy or in first trimester • Consider switch to carbimazole in second trimester — Aim to continue treatment until delivery • Monitor thyroid function tests 4–​6 weekly — Titrate dose where necessary • Check thyroid receptor antibodies (TRAB) in third trimester — Inform neonatologist if positive (risk of fetal thyrotoxicosis) • Review post-​partum — Check for recurrence Reference range TSH levels fT4 and T3 levels Thyrotoxic phase 2–6 months Hypothyroid phase 3–12 months Recovery Fig. 14.11.1  Pattern of thyroid dysfunction in post-​partum thyroid dysfunction.

Section 14  Medical disorders in pregnancy 2640 pregnancy. A  suggested algorithm for investigation is shown in Fig. 14.11.2. Surgery, if required, should be undertaken in the second trimester. Investigation of nodules identified in late pregnancy can be deferred until the post-​partum period. Parathyroid disease Diseases of the parathyroid glands are uncommon in women of childbearing age, but hyperparathyroidism during pregnancy can lead to acute pancreatitis or severe hypercalcaemia. There is an in- creased incidence of prematurity and neonatal hypocalcaemia and tetany if maternal calcium levels are high. The high maternal cal- cium levels suppress fetal parathyroid hormone causing the neonatal calcium to fall following cord clamping at delivery. Surgical man- agement can be undertaken safely in pregnancy and ideally in the second trimester. Hypoparathyroidism is treated with vitamin D analogues, with dosage often needing to be increased during pregnancy to maintain normocalcaemia, hence calcium levels should be monitored regu- larly throughout pregnancy, at least once in each trimester. Adrenal disease Addison’s disease Addison’s disease can rarely present in pregnancy. Diagnosis can be difficult, but should be considered in women with unexplained hypotension, hyponatraemia/​hyperkalaemia, or pigmentation. In women already known to have the condition, many will require an increase in steroid dose particularly in the third trimester, if hyperemesis develops, or during any intercurrent infection. Higher doses of intravenous hydrocortisone are required for labour or op- erative delivery, and anaesthetists should be informed of the patient’s condition. Cushing’s syndrome Cushing’s syndrome is associated with several adverse pregnancy outcomes, including diabetes, pre-​eclampsia, and wound healing problems. The presentation of Cushing’s syndrome in pregnancy is similar to outwith pregnancy, but diagnosis can be challen- ging: elevated cortisol levels are seen in the second and third tri- mesters in normal pregnancy, dexamethasone suppression testing is less reliable in pregnancy, and reference ranges for urinary free cortisol in pregnancy have not been established. Unlike the gen- eral population, where adrenocorticotropic hormone-​dependent Cushing’s is more common, the proportion of Cushing’s syn- drome due to adrenal lesions is higher in pregnancy than in the non​pregnant population. Since ongoing cortisol excess is associ- ated with significant maternal and fetal morbidity, a surgical cure should be pursued. Adrenal tumours Adrenal tumours in pregnancy are rare, but as with other tumours there is a risk of enlargement in pregnancy. Phaeochromocytoma can be mistaken for pre-​eclampsia, and should be considered in women with episodic hypertension, associated symptoms of head- ache or palpitations, or a family history. Diagnosis involves measure- ment of 24-​hour urinary or plasma metanephrines. In general, the lesion should be removed laparoscopically if identified in the first or second trimester; if the lesion is identified in the third trimester then adrenalectomy is usually deferred until a few weeks later. Women should be adequately α-​blocked (and then, if ­necessary, β-​blocked) prior to surgery and/​or delivery. Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a group of autosomal reces- sive conditions characterized by impaired cortisol synthesis. 21-​Hydroxylase deficiency is the most common cause, present in over 95% of cases. Fertility in women with the more severe variant (classical) congenital adrenal hyperplasia is reduced, owing to an- drogen excess, oligoanovulation, and chronically elevated levels of adrenal-​derived progesterone. Although androgen levels are often elevated in pregnancy, placental aromatase production prevents virilization of unaffected female fetuses. Fertility is less likely to be affected in women with the less severe (non​classical) form of the dis- ease. Management of congenital adrenal hyperplasia in pregnancy involves adequate steroid replacement and adrenal androgen sup- pression. In women with classical congenital adrenal hyperplasia, hydrocortisone should be used in pregnancy; dexamethasone, which can cross the placenta, should be avoided. Genetic counsel- ling may be considered for an index case desiring pregnancy, or in families with a previously affected infant. Pituitary Prolactinomas Prolactinomas are the most common type of functioning pitu- itary lesion and since they have a peak incidence in women during childbearing years they are commonly encountered in pregnancy. Monitoring of prolactin levels in pregnancy is unhelpful: the normal pituitary expands by 30% in pregnancy, largely due to lactotroph ex- pansion, and so normal pregnancy is associated with a 10-​fold in- crease in prolactin levels. Medical therapy with dopamine agonists is the treatment of choice for prolactinoma:  these reduce tumour bulk and Thyroid nodule detected in pregnancy History and examination TFTs Ultrasound reveals nodule >1cm Benign ultrasound appearances Defer further investigation until after pregnancy Consider FNA Refer for surgery Compressive symptoms Ultrasound suspicious for malignancy Fig. 14.11.2  Investigation algorithm for thyroid nodules.

14.11  Endocrine disease in pregnancy 2641 normalize prolactin levels in most patients. Women with lesions that are resistant to dopamine agonists or who are intolerant should be counselled regarding the benefits of surgery prior to pregnancy. Women with microprolactinomas should, in general, stop dopamine agonists when they find out they are pregnant, since the risk of enlargement causing visual field impairment is less than 1%. In women with macroprolactinomas, however, the risk is much higher, and such women may require to stay on their dopamine agonist therapy. After careful counselling they may wish to discontinue treatment in the last month of pregnancy to facilitate breast-feeding. Women with macroprolactinomas should have visual field monitoring throughout pregnancy, par- ticularly if dopamine agonists are discontinued or if they develop symptoms. Symptoms indicative of expansion include headache, visual field deterioration, and cranial nerve palsies. If a lesion enlarges in pregnancy, then restarting or increasing dose of dopa- mine agonist therapy should be considered; there are now exten- sive safety data available for both cabergoline and bromocriptine in pregnancy. Acromegaly Fertility is reduced in women with acromegaly because of co-​ secretion of prolactin along with growth hormone, and because of decreased gonadotrophin reserves due to the tumour expansion. In affected women wishing to conceive, growth hormone and prolactin levels should be normalized prior to conception. In general, women with microadenomas should discontinue medical therapy in pregnancy and be assessed at each trimester. Women with macroadenomas should be monitored closely, with visual field monitoring in each trimester and MRI scan when necessary. There are limited safety data for the use of somatostatin analogues in pregnancy, and if necessary use of dopamine agonists can be con- sidered instead. Non​functioning pituitary adenomas Although non​functioning pituitary adenomas represent 30% of pi- tuitary adenomas overall, they tend to present in older age and are associated with reduced fertility, hence they are rarely encountered in pregnancy. Non​functioning lesions do not usually increase in size in pregnancy,s but monitoring of visual fields is recommended for women with macroadenomas. If symptomatic enlargement occurs, medical treatment with dopamine agonists or trans-​sphenoidal sur- gery can be considered. Diabetes insipidus Central diabetes insipidus may present during pregnancy. It is seen in women with lymphocytic hypophysitis (see next) and in women with infiltrative disorders such as Langerhans’ cell histiocytosis. Synthetic desmopressin is normally used in the management of dia- betes insipidus and can be given orally or intranasally. Use during pregnancy seems to be safe for both mother and baby: synthetic desmopressin does not affect delivery and has no adverse effects on the neonate. Diabetes insipidus may be seen transiently at the end of otherwise normal pregnancy and in women with acute fatty liver of pregnancy. This is related to production of vasopressinase by the pla- centa, the breakdown of which is delayed in acute fatty liver. Lymphocytic hypophysitis Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period. The underlying aetiology is thought to be autoimmune, and pathology is characterized by dense infiltration of lympho- cytes. Women may present with a pituitary mass lesion, headache, or visual field disturbance, and imaging resembles a pituitary ad- enoma in 80% of patients. Affected women will commonly have par- tial hypopituitarism, with adrenocorticotropic hormone and TSH the most common deficiencies, and relative sparing of luteinizing hormone (LH) and follicle-​stimulating hormone. Treatment is usu- ally with corticosteroids. It has been speculated that many cases of Sheehans’s syndrome, a now rare condition characterized by hypo- pituitarism associated with post-​partum haemorrhage, may in fact have been caused by lymphocytic hyophysitis. FURTHER READING Casey BM, et al. (2017). Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med, 376(9), 815–25. de Groot L, et al. (2012). Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 97, 2543–​65. Frise CJ, Williamson C (2013). Endocrine disease in pregnancy. Clin Med, 13, 176–​81. Lazarus J, et al. (2014). 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J, 3, 76–​94. Lindsay JR, Nieman LK (2006). Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am, 35, 1–​20, v. Stagnaro-​Green A, et al. (2011). Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid, 21, 1081–​125.

14.12 Neurological conditions in pregnancy 2642

14.12 Neurological conditions in pregnancy 2642

ESSENTIALS Pregnancy can influence the clinical course of an underlying neuro- logical problem or precipitate the first presentation of a neurological disease. Epilepsy—​sodium valproate is associated with higher risk of major congenital malformations and impaired neuropsychological devel- opment than other antiepileptic drugs: lamotrigine or levetiracetam are preferred. Women taking antiepileptic drugs can breastfeed. Multiple sclerosis—​relapse rate is reduced in pregnancy but substantially increased for three months post-​partum. Cerebrovascular disease—​stroke syndromes specific to pregnancy in- clude pre-​eclampsia, which can lead to posterior reversible vasoconstric- tion syndrome. Reversible cerebral vasoconstriction syndrome presents after delivery and has many similarities to posterior reversible vasocon- striction syndrome. Cerebral venous thrombosis accounts for approxi- mately 20% of all strokes occurring in pregnancy and puerperium. There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture. Introduction Neurological conditions in pregnancy are an important cause of mor- tality and morbidity in the United Kingdom. From 2010 to 2015, there were 50 maternal deaths in the United Kingdom related to diseases of the central nervous system. The commonest causes identified were subarachnoid haemorrhage, intracerebral haemorrhage, and epilepsy. During pregnancy, a range of haemodynamic and biochemical changes occur in the mother, and these can significantly impact and influence the natural history of an underlying neurological problem or precipitate the first presentation of neurological disease in preg- nancy. This chapter will cover the management of common neuro- logical diseases during pregnancy. Imaging in pregnancy This causes safety concern during pregnancy, but the clinician should put maternal well-​being at the centre of all decision-​making. Computed tomography Computed tomography (CT) can be performed in pregnancy. The fetal exposure dose from a head CT scan is less than 0.1 mGy, which is low. The patient should be informed that no association has been proven between radiation exposure of less than 50 mGy and risk of spontaneous miscarriage or developmental malforma- tions. Iodinated contrast should only be given if required in preg- nancy: it does cross the placenta, but no teratogenic effects have been described. Magnetic resonance imaging This is the modality of choice in pregnancy. Despite theoretical concerns, there is no evidence to suggest that magnetic resonance imaging (MRI) exposure, irrespective of trimester, is associated with fetal harm. Contrast agents such as gadolinium are avoided in pregnancy because of an increased risk of harm; including still- birth and neonatal death. Headaches Headaches are common in women of childbearing age and preg- nancy is no exception to this. The commonest headache presenta- tions encountered in pregnancy include, tension headaches, and migraines. However, it is important to always be mindful of any red flag features, suggestive of a more sinister pathology, necessitating urgent evaluation (Box 14.12.1). Migraine Migraines usually improve during pregnancy and 60–​70% of women report fewer migrainous attacks during pregnancy. In women who are troubled by headaches in pregnancy, non​pharmacological steps 14.12 Neurological conditions in pregnancy Pooja Dassan Box 14.12.1  Red flags in headache presentation • Headaches of sudden onset • Headaches associated with neck stiffness • Patient reports worst headache ever • Headache with abnormal neurological signs

14.12  Neurological conditions in pregnancy 2643 are usually advocated as part of the first line management. This in- cludes advising patients to improve hydration, reduce consumption of caffeinated drinks, avoid sleep deprivation, and adopt regular eating patterns. Approaches to drug treatment should involve using non​opioid ­analgesics, such as paracetamol and non​steroidal anti-​inflammatory drugs, although the latter should be avoided after 30 weeks’ gesta- tion. A prokinetic agent such as domperidone is a helpful adjunct to these abortive medications. Opiates, although safe to use during pregnancy, are usually avoided in migrainous patients as they can exacerbate nausea and, if anything, worsen gastric motility prob- lems. If despite these initial measures the headaches are still trouble- some, then a preventative medication is usually prescribed. Both propranolol and amitriptyline are reasonable first line options and should be used at the lowest effective dose. Epilepsy An important aspect of the consultation with any female patient of childbearing age with epilepsy is preconception counselling (see Box 14.12.2). As approximately 50% of pregnancies are un- planned, clinicians must approach this subject at the earliest op- portunity to ensure that the patient’s therapy has been optimized and folic acid 5 mg per day has been initiated for at least three months preconception. Antiepileptic drugs Lamotrigine Lamotrigine’s teratogenic profile is more favourable than other antiepileptic drugs, in particular when compared with valproate. However, one drawback with lamotrigine use in pregnancy is that the apparent clearance increases steadily through pregnancy and notably peaks at 32 weeks, when it can be as high as 330% as compared with non​pregnant baseline. This can result in quite a significant fall in lamotrigine levels in the third trimester, with deterioration in seizure control as a consequence. This change in lamotrigine’s pharmacokinetics during pregnancy does revert back to pre-​pregnancy conditions within a few days of delivery. In our practice, we advocate checking serum lamotrigine level either pre-​pregnancy or in very early pregnancy and treating this as the mother’s baseline. Thereafter, the clinician should consider increasing the lamotrigine dose to prevent significant reduction of levels from baseline. Whether such increases should be based on clinical assessment or therapeutic drug monitoring is currently the subject of a multicentre randomized trial. Levetiracetam Levetiracetam is a newer generation antiepileptic mediation with a favourable side effect profile and is widely used to treat seizures. The emerging data suggest that the risk of major congenital mal- formation for mother’s taking levetiracetam is between 2 to 3%, which is comparable to the background risk. In addition, current evi- dence suggests that taking levetiracetam during pregnancy does not have a negative impact on the child’s cognitive and language develop- ment. Levetiracetam metabolism also increases in pregnancy and in our practice, we advocate checking drug levels once every trimester. Management of pregnancy and labour Several antiepileptic drugs, including phenytoin and carbamaze- pine, are hepatic enzyme inducers and thus lead to a reduction in vitamin K-​dependent clotting factors in the fetus. Previously oral vitamin K was prescribed for women taking hepatic enzyme- inducing antiepileptic drugs from 36 weeks’ gestation until de- livery, to prevent hemorrhagic disease of the newborn. This is no longer necessary as all babies receive intramuscular (IM) vitamin K after birth. Women with epilepsy should be encouraged to deliver in hospital as it is recognized that 3% will have a seizure within 24 hours of de- livery. The reasons behind this include fatigue and sleep deprivation, failure to adhere to usual antiepileptic drug regime during labour, and impaired absorption. If a mother is felt to be at particular risk of seiz- ures during this period, then short-​term clobazam (a benzodiazepine derivative) can be used as an effective adjunct to her usual medication. Breastfeeding All antiepileptic drugs are excreted in varying degrees into breast milk. Despite this, it is the opinion of experts to support breast- feeding in women using antiepileptic drugs, as the benefits of breast- feeding are likely to outweigh any theoretical risks. Multiple sclerosis Most women with multiple sclerosis (MS) can safely conceive, give birth, and breastfeed without any significant ill-​effects to the mother or baby. Important aspects to discuss during pre-​pregnancy counselling in women with MS are detailed in Box 14.12.3. Use of disease-​modifying drugs in pregnancy is de- scribed in Table 14.12.1. Box 14.12.2  Pre-​pregnancy counselling issues • Reassure the patient that most women with epilepsy give birth to a healthy child. • Aim to maintain the mother pre-​pregnancy on a single agent, at the lowest effective dose. Higher risk of malformations with polytherapy and dose-​related effects are likely to be observed with most antiepileptic drugs (e.g. valproate). • Teratogenicity is defined in the following categories: — Structural malformations and these can be either major or minor; — Impaired neuropsychological development; — Reduced intrauterine growth. • Sodium valproate—The MHRA (Medicines and Healthcare products Regulatory Agency) recently updated their guidance in March 2018 re- commending that valproate must no longer be used in any woman of childbearing age, unless she has a pregnancy prevention programme in place. This is designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant. If valproate is taken during pregnancy, up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects. • The magnitude of the risk of maternal seizures on the fetus is dif- ficult to quantify. Overall, women with epilepsy who are having generalized seizures during pregnancy should be informed that the fetus may be at risk of harm with multiple or prolonged seiz- ures, but the actual absolute risk—​particularly of a single seizure—​is probably low.

Section 14  Medical disorders in pregnancy 2644 Myasthenia gravis Myasthenia gravis affects skeletal muscles and does not affect the smooth muscles of the myometrium, thus uterine contractions are not impaired. The key to managing myasthenia gravis in pregnancy is the same as with any other autoimmune condition; to optimize control pre-​pregnancy. It is important to remember that several of the drugs used to treat myasthenia gravis (see Table 14.12.2) are safe in pregnancy and it is imperative that women are reassured of this. The issues pertaining to the management of myasthenia in the pre- conception stage, during pregnancy, and thereafter are covered in Table 14.12.3. Cerebrovascular disease Ischaemic strokes The estimated incidence of stroke in pregnancy is 4–​7 cases per 100 000. The three common aetiologies accounting for most cases of pregnancy-​related ischaemic strokes are cardioembolism, pre-​ eclampsia/​eclampsia and cerebral venous thrombosis. If a stroke is suspected, urgent imaging should be carried out, as in non​pregnant patients (see Fig. 14.12.1). In non​pregnant in- dividuals, intravenous recombinant tissue plasminogen activator (t-​PA) is the recommended treatment for an acute ischaemic stroke presenting within 4.5 hours of onset. There is very little evidence relating to the use of this treatment in pregnant women but, overall, the evidence suggests that treatment with t-​PA should be con- sidered in all pregnant patients with disabling strokes. Stroke syndromes specific to pregnancy Pre-​eclampsia This is a multisystem disorder, primarily thought to be a disorder of placental implantation and presents with a constellation of symp- toms including pregnancy-​induced hypertension and proteinuria. In approximately one-​third of cases of stroke diagnosed in preg- nancy or the puerperium, pre-​eclampsia/​eclampsia is also concomi- tantly diagnosed. Haemorrhagic strokes occur most commonly. The pathophysiology underpinning this is complex but appears to be re- lated to impaired endothelial function. In addition, pre-​eclampsia can lead to posterior reversible vaso- constriction syndrome, which is radiologically characterized with bi- lateral, symmetrical subcortical changes, often seen predominantly in the occipital and parietal areas (see Fig. 14.12.2). The imaging characteristics of this condition are of vasogenic oedema, although in a few patients areas of cytotoxic oedema have been identified, suggestive of irreversible ischaemic damage. It classically presents with a severe, often thunderclap, headache. Other clinical features include seizures, cortical blindness, fixed neurological deficits, and alteration in level of consciousness with eventual stupor. Urgent identification of these patients is paramount. Management entails adequate control of seizures (primarily with IV magnesium sulphate in patients with eclampsia), control of blood pressure and, on occasions, urgent delivery of the fetus is required. Reversible cerebral vasoconstriction syndrome This condition, like posterior reversible vasoconstriction syndrome, is recognized as a self-​limiting condition, occurring within the first week after delivery, often following an uncomplicated preg- nancy and delivery. This condition characteristically presents with Box 14.12.3  Key issues to discuss during pre-​pregnancy counselling in women with multiple sclerosis • Fertility is not affected in multiple sclerosis (MS). • There is no single genetic cause of MS. The risk of MS in the general population is 0.13%. However, when a parent has MS, risk to the child is 2–​2.5%. • Safety of disease-​modifying drugs (DMDs)—​see Table 14.12.1 • Relapse rate is reduced by up to 70% in pregnancy, especially during the third trimester. • This is followed by a substantial increase in risk of relapses in the im- mediate post-​partum period and for up to three months thereafter. • Vitamin D supplementation (up to 4000 IU/day) can be used safely during pregnancy to reduce the relapse rate. • Mild relapses during pregnancy can be managed conservatively, but significant relapses leading to new disability can be treated with ei- ther intravenous methylprednisolone or oral prednisolone. Less than 10% of the maternal dose of methylprednisolone or prednisolone reaches the fetus as a result of metabolism to the inactive form by the placenta. • Mode of delivery should be guided by obstetric reasons and there is no documented adverse effect of regional anaesthesia. Table 14.12.1  Use in pregnancy of disease-​modifying drugs for multiple sclerosis (MS) Disease-​modifying drugs (DMDs) FDA pregnancy category Advice in pregnancy β-​interferon C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks • Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least conception and that the benefits of breastfeeding outweigh any associated risks. Glatiramer acetate B—​animal studies have not shown adverse fetal effects; there are no adequate studies in pregnant women • Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least conception and that the benefits of breastfeeding outweigh any associated risks. Natalizumab C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks • Large molecule which crosses placenta via active transport after first trimester • During pre-conception counseling, the MS team should discuss the pros and cons of stopping vs continuing on this treatment during pregnancy. Evidence shows that women who stop Nataizumab can experience a rebound of their MS (severe relapse) during pregnancy.

14.12  Neurological conditions in pregnancy 2645 recurrent thunderclap headaches and other clinical features can in- clude seizures, confusion, or a fixed neurological deficit. Reversible cerebral vasoconstriction syndrome can occur in conjunction with pre-​eclampsia or posterior reversible vasoconstriction syndrome, and in fact, these three conditions are likely to be underpinned by similar pathophysiological processes. The characteristic feature of this condition is the reversible narrowing of the intracerebral vasculature and this can be identified via dedicated intracranial vascular imaging (see Fig. 14.12.3). Patients are expected to recover spontaneously within one to three months and treatment is gen- erally supportive. In some cases, complications can occur, and patients are left with permanent damage due to subarachnoid haemorrhage or parenchymal damage from infarction or intracerebral haemorrhage. Table 14.12.2  Use in pregnancy and when breast feeding of drugs for myasthenia Drug Pregnancy Breastfeeding Pyridostigmine • Very little crosses the placenta, no reports of fetal harm •​ <0.1% passes into breast milk Corticosteroids • Prednisolone can be used and usually at the lowest maintenance dose • Due to placental metabolism of prednisolone, only 10% is transferred
to fetal circulation • There is increased risk of gestational diabetes •​ Can be continued during breastfeeding Azathioprine • Safe to continue in pregnancy •​ Can be continued during breastfeeding Methotrexate and mycophenolate mofetil (MMF) • Contraindicated in pregnancy •​ Contraindicated in breastfeeding Table 14.12.3  Management of myasthenia gravis during pregnancy and delivery Pre-​pregnancy • Optimize management • Switch from teratogenic DMD to safer option (e.g. azathioprine) • Plan thymectomy pre-​pregnancy to optimize control • Check thyroid function tests and thyroid antibody status Pregnancy • Most patients who are stable preconception are unlikely to experience a relapse while pregnant • Reassure patient re concerns related to taking myasthenia gravis medications • Avoid drugs that can precipitate myasthenia gravis • Arthrogryposis in the fetus is rare but a well-​recognized complication of maternal myasthenia gravis Delivery • In stable patients, plan spontaneous vaginal delivery • Assisted delivery may be required to prevent maternal exhaustion • The mother should take usual myasthenia gravis medications throughout labour • If the mother’s maintenance dose of prednisolone is

7.5 mg/​day, the consensus is to give a stress dose of hydrocortisone 100 mg TDS intravenously in labour • Care with anaesthetic agents which can precipitate myasthenia gravis Baby • Transient neonatal myasthenia gravis is a well-​ recognized consequence of maternal myasthenia gravis and is independent of the severity of maternal myasthenia gravis • Presents within the first week of life • Occurs due to transplacental transfer of anticholinesterase receptor (AChR) antibodies • Presents with hypotonia, poor sucking, or even respiratory muscle weakness. Treatment is usually supportive, but some may need pyridostigmine or even intravenous immunoglobulin • Its presentation does not correlate with the onset of myasthenia gravis later in life Fig. 14.12.1  Large right middle cerebral artery infarction on a computed tomography (CT) brain scan. Fig. 14.12.2  Magnetic resonance imaging (MRI) of the brain showing symmetrical bilateral hyperintense lesions in the posterior cerebral hemispheres, typically seen in posterior reversible vasoconstriction syndrome.

Section 14  Medical disorders in pregnancy 2646 Cerebral venous thrombosis Cerebral venous thrombosis accounts for approximately 20% of all strokes occurring in pregnancy and puerperium. It com- monly presents with headaches (can be thunderclap), focal neuro- logical deficit, low Glasgow Coma Scale, and seizures. Cerebral venous thrombosis can be diagnosed with an unenhanced CT (see Fig. 14.12.4), but MRI with magnetic resonance venography is the modality of choice during pregnancy as it can provide a detailed view of the cerebral venous system without any X-​ray exposure and does not require administration of contrast. The treatment of cere- bral venous thrombosis involves anticoagulation, even if there is evidence of haemorrhage on the scan. Anticoagulation should be continued for a minimum of six months. Vascular malformations There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malforma- tion rupture. This is primarily due to paucity of evidence. Cerebral aneurysm In patients diagnosed with a ruptured aneurysm during preg- nancy, acute treatment should be offered during pregnancy as this leads to better outcomes. In pregnant patients with an unruptured aneurysm, the evidence suggests that there is not an increased risk of rupture during pregnancy or delivery. Recommendations re- garding delivery are difficult and decisions should be made on an individual patient basis. A caesarean section is not mandatory in patients with unruptured aneurysm. In our clinical practice, we would routinely avoid a prolonged second stage of labour in this group of patients and recommend assisted delivery, should the need arise. Similarly, pregnant women with treated cerebral an- eurysms should be encouraged to deliver vaginally without any specific considerations. Fig. 14.12.3  MRI brain and magnetic resonance angiogram (MRA) showing changes compatible with reversible cerebral vasoconstriction syndrome. Top row (left to right) shows MRI brain scan (coronal section) with hyperintensity in the sulci of the frontal lobes compatible with subarachnoid haemorrhage (solid arrow) and MRA reveals multifocal beading of the cerebral arteries (dashed arrows). The bottom row shows resolution of both these changes. (a) (b) Fig. 14.12.4  (a) Unenhanced CT head scan showing a hyperdensity in the superior sagittal sinus, suggestive of a thrombosis (solid arrow) with fragmented parenchymal haemorrhage seen in the left posterior temporal lobe (dashed line). (b) CT venogram showing a filling defect in the superior sagittal sinus, known as the ‘empty delta sign’ (arrow).

14.12  Neurological conditions in pregnancy 2647 Arteriovenous malformations Intracranial arteriovenous malformations are relatively uncommon but a recognized cause of catastrophic intracerebral haemorrhages. The evidence suggests that the risk of rupture in pregnancy is not increased. Furthermore, there are identified predictors of haemor- rhage, such as age, location, and deep venous drainage, and these can be useful for evaluating risk. Treatment of unruptured arteriovenous malformations should largely be restricted to outside of pregnancy. Treatment options include endovascular embolization, surgery, or stereotactic radiotherapy. In terms of the issues surrounding labour, these are similar to those mentioned in the management of cere- bral aneurysms, and decisions should be made on an individual patient basis. Peripheral nerve disorders The most frequent examples of peripheral nerve disorders encoun- tered during pregnancy, labour, and the post-​partum period are listed in Table 14.12.4. FURTHER READING Bove R, et al. (2014). Management of multiple sclerosis during preg- nancy and the reproductive years. Obstet Gynecol, 124, 1157–​68. Bove RM, Kleim JP (2014). Neuroradiology in women of childbearing age. Continuum, 20, 23–​41. Knight M, et al. on behalf of MBRRACE-UK (2017). Saving lives, improving mothers’ care - lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2013–15. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Harden CL (2014). Pregnancy and epilepsy. Continuum, 20, 60–​79. Macgregor EA (2014). Headaches in pregnancy. Continuum, 20, 128–​47. Marsh MS, Nashef LAM, Brex PA (2012). Neurology and pregnancy. Informa Healthcare, London. Norwood F, et al. (2014). Myasthenia in pregnancy: best practice guide- lines from a UK multispecialty working group. J Neurol Neurosurg Psychiatry, 85, 538–​43. Powrie RO, Greene MF, Camman W (2010). De Swiet’s medical disor- ders in obstetric practice. Blackwell Publishing, Chichester. Wiles KS, et al. (2015). Reversible cerebral vasoconstriction syndrome: a rare cause of postpartum headaches. Pract Neurol, 15, 141–​4. Table 14.12.4  Common peripheral nerve disorders associated with pregnancy Neuropathy Clinical presentation Treatment Bell’s palsy (facial nerve) Asymmetrical facial droop (lower motor neurone) Short course prednisolone treatment, eye protection, and artificial tears Carpal tunnel syndrome (median nerve) Paraesthesia and pain in lateral side of hand and wrist, especially at night Overnight wrist splints. Some require local steroid injections or even decompression Meralgia parasthetica (lateral cutaneous nerve of the thigh) Numbness and pain over anterior, lateral aspect of the thigh. Improves with sitting and lying down Usually improves spontaneously but treatment options can include lidocaine patch or capsaicin cream Femoral neuropathy Weakness of the quadriceps (i.e. knee extension) and sensory loss anterior thigh and medial calf. Common mechanism of injury is excessive flexion of hip in lithotomy position Conservative management with physiotherapy and analgesia Recovery usually within three to four months Common peroneal nerve Foot drop, foot eversion weakness compared with inversion and sensory loss over the dorsum of foot and lateral aspect of shin. Can be precipitated by prolonged squatting or stirrups See treatment of femoral neuropathy Obturator nerve Weakness of hip adduction and sensory loss medial aspect of thigh. Usually precipitated during assisted delivery See treatment of femoral neuropathy

14.13 The skin in pregnancy 2648

14.13 The skin in pregnancy 2648

ESSENTIALS Dermatoses in pregnancy are common, they may be very itchy and may impact the life of a pregnant woman dramatically. There are four classical dermatoses of pregnancy. It is particularly important to recognize these as they may have serious health implications for mother and child. Intrahepatic cholestasis of pregnancy—​occurs in 1/​40 to 1/​500 pregnancies and is the most serious cause of itch in pregnancy, with potentially substantial effects on mother and fetus. Treatment is with ursodeoxycholic acid. Atopic eruption of pregnancy—​affects 1/​300 pregnancies, typically with an eczematous eruption over abdomen and limbs. Treatment is
with topical steroids. Polymorphic eruption of pregnancy—​affects about 1/​240 preg- nancies, usually beginning with red papules and plaques on the abdomen and thighs before spreading more widely. Treatment is with reassurance and emollients, with topical steroids if neccessary. Pemphigoid gestationis—​occurs in 1/​50 000 pregnancies and
is due to circulating antibodies against the skin basement mem- brane zone. The eruption often begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet. If potent topical steroids fail systemic steroids are required. Transplacental transmis- sion to the fetus may occur. Recurrence in future pregnancies is to be expected. Introduction The skin undergoes profound alterations during pregnancy as a result of endocrine, metabolic, and physiological changes. Some of these are trivial and chiefly cosmetic, producing no or minor symptoms; some will improve during or after pregnancy and others can be distressing and/​or of major medical import- ance. Pregnancy will profoundly modify expression of pre-​ existing skin disease, and there are dermatoses that are specific to pregnancy. Common skin changes in pregnancy Vascular changes and lesions There is increased skin blood flow during pregnancy, possibly re- sulting in oedema (e.g. manifest as tightening of rings and shoes), erythema, and itch. Spider naevi and palmar erythema are common, and there maybe erythema of the gums (with gingivitis) and the vulvovaginal area. Unilateral telangiectasia may appear for the first time, as may haemangiomas. Varicose veins may develop during pregnancy. Swollen skin around the ankles may be a first sign, worsening during the day and improving over night when lying down. Supportive stockings or flight socks should be worn: special pregnancy types are avail- able. If there is a family or personal history of the development of varicose veins or thrombophlebitis/​phlebothombosis, further risk assessment for venous thromboembolism is required. Pyogenic granuloma, a benign tumour with a tendency to ul- cerate and bleed, may develop on the skin or oral cavity, where they are known as pregnancy tumours (Fig. 14.13.1). They are 14.13 The skin in pregnancy Gudula Kirtschig and Fenella Wojnarowska Fig. 14.13.1  Pyogenic granuloma on the finger. Courtesy of Dr Jonathan Bowling, Oxford Radcliffe Hospital NHS Trust, UK.

14.13  The skin in pregnancy 2649 sometimes confused with melanoma and often recur after local destruction. Pigmentary changes and pigmented lesions Increased skin pigmentation is common, particularly in dark-​ skinned women, up to 90% of whom may be affected. There is darkening of the nipples, genitalia, and linea alba. In some women recent scars will darken. The unsightly and sometimes psychologic- ally distressing facial pigmentation of melasma (chloasma, formerly known as the ‘mask of pregnancy’) affects many women. It gets worse with sunlight and can be reduced by using high protection factor (SPF 50) UVB and UVA sunscreens (Fig. 14.13.2). Melasma often disappears spontaneously after delivery, but treatment with topical vitamin A derivatives and hydrochinon may be indicated after pregnancy in some women. Pigmented naevi can increase in size, in particular around the abdomen due to the increased body circumference, and pigmenta- tion during pregnancy. Any asymmetrical change is suspicious of malignant change. Melanoma may occur and is not associated with a poorer prognosis in pregnant women. Any rapidly changing, ir- regularly shaped, or irregularly pigmented lesion larger than 6 mm in diameter should be excised under local anaesthesia to exclude a dysplastic naevus or melanoma. Risk factors for developing a mel- anoma are fair skin, high density of freckles, red hair, more than 50 moles, the presence of more than five atypical moles (irregular shape and colour), a history of severe sunburns during childhood, espe- cially with blistering, and a family history of melanoma. Hair changes There is diminished shedding of hair due to prolongation of the anagen phase. This is perceived as thickening of the hair. The synchronized shedding after parturition gives rise to the distressing post-​partum telogen effluvium three months after delivery. This is completed 6–​12 months later and treatment is not needed. Hirsutism may begin or worsen in pregnancy, driven by an increase in androgens and usu- ally resolving a few months after delivery. Pilosebaceous changes/​acne The development of acne during pregnancy is unpredictable. Skin in pregnancy is often more greasy, termed ‘pregnancy glow’. The increase in oestrogens usually improves acne, but there may be worsening of acne in some unfortunate patients. Acne treatment in pregnancy may be tricky as topical and oral vitamin A derivatives must be avoided because they are teratogenic. Topical treatment with benzoyl peroxide and clindamycin for limited areas (most com- monly the face) are the treatments of choice in pregnancy. Striae gravidarum Striae gravidarum (stretch marks) are common in pregnancy, af- fecting about 50% of women. They are more frequently seen in young women, in women with a raised body mass index, and those who have large babies. They are familial in about 50% of cases and are more likely if a woman has had them previously. The breasts and sides and lower areas of the abdomen are the typical sites, but thighs and arms can be affected. They start as linear depressed purple lines and fade to pale, atrophic, scar-​like lesions. They may be itchy. There is an associ- ation with subsequent tendency to prolapse. There is no good treat- ment. Olive oil massage, castor oil, cocoa butter, glycolic or fruit acids, homeopathic creams and/​or oils are used, but the benefit of these is not proven. Pruritus Itching occurs in about 20% of pregnancies, frequently in associ- ation with an inflammatory dermatosis such as atopic eczema, poly- morphic eruption of pregnancy, allergic reactions, or infectious diseases. The underlying dermatosis must be treated. Oral antihista- mines such as loratadine are safe to be used in pregnancy and can be used for symptomatic relief (see Table 14.13.1). Pruritus may occur without physical signs, other than scratch marks. The most serious cause is intrahepatic cholostasis of pregnancy, which is diagnosed in about 3% of itchy pregnant women (see below and Chapter 14.9). If no underlying dermatosis exists emollients and antihistamines may be useful. Urticaria Urticaria (hives) and dermographism (wealing in response to pres- sure, e.g. scratching) may be precipitated by pregnancy and are very itchy conditions. Urticaria has been attributed by some authors to physiological changes in vascular reactivity. Physical factors such as Fig. 14.13.2  Melasma. Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria. Table 14.13.1  Antihistamines safe to be used in pregnancy Group Generic name Sedating useful at night if pruritus prevents
sleep Chlopheniramine, chlorphenamine Clemastine Dimetinden Non​sedating treatment of choice Cetirizine Loratadine

Section 14  Medical disorders in pregnancy 2650 pressure and heat may evoke it. Particular drugs or foods may be the cause in some patients and must be avoided in such cases. Treatment with a non​sedating antihistamine such as loratidine, cetirizine or sedating chlopheniramine is safe. Cutaneous infections Candida of the vulva as well as the vagina is common and oc- curs in about 15% of pregnant women, causing itching, burning, and discharge. During pregnancy, treatment with miconazole or clotrimoxazole cream or vaginal pessaries is preferred and may need to be repeated several times or preventative treatment may be neces- sary. Oral antiyeast treatments must not be used for vulvo-​vaginal yeast infection during pregnancy. Dermatophyte infections (tinea/​ringworm) are common and may affect pregnant women. They typically manifest interdigitally (athlete’s foot) or in the groin, but can affect any body site including the nails. In uncomplicated cases tinea is usually treated with top- ical antifungals; in pregnancy, clotrimazole and miconazole are preferred. Oral antifungals must be avoided in pregnancy and treat- ment for onychomycosis postponed until after delivery. Cutaneous and genital warts thrive in pregnancy, often commen- cing, proliferating, or enlarging. Treatment for genital warts should be started as soon as possible. However, in the last eight weeks of pregnancy methods that destroy the warts and harm the skin over large areas should be avoided so there is no damage to the skin be- fore delivery. The choice of the therapy is dependent on the type, the extent, and the location of the warts. Localized lesions can be treated with freezing (cryotherapy), electro surgery or with trichloracetic acid (TCA, 33–​50%), which is a liquid that ‘burns’ or ‘peels’ the warts away and can be applied to the lesions with a cotton tip by a phys- ician once every one to three weeks. Imiquimod has been used in pregnancy without observed adverse effects, but it is not licensed for use in pregnancy. Podophyllin or 5-​Fluorouracil must not be used in pregnancy. Genital herpes simplex infections during pregnancy can affect the unborn child. The baby can catch the virus by transmission from the mother via the placenta or during delivery. If the baby is infected be- fore delivery it is at risk of abnormalities, mainly of the brain and the eyes, but herpes virus transmission predominantly occurs during delivery and not during pregnancy. The risk for infection depends mainly on the severity and timing of the mother’s infection (highest if the mother is very ill with herpes, or the baby is premature). If the baby is infected by the virus during delivery or as a newborn the infection may be restricted to the skin, mucosa, and/​or the eyes (45%), the infection may involve the brain (30%), or the infection may be wide spread involving many organs including lungs, liver, and the brain (25%). The risk of transmission from the mother to the baby at delivery is highest (30–​50%) among women who ac- quire genital herpes (primary herpes infection) near the time of de- livery (within six weeks). In a primary infection during the first or the second trimester of pregnancy aciclovir or valaciclovir may be used, depending on the severity of the disease. Antiviral treatment may be used for four weeks before delivery to prevent recurrences and viral shedding around delivery; a caesarean section is usually not indicated. Primary herpes infection during the third trimester must be treated with aciclovir or valaciclovir. A caesarean section in pregnant women developing a primary infection in the six weeks preceding delivery and in women with recurrent disease if they have lesions at the time of delivery is controversially discussed, but there is no certain reduction of the infectious risk for the baby. Lice may be seen as head lice or pubic/​crab lice. A very safe and effective treatment for head lice is combing with dimeticon or, al- ternatively, coconut oil or vinegar water. For easier combing, con- ditioner (possibly containing tea tree oil) may be used. Malathion (lice resistance is reported) or pyrethrum extract and synthetic pyrethroids (permethrin topical 5% cream/​scalp treatment) are the treatment of second choice. Pump sprays should be avoided because of the danger of systemic intake through the air. Pubic lice may be treated with malathion or permethrin 5% cream applied to the affected site. Scabies is a common and very itchy skin condition caused by human scabies mites. It can affect people of any age but is most common in the young. Itching is the main symptom, usually starting about a month after the mites were picked up. The itching affects the body and limbs but usually spares the head and neck, except in infants. The rash of scabies is a mixture of scratch marks and red scaly areas; later it can become superinfected. This itchy rash covers much of the skin, but the mites themselves show up mainly where they burrow, typically on the sides of the fingers and hands, and around the wrists, ankles, feet, breasts, and genitals. Usually several members of a family are affected and need to be treated. Permethrin seems more effective than other treatments, but there are no studies that prove absolute safety in pregnancy. Permethrin 5% cream is ap- plied all over the body, except the head, and washed off after about 12 hours; re-​treatment of hands if washed with soap in between is recommended. Taking a bath or shower before treatment is not re- commended. The treatment should be repeated after seven days. Benzyl benzoate, malathion, and crotamiton seem less effective but are considered safe. Oral Ivermectin (200 microgr/kg body weight in one dose) is not recommended during pregnancy, however, harm to the baby after accidental use is not reported. The pregnancy dermatoses Historical perspective The striking blistering eruption known as ‘pemphigoid gestationis’ was described in 1867 by Wilson and named by Milton in 1872 as ‘herpes gestationis’. During the 1980s it was characterized as an auto- immune blistering disease by Black, Charles-​Holmes, and Shornick, and renamed as ‘pemphigoid gestationis’ to emphasize the close relationship to the commoner autoimmune blistering disease bul- lous pemphigoid and to prevent confusion with viral herpes disease. Further skin diseases that arise in pregnancy have been confusing in their nomenclature and clinical descriptions, but recently Ambros-​ Rudolph and colleagues proposed a new and much simpler classifi- cation (Table 14.13.2). Intrahepatic cholestatis of pregnancy It is particularly important to recognize itch/​pruritus due to intrahepatic cholestasis of pregnancy (obstetric cholestasis, cholestasis of pregnancy, and pruritus/​prurigo gravidarum), which has important implications for the health of both mother and fetus (see Chapter 14.9). It is the most serious cause of itch in pregnancy.

14.13  The skin in pregnancy 2651 In Europe about 0.2–​2.4% of pregnant women will get the condi- tion; in Scandinavia and South America intrahepatic cholestatis of pregnancy is more common and it may also occur in women on the oral contraceptive pill. The itching begins typically in the third tri- mester and affects the abdomen, palms, and soles. The longer the itch persists, the more skin changes due to scratching may be present. Excoriations and prurigo nodules typically involve the shins, arms, and buttocks. Apart from these changes, there is usually no rash as- sociated with intrahepatic cholestatis of pregnancy. Loss of sleep, loss of appetite, and an inability to perform normal daily tasks can be a result of the intense itching. Less common symptoms include dark urine and/​or pale stools, jaundice, abdominal pain, and nausea. Liver function tests may be normal, but bile salts are typically raised. Other causes for itchy skin such as hepatitis, iron deficiency, specific derma- toses of pregnancy, or infectious causes should be excluded. The condition resolves post-​partum but will recur in subsequent pregnancies. Reducing the bile acids is essential. Ursodeoxycholic acid (UDCA—​a naturally occurring bile acid) is currently the best treatment for intrahepatic cholestatis of pregnancy. It is not licensed for use in pregnancy but may be prescribed on an individual basis. It improves liver function and helps to reduce the toxic bile acid concentration, and it is the only treatment that has been shown to reduce fetal risks in intrahepatic cholestatis of pregnancy. UDCA tablets, 15 mg/​kg/​day or simply 1 g daily, are given either as a single dose or divided into two to three doses and continued until delivery, when treatment can usually be stopped. Symptomatic management is with emollients and sometimes antihistamines. Atopic eruption of pregnancy This condition includes entities formerly known as prurigo of preg- nancy and pruritic folliculitis. It may affect 1 in 300 pregnancies. It oc- curs in women with an atopic background (personal or family history), of whom about 20% have had previous eczema. The immunological changes of pregnancy and the tendency to pruritus may both contribute to the worsening of atopic eczema or its first occurrence with preg- nancy. Atopic eruption of pregnancy thus affects women who already have atopic eczema but experience a flare-​up of the disease, and women with their first occurrence of eczema during pregnancy (80%). It can be severe and life-​ruining, and life-​threatening if secondary infection with herpes simplex (eczema herpeticum) or streptococci occurs. Atopic eruption of pregnancy commences early, in three-​quarters of women before the beginning of the third trimester. There is in- tense pruritus, it typically presents with an eczematous eruption over abdomen and limbs (Fig. 14.13.3). The lesions can be chiefly eczematous with red, dry, and scaly skin, with areas of excori- ation and thickening or lichenification. Pre-​existing atopic eczema often deteriorates becoming more widespread and may result in erythroderma in the most severe cases. Another presentation is with excoriated papules and nodules (prurigo of pregnancy). The least common form is follicular pruritic papules and pustules (prur- itic folliculitis), which may present in the third trimester and in a small series was associated with male infants and low birth weight. Secondary infection with Staphylococcus aureus and streptococci is a frequent complication. Histopathology is usually non​specific, but may show a perivascular infiltrate with thickened epidermis. Direct and indirect immunofluorescence are negative. Treatment is with moderate to potent topical steroids that al- though absorbed do not adversely affect the fetus. The use of emollients may lessen the requirements for topical steroids, and steroids should be used in the minimum quantities and strengths necessary to control the disease (see Table 14.13.3). Many topical Table 14.13.2  Four major pregnancy dermatoses (numbers are based on 505 pregnant patients with skin problems;
Ambros-​Rudolph et al. 2006) Pregnancy dermatosis Frequency (%) Effect on fetus Effect on mother Intrahepatic cholestatis of pregnancy   3 Can be substantial (see Chapter 14.9) Can be substantial (see Chapter 14.9) Atopic eruption of pregnancy 50 None described Usually improves after delivery Polymorphic eruption of pregnancy 22 None described Pemphigoid gestationis   4a Small for dates May be major, usually resolves months after delivery a Raised frequency as tertiary referral centre. Fig. 14.13.3  Atopic eruption of pregnancy in a 24-​year-​old gravida 2 at 19 weeks’ gestation: small red pruritic papules and eczematous features on the trunk (and limbs). Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria.

Section 14  Medical disorders in pregnancy 2652 steroids contain antiseptics and antibiotics that will be absorbed, and some may be contraindicated in pregnancy. The sedating anti- histamine chlorpheniramine may help with sleep. Secondary infec- tion often requires systemic antibiotics such as oral penicillins or erythromycin. The condition resolves in days to weeks after delivery. It may recur in one-​third of pregnancies. Polymorphic eruption of pregnancy Polymorphic eruption of pregnancy was formerly known as ‘pruritic urticated papules and plaques of pregnancy’ or ‘toxic erythema of pregnancy’. Its aetiology is unknown, but there is an association with a low serum cortisol. It affects 1 in 240 singleton pregnancies, being most common in first pregnancies, with multiple births (hence fol- lowing in vitro fertilization)—​perhaps related to the mechanical ef- fect of the abdominal stretching or to an increased immune complex load—​and with a male fetus. This condition usually begins in the third trimester and occasion- ally post-​partum. Red papules and plaques typically begin in striae on the abdomen and thighs and then spread to the whole trunk and limbs, including the hands and feet. They are very itchy, and the itching can be so severe as to prevent sleep. Initially the lesions are raised red papules (Fig. 14.13.4) and plaques; with time they become more diverse in morphology, occasionally polycyclic or blistering. The histopathology shows oedema, perivascular lymphocytes, and eosinophils. Immunofluorescence does not demonstrate any circulating or bound immunoreactants. Treatment is with reassurance and emollients (e.g. cold cream containing 1–​2% menthol). This is helpful, but not always sufficient. Antihistamines and moderate to very potent topical steroids, which may be absorbed through the skin (see Table 14.13.3), may be re- quired, and occasionally systemic steroids for induction of remission. The condition resolves over days to weeks after delivery. It does not usually recur. The outcome of the pregnancy is not adversely affected. Pemphigoid gestationis Pemphigoid gestationis, formerly herpes gestationis (a name best abandoned as ‘herpes’ refers to the herpetiform grouping of the blis- ters rather than herpes infection), is an autoimmune blistering disease characteristically occurring in pregnancy. Pemphigoid gestationis is the most severe of the pregnancy dermatoses. It is due to circu- lating antibodies against adhesion molecules of the skin basement membrane zone. Very potent topical or systemic steroids are usu- ally required. Transplacental transmission to the fetus may occur. Recurrence in future pregnancies is to be expected. The aetiology is only partially understood. The pathogenicity of the circulating basement membrane zone antibodies is demon- strated by transplacental transmission of the disease. The major target antigen is BP180/​collagen XVII (chief epitope being the trans- membrane NC16A domain); BP230 is a less common antigen. Both antigens are present in skin, mucosa, and amnion, associated with the hemidesmosome and adhesion complex linking epithelium to dermis/​mesenchyme, which are targets in other autoimmune blis- tering diseases. The placenta shows increased expression of antigen-​ presenting cells, but it is unclear why breakdown of tolerance occurs, and why normal components of amnion and stratified squamous epithelium become antigenic. The mothers have the HLA DR 3, 4, haplotype and are C4 null, and there is an association with thyroid and less commonly other autoimmune disease. Pemphigoid gestationis occurs in approximately 1 of 50 000 pregnancies. It commences from the second trimester onwards and quite often in the first week post-​partum (range from five weeks of gestation to four weeks post-​partum). It usually occurs in the first and subsequent pregnancies, although 8% of pregnancies are skipped. The eruption typically begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet, including the palms and soles, and rarely the face. The mouth and vulva may be involved showing blisters or erosions. Vesicles and blisters are character- istic, but lesions comprise annular lesions, papules, and plaques (Fig. 14.13.5). Pruritus is severe and sleep often impaired. Table 14.13.3  Examples of topical steroids. Prolonged treatment with very potent topical steroids may lead to fetal growth
restriction; see guidelines for the use of topical steroids in pregnancy Group Generic name Mild Hydrocortisone 1% Moderately potent Hydrocortisone 1% with urea Clobetasone butyrate 0.05% Flurandrolone Potent Betamethasone valerate 0.025%/​0.1% Betamethasone dipropionate Hydrocortisone 17-​butyrate Fluticasone propionate Mometasone furoate Very potent Clobetasol propionate 0.05% Fig. 14.13.4  Polymorphic eruption of pregnancy: urticated papules and plaques on the thigh.

14.13  The skin in pregnancy 2653 Transplacental transmission of antibodies to the fetus occurs in about 3% of affected pregnancies, the neonate developing transient self-​limiting blistering (Fig. 14.13.6). Histopathology demonstrates an eosinophilic infiltrate, papil- lary oedema, and subepidermal blisters. Direct immunofluores- cence demonstrates that C3 component of complement and IgG1 are bound at the basement membrane zone of the dermoepidermal junction. The patient’s serum has circulating IgG1 basement mem- brane zone antibodies that bind C3. These immunoreactants are also found at the basement membrane zone of the amnion (Fig. 14.13.7). Treatment with potent or very potent topical steroids and chlorpheniramine is recommended, however, systemic steroids (e.g. prednisolone 0.3–0.5 mg/kg body weight daily) may be required, the dose adjusted according to disease activity. There is usually a post-​ partum flare, necessitating increased steroids. Azathioprine and Ciclosporin may reduce steroid requirement in selected cases. The disease slowly resolves post-​partum, but may persist for sev- eral months. Recurrence in subsequent pregnancies is usual, only about 8% being spared. The classical teaching is that it recurs earlier and is more severe in subsequent pregnancies, but this has not al- ways been our experience. Onset of pemphigoid gestationis in the first or second trimester and presence of blisters may lead to adverse pregnancy outcomes, including decreased gestational age at delivery, preterm birth, and children with low birth weight. Such pregnancies should be considered high risk and appropriate obstetric care should be provided. Systemic corticosteroid treatment, in contrast, does not substantially affect pregnancy outcomes, and its use for pemphigoid gestationis in pregnant women is justified. Classical dermatoses affecting pregnant women Psoriasis Psoriasis improves in most women during pregnancy, but can de- teriorate. Therapy poses special problems as most systemic treat- ments are contraindicated. Methotrexate is a folic acid antagonist and can cause miscarriage; acitretin is teratogenic; fumaric acid causes leukopenia (whether this affects the fetus is unknown, but case reports have shown no harm). Oral psoralens with UVA (PUVA) are still not proven to be safe, but topical PUVA and UVB light treatment is safe. Ciclosporin and tumour necrosis factor (TNF) α inhibitors are reserved for severe cases. Topical therapy with steroids can be used if needed. Coal tars and dithranol have been widely used in pregnancy but are not proven to be safe. The new vitamin D analogues are not licensed for use in pregnancy, but there is no hint from case reports that indicate harm if used in usual doses. The ideal is minimum treatment, encouraging emollient use and if necessary UVB. A severe form of pustular psoriasis, impetigo herpetiformis, may occur in pregnancy and is best managed with bed rest, emollients, and moderate potent topical steroids or low doses of oral prednisolone. In severe cases topical PUVA or oral Ciclosporin are used, and induction of labour may be indicated if the mother is at risk. Cutaneous lupus erythematosus Cutaneous lupus erythematosus may be adversely affected or im- proved or unchanged by pregnancy. However, such patients should be screened for anti-​Ro and anticardiolipin antibodies, preferably prior to conception, to identify at-​risk pregnancies (see Chapter  14.14). Fig. 14.13.5  Pemphigoid gestationis: urticated papules and blisters. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission. Fig. 14.13.6  Pemphigoid gestationis: urticated papules in the neonate. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission. Fig. 14.13.7  Pemphigoid gestationis: linear deposition of C3 at the amnion basement membrane zone as demonstrated by immunofluorescence. The nuclei are counterstained with propidium iodide. Courtesy of B.S. Bhogal and M.M. Black, St John’s Institute of Dermatology, St Thomas’s Hospital, London.

Section 14  Medical disorders in pregnancy 2654 Autoimmune bullous diseases Linear IgA disease, an autoimmune blistering disease with linear IgA basement membrane zone antibodies, usually improves with pregnancy, such that some patients can discontinue their therapy, usually dapsone. Despite the deposition of immunoreactants in the amnion basement membrane zone, the fetus is not ad- versely affected. There is usually an exacerbation three months post-​partum. Pemphigus vulgaris is an autoimmune blistering disease with widespread mucosal and/​or cutaneous erosions caused by IgG antibodies to desmosomal components of the epithelium. The desmosomal antibodies are directed at desmoglein 3, a major adhesion molecule in mucosa and neonatal skin, and can be transmitted across the placenta, causing severe neonatal pem- phigus with devastating results to the fetus. This does not occur in the related pemphigus foliaceus, which is endemic in Brazil, characterized by superficial cutaneous erosions and mediated by desmoglein 1 antibodies that do not cause oral lesions or af- fect neonatal skin. Both forms of pemphigus may worsen in pregnancy and treatment may require systemic steroids and im- munosuppressants like azathioprine. Spontaneous remission after pregnancy is described. Vulval dermatoses Many dermatoses may affect the vulval skin, and this may be par- ticularly distressing in pregnancy as concerns regarding delivery may arise. A disease commonly seen at the vulva is lichen sclerosus, a chronic inflammatory condition of unknown cause. This is usually treated with very potent topical steroids. Their use should be limited during pregnancy to a minimum, but the disease may improve during pregnancy and does not inhibit vaginal delivery, although episiotomy may be required and should be anticipated. FURTHER READING Ambros-​Rudolph CM, et al. (2006). The specific dermatoses of preg- nancy revisited and reclassified:  results of a retrospective two-​ center study on 505 pregnant patients. J Am Acad Dermatol, 54, 395–​404. Chi CC, et al. (2009). Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol, 160, 1222–​8. Chi CC, et al. (2015). Safety of topical corticosteroids in preg- nancy. Cochrane Database Syst Rev. Oct 26;(10):CD007346. doi:10.1002/14651858.CD007346.pub3. Review. European Academy of Dermatology and Venereology. Patient Information Leaflets. http://​www.eadv.org/​patient-​corner/​leaflets/​ Jenkins RE, Hern S, Black MM (1999). Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol, 24, 255–​9. Kirtschig G, Cooper S (2016). Gynaecologic dermatology: symptoms, signs and clinical management. Jaypee Brothers, New Delhi. Kirtschig G, Schäfer C (2015). Dermatological medications and local therapeutics. In: Schaefer C, Peters P, Miller RK (eds) Drugs during pregnancy and lactation, 3rd edition. Elsevier, London,
pp. 467–​510. Muller S, Stanley JR (1990). Pemphigus: pemphigus vulgaris and pem- phigus foliaceus. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, Chapman & Hall, London, pp. 43–​62. Vaughan Jones S, Ambros-​Rudolph C, Nelson-​Piercy C (2014). Skin disease in pregnancy. BMJ, 348, g3489. Vaughan Jones SA, et al. (1999). A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol, 141, 71–​81. Zhang Y, et al. (2016). Ursodeoxycholic acid and S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy: a meta-analysis. Hepatitis Monthly, 16(8), e38558. doi:10.5812/hepatmon.38558.

14.14 Autoimmune rheumatic disorders and vasculiti

14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy 2655

ESSENTIALS Autoimmune diseases affect 5–​7% of people, are more common in women of childbearing age, and are frequently encountered in preg- nancy. They may remit or improve during pregnancy, but can flare or present in pregnancy or post partum. Systemic lupus erythematosus The mother—​pregnancy probably exacerbates systemic lupus erythematosus and increases the likelihood of a flare, which can be difficult to diagnose since many clinical features also occur in normal pregnancy. Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult: renal flares are more common if disease is active within six months of conception, in particular in women with hypertension, heavy proteinuria, or high baseline serum creatinine. There is an increased risk of maternal thrombosis and premature atherosclerosis. The fetus—​systemic lupus erythematosus is associated with in- creased risks of adverse pregnancy outcome including fetal death and intrauterine growth restriction. Most fetal losses occur in associ- ation with secondary antiphospholipid syndrome or active disease, particularly renal. For women with systemic lupus erythematosus in remission and without hypertension, renal involvement, or the antiphospholipid syndrome, the risk of problems in pregnancy is similar to that of the general population. Management—​flares of systemic lupus erythematosus must be ac- tively managed, pre-​pregnancy counselling should be encouraged with treatment depending on both organ involvement and severity. Mild cases can be managed with analgesics alone (paracetamol); rash and arthritis will usually respond to non​steroidal anti-​inflammatory drugs, low-​dose prednisolone and/​or hydroxycholorquine; more se- vere disease may require introduction of a disease-​modifying agent (e.g. azathioprine or higher steroid dose). Steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune conditions). The baby—​neonatal lupus syndromes are caused by transplacental passage of autoantibodies directed against cytoplasmic ribonucleoproteins Ro and La. Cutaneous neonatal lupus is the most common manifestation (5%) and congenital heart block the most serious (20% mortality). Antiphospholipid syndrome Clinical features—​antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​or IgM), lupus anticoagulant, and anti-​ β2-​glycoprotein-​I antibody. Antiphospholipid syndrome is the combination of any of these with one or both of the following clinical features:  (1) thrombosis—​arterial, venous, or small vessel;
(2) specific pregnancy morbidity. Women with isolated but per- sistent antiphospholipid antibodies without clinical features of antiphospholipid syndrome have obstetric outcomes similar to the general population. Management—​aim is to improve pregnancy outcome and pre- vent maternal thrombosis. This requires low-​dose aspirin from early pregnancy for prevention of pre-​eclampsia ± low-​molecular-​ weight heparin. Close fetal and maternal surveillance are required. Rheumatoid arthritis Rheumatoid arthritis improves with pregnancy in some women. Methotrexate is teratogenic, but with the advent of treatment with biologics, more women with rheumatoid arthritis are now attempting pregnancy. Birth outcomes of women on anti-​TNFα agents are re- assuring and there is no link with teratogenicity, but concern about immunosuppression of the fetus through transplacental transfer means treatment with some agents should be discontinued in later pregnancy. Overall the risk of adverse obstetric outcomes remains minimal and similar to the normal population. Post-​partum flares of rheumatoid arthritis are common. Introduction Autoimmune diseases affect 5–​7% of the population and are more common in women of childbearing age. Many women with auto- immune rheumatic diseases have been advised against pregnancy in the past, but this is no longer appropriate with a new generation of pregnancy-​friendly disease-​modifying antirheumatic drugs and biological agents that afford excellent disease control without com- promising fertility. Nevertheless, many women with autoimmune rheumatic diseases are older and have more comorbidities (i.e. hypertension, obesity, diabetes, cardiovascular disease, and so on) when they do attempt pregnancy. 14.14 Autoimmune rheumatic disorders
and vasculitis in pregnancy May Ching Soh and Catherine Nelson-​Piercy

Section 14  Medical disorders in pregnancy 2656 The importance of planned pregnancies with good preconception advice from clinicians knowledgeable in both the disease process and its effects on pregnancy (and lactation), and vice versa, cannot be overemphasized. Pregnancy is associated with suppressed cell-​mediated immunity (Th1) and enhanced humoral immunity (Th2), but these changes revert post-​partum accompanied by rapid reductions of oestrogen, progesterone, and cortisol levels. The post-​partum period is there- fore a time of susceptibility to autoimmune disorders; and women who already have an autoimmune disorder may suffer disease ex- acerbation following pregnancy. Conversely, some autoimmune diseases may remit or improve during pregnancy, but this is not a universal rule. Flares in pregnancy are often accompanied by adverse obstetric outcomes for both mother and fetus. This chapter considers the relationship between pregnancy and systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, vasculitides, and scleroderma, and how preg- nancy affects treatment of these conditions. Systemic lupus erythematosus Systemic lupus erythematosus is much more common in women than men (ratio 9:1), with peak onset during the childbearing years. A  recent extensive review of published epidemiological studies demonstrated that the prevalence ranges from 0.07/​1000 in Caucasian Americans to 1.59/​1000 in a British Afro-​Caribbean population. Effect of pregnancy on systemic lupus erythematosus Flares of systemic lupus erythematosus may be difficult to diagnose during pregnancy since many features such as hair loss, oedema, fa- cial erythema, fatigue, musculoskeletal pain, anaemia, and raised erythrocyte sedimentation rate (ESR) also occur in normal preg- nancy. Several disease activity scores are being validated for use in pregnancy. Active systemic lupus erythematosus in the four to six months preceding conception increases the likelihood of a flare during pregnancy. Several case–​control studies have addressed this issue, but differ in patient ethnicity, criteria for flare and systemic lupus erythematosus activity scales employed. The type of flare usually fol- lows previous disease pattern. Hydroxychloroquine has been linked with better disease control and improved obstetric outcomes, and therefore should be continued in pregnancy. Conversely, steroids do not prevent flares, hence it is not appropriate to prescribe or increase the dose of steroids prophylactically during pregnancy or during the post-​partum period. Ideally, pregnancy should be planned when systemic lupus erythematosus is in remission, while on drugs that are suitable to be continued in pregnancy. Renal flares are more common if disease is active within six months of conception. There is a risk of deterioration of renal function in pregnancy, particularly if the patients are hyperten- sive, have pre-​existing heavy proteinuria, or a high baseline serum creatinine. A recent meta-​analysis reported that the in- cidence of renal lupus flares during pregnancy was 11–​69% and renal impairment occurred in 3–​27%, which was irreversible in up to 10%. Tacrolimus is being increasingly used as a treatment for lupus nephritis. De novo presentations of lupus nephritis during pregnancy are not uncommon, particularly in those who are not treated. Women with systemic lupus erythematosus and secondary antiphospholipid syndrome have an increased risk of maternal thrombosis, especially in the puerperium. There should be a low threshold for empiric treatment with low-​molecular weight heparin pending appropriate diagnostic imaging. Young women with systemic lupus erythematosus are also at risk of premature atherosclerosis, even in the relative paucity of cardio- vascular risk factors. It is possible the pregnancy and its associated complications accelerate this process. Hence, myocardial infarction should be considered as a differential if she presents with chest pain or shortness of breath. Pulmonary hypertension present in up to 14% of patients. It carries a significant risk of maternal death. Idiopathic pulmonary hypertension is associated with an up to 25% risk of maternal mortality, and this risk is even higher in women with underlying connective tissue disorders. Women who have pulmonary hyper- tension should be advised against pregnancy and when pregnant, offered the option of termination on the basis of life-​threatening maternal disease. Nevertheless, the most common cause of ma- ternal death in women with systemic lupus erythematosus is infection. Effect of systemic lupus erythematosus on pregnancy Women with systemic lupus erythematosus remain fertile, except during severe flares or after exposure to prolonged high doses of cyclophosphamide, which results in premature ovarian failure. However, systemic lupus erythematosus is associated with in- creased risk of early pregnancy losses and the later adverse preg- nancy outcome as a result of placental insufficiency, and manifest as pre-​eclampsia, fetal growth restriction, or small for gestational age infants, placental abruption, and stillbirth—​collectively known as maternal-​placental syndrome. These complications often lead to preterm deliveries. The main factors influencing pregnancy out- comes in women with systemic lupus erythematosus are disease activity (especially at time of conception), hypertension, renal in- volvement, secondary antiphospholipid syndrome, and anti-​Ro/​La antibodies (see next). Pregnancy outcomes in women with systemic lupus erythematosus have greatly improved in recent years due to continuation of hydroxychloroquine in pregnancy, fetal surveillance in women who are Ro and La positive, improved disease control even in the non-​ pregnant cohort, likely milder disease course as diagnostic latency is shortened and clinicians are now more comfortable with the man- agement of systemic lupus erythematosus in pregnancy thereby re- ducing the rate of iatrogenic preterm delivery. Presence of renal disease is closely associated with pregnancy outcomes in women with systemic lupus erythematosus. In a meta-​ analysis active nephritis at conception was associated with 25–​50% rate of fetal loss as compared to 8–​12% if the disease was inactive. One case–​control study showed that 28% of patients with class III or IV lupus nephritis developed pre-​eclampsia, 35% had a pre- term delivery, and a significantly lower birth weight compared to the women with systemic lupus erythematosus without nephritis. A higher baseline creatinine is also associated with poor pregnancy outcomes. Women with systemic lupus erythematosus in clinical remission but with persistently low complement levels or positive anti-​double

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2657 stranded DNA (anti ds-​DNA) in the second trimester have worse pregnancy outcomes than seen in women with normal complement or negative anti ds-​DNA. However, it is women with both serological and clinically active disease who have the highest rates of pregnancy loss and preterm delivery. Positive anti ds-​DNA was more closely associated with high clinical systemic lupus erythematosus activity in pregnancy, but low complement alone was not. Management of systemic lupus erythematosus in pregnancy Preconception counselling When possible, management should begin with preconception counselling. Baseline renal function, blood pressure, and the anti­ phospholipid and anti-​Ro/​La antibody status allow prediction of the risks to the woman and her baby (see later). Appropriate baseline investigations are listed in Box 14.14.1. A decision should be made as to whether to start aspirin and/​or low-​molecular weight heparin if the woman is at risk of thromboses. The outlook is better if conception occurs during remission, and women should be advised to avoid pregnancy for at least 6 months post-​flare, especially if there is renal involvement. Her medications should be reviewed and changed to pregnancy-​friendly drugs (if possible). It is important to ensure clinical stability on this regime for at least six months preconception. Maternal surveillance Pregnancy care is best undertaken in multidisciplinary, combined clinics where physicians and obstetricians can monitor disease ac- tivity, fetal growth, and uterine and umbilical artery Doppler blood flow. Women will need to be regularly reviewed for any signs of pre-​ eclampsia or a flare. Frequency of visits depends on gestation and maternal disease activity. As a rule of thumb, the visits increase in frequency towards and during the third trimester—​when superim- posed pre-​eclampsia is commonest. Diagnosis of flare Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult, and the two conditions may co-​exist. Table 14.14.1 lists fea- tures to help to distinguish them. The gold standard is a renal biopsy to differentiate a renal lupus flare from pre-​eclampsia. Renal biopsies can be performed in pregnancy, but there is an increased risk of bleeding and haematoma formation due to increased vascular perfusion to kid- neys during pregnancy. Renal biopsies are performed rarely in preg- nancy and only before 24 weeks’ gestation. Other useful markers for a flare of lupus nephritis include a raised ds-​DNA and active urinary sediment or the presence of casts in the urine. Management of flare Disease flares must be actively managed. Delivery is seldom the sole management of choice as post-​partum flares are common and severe. Treatment will depend on the organ involvement and severity (see the later section in this chapter, ‘The use of antirheumatic drugs, immuno- suppressive agents, and biologics in pregnancy’ for a summary of the therapeutic options available). Most drugs can be used in pregnancy. Teratogenic agents such as cyclophosphamide should be avoided in the first 12 weeks during which organogenesis occurs. There are long-​term safety data on the use of cyclophosphamide later in preg- nancy with a cohort of children exposed in utero showing no signs of neurodevelopmental delay or other adverse effects when followed up to adolescence. Due to the prolonged action of rituximab, it is best avoided for six months prior to delivery. However, its use in pregnancy (for other indications, e.g. idiopathic thrombocytopenic purpura or as part of a chemotherapy regimen) has not been associated with adverse neonatal effects, and the exposed infants are able to mount an adequate response to vaccination despite the reduction of lymphoid B cells in the reticuloendothelial system seen in the offspring of exposed primates. Corticosteroids are the most widely prescribed drug for a flare in pregnancy as they have a well-​established safety profile. Non-​ fluorinated steroids (e.g. prednisolone), are metabolized by the placenta, and the fetus also inactivates steroids by way of sul- phate conjugation, hence very little (<10%) active drug reaches the fetus. Conversely, fluorinated steroids like dexamethasone and betamethasone cross the placenta more readily and are often used for antenatal fetal lung maturation in women at risk of preterm delivery. A recent population-​based study of over 800 000 births over a 12-​ year period in Denmark did not show an increased risk of orofacial clefts with use of oral corticosteroids. However, there is increasing evidence that repeated courses of fluorinated steroids, particularly Box 14.14.1  Baseline investigations to assess risk of pregnancy in patients with systemic lupus erythematosus • Blood pressure • Urinalysis and quantification of proteinuria (albumin/​protein cre- atinine ratio and/​or 24 h urinary protein) • Full blood count, ESR • Urea, creatinine, and electrolytes • Liver function tests • Uric acid • Serology—​antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies, anti-​β2glycoprotein I antibodies), ENA (esp. Ro and La antibodies), ANA, ds-​DNA • Complements: C3 and C4 Table 14.14.1  Features to help distinguish lupus nephritis flare and pre-​eclampsia Pre-​eclampsia Flare of SLE Hypertension Yes Often present Other organs No Malar rash, photosensitive rash, or arthritis Seizures If eclampsia Only if there is neurological involvement Proteinuria ++ ≥0.3 g/​ day or
PCR ≥30 ++ (in lupus nephritis) Urinary casts Absent Present (if lupus nephritis) RBC in urine Absent Present (if nephritic) Urate Elevated Not elevated unless CKD Albumin Low Very low if nephrotic syndrome LFT May be deranged Rarely deranged in a flare of SLE C3 and C4 Unchanged from baseline in early pregnancy Low compared to baseline in early pregnancy Anti-​ds-​DNA Unchanged Elevated CKD, chronic kidney disease; LFT, liver function test; RBC, red blood count; SLE, systemic lupus erythematosus.

Section 14  Medical disorders in pregnancy 2658 dexamethasone, can adversely affect the child’s later neuropsycho- logical development. Corticosteroid usage in pregnancy does in- crease the maternal risk of gestational diabetes, hypertension, infection, risk of preterm rupture of membranes and osteoporosis. Women on long-​term maintenance steroids (>7.5 mg/​day for

2 weeks) require parenteral steroids to cover the stress of labour and delivery. Prednisolone is safe in breastfeeding mothers since less than 10% of active drug is secreted into breast milk. Notwithstanding the above risks, steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune condi- tions), as the benefits of rapid disease control outweigh the risks. Disease-​modifying antirheumatic drugs are discussed later in this chapter, in the section ‘The use of antirheumatic drugs, immunosup- pressive agents, and biologics in pregnancy’. Neonatal lupus syndromes About 30% of patients with systemic lupus erythematosus are anti-​ Ro positive. In such women the risk of transient cutaneous lupus is about 5% and the risk of congenital heart block about 2%, with the two conditions rarely coexisting. Anti-​Ro antibodies are present in 90 to 100% of mothers of affected offspring, and 68 to 91% have anti-​La antibodies. Maternal titres of anti-​Ro antibodies as high as 50 U/​ml or more are more likely to be associated with congenital heart block. There is no relationship between anti-​La titre and neonatal lupus. The risk of neonatal lupus is increased if a previous child has been affected, at 15–​25% if one and 50% if two previous children are affected. Not all anti-​Ro/​La positive mothers of neonates with congenital heart block have systemic lupus erythematosus or Sjögren’s syndrome, some are asymptomatic, but 48% of these de- veloped symptoms of connective tissue disease in a median 3.7 years follow-​up in one study. In mothers who do have systemic lupus erythematosus there is no correlation between the severity of ma- ternal disease and the incidence of neonatal lupus. Cutaneous neonatal lupus usually manifests in the first two weeks of life. The infant develops typical annular skin lesions similar to those of adult subacute cutaneous lupus, usually of the face and scalp, which appear after sun or UV light exposure. The rash disappears spontaneously within six months. Residual hypopigmentation or tel- angiectasia may persist for up to two years, but scarring is unusual. No specific treatment is required, except topical steroids in severe cases. Congenital heart block usually appears in utero, around 18–​ 20 weeks and is associated with a structurally normal heart. The mechanism of damage appears to involve binding of the anti-​Ro/​La antibodies to antigens on the fetal cardiocytes, inducing an inflam- matory process which leads to tissue damage and fibrosis of the con- ducting system. In women known to be anti-​Ro/​La positive, the fetal heart rate should be monitored at each visit (from 16 weeks onwards), and fetal cardiology scans offered at approximately 18–​20 weeks’ ges- tation and again at 28 weeks. Complete heart block causes brady- cardia which can be detected on auscultation, but lesser degrees of heart block require Doppler echocardiography. Overall mortality is around 20%, with deaths usually occurring in utero (after developing hydrops, pleural and pericardial effusions) or the neonatal period, but can occur up to three years of age. Most infants who survive the neonatal period do well, although two-​thirds require pacemakers. There is no treatment that reverses complete heart block. In the past, intravenous immunoglobulins, fluorinated glucocorticosteroids, plasmapheresis, salbutamol, and digoxin have all been tried and found to be ineffective. Studies on congenital heart block have been difficult to conduct due to the rarity of the condition. However, a large retrospective study did find an association between maternal hydroxychloroquine use, and a reduction in heart block in the offspring. Its follow-​on study focusing on subsequent pregnancies of women whose off- spring were affected found that there was a definite reduction in the incidence of heart block in the offspring of the women who were re- ceiving hydroxychloroquine. Hence, hydroxychloroquine should be used in women who are planning pregnancy (or in early pregnancy) and are Ro or La antibody positive, even if they are asymptomatic. Antiphospholipid syndrome and antiphospholipid antibodies Antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​or IgM), lupus anticoagulant, and anti-​β2-​glycoprotein-​I antibody. The combination of any of these with one or more of the characteristic clinical features of thrombosis, recurrent pregnancy loss, or adverse pregnancy outcome (as detailed in Table 14.14.2) is known as the antiphospholipid syndrome. antiphospholipid Table 14.14.2  Revised (2006) classification criteria for the antiphospholipid syndrome Revised classification criteria (Sydney criteria) for antiphospholipid syndrome. Vascular thrombosis: ≥1 clinical episode of arterial, venous, or small vessel thrombosis. Thrombosis must be objectively confirmed. For histopathologic confirmation, thrombosis must be present without inflammation of the vessel wall. Pregnancy morbidity: a. ≥1 unexplained death of a morphologically normal fetus ≥10 weeks of gestation. b. ≥1 premature delivery of a morphologically normal fetus <34 weeks’ gestation because of: (i) severe pre-​eclampsia or eclampsia defined according to standard definitions. (ii) recognized features of placental insufficiency. c. ≥3 unexplained consecutive miscarriages <10 weeks’ gestation, with maternal and paternal factors (anatomic, hormonal, or chromosomal abnormalities) excluded. Laboratory criteria: The presence of antiphospholipid antibodies (antiphospholipid antibodies), on two or more occasions at least 12 weeks apart and no more than five years prior to clinical manifestations, as demonstrated by ≥1 of the following. a. Presence of lupus anticoagulant in plasma b. Medium to high-​titre anticardiolipin antibodies (>40 GPL or MPL, or >99th percentile) of IgG or IgM isoforms c. anti-​ß2 glycoprotein-​I antibody (anti-​ ß2GP I) of IgG or IgM present in plasma. Adapted from Miyakis S, et al. (2006). International consensus statement on an update of the classification criteria for definite antiphopholipid syndrome (APS). J Thromb Haemost, 4, 295–​306.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2659 antibodies are common and are not always associated with a clinical picture of pregnancy losses, obstetric complications, or thrombosis. The implications of antiphospholipid antibodies
and antiphospholipid syndrome in pregnancy Antiphospholipid syndrome is the most commonly acquired thrombophilia. Antiphospholipid antibodies are prevalent in the general population. In a cross-​sectional study of healthy blood donors, lupus anticoagulant was present in 8% and anticardiolipin antibodies in 10%. However, these antibodies were transient and persistence occurred in less than 2%. Antiphospholipid antibodies can be generated after exposure to certain medications, after infec- tion (e.g. with HIV, HTLV-​1, hepatitis A, B, or C, CMV, EBV, VZV, TB, or poststreptococcal rheumatic fever, syphilis, Klebsiella, mal- aria), following a miscarriage, or in association with certain malig- nancies. However, these antiphospholipid antibodies—​particularly those generated after infection or following a pregnancy loss—​are transient and are unlikely to be of clinical significance, hence the importance of retesting antiphospholipid antibodies after more than 12 weeks. The presence of antiphospholipid antibodies does not equate to clinical disease. Only 8% of those with primary antiphospholipid syndrome devel- oped systemic lupus erythematosus or 5% a ‘lupus-​like’ disease over a nine-​year follow-​up interval. The association with thrombosis is more robust in lupus anticoagulant than with anticardiolipin anti- bodies (OR 11.0 vs. 1.6). For those with antiphospholipid antibodies only, several case–​control studies, and a prospective multicentre study have shown the incidence rate of thrombosis is 1.86% per 100 patients per year. In the obstetric setting, women with antiphospholipid syndrome are at increased risk of recurrent early fetal loss, severe early onset pre-​eclampsia, placental abruption, intrauterine fetal death, or fetal growth restriction without hypertension. Recurrent pregnancy loss in women with antiphospholipid syndrome is typically in the second trimester. Fetal death is typically preceded by fetal growth restric- tion and superimposed pre-​eclampsia. Quantifying the risk is diffi- cult. In a meta-​analysis, lupus anticoagulant in particular was more strongly and consistently associated with fetal loss (OR 7.79; 95% CI:2.3–​26.45). The pathogenesis of fetal loss in these patients is not fully understood, although a variety of mechanisms have been sug- gested and there appear to be both thrombotic and inflammatory components. Women with obstetric antiphospholipid syndrome have a much higher risk of severe early onset (<34 weeks’ gestation) pre-​ eclampsia. One study showed 20.9% of these women were found to have anticardiolipin antibodies compared with 7.5% of controls. A systematic review has shown pre-​eclampsia to be more common in women with antiphospholipid antibodies with an OR:  2.73 (95%CI:1.65–​4.51) for anticardiolipin antibodies, and OR 1.45 (95% CI:0.70–​4.61) for lupus anticoagulant. All women with severe early onset pre-​eclampsia should be screened for antiphospholipid syn- drome. However, the presence of antiphospholipid antibodies does not preclude successful pregnancy. Previous poor obstetric history remains the most important predictor of pregnancy outcome in these women. Studies on obstetric outcome in women known to have antiphospholipid syndrome show differing rates of compli- cations depending on their presentation:  those found to have antiphospholipid syndrome as a result of recurrent early miscarriage have lower rates of complications than those with late fetal losses, thrombosis, or other systemic manifestations. By contrast, women with isolated but persistent antiphospholipid antibodies without clinical features of antiphospholipid syndrome have obstetric out- comes similar to the general population. Management of antiphospholipid syndrome
and antiphospholipid antibodies The management of pregnancy in women with antiphospholipid syndrome, in particular the use of anticoagulation, is controversial and will be further discussed. Maternal and fetal surveillance Pregnancy complicated by antiphospholipid syndrome requires ex- pert care and a team approach by obstetricians, obstetric physicians, and rheumatologists/​haematologists. Close monitoring of both mother and fetus is essential. Pre-​eclampsia is the most common complication and should be screened for at each visit with BP check and urine dipstick for proteinuria. Uterine artery Doppler wave- forms are assessed between 20 and 24 weeks’ gestation, and those pregnancies with evidence of compromised blood flow should be monitored more closely with 4-​weekly growth scans because of the high risk of fetal growth restriction. If there is evidence of fetal growth restriction, then use of umbilical artery Dopplers can be fur- ther quantified. Absent or reversed end-​diastolic flow is indicative of poor fetal outcome and delivery should be expedited. By contrast to the patient with antiphospholipid syndrome, women with antiphospholipid antibodies alone do not require add- itional surveillance in pregnancy. Women with isolated but per- sistent antiphospholipid antibodies have normally grown babies and do not have the same complications of pre-​eclampsia, placental abruption, and stillbirth as those with obstetric antiphospholipid syndrome (Table 14.14.3). They can therefore be treated as ‘normal’, except for the use of low-​dose antenatal aspirin 75 mg daily. Pharmacologic options and low-​molecular weight
heparins for antiphospholipid antibodies and antiphospholipid syndrome The main pharmacologic options are low-​dose aspirin (75–​100 mg/​ day) or low-​molecular-​weight heparin, neither, or both. Low-​ molecular-​weight heparin does not cross the placenta. There are few randomized controlled trials in the area of antiphospholipid syn- drome/​antiphospholipid antibodies to guide management of this condition in pregnancy. Many studies are small and of heteroge- neous cohorts that included women who did not fulfil the classifica- tion criteria for antiphospholipid syndrome. Use of aspirin for risk reduction of pre-​eclampsia is almost uni- versally accepted for all women with either antiphospholipid anti- bodies or antiphospholipid syndrome. Two studies have shown that live birth rates are 70% with low-​dose aspirin alone, although a single placebo-​controlled randomized controlled trial showed no difference in live birth rates between the group on aspirin versus those on the placebo. The use of low-​molecular-​weight heparin for pregnant women with antiphospholipid syndrome and previous thrombosis, late preg- nancy losses, or adverse pregnancy outcomes due to placental insuf- ficiency is undisputed, though few recent studies have demonstrated

Section 14  Medical disorders in pregnancy 2660 any improvement in obstetric outcomes. However, in women with only recurrent, early (≤10 weeks) miscarriage, the evidence is less robust, and therefore low-​molecular-​weight heparin should not be routinely started. Laskin’s study looking at low-​molecular-​weight heparin for recurrent pregnancy loss in women (n  =  88) with thrombophilias (47.7% of them had antiphospholipid antibodies) found that live birth rates were 79.1% on aspirin alone and 77.8% on low-​molecular-​weight heparin + aspirin (p = 071). Farquharson’s study (n = 98) also showed no benefit with low-​molecular-​weight heparin use (i.e. 72% live births on low-​dose aspirin vs. 78% with additional low-​molecular-​weight heparin, p = 0.89). In women with antiphospholipid antibodies who are under- going assisted reproduction, low-​molecular-​weight heparin does not improve implantation rates. However, prophylactic low-​ molecular-​weight heparin should be considered due to the high risk of thrombosis in this cohort, especially if they have additional risk factors (i.e. older than 35 years, obese, smokers, or having ovarian hyperstimulation syndrome). low-​molecular-​weight heparin should be discontinued at 12 weeks’ gestation if there are no additional risk factors for thrombosis. For women with antiphospholipid antibodies alone, there is very little evidence to support the use of low-​molecular-​weight heparin antenatally. Most would elect to use low-​dose aspirin as the risk of toxicity is low and there is a modest beneficial effect for the preven- tion of pre-​eclampsia. Aspirin can be discontinued at delivery. Its use does not increase the risk of post-​partum haemorrhage nor is it a contraindication to regional anaesthesia. Women with previous thrombosis on long-​term warfarin should be swapped to low-​molecular-​weight heparin before six weeks’ ges- tation to avoid warfarin embryopathy. Other agents Treatment with high-​dose corticosteroids (in the absence of ac- tive lupus) to suppress antiphospholipid antibodies has previously been recommended (in combination with aspirin), however, high doses of prednisolone (up to 40 mg) caused considerable maternal morbidity and subsequent studies have failed to demonstrate better fetal outcome compared to aspirin and heparin. Steroids may even worsen outcome because of an increased risk of preterm labour. Lower doses have been used successfully in women with recurrent miscarriage despite the use of aspirin and low-​molecular-​weight heparin. Immunosuppression with intravenous immunoglobulin (IVIg) has been used, particularly for recurrent miscarriage. However, more recent studies have shown no benefit either compared to, or in addition to, aspirin and heparin. In the comparison study in re- current miscarriage there was a higher rate of live births (84%) with aspirin and heparin than with immunoglobulin (57%): the study in which IVIg was added showed no significant difference in live birth rate. Other immunosuppressive agents have also been used, including azathioprine and plasmapheresis, but the numbers treated do not allow firm conclusions regarding efficacy. Post-​partum Women with antiphospholipid syndrome and previous thrombo- embolism are at particularly high risk in the puerperium. If the woman has been on aspirin prior to pregnancy, this should be con- tinued. Warfarin can be restarted in the women who were previously taking it once the risk of bleeding is minimal (usually after 10 days) (Table 14.14.4). Aspirin, low-​molecular-​weight heparin, and warfarin are safe for women who are breastfeeding. The combined oral contraceptive pill should be avoided due to the increased risk of thrombosis. The progesterone-​only pill is safe for women with antiphospholipid syndrome and can be used during breastfeeding. Alternative methods such as intrauterine de- vices or depot progesterone, either intramuscularly or subdermally, can be safely used in women with antiphospholipid syndrome. Women with antiphospholipid syndrome, particularly thrombotic antiphospholipid syndrome on warfarin, should be advised to plan their pregnancies. Rheumatoid arthritis Rheumatoid arthritis is common in women (female to male ratio 3:1), with a prevalence of 1–​2 per 1000 women per year in the Table 14.14.3  Risk of adverse obstetric outcomes in women with antiphospholipid antibodies and obstetric antiphospholipid syndrome compared to the normal population Control (n = 292) Isolated persistent aPL (n = 73) Obstetric APS (n = 73) Birthweight g, median (IQR) 3400 (1760–​4580) 3445 (3110–​3685) 3100 (2710–​3380) Small for gestational age, n (%) 31 (11.0) 4 (5.9) 17 (27.0) Adjustedb OR for SGA (95% CI) 1.0 0.5 (0.2–​1.4) 2.9 (1.5–​5.7) All APS-​type complicationsa, n (%) 31 (10.6) 9 (12.3) 28 (38.4) Adjustedb OR for all APS-​type complications (95% CI) 1.0 1.3 (0.6–​2.9) 5.7 (3.0–​10.9) aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; SGA, small for gestational age. a APS-​type complications include fetal loss >10 weeks’ gestation, early onset pre-​eclampsia necessitating <34-​week delivery, placental abruption, SGA. b Adjusted for maternal age and medical comorbidities (hypertension, renal disease, and diabetes mellitus). Adapted from Soh MC, Pasupathy D, Gray G, et al. (2013) Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. Rheumatology (Oxford), Sep; 52(9):1642–​7.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2661 18–​44-​year age bracket. In the past, pregnancy in young women with rheumatoid arthritis was rare as methotrexate (MTX)—​a known teratogen—​was often the first-​line drug used for it treatment. With the advent of biologics, there has been a surge of women with rheumatoid arthritis now attempting pregnancy. Effect of pregnancy on rheumatoid arthritis Newer prospective multicentre studies have challenged the belief that 75% of women with rheumatoid arthritis go into remission in pregnancy. Studies carried out in the United Kingdom and the Netherlands indicate that only 40–​66% of women experience an im- provement in pregnancy, and less than a quarter of women achieve remission by the third trimester. Women without rheumatoid factor (RF), anticyclic citrullinated peptide (CCP), or with less joint damage were more likely to improve in pregnancy. There have been several hypotheses to explain why pregnancy might, in some cases, lead to improvement in rheumatoid arth- ritis. These include the shift in pregnancy from a predominantly Th1 to Th2 immune response and cytokine repertoire; raised levels of circulating hormones (including cortisol, progesterone, and oestrogen); the maternal immune response to fetal paternally in- herited human leukocyte antigen (HLA) class II gene products, with maternal-​fetal mismatch for certain HLA alleles being beneficial; pregnancy-​specific proteins such as a2-​glycoprotein; removal of im- mune complexes by the placenta, and changes in adipocytokine and PPAR​1 signalling pathways. Anti-​CCP, IgM-​RF, and IgA-​RF titres all decline during pregnancy and post-​partum when disease-​modifying antirheumatic drugs are restarted. In the post-​partum period, however, low antibody levels are not linked to quiescent disease, nor are they useful in predicting risk of post-​partum flares of rheumatoid arthritis, which will occur in a third of women within a month; up to 90% will have experienced a deterioration in symptoms within four months post-​partum. There is an increased incidence of developing rheumatoid arth- ritis during the post-​partum period, with an incidence rate ratio of 1.73 (95% CI 1.11–​2.70) within 24 months of delivery of the first offspring. Studies looking at the effect of breastfeeding on disease have shown conflicting results, with some suggesting it is protective against disease development and others that it increases post-​ partum flare. Overall the evidence of an adverse effect is not strong enough to advise women against breastfeeding. Effect of rheumatoid arthritis on pregnancy Women with rheumatoid arthritis appear to have reduced fertility, with a recent study showing increased use of artificial reproductive techniques. A nationwide prospective study of women with rheuma- toid arthritis (n = 152) has shown that active disease in pregnancy is associated with a lower gestational age at delivery and a lower birthweight. In particular, women on prednisone had a significantly higher rate of preterm delivery (<37 weeks’ gestation) compared to those not taking prednisolone. Data from a nationwide database of obstetric hospitalizations in the United States of America indicate Table 14.14.4  Anticoagulation during pregnancy and puerperium in women who have antiphospholipid syndrome or have persistent antiphospholipid antibodies Antiphospholipid antibodies present in medium to high titre 12 weeks apart Antenatal management Postnatal Previous obstetric adverse events Previous thrombosis Aspirin (75 mg/ day) LMWH LMWH None None Yes, but controversial
(see text) No (unless other risk factors for thrombosis, e.g. family history of thrombosis, raised BMI, and so on) Yes for the usual indications Recurrent 1st-​trimester miscarriage (at least three consecutively) None Yes Controversial (see text). Low prophylactic dose from beginning of pregnancy (e.g. enoxaparin 40 mg once daily), but stop either after 1st trimester, or after 20–​24 weeks if uterine artery Dopplers normal (if no history of thrombosis or late fetal loss) Yes Late fetal loss (2nd or 3rd trimester) or Premature delivery <34 weeks because of severe pre-​eclampsia/
​eclampsia or other features of placental insufficiency None Yes Low prophylactic dose throughout pregnancy Yes Previous unprovoked thrombosis but not on long-​term anticoagulation Yes Yes Commence LMWH at prophylactic doses upon confirmation of intrauterine pregnancy Yes for at least six weeks post-​partum Previous recurrent thrombosis and on long-​term warfarin Yes Yes Swap warfarin to LMWH before 6 weeks’ gestation. High prophylactic dose, e.g. enoxaparin 40 mg twice daily, but may need to be therapeutic doses of LMWH esp. if history of recent thromboses Yes. Swap back to warfarin in the post-​ partum interval Thromboses that are recurrent
in pregnancy Yes Yes Full anticoagulant dose, e.g. enoxaparin 1 mg/​kg twice daily. May also consider re-​warfarinizing between 14 and 34 weeks’ gestation (INR 2–​3) esp. if recurrent symptoms of thromboses on therapeutic doses of LMWH Yes. Swap back to warfarin in the post-​ partum interval BMI, body mass index; CNS, central nervous system; LMWH, low-​molecular-​weight heparin.

Section 14  Medical disorders in pregnancy 2662 that women with rheumatoid arthritis have an increased risk of fetal growth restriction—​3.4% compared to the 1.6% incidence in the normal population. There was also a trend towards an increased risk of developing pre-​eclampsia, but this association was less ro- bust compared to women with systemic lupus erythematosus. The odds ratio in various studies for women with rheumatoid arthritis developing pre-​eclampsia is 1.4–​2.2; small for gestational age infants 1.20–​1.56; fetal growth restriction 2.2. Overall, the absolute risk of adverse obstetric outcomes remains minimal and similar to the normal population. Nevertheless, there is an unusually higher rate of elective cae- sarean section in women with rheumatoid arthritis compared to the normal population. This is most likely iatrogenic because of provider-​initiated clinical decision. Limitation of hip abduction is rarely severe enough to impede vaginal delivery, but particular care is necessary in women with juvenile idiopathic arthritis who have had hip joint replacements. Atlantoaxial subluxation (due to erosive disease affecting the cer- vical spine) is a rare complication of a general anaesthetic for an emergency caesarean section. Hence women should be reviewed by an obstetric anaesthetist to assess cervical spine involvement and de- gree of jaw excursion, and to anticipate any problems if they were to require a general anaesthetic. Management of rheumatoid arthritis in pregnancy All women with rheumatoid arthritis should ideally receive pre- conception counselling and their disease activity and medications reviewed prior to pregnancy. First-​line therapy for rheumatoid arthritis is methotrexate, which is highly teratogenic and requires a three-​month washout period and high-​dose folic acid supplementa- tion (5 mg a day) before conception. The risk of teratogenicity ranges between 5 to 25%, and there is a 23% risk of miscarriage in women taking methotrexate in the first trimester. The effect of methotrexate on organogenesis is proportional to the weekly dose ingested. Leflunomide is similarly contraindicated because of its teratogenic potential as a pyrimidine synthesis inhibitor. However, recent data have emerged showing that if cholestyramine washout (8 g a day for 11 days) of leflunomide occurs in early pregnancy, then the risk of fetal malformations is not increased above the normal population (5.4% vs. 4.2%). Confirmation of successful cholestyramine washout with undetectable drug levels (<0.03 µg/​ml) taken two weeks apart is necessary. If in doubt, ongoing washout with cholestyramine should continue until the woman is past the interval of organogenesis (12 weeks’ gestation). Biologics (and other drugs) in pregnancy Biological agents, especially tumour necrosis factor α-antagonists (anti-​TNFα), are now an established treatment for rheumatoid arth- ritis. Many women on anti-​TNFα who have excellent disease control are contemplating pregnancy. Large biologic databases and observational studies of birth out- comes of women on anti-​TNFα agents are reassuring that there is no link with teratogenicity. Current practice is therefore to encourage all women to continue on their anti-​TNFα therapy while attempting to conceive. For many, cessation of these drugs—​particularly if there is a prolonged interval between discontinuing the drug and suc- cessful conception—​could result in recurrent active disease, which in itself is a barrier to a pregnancy. At present, the biggest concern of anti-​TNFα use in pregnancy relates to the transplacental transfer that occurs predominantly after 20 weeks’ gestation. There are two factors that influence this: (i) the efficiency of the transplacental transfer—​which is dependent on the molecular structure of the Fc portion of the anti-​TNFα molecule; (ii) the half-​life of the drug used. Anti-​TNFα agents are immuno- globulins (Ig), so transplacental transfer increases exponentially as the pregnancy progresses with maximal active transplacental transfer occurring after 28 weeks. Immunosuppression of the neo- nate is a major theoretical concern, but small observational studies have not demonstrated an increased risk of infections. Infliximab, adalimumab, and golimumab are IgG1 monoclonal antibodies, which is the Ig subclass with the most active trans- port across the placenta. In early pregnancy, transfer is limited by a cytotrophoblast. By week 14, Fc receptors begin to develop on the trophoblasts and active transport is increasingly efficient as pregnancy progresses. Thus, at the time of delivery infliximab and adalimumab levels in the neonate (as measured in umbilical cord blood) often exceed maternal levels. Moreover, the very long half-​ lives of adalimumab and infliximab (8–​20 days) have led to very high levels (98–​400% of maternal drug levels) of the active drug de- tected in the cord blood of the neonate. Etanercept has a much shorter half-​life (four days) and with its modified Fc portion, may not bind quite as effectively to the pla- cental Fc receptors. Cord etanercept levels have been demonstrated to be much lower, at 3.6–​7.4% of maternal drug levels. The pegylated anti-​TNFα agent, Certolizumab, lacks an Fc por- tion which prohibits active transplacental transport. Therefore, it is reliant on slow diffusion across the placental barrier to reach the developing fetus. Studies have demonstrated negligible transplacental transfer and this drug therefore has a license for use throughout pregnancy. The decision about whether and when to discontinue anti-​TNFα agents in pregnancy should be individualized to the woman’s risk of a flare, the availability of other agents to manage a flare, and the mo- lecular structure of the drug itself. Longer acting anti-​TNFα agents which are actively transported across the placenta (i.e. adalimumab and infliximab), may have to be discontinued earlier than etanercept and certolizumab. A  blanket statement of discontinuing all anti-​ TNFα agents at 28 weeks may not be appropriate, especially if the woman has a preterm delivery and the infant has had recent exposure to the anti-​TNFα agent. There are suggestions when to contemplate discontinuing anti-​TNFα agents based on available published lit- erature (Table 14.14.5). The 2016 British Society of Rheumatology (BSR) guidelines suggest that if we were to aim for low or undetect- able anti-​TNF levels, then infliximab be discontinued by 16 weeks and etanercept and adalimumab should be discontinued in the late second trimester, but certolizumab could be continued throughout pregnancy. New data on the infant’s immune response to vaccination for those exposed to anti-​TNFα agents in utero in the third trimester show that the responses to Haemophillus influenza type B, Streptococcus pneumoniae, and tetanus were normal, and there were no immune deficits of concern in these infants. There is a single case report in the literature detailing a neonatal death from presumed dissem- inated tuberculosis infection following Bacillus Calmette–​Guérin (BCG) vaccination, although Ziehl–​Neelsen stain for acid-​fast ba- cilli and TB PCR methods were equivocal. The infant was exposed to

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2663 infliximab in utero with the last maternal infusion of infliximab for the treatment of her inflammatory bowel disease occurring just two weeks prior to delivery. Based on these data and several other anecdotal cases, all infants with exposure to anti-​TNFα agents after suggested gestation (with the possible exception of pegylated anti-​TNFα agent certolizumab) should not receive any live vaccines in the first six to eight months of life. The BSR suggests an avoidance of live vaccines in an exposed neonate for the first seven months. There is delayed clearance of these antibodies due to the infant’s immature reticuloendothelial system and supra-​therapeutic drug levels (Table 14.14.5). Common live vaccines during that neonatal period include BCG vaccination and the rotavirus vaccine (an orally administered vaccine). The caregivers of exposed neonates should be vigilant that these vac- cines are not routinely administered. All other vaccines should be given. Additionally, despite the lack of direct correlation between drug exposure and neonatal infection, we would still advise that exposed neonates should be carefully examined, and infection ex- cluded if they become unwell. Clinicians probably should have a lower threshold for screening and treating the exposed neonate for a presumed infection. B-​cell depleting agents such as rituximab are being increasingly used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and many vasculitides. In 2011 a case series of 253 pregnan- cies from the manufacturer’s global drug safety database (dependent on voluntary self-​reporting) has shown that there was a 60% live birth rate and 21% first-​trimester miscarriage rate. The high rate of early pregnancy losses could be related to the underlying disease for which the woman was being treated with rituximab. Rituximab can be detected in cord blood if given within 12 weeks of delivery, and this corresponds to neonatal B-​cell depletion. Yet there does not ap- pear to be any increased risk of infections. Long-​term outcome studies are awaited to determine if there is a future risk of autoimmune disease or lymphoid-​cell malignancies in offspring exposed in utero to biologics. Most disease-​modifying antirheumatic drugs used in rheumatoid arthritis overlap with those used in systemic lupus erythematosus, but additional agents include D-​penicillamine, sulphasalazine, and gold (Table 14.14.6). All disease-​modifying antirheumatic drugs, other than the teratogenic ones (i.e. methotrexate, leflunomide, cyclo- phosphamide, and mycophenolate mofetil), should be continued in pregnancy to prevent flares. Most women with flares of rheumatoid arthritis can be managed on analgesics and low-​dose prednisolone. Non​steroidal anti-​inflammatory drugs (NSAIDs) are not terato- genic and can be used if needed up to 32 weeks’ gestation, after which there is a risk of premature closure of the patent ductus arteriosus and neonatal pulmonary hypertension. The effect is usually reversible within 48-​hours after discontinuation of the NSAID. NSAIDs also have reversible effects on the fetal kidneys with oligohydramnios. Hence their occasional use in late pregnancy for the treatment of polyhydramnios. Data on selective COX-​2 inhibitors in pregnancy are emerging with a population-​based study indicating that there is no teratogenic effect with first trimester exposure. However, there were five cases of musculoskeletal limb defects seen in the group on selective COX-​2 inhibitors. Inflammatory arthritides were also more common in the group on selective COX-​2 inhibitors. Therefore, it is possible that this group were also exposed to methotrexate—​which is associated with limb defects. The future of selective COX-​2 inhibitor in preg- nancy will lie in its improved safety profile in late pregnancy with a less deleterious effect on the fetal ductus arteriosus and kidneys late pregnancy compared to the non​selective COX-​2 inhibitors (or NSAIDs). Vasculitides Granulomatous polyangiits (previously Wegener’s granulomatosis), polyarteritis nodosa, and eosinophilic granulomatosis with polyangiitis (previously Churg–​Strauss syndrome), occur princi- pally in the post-​childbearing years and more often in men, so preg- nancy is very uncommon in these conditions. Henoch–​Schönlein purpura tends to affect the paediatric population, but there have been a few case reports of presentation in pregnancy, or pregnancy after previous Henoch–​Schönlein purpura. Pregnancy is more likely in Takayasu’s arteritis and Behçet’s disease, as they usually occur in the reproductive years. In general, maternal and fetal outcome are dependent on disease activity and pre-​existing complications. Numbers of reported cases are generally too small to determine definitively if disease onset or flare is more likely during pregnancy or post-​partum. The standard advice to plan pregnancy after the disease is in remission still holds as quiescent disease at conception or early pregnancy is usually linked with stable disease in pregnancy. Flares for most conditions are common in the post-​partum interval with maternal immune reconstitution. Table 14.14.5  Accumulation of commonly used anti-​TNFα agents in the neonate and suggested gestation to discontinue Anti-​TNFα agent Half-​life (days) Cord blood to maternal serum concentrations (%) Suggested gestation to discontinue (weeks) Infliximab 8–​10 83–​400 21–​22 Adalimumab 10–​20 98–​293 26–​28 Etanercept 4 3.6–​7.4 30–​32 Certolizumab 14 0–​24.0 Continue throughout Adapted from Soh MC, Nelson-​Piercy, C. (2015) High-​risk pregnancy and the rheumatologist. Rheumatology (Oxford), 54(4), 572–​87, by permission of Oxford University Press, and Soh MC, Mackillop L. (2016) Biologics in Pregnancy—​for the Obstetrician. The Obstetrician and Gynaecologist, January [in press].

Section 14  Medical disorders in pregnancy 2664 Pregnancy outcomes in granulomatous polyangiits are worse with active disease at conception or if there is disease onset during pregnancy, with 57% resulting in miscarriages. Antineutrophil cyto- plasmic antibody (ANCA) titres do not influence obstetric out- comes. If disease is in remission at the beginning of pregnancy, there is still a significant risk of pre-​eclampsia (28.6%) and median gesta- tion at delivery was 35–​36 weeks. There were two maternal deaths from severe flares of the disease out of 43 pregnancies reported in the literature. Pre-​eclampsia was more common with renal involve- ment. Flares post-​partum are common and severe. Flares of granulomatous polyangiits should be aggressively treated. One paper suggests that the use of azathioprine and pred- nisolone to treat a severe flare in pregnancy may be insufficient. Cyclophosphamide—​a known teratogen, but efficacious against severe flares can be used after the first trimester if there is life-​ threatening maternal disease. However, with the advent of rituximab to treat granulomatous polyangiits, this may soon become the pre- ferred option. Other agents to maintain remission in limited granulomatous polyangiits include cotrimoxazole. Although it is a folate antagonist, Table 14.14.6  Commonly used drugs used for the treatment of rheumatic diseases and their effect on pregnancy and breastfeeding Drug Effects on organogenesis (exposure ≤12 weeks’ gestation) Effects on fetus/​neonate (exposure beyond 12 weeks’ gestation) Breastfeeding Authors’ recommendations on its use in pregnancy NSAIDs None Reversible constriction of ductus arteriosus; oligohydramnios. Avoid after 32 weeks or within 48 hours of delivery ✓ Likely a class effect for all NSAIDs. Use if indicated at lowest dose possible until 32 weeks’ gestation COX-​2 inhibitors No teratogenic effects seen in population-​based study Similar effect, but to a lesser degree, as the NSAIDs on fetal heart and kidneys ✓ In the first trimester, till more data emerge, it may be safer to change to a NSAID; though use later in gestation may be less deleterious than NSAIDs Prednisone None Fetus receives <10% of maternal dose ✓ Use lowest dose possible. Plan to taper. To consider addition of a DMARD or biologic if persistently active disease Hydroxychloroquine None None ✓ Continue in pregnancy and breastfeeding Sulfasalazine None None ✓ Commence folic acid supplementation 5 mg/​day, 3 months prior to pregnancy. In men it may affect spermatogenesis and motility Methotrexate Aminopterin syndrome. 15% rate of congenital anomalies—​likely dose related. High rates of pregnancy loss. Safe to be used in men If no congenital anomalies, long-​term follow-​up of children exposed to MTX did not reveal any problems Case report indicates very low levels excreted Reliable contraception advised. Discontinue at least 3 months prior to pregnancy with daily high-​ dose folic acid supplementation. Exposed fetuses should be scanned at 16/​40 to determine if there are any congenital anomalies to facilitate elective termination if the mother wishes. Minimal amounts excreted in breast milk 24 hours after a sc dose of weekly methotrexate—​based in a case report Leflunomide In animal studies, malformations of the head, rump, vertebral column, and limb defects. Increased rate of miscarriages If pregnancy continues, no major structural anomalies noted esp. after cholestyramine wash out as suggested by manufacturer ✘ Reliable contraception advised. Wash out with cholestyramine 8 g TDS 11 days—​repeat till drug level <0.03 μg/​ml taken two weeks apart, or until past 12 weeks’ gestation Azathioprine None Low birth weight and preterm delivery—​could be secondary to maternal disease ✓ Continue in pregnancy and lactation Ciclosporin None Transient immune alterations in the neonate ✓ Continue in pregnancy; probably safe in breastfeeding though a variety of concentrations excreted in breast milk Cyclophosphamide Cyclophosphamide embryopathy with high rate of miscarriages Transient cytopenias. No long-​term effect on the infant ✘ Use only if there is life-​threatening maternal disease >12 weeks. If maternal disease necessitates cyclophosphamide ≤12 weeks’ gestation–​ discuss termination Mycophenolate mofetil OMENS and congenital cardiac defects Most neonates described in the literature, had also been exposed in the period of organogenesis. Phenotype is not dose dependent ✘ Discontinue for at least 3 months prior to pregnancy DMARD, disease-​modifying antirheumatic drug; OMENS, orbital distortion, mandibular hypoplasia, ear anomaly—​N is for seventh cranial nerve involvement, and soft tissue deficiency. † Azathioprine converts to active metabolite 6-​thioguanine nucleotides in 15 minutes but the half-​life of the active metabolite in erythrocytes is weeks to months. ✓—​safe for breastfeeding; ✘—​unsafe or not recommended for breastfeeding Adapted from Soh MC, Nelson-​Piercy C (2015). High-​risk pregnancy and the rheumatologist. Rheumatology (Oxford), 54(4), 572–​87.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2665 studies have demonstrated its safety in pregnancy, though folic acid 5 mg daily should be co-​prescribed. Polyarteritis nodosa is a rare necrotizing vasculitis with a yearly incidence of two per million, occurring predominantly in those aged 50–​60 years. It is a great mimic, with presenting features of abdom- inal pain, hypertension, and proteinuria, all of which are common in pregnancy. It carries a high risk of maternal mortality (up to 100%) if diagnosed during pregnancy or immediately post-​partum, whereas the maternal and fetal outcome is much better if it is diagnosed pre-​ pregnancy and disease is in remission. There are case reports of neo- natal cutaneous vasculitis in babies born to mothers with cutaneous polyarteritis nodosa. This is thought to be a result of transplacental transfer of maternal antibodies and the neonatal cutaneous changes remit spontaneously. Eosinophilic granulomatosis with polyangiitis which is asso- ciated with late onset asthma, nasal polyps, pulmonary infiltrates, and asthma, is also rare (two to three per million), with a peak incidence in the fourth decade. It tends to be less aggressive than granulomatous polyangiits or polyarteritis nodosa, especially if women conceive during remission. Many women with eosinophilic granulomatosis with polyangiitis will require ongoing aggressive glucocorticoid therapy to keep their pulmonary symptoms under control. Exacerbations of the disease are often due to the reluctance of pregnant women to take medications, in addition to loss of lung capacity from the growing fetus. Maternal and fetal outcomes are significantly worse if eosinophilic granulomatosis with polyangiitis presents during pregnancy, and cardiac disease (from coronary vas- culitis, myocardial fibrosis, and eventual congestive cardiac failure) is an important cause of maternal death. Of the vasculitides, Takayasu’s, the ‘pulseless disease’, is most common in oriental women of childbearing age. Pregnancy has a positive effect on the disease course with lower C-​reactive pro- teins (CRPs) and improved digital plethysmography up to a year following delivery. Issues with Takayasu’s arteritis include hyper- tension and involvement of the aortic valve and abdominal aorta, and superimposed pre-​eclampsia and fetal growth restriction are common, with up to 62% and 11–​52% of pregnancies affected re- spectively. In the past, pre-​eclampsia affected 75% of all pregnant women with Takayasu’s especially if they had hypertension diag- nosed prior to pregnancy. Aspirin use has helped reduce the in- cidence of pre-​eclampsia in the more recent studies. Pulmonary hypertension should be excluded before pregnancy. Obstetric out- comes are likely dependent on the extent of vessel involvement. Fetal growth restriction is common and likely due to a combination of impaired placental perfusion as a result of vascular narrowing of the abdominal aorta and its branches and hypertension. There is a cor- relation between disease severity and poor obstetric outcomes; those with Ishikawa class IIb (two or more vessels affected) have poorer outcomes than those with milder disease. Disease activity can be monitored with ESR and CRP in pregnancy and active disease usu- ally responds well to low doses of steroids. Maintenance doses of prednisolone and azathioprine should be continued in pregnancy. Recent publications on Behçet’s disease in pregnancy suggest, that pregnancy seems to positively affect disease course with a reduction in flares (threefold lower) in pregnancy. Flares occurred in about 30% of patients and were more common in those off their medications. The flares are usually mucocutaneous in nature and usually in the third tri- mester. Behçet’s does not appear to adversely affect maternal and fetal outcomes in case–​control studies. A history of previous thromboses and vascular complications was associated with poorer outcomes. Acute thromboses, including deep vein thromboses (DVTs), inferior vena cava, and dural sinus thrombosis, have been reported and clin- icians should be vigilant that thrombotic complications are prob- ably more likely to recur in pregnancy—​a naturally pro-​thrombotic state. Thromboprophylaxis should be strongly considered in women with any additional risk factors (i.e. age, grand multiparity, maternal obesity, and so on). Colchicine, which is the mainstay of treatment in mucocutaneous Behçet’s, was not teratogenic in a study involving 238 colchicine-​exposed pregnancies when compared to 964 control preg- nancies. Behçet’s is one of the rare indications for thalidomide, and women of childbearing age who are commenced on it should be using reliable contraception. The high rate of early pregnancy losses seen in Behçet’s could be due to elective terminations. Henoch–​Schönlein purpura is typically a disease of childhood, presenting with colicky abdominal pain and purpuric rash as a result of IgA-​mediated vasculitis. It is usually a relatively benign condi- tion with an indolent course, with favourable maternal and fetal out- comes. The main concern regarding Henoch–​Schönlein purpura in pregnancy is renal involvement, which is usually mild and resolves spontaneously, but may lead to nephrotic syndrome or acute kidney injury and needs to be distinguished from pre-​eclampsia. In general, in view of the significant maternal and fetal morbidity and mortality associated with active vasculitides, women should be advised to delay pregnancy until disease is in remission. In the case of flare or onset of disease in pregnancy, it is important to adopt an aggressive approach to treatment with immunosuppression. Corticosteroids are usually first-​line treatment. Depending on the underlying vasculitis and the severity of the flare, this can be followed by azathioprine. Life-​threatening disease may necessitate the use of pulsed cyclophosphamide (especially in granulomatous polyangiits) or rituximab. There are cases in the literature where intravenous im- munoglobulins (IVIG) or plasmapheresis has been successfully used in refractory disease, thus minimizing the fetal risk. Scleroderma Scleroderma (or systemic sclerosis) is more common in women (female to male ratio 3:1), with peak age of onset 30–​50 years old. Although it is a rare disease, more cases are being reported in preg- nancy as maternal age increases. Effect of pregnancy on scleroderma In general, women with limited scleroderma without organ involve- ment do better than those with diffuse disease. The extent of diffuse disease and systemic involvement (particularly lung, cardiac, and renal) influences prognosis. Those with early (<4 years) or diffuse disease, or with antitopoisomerase (anti-​Scl-​70) antibodies, are at greater risk of having more active aggressive disease than those with long-​standing disease and anticentromere antibodies. Pregnancy does not affect the course of scleroderma, with 60% having a stable disease course, 20% improving, and 20% deteriorating in pregnancy. The rationale for deferring pregnancy until at least four years after diagnosis is to ensure that early disease can be aggressively treated with potent and sometimes teratogenic immunosuppressants; and if renal crises occur, they tend to be in early disease.

Section 14  Medical disorders in pregnancy 2666 Renal crisis is the main cause of death, with 33% dying in the post-​ partum interval. With the introduction of angiotensin converting enzyme (ACE) inhibitors, the numbers of such deaths have fallen significantly, and many women with previous renal crisis have sub- sequently had successful pregnancies. In a woman with a previous renal crisis, ACE inhibitors should not be discontinued in preg- nancy and the woman should be carefully counselled about the fetal effects. Avoidance of high doses of steroids, which may precipitate renal scleroderma, is essential. The benefits of antenatal steroids for fetal lung maturation should be very carefully weighed against the risk of a maternal renal crisis. Women with renal involvement often have accelerated hypertension and acute deterioration of renal function necessitating temporary renal replacement therapy. Progressive cutaneous disease is unusual during pregnancy but may occur in the post-​partum period. Raynaud’s phenomenon usually improves as a result of vasodilation. Gastro-​oesophageal reflux is exacerbated by a reduced lower oesophageal tone. Arthralgias also worsen. There is no evidence that pregnancy worsens cardiac or re- spiratory disease. However, symptomatic shortness of breath from the expanding gravid uterus is common. Women with severe pul- monary fibrosis and pulmonary hypertension are at extremely high risk of post-​partum deterioration, with a 30–​50% chance of ma- ternal mortality, as with pulmonary hypertension from any cause. In a study exclusively of pregnant women with pulmonary hyper- tension as a result of scleroderma (n = 85), the authors found a five- fold risk of maternal hypertensive disease and a twofold risk of fetal growth restriction. Worsening skin thickening has been observed in post-​partum women. It has been suggested that pregnancy, including miscarriage, may have an aetiological role in scleroderma, with some studies showing that persistent fetal microchimerism and HLA-​DR compatibility be- tween mother and fetus are more common in women with sclero- derma than controls. Hypotheses implicating the persistence of these fetal cells in the pathogenesis of scleroderma include the de- velopment of a fetal antimaternal graft-​versus-​host reaction and/​or the maternal response to fetal cells becoming redirected against the mother herself. Effect of scleroderma on pregnancy Fertility is unimpaired in women with scleroderma. However, spon- taneous miscarriage is more common in those with established scleroderma compared to those with early disease. Women with dif- fuse disease have twice the rate of miscarriages compared to those with limited disease (24% vs. 12%). There is a 9% risk of preterm deliveries, with a higher risk in those with diffuse disease. Overall, the live birth rate is 84% in those with limited disease and 77% in those with diffuse disease. The risk of adverse outcome is highest for women with early diffuse disease. A subset of women with scleroderma may have concurrent Ro and La positivity, with ranges of 12–​37% for the former and 4% for the latter. Antenatal monitoring for congenital heart block should be undertaken in those women who have tested positive. Management of scleroderma in pregnancy Women should be assessed before conception for the extent of organ involvement. Those with significant renal impairment, severe restrictive lung disease, pulmonary hypertension, or severe cardio- myopathy should be advised against pregnancy. Any woman with previous pulmonary involvement should have lung function tests done in the first trimester and repeated at the latter stages of preg- nancy if clinically indicated. Those with early diffuse disease should delay pregnancy until the disease stabilizes Pulmonary hypertension is a complication in about 8–​12% of patients with scleroderma and is the main cause of disease-​related mortality. Whether corticosteroids (prednisone >15  mg/​day or equiva- lent) precipitate renal crisis remains contentious. High-​dose fluorinated steroids (i.e. dexamethasone and betamethasone) are used for fetal lung maturation, and there are concerns that use in the third trimester, when preterm delivery of a neonate is immi- nent, could precipitate this condition. However, none of the cases of renal crisis during the peripartum interval in the published literature have been caused by antenatal steroids for fetal lung maturation. Anti-​RNA polymerase III (and antitopoisomerase antibodies—​in certain cohorts) may be useful in prognosticating risk of renal crisis, but the strongest predictor remains new onset (<4  years) diffuse disease with rapidly progressive cutaneous involvement. The features of renal scleroderma crisis are almost exactly the same as pre-​eclampsia or HELLP (haemolysis, elevated liver func- tion tests, and low platelets) syndrome. Renal histological changes may aid in differentiating the two pathologies, but renal biopsy is rarely performed in late pregnancy. Most scleroderma renal crisis develop in the third trimester, therefore the management includes prompt delivery prior to initiation of an ACE inhibitor. ACE in- hibitors are usually contraindicated in pregnancy, but the benefits in treating uncontrolled hypertension and preventing maternal mortality usually far outweigh the fetal risks. Otherwise, the management of scleroderma during pregnancy is largely symptomatic, including calcium antagonists for Raynaud’s phenomenon, and histamine antagonists and proton pump inhibi- tors for reflux. NSAIDs are best avoided. Venepuncture, venous access, oxygen saturation, and blood pres- sure measurements may be difficult because of skin, nail, or blood vessel involvement. General anaesthesia may be complicated by dif- ficult endotracheal intubation from microstomia, risk of aspiration, and trauma to telangectatic areas in the nasopharynx. Regional anaesthesia is usually the preferred option. Early assessment by an obstetric anaesthetist is advisable, and epidural anaesthesia and analgesia are encouraged as vasodilation improves skin perfusion of the extremities. Other measures to reduce problems related to Raynaud’s phenomenon include warming of the delivery room and any intravenous fluids as well as socks and gloves. Close observation must continue in the immediate postnatal period, particularly in those with cardiac, pulmonary, or renal in- volvement. Carers must be vigilant of any pressure areas, which may result in cutaneous necrosis. The use of antirheumatic drugs, immunosuppressive agents, and biologics in pregnancy Active disease in early pregnancy often leads to poor placenta- tion or placental insufficiency that manifests itself clinically as maternal-​placental syndrome (as described earlier) and results in

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2667 a preterm delivery of a growth restricted infant. Moreover, there is increasing evidence that antenatal ill-​health affects long-​term maternal well-​being and survival, this is particularly true in those with systemic lupus erythematosus. One of the greatest challenges for clinicians caring for pregnant women is to provide sufficient reassurance that most medications are safe in pregnancy. Active or uncontrolled disease activity has a more deleterious effect on both the mother and developing fetus, therefore every effort should be made to optimize disease control in pregnancy. Counselling a woman about drugs in pregnancy therefore requires not only careful interpretation of the published literature, but also a ro- bust understanding of the basic pathophysiological process and pharmacologic effects of the drugs. Table 14.14.6 lists the various uses of disease-​modifying drugs in rheumatic disorders in pregnancy and breastfeeding. When pregnancy should be avoided There are some circumstances when the risk to mother or fetus are very high. These include the following: • Pulmonary hypertension—​maternal mortality is up to 40%. Effective and reliable contraception should be discussed at each visit. In the event of an unplanned pregnancy, termination of pregnancy before 12 weeks is advised. • Chronic kidney disease (CKD) stage 4 or 5—​prospective studies involving women with CKD have demonstrated 36–​40% chance of pre-​eclampsia and 54–​80% chance of preterm delivery; threefold increased risk of a small for gestational age infant and fivefold increased risk of perinatal mortality. Women with CKD 4/​5 prior to pregnancy are at greater risk of an acceler- ated decline in renal function with the risk of reaching end stage and needing renal replacement therapy either in pregnancy or shortly after. • Severe maternal rheumatic disease in early pregnancy, or ongoing active or poorly controlled disease—​these are seldom conducive to the development of a healthy fetus. • Antiphospholipid syndrome with recurrent placenta-​mediated adverse pregnancy outcomes despite optimal management and anticoagulation. • Women with recurrent intrauterine death, early onset severe pre-​ eclampsia, HELLP syndrome, and severe intrauterine growth restriction with poor neonatal survival despite treatment with aspirin and low-​molecular-​weight heparin may wish to continue attempting pregnancy, but their chances of successful outcome are low. Future maternal health There is increasing evidence that obstetric complications, particu- larly those related to placental insufficiency, are associated with the future development of vascular disease. Pregnancy is a ‘stress test for life’ and many future morbidities that a woman will have are un- masked by the physiological stresses of pregnancy. In the general population, women who have had maternal-​ placental syndrome in pregnancy are four-​times more likely to develop hypertension and future renal disease and also to suffer various forms of vascular complications. Maternal-​placental syndrome-​type complications and preterm deliveries are more common in women with autoimmune connective tissue diseases. These women, particularly those with systemic lupus erythematosus, are at greater risk of future vascular disease, even without trad- itional cardiovascular risk factors. In large population-​based cohort studies, women with systemic lupus erythematosus who have had maternal-​placental syndrome-​type complications in pregnancy are at risk of future cardiovascular events and have a 2.2-​fold risk of pri- mary cardiovascular death. Clinicians caring for women with systemic lupus erythematosus (and like all autoimmune rheumatic diseases) should consider adverse pregnancy outcomes and preterm deliveries as a ‘red-​ flag’ and may wish to commence primary prevention earlier in this group. Acknowledgements We would like to acknowledge the contributions of Sarah Germain and Kate Bramham to the previous versions of this chapter. FURTHER READING General Chakravarty E, et al. (2014). Family planning and pregnancy issues for women with systemic inflammatory diseases: patient and physician perspectives. BMJ Open, 4, e004081. Østensen M, et al. (2015). State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev, 14, 376–​86. Østensen M, Forger F, Villiger PM (2006). Cytokines and pregnancy in rheumatic disease. Ann N Y Acad Sci, 1069, 353–​63. Petri M (2007). The Hopkins Lupus Pregnancy Center: ten key issues in management. Rheum Dis Clin N Am, 33, 227–​364. Soh MC, Nelson-​Piercy C (2015). High-​risk pregnancy and the rheumatologist. Rheumatology, 54, 572–​87. Systemic lupus erythematosus Bramham K, Lightstone L (2012). Pre-​pregnancy counseling for women with chronic kidney disease. J Nephrol, 25, 450–​9. Bramham K, Soh MC, Nelson-​Piercy C (2012). Pregnancy and renal outcomes in lupus nephritis: an update and guide to management. Lupus, 21, 1271–​83. Chakravarty EF, Nelson L, Krishnan E (2006). Obstetric hospi- talizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum, 54, 899–​907. Clowse ME, Magder LS, Petri M (2011). The clinical utility of measuring complement and anti-​dsDNA antibodies during preg- nancy in patients with systemic lupus erythematosus. J Rheumatol, 38, 1012–​16. Clowse MEB, et al. (2005). The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum, 52, 514–​21. Lisnevskaia L, Murphy G, Isenberg D (2014). Systemic lupus erythematosus. Lancet, 384, 1878–​88. Peart E, Clowse ME (2014). Systemic lupus erythematosus and preg- nancy outcomes: an update and review of the literature. Curr Opin Rheumatol, 26, 118–​23.

Section 14  Medical disorders in pregnancy 2668 Ritchie J, et al. (2012). Maternal deaths in women with lupus neph- ritis: a review of published evidence. Lupus, 21, 534–​41. Salmon JE, et al. (2011). Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE co- hort. PLoS Med, 8, e1001013. Smyth A, et al. (2010). A systematic review and meta-​analysis of preg- nancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol, 5, 2060–​8. Soh MC, et  al. (2015). Accelerated development of cardiovascular events in Swedish women with systemic lupus erythematosus—​does pregnancy and its outcomes play a role? A population-​based retro- spective study [OP0050]. Ann Rheum Dis, 7, 85–​6. Webster P, et al. (2014). Tacrolimus is an effective treatment for lupus nephritis in pregnancy. Lupus, 23, 1192–​6. Neonatal lupus Cimaz R, et  al. (2003). Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-​Ro autoantibodies. J Pediatr, 142, 678–​83. Clancy RM, et al. (2006). Impaired clearance of apoptotic cardiocytes is linked to anti-​SSA/​Ro and SSB/​La antibodies in the pathogenesis of congenital heart block. J Clin Invest, 116, 2413–​22. Friedman DM, et al. (2010). Evaluation of fetuses in a study of intra- venous immunoglobulin as preventative therapy for congenital heart block: results of a multicenter, prospective, open-​label clinical trial. Arthritis Rheum, 4, 1138–​46. Friedman DM, Rupel A, Buyon JP (2007). Epidemiology, etiology, de- tection and treatment of autoantibody-​associated congenital heart block in neonatal lupus. Curr Rheumatol Rep, 9, 101–​8. Izmirly PM, et al. (2010). Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum, 62, 1153–​7. Izmirly PM, et al. (2012). Maternal use of hydroxychloroquine is as- sociated with a reduced risk of recurrent anti-​SSA/​Ro-​antibody-​ associated cardiac manifestations of neonatal lupus. Circulation, 126, 76–​82. Routsias JG, et al. (2011). Association of idiotypic-​anti-​idiotypic anti- body ratio with therapeutic response of IVIG in the prevention of recurrent autoimmune associated congenital heart block. Arthritis Rheum, 63, 2783–​9. Antiphospholipid syndrome Bramham K., et al. (2010). Pregnancy outcome in different clinical phenotypes of antiphospholipid syndrome. Lupus, 19, 58–​64. Bramham K., et al. (2011). First-​trimester low-​dose prednisolone in refractory antiphospholipid antibody-​related pregnancy loss. Blood, 117, 6948–​51. de Swiet M, Redman CW (1992). Aspirin, extradural anaesthesia and the MRC Collaborative Low-​dose Aspirin Study in Pregnancy (CLASP). Br J Anaesth, 69, 109–​10. Farquharson RG, Quenby S, Greaves M (2002). Antiphospholipid syn- drome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol, 100, 408–​13. Gomez-​Puerta JA, et al. (2005). Long-​term follow-​up in 128 patients with primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore), 84, 225–​30. Laskin CA, et al. (1997). Prednisone and aspirin in women with auto- antibodies and unexplained recurrent fetal loss. N Engl J Med, 337, 148–​53. Laskin CA et al. (2009). Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial. J Rheumatol, 36, 279–​87. Lim W, Crowther MA, Eikelboom JW (2006). Management of antiphospholipid antibody syndrome:  a systemic review. JAMA, 295, 1050–​7. Miyakis S, et al. (2006). International consensus statement on an up- date of the classification criteria for definite antiphopholipid syn- drome (APS). J Thromb Haemost, 4, 295–​306. Ruiz-​Irastorza G, et al. (2010). Antiphospholipid syndrome. Lancet, 376, 1498–​509. Soh MC, Nelson-​Piercy C (2010). Antiphospholipid syndrome in pregnancy. Expert Rev Obstet Gynecol, 5, 741–​61. Soh MC, et al. (2013). Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. Rheumatology, 52, 1642–​7. Tincani A, et al. (2006). Pregnancy, lupus and antiphospholipid syn- drome (Hughes syndrome). Lupus, 15, 156–​60. Triolo G, et al. (2003). Randomized study of subcutaneous low mo- lecular weight heparin plus aspirin versus intravenous immuno- globulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum, 48, 728–​31. Rheumatoid arthritis Bowden AP, et  al. (2001). Women with inflammatory polyarthritis have babies of lower birth weight. J Rheumatol, 28, 355–​9. Chakravarty EF (2011). Rheumatoid arthritis and pregnancy: beyond smaller and preterm babies. Arthritis Rheum, 63, 1469–​71. Chakravarty EF, Nelson L, Krishnan E (2006). Obstetric hospi- talizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum, 54, 899–​907. Chambers CD, et al. (2006). Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strat- egies for developing post-​marketing data. Arthritis Res Ther, 8, 215. Cheent K, et al. (2010). Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J Crohns Colitis, 4, 603–​5. de Man YA, et  al. (2008). Disease activity of rheumatoid arthritis during pregnancy:  results from a nationwide prospective study. Arthritis Rheum, 59, 1241–​8. de Man YA, et al. (2009). Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum, 60, 3196–​206. de Man YA et  al. (2010). Women with rheumatoid arthritis nega- tive for anti-​cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-​ positive women autoantibody levels are not influenced by preg- nancy. Ann Rheum Dis, 69, 420–​3. Lin HC, et al. (2010). Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a nationwide population-​based study. Ann Rheum Dis, 69, 715–​7. Nørgaard M, et al. (2010). Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med, 268, 329–​37. Skomsvoll JF, et  al. (1999). Perinatal outcomes in pregnancies of women with connective tissue disease and inflammatory rheumatic disease in Norway. Scand J Rheumatol, 28, 3526. Skomsvoll JF, et  al. (2000). Pregnancy complications and delivery practice in women with connective tissue diseases and inflamma- tory rheumatic disease in Norway. Acta Obstet Gynaecol Scand, 79, 490–​5. Soh MC, Nelson-​Piercy C. (2012). Update of the management of rheumatoid arthritis in pregnancy. Expert Rev Obstet Gynecol, 7, 77–​96.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy 2669 Verstappen SM, et al. (2011). Concise report: anti-​TNFα therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis, 70, 823–​6. Wallenius M, et al. (2011). Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth. Arthritis Rheum, 63, 1534–​42. Winger EE, Reed JL (2009). Was risk properly assessed in Carter, et al’s safety assessment of tumor necrosis factor antagonists during preg- nancy? J Rheumatol, 36, 2122; author reply 2123. Wolfberg AJ, et al. (2004). Association of rheumatologic disease with preeclampsia. Obstet Gynecol, 103, 1190–​3. Vasculitides Chakravarty EF, et al. (2011). Pregnancy after maternal exposure to rituximab. Blood, 117, 1499–​506. Diav-​Citrin O, et al. (2010). Pregnancy outcome after in utero exposure to colchicine. J Obstet Gynecol, 203, 144.e1–​6. Gatto M, et al. (2010). Pregnancy and vasculitis: a systemic review of the literature. Autoimmun Rev, 11, A447–​59. Hot A, et al. (2007). Marked improvement of Churg–​Strauss vascu- litis with intravenous gamma globulins during pregnancy. Clin Rheumatol, 26, 2149–​151. Ioscovich A, et al. (2008). Peripartum anesthetic management of pa- tients with Takayasu’s arteritis: case series and review. Int J Obstet Anesth, 17, 358–​64. Ishikawa K, Matsuura S (1982). Occlusive thromboaortopathy (Takayasu’s disease) and pregnancy:  clinical course and man- agement of 33 pregnancies and deliveries. Am J Cardiol, 50, 1293–​300. Iskender C, et  al. (2014). Behçet’s disease and pregnancy:  a retro- spective analysis of course of disease and pregnancy outcome. Obs Gyn Res, 40, 1598–​602. Koizumi M, et al. (2004). Schönlein–​Henoch purpura during preg- nancy: case report and review of the literature. J Obstet Gynecol Res, 30, 37–​41. Lakhi NA, Jones J (2012). Takayasu’s arteritis in pregnancy complicated by peripartum aortic dissection. Arch Gynecol Obstet, 282, 103–​6. Noel N, et al. (2013). Behçet’s disease and pregnancy. Arthritis Rheum, 65, 2450–​6. Seo P (2007). Pregnancy and vasculitis. Rheum Dis Clin North Am, 33, 299–​317. Soh MC, et al. (2009). Pregnancy complicating Wegener’s granulomatosis. Obstet Med,  2, 77–​80. Suri V, et al. (2010). Pregnancy and Takayasu’s: a single centre experi- ence from Northern India. J Obstet Gynaecol Res, 36, 519–​24. Scleroderma Bose N, Chiesa-​Vottero A, Chatterjee S (2015). Scleroderma renal crisis. Semin Arthritis Rheum, 44, 687–​94. Cassina M, et al. (2012). Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum, 64, 2085–​94. Chambers CD, et al. (2010). Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum, 62, 1494–​503. Chakravarty EF, et al. (2011). Pregnancy outcomes after maternal ex- posure to rituximab. Blood, 117, 1499–​506. Chung L, et al. (2006). Outcome of pregnancies complicated by sys- temic sclerosis and mixed connective tissue disease. Lupus, 15, 595–​9. Codullo V, et al. (2009). Serologic profile and mortality rates of sclero- derma renal crisis in Italy. J Rheumatol, 36, 1464–​9. Lidar M, et al. (2012). Pregnancy issues in scleroderma. Autoimmun Rev, 11, A515–​19. Nguyen B, et al. (2010). Association of RNA polymerase III antibodies with scleroderma renal crisis. J Rheumatol, 37, 1068; author reply 9. Steen VD (2007). Pregnancy in scleroderma. Rheum Dis Clin North Am, 33, 345–​58. Taraborelli M, et al. (2012). Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum, 64, 1970–​7. Antirheumatic drugs and immunosuppressive agents in pregnancy Anderka MT, et al. (2009). Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A, 149A, 1241–​8. Arsenescu R, et al. (2011). TNF-​alpha and the development of the neo- natal immune system: implications for inhibitor use in pregnancy. Am J Gastroenterol, 106, 559–​62. Ben-​Horin S, et  al. (2010). Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol, 8, 475–​6. Ben-​Horin S, et al. (2011). Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease. J Crohns Colitis, 5, 555–​8. Berthelsen BG, et al. (2010). Etanercept concentrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology, 49, 2225–​7. Chambers CD, et al. (2006). Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strat- egies for developing post-​marketing data. Arthritis Res Ther, 8, 215–​24. Daniel S, et al. (2012). Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy. J Rheumatol, 39, 2163–​9. Flint J, et al. (2016). BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—​Part I: standard and biologic disease modifying anti-​rheumatic drugs and corticosteroids. Rheumatology (Oxford), 55, 1693–​7. Hviid A, Molgaard-​Nielsen D (2011). Corticosteroid use during preg- nancy and risk of orofacial clefts. CMAJ, 183, 796–​804. Hyrich KL, Verstappen SM (2013). Biologic therapies and preg- nancy: the story so far. Rheumatology, 53, 1377–​85. Kane S, et al. (2009). Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn’s disease before and after delivery. J Clin Gastroenterol, 43, 613–​6. Koren G, et al. (2006). Nonsteroidal anti-​inflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-​analysis. Ann Pharmacother, 40, 824–​9. Liew Z, et al. (2014). Acetaminophen use during pregnancy, behav- ioral problems, and hyperkinetic disorders. JAMA Pediatrics, 168, 313–​20. Lin AE, et  al. (2011). An additional patient with mycophenolate mofetil embryopathy: cardiac and facial analyses. Am J Med Genet A, 155A, 748–​56. Mahadevan U, et al. (2013). Placental transfer of anti-​tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol, 11, 286–​92. Mahadevan U, Terdiman JP, Church J (2007). Infliximab levels in infants born to women with inflammatory bowel disease. Gastroenterology, 132 (Suppl. 1), A144. Mahadevan U, Martin CF, Sandler RS (2012). PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD ex- posed to immunomodulators and biologic therapy. Gastroenterology, 142(Suppl 1), S149. Martinez Lopez J, et  al. (2009). Systematic review of the safety of methotrexate in rheumatoid arthritis regarding the reproductive

Section 14  Medical disorders in pregnancy 2670 system (fertility, pregnancy and breastfeeding). Clin Exp Rheumatol, 27, 678–​84. Mendonca LLF, et al. (2000). Non-​steroidal anti-​inflammatory drugs as a possible cause for reversible infertility. Rheumatology (Oxford), 39, 880–​2. Murashima A, et al. (2008). Etanercept during pregnancy and lacta- tion in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann Rheum Dis, 68, 1793–​4. Østensen M (2009). Are TNF inhibitors safe in pregnancy? Nat Rev Rheumatol, 5, 184–​5. Østensen M, Eigenmann GO (2004). Etanercept in breast milk. J Rheumatol, 31, 1017–​8 Perez-​Aytes A, et  al. (2008). In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A, 146A, 1–​7. Soh MC, Mackillop L (2016). Biologics in pregnancy—​for the obstetri- cian. The Obstetrician and Gynaecologist, 18, 25–​32. Soh MC, Nelson-​Piercy C (2012). Update of the management of rheuma- toid arthritis in pregnancy. Expert Rev Obstet Gynecol, 7, 77–​96. Soh MC, Nelson-​Piercy C (2015). Comment on: high-​risk pregnancy and the rheumatologist: reply. Rheumatology, 54, 2293. Thorne JC, et al. (2014). Methotrexate use in a breastfeeding patient with rheumatoid arthritis. J Rheumatol, 41, 2332. Weber-​Schoendorfer C, et al. (2014). Pregnancy outcome after metho- trexate treatment for rheumatic disease prior to or during early preg- nancy: a prospective multicenter cohort study. Arthritis Rheum, 66, 1101–​10. Weber-​Schoendorfer C, et al. (2014). No evidence for an increased risk of adverse pregnancy outcome after paternal low-​dose metho- trexate: an observational cohort study. Rheumatology, 53, 757–​63. Winger EE, et al. (2009). Treatment with adalimumab (Humira) and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol, 61, 113–​20. Winger EE, et al. (2011). Degree of TNF-​alpha/​IL-​10 cytokine eleva- tion correlates with IVF success rates in women undergoing treat- ment with adalimumab (Humira) and IVIG. Am J Reprod Immunol, 65, 610–​8. Wolf D, Mahadevan U (2010). Certolizumab pegol use in preg- nancy:  low levels detected in cord blood. American College of Rheumatology (ACR). Arthritis Rheum. Abstract 718. Zelinkova Z, et al. (2011). High intra-​uterine exposure to infliximab following maternal anti-​TNF treatment during pregnancy. Aliment Pharmacol Ther, 33, 1053–​8. Zelinkova Z, et al. (2013). Effects of discontinuing anti-​tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin Gastroenterol Hepatol, 11, 318–​21. Future maternal health Bellamy L, et al. (2007). Pre-​eclampsia and risk of cardiovascular dis- ease and cancer in later life: systematic review and meta-​analysis. BMJ, 335, 974. Magnussen EB, et al. (2007). Prepregnancy cardiovascular risk factors as predictors of pre-​eclampsia: population-​based cohort study. BMJ, 335, 978. Magnussen EB, et al. (2009). Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol, 114, 961–​70. Romundstad PR, et al. (2010). Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation, 122, 579–​84. Smith GN, et al. (2012). Ten-​year, thirty-​year, and lifetime cardiovas- cular disease risk estimates following a pregnancy complicated by preeclampsia. J Obstet Gynaecol Can, 34, 830–​5. Smith GC, Pell JP, Walsh D (2001). Pregnancy complications and ma- ternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet, 357, 2002–​6. Soh MC, et  al. (2015). Accelerated development of cardiovascular events in Swedish women with systemic lupus erythematosus—​does pregnancy and its outcomes play a role? A population-​based retro- spective study. Ann Rheum Dis, 7(Suppl 2), 85–​6. Soh MC, et al. (2015). Association between pregnancy outcomes and death from cardiovascular causes in parous women with systemic lupus erythematosus: a study using Swedish population registries. Arthritis Rheum, 67, 2376–​83. Soh MC, et al. (2016). Maternal-​placental syndrome and future risk of accelerated cardiovascular events in parous Swedish women with systemic lupus erythematosus—​population-​based retrospective co- hort study with a time-​to-​event analysis. Rheumatology, 55, 1235–​42. Williams D (2003). Pregnancy: a stress test for life. Curr Opin O&G, 15, 465–​71.

14.15 Maternal infection in pregnancy 2671

14.15 Maternal infection in pregnancy 2671

ESSENTIALS Human Immunodeficiency Virus—​the global roll-​out of antiretro- viral therapy has significantly improved survival for people living with HIV and reduced mother-​to-​child transmission, but HIV in- fection remains a leading cause of maternal mortality, infant death, and early childhood death. Most women with HIV infection are in sub-​Saharan Africa, where the highest prevalence is among young women of reproductive age. Mycobacterium tuberculosis—​a major cause of maternal mor- tality. Active tuberculosis also adversely affects pregnancy outcomes, with an increased risk of preterm delivery, growth restriction, and perinatal death. Malaria—​a major cause of maternal and neonatal morbidity and mortality. Pregnant women are more susceptible to malaria, have more severe disease, and may deteriorate rapidly. In severe mal- aria, mortality is 15–​20% in non​pregnant women, compared to 50% in pregnancy. Primigravidae are at highest risk of severe malaria and death. Introduction This chapter will consider infection with human immunodeficiency virus (HIV), tuberculosis, and malaria in pregnancy. HIV and pregnancy Vertical transmission of HIV In the absence of preventive measures, mother-​to-​child transmis- sion of HIV occurs in 30–​40% of pregnancies in a breastfeeding population: • 10–​25% of HIV-​positive infants are infected in pregnancy • 30–​40% are infected during labour and delivery: this is the period of highest risk • 35–​40% are infected during breastfeeding; in resource-​poor coun- tries women may breastfeed for up to two years Both antiretroviral therapy to the mother during pregnancy and breast- feeding, and post-​exposure prophylaxis to the infant after delivery and during breastfeeding substantially reduce the risk of transmission. HIV counselling and testing During pregnancy, provider-​initiated counselling and testing should be available at all maternity services, and all pregnant women offered testing at booking. However, seroconversion during preg- nancy and breastfeeding is high risk for vertical transmission due to the high maternal viral load, and the lack of preventive measures. In countries with effective ‘prevention of mother-​to-​child transmis- sion’ services, seroconversion in pregnancy contributes significantly to vertical transmission. The World Health Organization (WHO) therefore recommends testing during labour or shortly after de- livery. In countries with high HIV prevalence, for example South Africa, HIV testing is even more extensive: three-​monthly during pregnancy, at delivery, and three-​monthly during breastfeeding. Management of HIV-​positive women during pregnancy Screening, diagnosis, and management
of opportunistic infections Opportunistic infections need prompt diagnosis and treatment in pregnant women. Treatment is the same as for the non​pregnant population. Co-​trimoxazole is safe in pregnancy, both for prophy- laxis and treatment. High-​dose (5 mg) folic acid should be given if co-​trimoxazole is used in the first trimester. Screening for tuberculosis (TB) and cryptococcal disease is an important part of antenatal care. TB is a leading cause of ma- ternal death in countries with high HIV and TB burdens. Symptom screening should be performed at all maternity visits, asking about the presence of cough of any duration, fever, night sweats, or loss of weight. If positive for any symptom, TB investigation is necessary. If CD4 count is less than 200, serum screening for the cryptococcal antigen (CRAG test) should be performed. Antiretroviral treatment for pregnant and breastfeeding women WHO guidelines provide an evidence-​based framework for coun- tries to use as a basis for their national guidelines. The WHO 14.15 Maternal infection in pregnancy Rosie Burton

Section 14  Medical disorders in pregnancy 2672 guidelines are discussed here, but it is important that individual country guidelines are also consulted. People living with HIV should be provided with lifelong ART re- gardless of age, pregnancy, CD4 count or WHO stage. Newly diag- nosed pregnant and breastfeeding women, and women previously diagnosed but ART naïve or currently interrupted treatment should be offered same day initiation. It is not necessary to await CD4 count or other baseline investigations (e.g. creatinine). If clinical assessment raises concerns about TB or other opportunistic infec- tions, rapid investigation and management is necessary before ART is started. If HIV is newly diagnosed in labour, and for pregnant women not taking ART for any reason, the first dose should be given before delivery. Initiation of antiretroviral therapy in pregnancy The WHO recommends the same regimen for pregnant women and for non​pregnant adults (Fig. 14.15.1). Counselling and support are essential to optimize adherence and ensure this is maintained during pregnancy, breastfeeding, and beyond. WHO recommends fixed dose combination regimens for first line ART; either tenofovir/lamivudine or emtricitabine/efavirenz (TLE) or tenofovir/lamividine/dolutegravir (TLD). At the time of going to press, dolutegravir is not recommended for women of reproductive age who are not using reliable contraception; this is due to concerns about a possible increased risk of neural tube defects when taken during the first trimester of pregnancy. Women of reproductive age not using reliable contraception should therefore take efavirenz. Because neural tube closure occurs by 8 weeks of gestation, there is no benefit to switching to EFV for women who are already pregnant, however they should be changed after pregnancy if not using reliable contraception. More data are likely to be available in the near future; check the latest WHO guidelines for the most recent update. Viral load monitoring for pregnant women on antiretroviral therapy Virologic suppression prevents vertical transmission. Viral load monitoring in pregnant and breastfeeding women should be per- formed if available, and according to country guidelines. Some Not on ART:
• Newly diagnosed during pregnancy, in labour or while breastfeeding • Previously diagnosed HIV positive but not on ART for any reason Currently taking ART: • Assess adherence • Assess for virological suppression (VL < 1000 copies/ml): check previous viral load results. If results not available or VL testing not performed according to national programme, request targeted viral load. • If viral load monitoring not available, assess for clinical or immunological failure3. • Same day initiation of ART
• First line regimen: TLE or TLD1, 2 • In labour, give first dose before delivery
• Change to second line ART if first line ART failure is proven (VL monitoring available) or suspected (if clinical or immunological failure)
• See latest WHO guidelines for second line regimens • Continue lifelong ART • Viral load monitoring according to National Guidelines: more frequent viral load monitoring may be possible for pregnant and breastfeeding women
1If tenofovir is contraindicated (creatinine clearance < 50ml/min), substitute with abacavir (ABC) or zidovudine (AZT).
Renal impairment is rare in women of reproductive age without a history of renal disease. Routine creatinine monitoring may not be available in many countries, and for this reason is not routinely recommended by WHO. 2If efavirenz contraindicated (psychosis) substitute with nevirapine if CD4 ≤ 250 cells/mm3, or a protease inhibitor (lopinavir/ritonavir or atazanavir/ritonavir) if CD4 > 250. There is a higher risk of nevirapine hypersensitivity in women if CD4 > 250 cells/mm3. 3Clinical failure: new or recurrent WHO stage 4 condition after 6 months of effective treatment. Immunological failure: CD4 count ≤ 250 cells/mm3 following clinical failure or persistent CD4 count < 100 cells/mm3. Notes: Fig. 14.15.1  Antiretroviral therapy for pregnant and breastfeeding women with HIV. TLE, tenofovir/lamivudine or emtricitabine/efavirenz; TLD, tenofovir/lamividine/dolutegravir.

14.15  Maternal infection in pregnancy 2673 countries recommend more frequent viral load monitoring in preg- nant women. Women who are established on antiretroviral therapy prior to pregnancy should have a viral load measured at booking. Intrapartum care WHO guidelines state there is no HIV-​related indication for cae- sarean section, which should be performed only for obstetric or medical indications. However, many resource-​rich countries offer elective caesarean section to women with a raised viral load (>1000 copies/​ml) close to term. Universal infection control precautions are necessary during labour and delivery, as for all pregnant women. Unnecessary instrumentation should be avoided (e.g. fetal scalp clips, fetal blood sampling, and instrumental delivery). Post-​partum management It is important that there is continuity of antiretroviral therapy care and ongoing vigilance for opportunistic infections. The mother should be counselled regarding safe feeding, infant prophylaxis, adherence and viral load monitoring. The essential management steps are shown in Fig. 14.15.2. Safe infant feeding • National policy should promote either exclusive breast feeding1 or formula feeding. • In countries where diarrhoea, pneumonia and malnutrition remain significant causes of child mortality, breastfeeding is recommended. • Maternal virological suppression is critical to prevent vertical transmission throughout breastfeeding High risk infants: any of the above criteria • Zidovudine (AZT) plus Nevirapine for 6 weeks Breastfeeding infants: • Continue prophylaxis for a further 6 weeks; either AZT plus nevirapine or nevirapine alone Early infant diagnosis: • NAT2 at birth if available • NAT2 for all infants at 4–6 weeks • Early initiation of ART if positive
Final Infant diagnosis: • Antibody test at 9 months, PCR if positive • Antibody test at 18 months, and/or 3 months after cessation of all breastfeeding (whichever is the later)
• Early Initiation of ART if positive
Notes: 1Exclusive breastfeeding is recommended for the first 6 months of life, followed by continued breastfeeding with appropriate complementary foods for up to 2 years or beyond. Breastfeeding should stop only once a nutritionally adequate and safe diet without breast milk can be provided. 2NAT: Nucleic Acid Testing. Infant ART prophylaxis Is the infant high risk for HIV transmission? High risk infants are defined on basis of whether the mother is on ART and virologically suppressed: • born to women who have received less than 4 weeks of ART at the time of delivery • born to women with viral load > 1000 copies/ml in the 4 weeks before delivery if viral load available • born to women with incident HIV infection during pregnant or breastfeeding • women identified HIV positive for the first time during breastfeeding, with or without a negative HIV test antenatally Low risk infants; none of the above criteria • Nevirapine for 6 weeks Fig. 14.15.2  Infant feeding, post-​exposure prophylaxis, and HIV testing.

Section 14  Medical disorders in pregnancy 2674 Tuberculosis and pregnancy Risk of TB in pregnancy It is unclear whether there is an increased risk of TB in pregnant women, and whether TB is more severe. Published studies have differed in their findings, but in countries with a high prevalence of HIV infection there is also a high disease burden of TB. HIV is the major factor driving the high incidence of TB in these regions, and both disproportionately affect women of reproductive age. Resource-​limited countries have the highest burden of TB. In low burden countries, immigrants from high prevalence countries and intravenous drug abusers are at increased risk of TB. In the United Kingdom, non​pulmonary TB makes up 50% of cases of TB diag- nosed in pregnancy. Diagnosis of TB in pregnant women If TB is diagnosed and treatment initiated early in pregnancy, out- comes are good for both mother and infant. However, the diagnosis may be delayed or missed in pregnancy, for instance when pregnant women present with non​specific symptoms such as tiredness and lethargy that may be mistaken for normal during pregnancy. This is especially so for HIV-​positive women. Symptom screening for TB As described earlier, the WHO recommends symptom screening for TB at all antenatal visits in countries with a high TB burden. The presence of any relevant symptom requires sputum investigation for TB, according to country guidelines. In many resource-​poor countries a rapid, automated polymerase chain reaction test for the detection of Mycobacterium tuberculosis and rifampicin resist- ance (Xpert MTB/​RIF) is now available. Point of care testing for the presence of TB lipoarabinomannan (TB-LAM) in urine enables rapid diagnosis of TB in HIV positive patients with low CD4 counts (CD4 < 100 cells/mm3) or seriously ill; sensitivity is low at higher CD4 counts, and in HIV negative patients. Chest X-​ray is indicated if there are abnormal findings on chest auscultation suggesting an additional or alternative diagnosis, such as community acquired pneumonia, Pneumocystis jirovecii pneumonia, or if a pleural ef- fusion is present. This should be done with abdominal shielding to ensure that the radiation exposure risk to the fetus is minimal. TB diagnosis in HIV-​positive pregnant women may be challenging (Table 14.15.1). If TB is suspected but not confirmed on investiga- tion, and no other cause is found to explain the clinical presentation, empiric treatment should be considered. Delay in treatment initi- ation in pregnancy results in poor maternal and perinatal outcomes. HIV-​positive patients with low CD4 counts may have a rapidly pro- gressive course and high mortality. TB treatment TB treatment is the same in pregnant women as in the non​obstetric population. The WHO first-​line regimen for new or recurrent TB consists of two months’ treatment with rifampicin, isoniazid, etham- butol, and pyrizinamide; followed by a four-​month intensive phase of rifampicin and isoniazid. All of these drugs are considered safe in both pregnancy and breastfeeding. From an infection control per- spective, mothers with drug-​sensitive TB can breastfeed. If they have pulmonary TB they should wear a surgical mask to prevent airborne transmission to the infant until they have been on treatment for two weeks, by which time drug-​sensitive pulmonary TB is no longer considered transmissible. Drug-​resistant TB (DRTB) and pregnancy DRTB is an increasing global problem, detection of which relies on the availability of drug sensitivity testing. Multidrug-​resistant TB (MDRTB) is resistance to rifampicin and isoniazid, the most im- portant drugs for treatment of drug-​sensitive TB. Extremely drug-​ resistant TB (XDRTB) is additional resistance to both a quinolone and aminoglycoside, which are the most important drugs for treat- ment of MDRTB. Outcomes for DRTB are generally poor, and there is little experience of DRTB regimens in pregnant women. Expert advice should be sought on both treatment and infection control. However, the general principle is that the benefits of treatment out- weigh potential risks to the fetus. TB preventive therapy TB infection occurs via inhalation of mycobacterial spores and may remain latent for many years. In immunocompetent people, the risk of reactivation and developing active TB disease is 10–​15% over a life- time. In HIV-​positive patients the risk is up to 10% per year. Latent tuberculosis infection can be diagnosed by Mantoux tu- berculin skin testing; interferon-γ-release assays are a more expen- sive alternative. Active TB can be prevented by identifying people with latent tuberculosis infection and treating them with preventive therapy. Isoniazid is most commonly used (isoniazid preventive therapy) and is given together with pyridoxine to prevent periph- eral neuropathy. Active TB must be excluded by symptom screening prior to treatment initiation. Isoniazid preventive therapy should be offered to all HIV-​positive pregnant women who have no symptoms of TB and no contra- indications to treatment (liver disease, alcohol excess, peripheral neuropathy). While antiretroviral therapy reduces the risk of TB, isoniazid preventive therapy has been shown to have an additive ef- fect. It is most effective in those with positive tuberculin skin testing, which should be done prior to starting isoniazid preventive therapy if available. If not, all HIV-​positive pregnant women in whom TB has been excluded should be started on isoniazid preventive therapy for at least six months. Case reports have suggested that women starting isoniazid preventive therapy in pregnancy may be at in- creased risk of hepatotoxicity, but definitive evidence is lacking, and routine monitoring of liver function tests is not required. There is no published evidence from clinical trials to show when isoniazid pre- ventive therapy should be started in HIV-​positive pregnant women, Table 14.15.1  Tuberculosis diagnosis in HIV-​positive patients Pulmonary TB is more difficult to diagnose: • Sputum microscopy is more frequently negative • Xpert MTB/​RIF has a lower sensitivity • Chest X-​ray may be normal Extrapulmonary TB is more frequent. Common manifestations include: • TB meningitis • Cervical lymphadenitis • Pleural effusion • Pericardial effusion • Abdominal TB with ascites and lymphadenopathy Samples from these sites are helpful in TB diagnosis; for example, CSF, fine needle aspirates from lymph nodes, pleural aspirates TB, tuberculosis; MTB/​RIF, Mycobacterium tuberculosis/​resistance to rifampicin; CSF, cerebrospinal fluid.

14.15  Maternal infection in pregnancy 2675 both in relation to initiation of antiretroviral therapy and gestation; country guidelines should be followed. Malaria and pregnancy Plasmodium falciparum is the major cause of severe malaria and will be discussed here. Pathogenesis of placental malaria Malaria-​infected erythrocytes have malarial antigens on the surface (variant surface antigens), which bind to specific receptors. In non​pregnant patients, these antigens bind to two common recep- tors, CD36 and ICAM-​1, on endothelial cells, causing sequestration of infected erythrocytes in the microvasculature, causing organ dys- function. In pregnant women, a specific subset of variant surface antigens is expressed, which adhere to chondroitin sulphate A in the intervillous space of the placenta, resulting in placental sequestration of infected erythrocytes. Women in areas of high transmission with pre-​existing immunity do not have immunity to pregnancy-​specific variant surface antigens with their first pregnancy. Antibodies to the pregnancy-​specific variant surface antigens are not found in men, in- crease with parity, and are associated with good pregnancy outcomes. Severe malaria in pregnancy: Who is most at risk? Severe malaria occurs in three groups of pregnant women: • Pregnant women living in areas of low and unstable malaria transmission • Pregnant women from non​endemic areas who travel to malaria areas • Pregnant women originally from countries with high malaria trans- mission now residing in non​endemic countries and returning home to visit friends and relatives; immunity is lost over time In women living in areas of moderate or high transmission, pla- cental malaria is common; however, most infections are asymp- tomatic. Severe anaemia is the most common symptom and is more common in primigravidae. Fetal growth restriction is also common. Clinical presentation of malaria There are no specific symptoms or signs of malaria. The differential diagnosis is wide, including infectious diseases, medical problems, and pregnancy-​related causes. In the early stages it may present as a flu-​like illness. Jaundice, respiratory, or gastrointestinal symp- toms may be the presenting complaint. Failure to diagnose malaria is one of the common errors resulting in mortality. Symptoms and signs of malaria are shown in Table 14.15.2. A high clinical sus- picion is essential. In non​endemic areas, a travel history must be taken for all pregnant women presenting with fever or other com- patible symptoms or signs. Malaria may still occur despite taking chemoprophylaxis. Definitions Severe malaria is acute malaria with major signs of severity or vital organ dysfunction (Table 14.15.3). It can occur without high parasit- aemia due to sequestration of infected erythrocytes. Uncomplicated malaria is symptomatic parasitaemia with no signs of severity or evi- dence of vital organ dysfunction. However, these criteria are a guide, and healthcare workers should have a low threshold for intravenous treatment even if they are not met or laboratory results are awaited. Diagnosis of malaria Two diagnostic tests are commonly available: • Microscopy of thick and thin blood films—​this is the gold standard test for peripheral blood. It allows identification of the malaria species and estimation of the degree of parasitaemia. Response to treatment can be monitored by repeated daily blood  films. In a febrile patient, the presence of three negative malaria films 12–​24 hours apart rules out the diagnosis of malaria. • Rapid detection tests—​these identify circulating malaria antigens. They have lower sensitivity than malaria blood films and cannot determine parasitaemia. However, they are simple to perform and do not require a laboratory. They stay positive for around four weeks after clearance of parasites and cannot be used to monitor response to treatment. In pregnant women, placental histology is the gold standard for diagnosis of malaria. Parasitaemia in peripheral blood may be very low in pregnant women from malaria-​endemic areas, with parasites sequestered in the placenta. The peripheral blood film may be nega- tive, and unexplained severe anaemia the only marker of malaria. Obstetric complications There are two processes contributing to adverse obstetric outcomes. First, the effect of a severe febrile illness in pregnancy, which con- tributes to maternal and fetal mortality, miscarriage, stillbirth, and Table 14.15.2  Clinical presentation of malaria Symptoms Signs • Fever • Chills, sweats • General malaise • Headache • Muscle pain • Nausea, vomiting, diarrhoea • Cough, dyspnoea • General malaise • Pyrexia • Sweating • Pallor • Jaundice • Respiratory distress • Splenomegaly Table 14.15.3  Clinical and laboratory features of severe malaria Clinical features • Impaired consciousness: Glasgow coma score less than 11 • Prostration: generalized weakness, unable to sit, stand, or walk without assistance • Multiple convulsions: more than two episodes within 24 hours • Respiratory distress: (acidotic breathing or respiratory rate >30 breaths/​min) • Hypotension (systolic BP <80 mm Hg) • Jaundice • Abnormal bleeding Laboratory features • Hypoglycaemia: (<2.2 mmol/​litre or <40 mg/​dl) • Pulmonary oedema: radiological diagnosis • Metabolic acidosis: plasma bicarbonate less than 15 mmol/​litre • Hyperlactataemia: lactate more than 5 mmol/​l • Acute kidney injury: serum creatinine more than 265 µmol/​l or blood urea more than 20 mmol/​l • Severe anaemia: haemoglobin less than 7 g/​dl, or packed cell volume less than 20% • Jaundice: bilirubin more than 50 µmol/​l (3 mg/​dl) • Hyperparasitaemia: more than 4% parasitaemia

Section 14  Medical disorders in pregnancy 2676 premature labour. Secondly, the effects of placental parasitaemia: this causes fetal growth restriction, maternal and fetal anaemia. Management of malaria in pregnancy Malaria in pregnancy is a medical and obstetric emergency. All pregnant women with symptomatic malaria should be admitted to hospital, and those with severe malaria to an intensive care unit. Table 14.15.4 shows recommended treatments for malaria. Intravenous artensunate is the treatment of choice for severe malaria in all trimesters of pregnancy. Treatment should be initiated immediately on diagnosis: delay increases mortality. If artesunate is not available, intravenous quinine should be used, with an ini- tial loading dose to ensure therapeutic levels are reached as soon as possible, although WHO guidelines no longer recommend intra- venous quinine for severe malaria in adults, which causes severe hypoglycaemia secondary to hyperinsulinaemia. Prolonged and profound hypoglycaemia is a severe complication of malaria in pregnancy, hence intravenous quinine is particularly hazardous in pregnant women. • Plasmodium vivax can occasionally cause severe malaria. This is treated as for severe Plasmodium falciparum malaria, with the addition of a 14-​day course of primaquine to eradicate the hypnozoite (liver) stage and prevent relapse. • Primaquine is contraindicated during pregnancy and breast- feeding. Weekly chloroquine should be given until pregnancy and breastfeeding are completed to prevent relapse; the course of primaquine should then be given. Complications of malaria should be treated aggressively. In par- ticular, fluid balance can be challenging, with fluid overload re- sulting in refractory pulmonary oedema due to capillary leak, which has an 80% mortality. Obstetric complications may also need specific management. Saving the mother’s life is the priority, and prompt antimalarial treatment will improve the outcome for the fetus. If spontaneous labour does not occur, there is no indication for delivery during the acute stages of malaria. Preventing malaria in pregnancy In regions of moderate and high transmission in Africa, the WHO recommends the use of insecticide treated bed nets and inter- mittent preventive treatment with sulfadoxine-​pyrimethamine to prevent malaria in pregnancy. This reduces maternal and pla- cental parasitaemia, maternal and fetal anaemia, low birth weight. and neonatal deaths. It should be given to all pregnant women in endemic regions, starting in the second trimester, with at least three doses at least one month apart in total. Sulfadoxine-​pyri- methamine should not be given to HIV-​positive women taking co-​trimoxazole prophylaxis due to shared mechanisms of action and an increased risk of adverse drug reactions. Co-​trimoxazole prophylaxis also prevents malaria, in addition to preventing HIV-​ related opportunistic infections. Pregnant women residing in non​endemic regions should be advised to avoid travel to malaria areas. Malaria prophylaxis is not 100% effective, hence there is a risk of severe malaria even with complete adherence. There is limited experience of drugs for prophylaxis in pregnant women. Should travel be essential, mefloquine is the recommended drug in second and third tri- mesters; it can be used in the first trimester if travel to an area of high falciparum transmission cannot be avoided or postponed. Malaria in HIV-​positive pregnant women Many countries with high transmission of malaria also have a high HIV prevalence. HIV-​positive women have a lower level of acquired immunity to malaria and are at higher risk of symp- tomatic malaria, irrespective of parity. There is an increased risk Table 14.15.4  Treatment of severe (A) and uncomplicated (B) malaria in pregnancy, and when breastfeeding (C) A—​Severe malaria All trimesters, Preferred treatment • Intravenous or intramuscular artesunate
2.4 mg/​kg at 0, 12, 24 hours, and daily thereafter • Treat for at least 24 hours, or until able to tolerate oral medication • Complete treatment with 3 days of artemisinin-​ based combined therapy (ACT) If artesunate is not available • Intramuscular artemether • 3.2 mg/​kg as loading dose, followed by 1.6 mg/​kg daily until able to tolerate oral medication • Complete treatment with three days of artemisinin-​based combined therapy (ACT) If both artesunate and artemether are unavailable Intravenous quinine plus clindamycin • IV quinine: loading dose of 20 mg/​kg in 5% dextrose over 4 hours, then 10 mg/​kg over hours every 8 hours. Maximum dose of quinine 1.4 g • IV clindamycin 450 mg every 8 hours When able to take oral medication: • Oral quinine 600 mg three times daily to complete 5–​7 days, plus oral clindamycin 450 mg three times daily to complete 7 days B—​Uncomplicated malaria First trimester • Either artemether + lumefantrine (AL) for 3 days, or oral quinine and clindamycin for 7 days • WHO recommendations to avoid ACTs in the first trimester were updated in 2015, following updated evidence showing no increase in the risk of miscarriage, stillbirths, or major congenital malformations compared to quinine. Most of the evidence relates to AL, therefore this should be the preferred ACT.a Second and third trimesters Use one of the recommended ACTs for 3 days: • Artemether + lumefantrine • Artesunate + amodiaquine • Artesunate + mefloquine • Dihydroartemisinin + piperaquine • Artesunate + sulfadoxine +pyrimethamine C—​Breastfeeding Safe • Artemisinin-​based combination therapy • Quinine Contraindicated • Doxycycline Complicated malaria • As for treatment of complicated malaria during pregnancy Uncomplicated malaria • Artemisinin-​based combination therapy • Quinine plus clindamycin is an alternative a WHO Evidence Review Group. Malaria in pregnancy. Malaria Policy Advisory Committee Meeting. September 2015. Available at: http://​www.who.int/​malaria/​mpac/​ mpac-​sept2015-​erg-​mip-​report.pdf. Last accessed 30 July 2017.

14.15  Maternal infection in pregnancy 2677 of severe anaemia, growth restriction, preterm labour, and low birth weight infants. In areas of low or unstable transmission, HIV-​infected pregnant women have an increased risk of severe malaria and death. FURTHER READING HIV and pregnancy World Health Organization (WHO) (2016). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. http:// www.who.int/hiv/pub/arv/arv-2016/en/​ World Health Organization (WHO) (2016). Guideline: updates on HIV and infant feeding. The duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. http://www.who.int/maternal_child_adolescent/documents/ hiv-infant-feeding-2016/en/​ World Health Organization (WHO) (2018). Interim guidance: update on antiretroviral regimens for treating and preventing HIV infection and update on early infant diagnosis of HIV. http://www.who.int/hiv/ pub/guidelines/ARV2018update/en/ Tuberculosis and pregnancy World Health Organization (WHO) (2010). Guidelines for the Treatment of Tuberculosis, 4th edition. World Health Organization, Geneva. http://​www.who.int/​tb/​publications/​2010/​9789241547833/​en/​ World Health Organization (WHO) (2015). Guidelines on the Management of Latent TB Infection. World Health Organization, Geneva. http://​www.who.int/​entity/​tb/​publications/​latent-​tuber- culosis-​infection/​en/​ Malaria and pregnancy Royal College of Obstetricians and Gynaecologists (RCOG) (2010). Malaria in Pregnancy, Diagnosis and Treatment (Green-​top Guideline No. 54B). Royal College of Obstetricians and Gynaecologists, London. https://​www.rcog.org.uk/​en/​guidelines-​research-​services/​ guidelines/​gtg54b/​ World Health Organization (WHO) (2013). Management of Severe Malaria:  a Practical Handbook, 3rd edition. World Health Organization, Geneva. http://​www.who.int/​entity/​malaria/​publica- tions/​atoz/​9789241548526/​en/​ World Health Organization (WHO) (2015). Guidelines for the Treatment of Malaria, 3rd edition. World Health Organization, Geneva. https://​www.who.int/​entity/​malaria/​publications/​atoz/​ 9789241549127/​en/

14.16 Fetal effects of maternal infection 2678

14.16 Fetal effects of maternal infection 2678

ESSENTIALS The fetal effects of maternal infection in pregnancy can be broadly categorized as follows (these are not mutually exclusive): (1)  transplacental infection causing fetal malformation (e.g. syph- ilis, rubella); (2)  transplacental infection causing severe in utero illness (e.g. parvovirus); (3)  neonatal infection/​carrier status as a result of transplacental or intrapartum infection (e.g. HIV, Varicella zoster); such neonatal infection may be severe; (4)  preterm delivery, late miscarriage, perinatal death, and cerebral palsy at term delivery are more common in the presence of in utero and placental infection (chorioamnionitis) (e.g. group B streptococcus). Viral Human immunodeficiency virus—​transplacental transmission oc- curs most frequently during delivery and breastfeeding. Prevention is achieved by the use of antiretrovirals, mode of delivery planned according to the viral load at 36 weeks, and the avoidance of breastfeeding. Parvovirus—​transplacental infection can cause fetal anaemia and cardiac failure. Severely anaemic fetuses can be transfused in utero. Cytomegalovirus—​transplacental infection is variable, but severe neurological damage, impaired growth and deafness may follow. Herpes simplex—​intrapartum infection can cause severe neonatal illness following a recent primary attack and is prevented by cae- sarean section. Varicella zoster—​severe neonatal illness can follow late pregnancy disease; maternal disease is often severe. Hepatitis B—​transplacental transmission usually causes chronic carrier status and is reduced by neonatal active and passive immunization. Zika virus—​infection in the first trimester can cause microcephaly and ocular abnormalities Other Bacterial vaginosis—​associated with preterm delivery. Treatment of women with a previous preterm delivery may reduce the risk of recurrence. Streptococcal infection—​group B can cause severe neonatal illness following intrapartum infection and is reduced by intrapartum anti- biotics for either screen positive women or those with intrapartum risk factors. Chlamydia—​associated with preterm delivery and neonatal conjunctivitis. Syphilis—​although rare in the West, syphilis is endemic in many countries, with transplacental infection causing congenital syphilis and perinatal death. Toxoplasmosis—​transplacental infection can cause severe fetal disease; treatment may prevent transmission and reduce disease severity. Malaria—​a major cause of neonatal mortality in parts of Africa; prevention is with nets and chemoprophylaxis. Severe malaria is usually treated with artesunate. Introduction Immunity is mildly suppressed in pregnancy, and the fetal immune system is developmentally immature. Infections in pregnancy can therefore be devastating both for the mother, as is occasionally seen with varicella, and for the fetus, as exemplified by congenital infec- tions such as those caused by rubella, cytomegalovirus, syphilis, and toxoplasmosis. Preterm delivery accounts for 80% of neonatal unit cot days, is the single most important contributor to long-​term handicap, and is a major cause of perinatal mortality. In addition to the specific effects of individual infections, infection in pregnancy is an important risk factor for these adverse outcomes. Infection is implicated in over 50% of preterm deliveries and considerably worsens the prognosis for the neonate at any given preterm gestation. The vaginal pathogens, including bacterial vaginosis and group B streptococcus are varied and only intermittently associated with adverse outcomes: it is likely that cervical integrity is both affected by bacteria and affects the access of bacteria to the uterus. Non- ​‘ascending’ infection may also be important, with periodontal dis- ease associated with an increased risk of preterm delivery. At term, clinical or histological chorioamnionitis are associ- ated with a large increase in the risk of neonatal death, neonatal 14.16 Fetal effects of maternal infection Lawrence Impey

14.16  Fetal effects of maternal infection 2679 encephalopathy, and cerebral palsy. The relative contributions of infection and an inflammatory response associated with other risk factors (e.g. pre-​eclampsia) are not known, although the limited but potentially devastating role played by bacteria such as group B streptococcus is clearly understood. Currently, with the exception of group B streptococcus, it remains unknown whether the use of anti- biotics or antipyretics reduces the associated risks. The most important infective organisms in pregnancy are de- scribed in this chapter: detailed discussion of their pathology and features in adults are described in Section 8. Viral infections Human immunodeficiency virus (HIV) Human immunodeficiency virus (HIV) HIV/AIDS is caused by the HIV-1 and HIV-2 retroviruses. In 2017, there were 18.2 million women aged >15 years living with HIV worldwide, of whom 1.5 mil- lion were pregnant. Ninety one percent of HIV-positive pregnant women live in sub-Saharan Africa, where up to 40% of the women attending antenatal services in some areas are HIV positive. HIV and complications related to pregnancy are two of the leading causes of death globally for women of reproductive age. In 2016, an esti- mated 89  400 people were living with HIV infection in England; the prevalence of HIV infection among pregnant women in the UK is approximately 2 per 1000 women. The predominant mode of infec- tion is heterosexual sexual contact, with a risk of infection per epi- sode of <1%. Universal antenatal HIV screening was implemented in the United Kingdom in 2000, and by 2014 the uptake was estimated to be 97.3%, with 0.15% testing positive (0.03% new diagnoses). In 2009–2014, 99.2% of all diagnosed pregnant women in the UK had received some form of antiretroviral treatment before delivery. The increase in diagnosis and treatment, as well as the implementation of successful obstetric and neonatal interventions has led to a de- cline in the incidence of mother-to-child transmission (MTCT) in the UK, from 25.6% in 1993 to 0.27% in 2012–2014. In developing countries where there are large service gaps, however, the incidence of MTCT remains as high as 20–30%. Pregnancy does not affect the progression of HIV, but the effect of HIV on pregnancy remains unclear. There is some evidence sug- gesting an increase in the rates of pre-eclampsia and gestational dia- betes. Maternal HIV infection is also associated with increased risks of preterm delivery, small-for-gestational-age, low birth weight and stillbirth. These effects may be higher in women on highly active antiretroviral therapy (HAART), especially if ART was initiated be- fore conception, although further studies are required. MTCT occurs largely, but not exclusively, during delivery or breastfeeding. Its prevalence is highest in sub-Saharan Africa, as a result of low rates of diagnosis and treatment, poor availability of obstetric care, and the high prevalence of breastfeeding. The issues surrounding breastfeeding in the developing world are complex, as its avoidance is associated with a high incidence of infant death, particularly due to scarcity of safe drinking water. Other factors influencing MTCT include concomitant sexually transmitted infec- tions (especially Hepatitis C), preterm delivery, and high viral loads. Practical prevention of MTCT needs to vary according to re- sources and availability of healthcare. A multidisciplinary approach is required to optimize obstetric and neonatal management. Under ideal circumstances, combination therapy using HAART is advised; zidovudine alone is less effective and allows the emergence of re- sistant strains. If not already taking combined anti-retroviral therapy (cART), HIV-positive pregnant women should start ART during pregnancy, at the latest by week 24, and continue lifelong. Women should be screened and treated for other sexually transmitted infections early in gestation and again at 28 weeks. Antenatal blood tests include renal and liver function tests to look for drug toxicity. In women con- ceiving on cART, the CD4 count and viral load should be checked at baseline and at 36 weeks and delivery. In women who commence cART in pregnancy, these are checked as per routine initiation of cART, at least once every trimester, at 36 weeks and at delivery. The treatment regimen should be modified if viraemia is not suppressed. The mode of delivery should be individualized and is largely de- termined by the viral load at 36 weeks. Two large European cohort studies have shown MTCT rates of less than 0.5% in women with viral loads less than 50 copies/ml irrespective of the mode of de- livery. This has led to an increase in planned vaginal deliveries in this group in the UK. Intrapartum strategies have included the avoid- ance of early amniotomy, fetal blood sampling, and the use of fetal scalp electrodes; low-cavity forceps should be used in preference to Ventouse if necessary. Planned caesarean section at 39 weeks re- mains the preferred modality of delivery in women with viral loads more than 50 copies/ml, those on zidovudine monotherapy, and in the presence of Hepatitis C co-infection. Antiretroviral treatment should be given to the neonate for 2–4 weeks, depending on ma- ternal viral load at delivery. Breastfeeding should be avoided and cabergoline offered to suppress lactation. In developing countries where resources are scarce, a different strategy is required: caesarean section is less readily available and associated with higher operative and future obstetric risks, and the avoidance of breastfeeding has more serious implications. In the absence of triple therapy, zidovudine monotherapy ante- natally after 14 weeks, with the addition of single-dose nevirapine and lamivudine in labour, or even a single dose of nevirapine admin- istered in labour are among less effective alternatives. Amniotomy is avoided as the rate of MTCT is directly related to the duration of ruptured membranes in women with high viral loads. Breastfeeding is exclusive, limited to six months, and combined with antiretroviral treatment. Rubella Up to 20% of women in the United States, and more in developing countries, are non​immune, hence small outbreaks of rubella still occur. Immunization programmes vary worldwide; in the United Kingdom rubella forms part of the measles, mumps, and rubella (MMR) vaccination in early childhood and most women are im- mune: fewer than 10 affected neonates are born each year in the United Kingdom. The incubation period is 14–​21  days, with in- fectivity seven days before and seven days after the appearance of the characteristic rash, which is preceded by a short prodrome of low-​grade fever, headache, malaise, and lymphadenopathy. Arthritis and arthralgia occur in up to 70% of adult women, and rare ma- ternal complications are thrombocytopenia, acute post-​infectious encephalitis, myocarditis, Guillain–​Barré syndrome, relapsing en- cephalitis, optic neuritis, bone marrow aplasia, and progressive panencephalitis.

Section 14  Medical disorders in pregnancy 2680 The fetus is at greatest risk during the first trimester, when 90% will be affected, either by miscarriage or congenital rubella syndrome. This consists of congenital heart disease (especially pulmonary ar- terial hypoplasia, patent ductus arteriosus, and coarctation of the aorta), learning difficulties, ocular defects such as cataracts, glau- coma, and microphthalmia, and sensorineural deafness. Between 12 and 16 weeks the sequelae are less severe, with sensorineural deaf- ness predominating. At 25 weeks vertical transmission is approxi- mately 25%, rising to 100% at term, but the fetus is almost invariably unaffected. Congenital rubella can only be prevented by immunization. Immunity is no longer routinely checked in early pregnancy. If IgG is absent, maternal IgM suggests recent infection. Termination of pregnancy may be offered where infection has occurred in the first trimester. In the absence of IgM, postnatal vaccination is recom- mended. The vaccine is live, attenuated, and therefore contraindi- cated in pregnancy, although inadvertent administration has not led to recorded problems. Parvovirus The parvovirus B19 is the only pathogenic parvovirus in humans. Infectivity is high and via respiratory secretions, often from children. More than 50% of adults in Western countries are immune; 0.25% of women are infected in pregnancy, but infection can be epidemic. Viraemia appears about seven days after infection and has disap- peared within a few days, before symptoms occur. The classic ‘slapped cheek’ rash is not invariable and most have an arthralgia; 50% of adults have no symptoms. Pregnancy does not alter these symptoms. Infection in pregnancy has an approximately 30% rate of fetal infection; the excess loss rate in pregnancy is 10%, largely with ex- posure before 20 weeks’ gestation. A characteristic effect is due to the parvovirus binding to the P antigen present on erythrocytes, erythroblasts, and myocardium. This can cause a predominantly aplastic anaemia that is of minimal significance in healthy children or adults. By contrast, the fetus is vulnerable, largely because of the short half-​life of fetal red blood cells and the need for erythropoiesis, and it may develop a severe aplastic anaemia with a variable but oc- casionally severe thrombocytopenia. This is a cause of non​immune hydrops (Fig. 14.16.1c), exacerbated in some cases by cardiac dys- function, which is self-​limiting in more than 50% of cases but fatal in the rest. Fetal death typically occurs three to six weeks after infection and is very unusual more than 18 weeks afterwards. Management of the woman infected by parvovirus involves ultra- sound scans assessing the middle cerebral artery, peak systolic vel- ocity which is increased in anaemic fetuses: initially every week, and up until four months after infection, after which the mother can be reassured that her risk of fetal loss is extremely low. The anaemic fetus can be given an in utero blood transfusion. Cytomegalovirus Cytomegalovirus is the commonest congenital infection in devel- oped countries. Immunity is present in up to 75% of women; less in higher socioeconomic classes or in developing countries. Infection in pregnancy occurs in about 1%. Maternal infection is usually asymp- tomatic but can cause an infectious mononucleosis-​like illness. Vertical transmission occurs during pregnancy following 40% of primary infections and less than 1% of secondary recurrences. After primary infection, 5–​15% of neonates are symptomatic, and of these more than 80% develop severe neurological sequelae, including (a) (b) (c) Fig. 14.16.1  Antenatal ultrasound scans: (a) fetal head showing ventriculomegaly secondary to congenital toxoplasmosis; (b) fetal abdomen showing intrahepatic calcification seen in congenital varicella infection; (c) fetal abdomen showing ascites in parvovirus infection. Parvovirus in pregnancy is encountered either during investigation of fetal hydrops, or where there has been maternal infection or contact with an infected individual. For the former, the diagnosis is made when the hydropic fetus is established to be anaemic, usually by the finding of a raised peak systolic velocity in the fetal middle cerebral artery, and by exclusion of other causes of hydrops. Maternal blood will usually show IgM; if IgG is present, a stored early pregnancy booking sample can be checked for comparison, although viral identification by PCR of a fetal blood sample is more reliable. An in utero transfusion greatly improves survival and is given if the degree of anaemia appears to be increasing and the fetal state worsens. This involves injection of high haematocrit irradiated cytomegalovirus-​negative blood into the umbilical vein, usually at the cord insertion. When the disease appears to be severe, an in utero platelet transfusion is recommended by some because of the potential for thrombocytopenia and reports of severe and fatal fetal bleeding following in utero transfusion. Long-​ term follow-​up of successfully treated babies is reassuring, but there are reports both of fetal loss at transfusion and of severe cerebral damage following very severe fetal anaemia, as well as in utero demise from cardiac failure.

14.16  Fetal effects of maternal infection 2681 intellectual impairment and sensorineural hearing loss. Even asymptomatic infants have a 5–​15% risk of hearing impairment. Overall, the chance of normal childhood development without evi- dence of fetal damage is approximately 75%. Recurrent cytomegalo- virus infection is less often vertically transmitted, with sensorineural deafness most common among affected infants. The outcomes of primary cytomegalovirus infection in pregnancy are shown in Fig. 14.16.2. Ultrasound abnormalities, particularly intracranial or hepatic calcifications, cerebral ventriculomegaly, oligohydramnios, and intrauterine growth restriction are detected in only 20%. Cytomegalovirus is diagnosed in pregnancy usually because IgM is found incidentally, although it may be detected as part of the in- vestigation of a fetus with abnormalities (e.g. small for gestational age, cerebral ventriculomegaly, or where the fetal bowel appears echogenic to ultrasound). Cytomegalovirus IgM is long-​lasting and its identification in pregnancy may predate the pregnancy, hence a negative retrospectively tested booking sample, or low IgG avidity, or rising IgG or IgM titres are required to confirm maternal infec- tion. Vertical transmission is detected using amniocentesis and polymerase chain reaction (PCR), which need to be performed no earlier than 20 weeks’ gestation and six weeks after maternal infec- tion, or in the presence of ultrasound abnormalities (which have multiple other causes), to exclude fetal infection. Ultrasound abnor- malities, high viral load, and thrombocytopenia are associated with more severe sequelae. However, prediction of severe disease is still imprecise. Administration of hyperimmune globulin shows promise in re- ducing vertical transmission rates, but there is no effective in utero therapy and termination of pregnancy may be offered: currently in the United Kingdom this can be performed late in the pregnancy. Intravenous ganciclovir given to the infant reduces hearing loss in the most severely affected. Cytomegalovirus screening is currently not recommended because of the risk of amniocentesis and absence of proven in utero treatment. Herpes simplex (HSV) HSV-​2 is the predominant cause of genital herpes, but in up to 30% of cases it is HSV-​1 that is responsible. Primary infection in preg- nancy occurs in 2% of susceptible women. This is usually asymp- tomatic, but primary herpes may be characterized by genital pain and ulceration, discharge, dysuria, lymphoedema, and systemic symptoms. The development of vesicles may occur for the first time in a woman previously infected: it does not necessarily imply recent transmission. Herpes simplex is transmitted vertically at vaginal delivery, but very rarely during pregnancy. Transmission is up to 40% in ac- tive primary infection, with the greatest risk in late pregnancy, but nearer 1% with active recurrent herpes because of passive fetal immunity. Nevertheless, most neonatal herpes occurs in women without a history and may be acquired postnatally (25%). It is rarer in the United Kingdom (3/​100 000 live births) than in the United States or Europe, but causes severe illness including encephalitis and death, particularly in preterm neonates. Where characteristic vesicles are seen, viral swabs are taken. The absence of maternal IgG to HSV-​1 and HSV-​2 confirms a primary infection. Herpes simplex is treated with aciclovir 400  mg three times daily for five days, usually continued until delivery if diag- nosed in the third trimester. This reduces symptoms, recurrence, and viral shedding. Caesarean delivery is recommended if delivery occurs within six weeks of the diagnosis of a primary infection, irre- spective of whether lesions are visible. If the infection has occurred more than six weeks previously, and no lesions are visible, vaginal birth is appropriate. This should be performed before, or as soon as possible after the membranes have ruptured. If vaginal delivery is un- avoidable or the membranes have been ruptured for more than four hours, the mother and neonate are usually treated with intravenous aciclovir. Caesarean delivery is not advised if primary infection has occurred earlier in the pregnancy or where there is asymptomatic recurrent herpes. Screening and searching for asymptomatic viral shedding is not advised. Varicella zoster In Western countries, more than 90% of adults are immune to varicella zoster virus, with infection only occurring in 3 per 1000 pregnancies. In developing countries, many more are non​immune. Transmission is by respiratory droplets and personal contact with the vesicles. Primary infection causes chickenpox; reactivation of the virus that has lain dormant in sensory nerve root ganglia causes shingles. The incubation period is 10–​21 days, infectivity being from 48 h before the rash appears to when all the vesicles are covered. Primary infection in pregnancy may be severe. Maternal shingles is not associated with neonatal risk. 1–2% primary infection in pregnancy 40% transmission to fetus 10–15% newborns have clinical disease 85–90% newborns are asymptomatic 10% develop normally 90% have sequelae Usually severe 90% develop normally 10% have sequelae Usually sensorineural deafness Fig 14.16.2  The outcome of cytomegalovirus infection in pregnancy.

Section 14  Medical disorders in pregnancy 2682 The principal risk to the fetus is with primary infection in late pregnancy, when varicella infection of the newborn occurs in 50% and is associated with a neonatal mortality approaching 30%. Infection between 28 and 36 weeks’ gestation, in the absence of pre- term delivery, does not have sequelae. Before 28 weeks, however, 1–​2% of fetuses develop the fetal varicella syndrome, characterized by neurological, optical, and limb anomalies. Ultrasound findings around five weeks after infection may also show polyhydramnios and echogenic foci in the fetal liver (Fig. 14.16.1b). Where a pregnant woman is exposed to chickenpox or shingles, her IgG should be checked and if present indicates immunity. A  non​immune mother with significant exposure should be given vari- cella zoster immune globulin (VZIG) within 10 days, and should be regarded as infectious for 4 weeks. If clinical chickenpox develops, aciclovir is recommended, IV if maternal illness is severe. Before 28 weeks, careful fetal ultrasound evaluation is required; the use of amniocentesis is controversial. In later pregnancy, VZIG is given to the neonate if delivery occurs between five days after and two days before maternal infection. Vigilance for neonatal infection is required: this is treated with aciclovir. Hepatitis B Less than 1% of pregnant women in Western countries are HBsAg positive, although the incidence is rising; in parts of Africa and Asia the rate is 25%. Vertical transmission can occur throughout pregnancy and is particularly important because 90% of infected neonates become chronic carriers (in contrast to adults, 10% of whom become chronic carriers) that are both infectious and at risk of liver disease. The risk of transmission relates to maternal viral antigen status: in HBsAg positive/​HBeAg negative mothers the risk is 5–​20%; in HBsAg positive/​HBeAg positive it is 70–​90%. Transmission is higher with high activity of replication or high viral load. Targeted screening only identifies about half of chronic carriers, so universal screening has been adopted in developed countries. Vertical transmission can be reduced by more than 90% by active neonatal immunization, using 0.5 ml hepatitis B vaccine. This is recommended to all infants born to HBsAg positive mothers; additional passive immunization (200 IU of hepatitis B immunoglobulin within 12 h of birth) for infants born to HBeAg positive or HBsAb negative mothers is also advised. For women with a very high viral load, the European Association for the Study of the Liver now advises treatment with antiviral agents during pregnancy, starting at 32 weeks. The World Health Organiza­ tion recommends universal vaccination in countries with high prevalence. Hepatitis C Worldwide, 3% of pregnant women have been infected with hepa- titis C virus (HCV), but the figure is up to 50% in HIV-​positive women. The principal risk factor in the United Kingdom, where about 0.5% of women have been infected, is intravenous drug abuse, and sexual transmission is unusual. Hepatitis C leads to chronic hepatitis in about 80%; progression is insidious and most pregnant women are asymptomatic. Vertical transmission of HCV occurs in approximately 5% but is higher with higher viral loads and with coexisting HIV infection. Transmission is not thought to be signifi- cantly affected by mode of delivery. Transmission by breast feeding is unlikely. Elective caesarean section, formula feeding, and admin- istration of immune globulin do not reduce vertical transmission to the neonate. Maternal antibodies may persistent for months, hence PCR is used to confirm infection in infants. Infected infants usually remain viraemic and prone to chronic hepatitis. Zika An outbreak of Zika virus, a flavivirus transmitted primarily through the bite of an infected Aedes species mosquito, was identi- fied in Brazil in early 2015 and has spread rapidly in the Americas. Zika infection during pregnancy has been linked with micro- cephaly, with strong evidence of causality, most notably by demon- stration of Zika virus in the brains of affected fetuses and infants. The estimated risk of microcephaly following infection in the first trimester is uncertain, but probably in the range 0.9–​13.2%: there does not appear to be enhanced risk with infection in the second or third trimesters. Many (35%) babies with microcephaly also have ocular abnormalities, most commonly focal pigment mot- tling, chorioretinal atrophy, and optic nerve abnormalities. It is not known whether ocular manifestations occur after congenital Zika virus infection in infants who do not have microcephaly. The long-​ term prognosis of infants with Zika virus-​induced microcephaly is likely to be poor. Bacterial diseases Bacterial vaginosis This occurs when there is an overgrowth of anaerobic organisms such as Gardnerella vaginalis and Mycoplasma hominis and charac- terized by excessive Gram-​negative bacilli and cocco-​bacillary or- ganisms compared to lactobacilli on Gram staining. The prevalence varies from 5 to 20%, depending much on the diligence with which the diagnosis is sought. Bacterial vaginosis is not sexually trans- mitted but is associated with sexually transmitted infections and is rare before the onset of sexual activity. Three of four Amsel’s criteria are required for diagnosis: a thin white homogeneous discharge, clue cells, raised vaginal pH (>4.5), and a positive ‘whiff test’ (fishy odour when 10% potassium hydroxide is added to the discharge). At least 50% of women with bacterial vaginosis have no symptoms, but an offensive, thin white discharge is often found. Bacterial vaginosis is associated with late miscarriage and preterm birth, a major cause of neonatal mortality and morbidity, possibly because of a depletion in lactobacilli. There is little evidence that treatment, usually with clindamycin, reduces the incidence of pre- term birth; however, it does appear to do so when given prior to 20 weeks in women with a history of prior preterm birth or late mis- carriage. The use of other methods to promote lactobacillus growth merits investigation. Streptococci Group A streptococci (Streptococcus pyogenes) are an important cause of puerperal sepsis worldwide but may also cause chorioamnionitis and late miscarriage or preterm labour. Group B streptococci (Streptococcus agalactiae) are an important cause of neonatal sepsis in the first week:  early onset infection. Approximately 25% of pregnant women are colonized by group

14.16  Fetal effects of maternal infection 2683 B streptococcus, usually without symptoms, although maternal urinary tract infection is not uncommon. Group B streptococcus is associated with preterm delivery but it is ascending infection at the time of delivery that is best understood. Although 70% of neo- nates born to carriers are colonized, only 1–​2% will develop dis- ease of chorioamnionitis and fetal infection leading to early onset neonatal streptococcal sepsis. The incidence of this is 0.5/​1000 live births in the United Kingdom and 0.24% in the United States (2010). The mortality is 7% at term and 18% preterm. Intrauterine infec- tion can also occasionally cause antepartum stillbirth. Infection usually but not always occurs following rupture of the amniotic membranes: risk factors are prematurity, prolonged rupture of the membranes, intrapartum maternal fever, heavy colonization, low maternal antibody levels, and a previously affected infant. Intrapartum high-​dose intravenous penicillin greatly reduces early onset neonatal disease. Late onset (after the first week) group B streptococcus infection has an incidence of 0.35/​1000 live births and is not altered by intrapartum antibiotics. Antibiotic resistance is virtually zero, but penicillin-​allergic women are a problem: 12% of group B streptococcus are resistant to clindamycin. Universal screening is performed in many countries; in the United States, this has been followed by a fall in the incidence from 1.5/​1000 live births in 1993 to 0.24/​1000 in 2010. Women are screened at 35–​37 weeks with vaginal and anal swabs and given high-​dose penicillin intrapartum if they are carriers. If there was group B streptococcus in the urine at any time, or a previously infected infant, they are also treated. This policy leads to approximately 25% of all pregnant women being treated, with 86% of cases of sepsis prevented. In the United Kingdom, a risk-​based strategy is recommended: women are treated if they have a previous history, intrapartum fever, are in con- firmed preterm labour, or where the membranes have been ruptured for more than 18 h. This leads to at least 70% of neonatal sepsis being prevented by treating approximately 18% of women. The arguments against universal screening are concerns with anaphylaxis, the low UK incidence of early onset disease, the lack of randomized con- trolled trial evidence, and the potential medicalization of pregnancy. A result of the UK policy is increased monitoring and treatment of more newborns. Recent advances include rapid diagnostic tests, but unless en- riched samples are tested the reported sensitivity is not as good as with swabs, and these have not yet been widely adopted. Vaccination against group B streptococcus is under development using a triva- lent polysaccharide-​protein conjugate vaccine that could ultimately be offered to all pregnant women. Listeria Infection is from salads contaminated with animal faeces, under- cooked meats, unpasteurized milk, soft cheeses, some fruit, hummus, and patés. In the United Kingdom the incidence is up to 5 per 100 000 live births. Worldwide the incidence has fallen as a result of public health campaigns about the likely source of infection. Maternal disease manifests as bacteraemia, with fever, sore throat and headache: diarrhoea, pyelitis, and backache may also occur. It is treated with ampicillin with an aminoglycoside for synergy. Infection of the fetus occurs transplacentally. Before 24 weeks’ gestation, this usually results in miscarriage; after 24 weeks, neonatal mortality is approximately 20%. Chlamydia Chlamydia trachomatis is the most common sexually trans- mitted infection, with up to 7% of pregnant women being in- fected, depending on age, marital status, and socioeconomic class. Infection is mostly asymptomatic. Maternal infection, particularly if recently acquired, is associated with a fourfold increase in se- vere preterm delivery. Treatment reduces but does not eradicate these risks. Neonatal conjunctivitis occurs in up to 50% of neo- nates exposed to chlamydia, with a smaller proportion developing pneumonia. The identification of maternal infection warrants referral to a genitourinary medicine clinic, with contact tracing for treatment of sexual partners. Erythromycin is effective, but a single dose of azithromycin (1 g) ensures compliance and is also known to be safe. Tetracyclines are contraindicated in pregnancy as they cause tooth discoloration in the child. Reinfection rates are high and repeat testing is advised after at least three weeks to ensure a cure has been achieved. Screening or even prophylaxis of all mothers following termination is cost-​effective, but routine screening in pregnancy using urine PCR should currently be limited to those at risk of infec- tion, who are also at increased risk of preterm delivery. Gonorrhoea Neisseria gonorrhoea is endemic in many developing countries, and having fallen to low rates in many areas of the developed world by the early 1990s is now gradually increasing again. Pharyngeal and disseminated systemic infection with fever, rash, and septic arthritis are more common in pregnancy, but salpingitis is rare. Cervical cul- ture detects most infections; PCR testing is expensive and does not enable antibiotic sensitivity testing. As with non​pregnant women, 80% are asymptomatic. Gonococcal cervicitis is associated with a fourfold increase in pre- maturity and chorioamnionitis. Further, 40% of neonates exposed to gonorrhoea at delivery will develop ophthalmia neonatorum. Gonococci have also been implicated in post-​partum and post-​ abortion endometritis and salpingitis. Treatment is best with a single intramuscular dose of ceftriaxone (250  mg). Disseminated infection warrants intravenous therapy. Penicillinase-​producing strains are common. The patient should be screened for other sexually transmitted infections and antichlamydia therapy is often given at the same time. A test of cure should be taken at least three days after antibiotics. Because of the frequency of infec- tion and the serious risks, screening is warranted in high-​risk groups such as those undergoing first-​trimester termination. Syphilis The incidence of infection in pregnancy is 0.02% in the United Kingdom, but in Africa, Southeast Asia, and Russia it is endemic. Pregnancy does not alter the clinical manifestations. Screening with non​treponemal tests (e.g. the venereal disease research laboratory test) is routine in many countries, including the United Kingdom. Sensitivity is highest in secondary syphilis and lowest early in the in- fection, and false-​positive results occur with concomitant infections or autoimmune disease. Vertical transmission is predominantly transplacental, occurring in up to 90% of untreated women, particularly those with early

Section 14  Medical disorders in pregnancy 2684 disease. Most affected pregnancies result in congenital syphilis, miscarriage, preterm delivery, or perinatal death. Ultrasound examination of the infected fetus may be normal or show hepato- megaly and other abnormalities. At birth, babies exhibit rhinitis, osteitis, and skin bullae. Hutchinson’s triad of abnormal teeth, interstitial keratitis, and sensorineural deafness arise later in the untreated child. Syphilis is usually diagnosed in pregnancy after the development of suggestive symptoms or a positive screen. A positive venereal disease research laboratory test should be confirmed with a spe- cific treponemal test (e.g. FTA-​ABS). Treatment is with two intra- muscular doses of benzyl penicillin (2.4 MU, one week apart). In true penicillin allergy, a 5-​ to 10-​day regimen of high-​dose oral ceftriaxone is recommended. Venereal disease research labora- tory test titres should fall until undetectable or less than one in four, otherwise retreatment is necessary. Treatment will prevent congenital infection in 98% of cases. The rare Jarisch–​Herxheimer reaction to treatment may precipitate preterm labour. Screening in pregnancy is cost-​effective, even where the disease is rare: 121 women were identified by antenatal screening in the United Kingdom from 1994 to 1997, with 18 600 tests needing to be per- formed to detect one case. Tuberculosis Mycobacterium tuberculosis infection (TB) is extremely common in the developing world. The proportion of younger people infected—​ including women of reproductive age—​is rising, in part due to HIV infection. Pregnancy has little effect on the course of either symp- tomatic or latent TB, but the diagnosis may be delayed in pregnancy because of the non​specific symptoms. Congenital tuberculosis is acquired transplacentally and is po- tentially fatal but extremely rare: treatment is advised principally for maternal health. Co-​infection with HIV should be considered. Isoniazid, ethambutol, pyrazinamide, and rifampicin are safe in pregnancy; streptomycin can cause ototoxicity. Vitamin B6 and vitamin K supplementation are indicated. Breastfeeding is not contraindicated. Infectivity is greatly reduced after two weeks of therapy, hence separation of mother and child is inappropriate. Protozoal infections Toxoplasmosis In the United Kingdom and North America 15–​20% of adults have antibodies to Toxoplasma gondii; infection in pregnancy occurs in 0.2%. It is more common in mainland Europe and in developing countries. Infection is acquired from contact with soil, uncooked meat, or contaminated salad, and is more common in women with HIV. The condition is frequently asymptomatic, but 10–​20% of mothers have lymphadenopathy or a flu-​like episode. Vertical transmission occurs during pregnancy in about 30%. Transmission is lower (<10%) in early gestation, but has greater im- pact: over 75% will have clinically apparent disease. This includes the classic neonatal triad of chorioretinitis, cerebral calcification, and microcephaly. Prenatal ultrasound findings include intra- cranial calcification, cerebral ventriculomegaly (Fig.  14.16.1a), ascites, and hepatomegaly. With increasing gestation, vertical transmission increases to about 75% by term, but the risks of se- vere sequelae (Fig. 14.16.3) are less. The highest risk for congenital toxoplasmosis with a poor outcome is therefore when maternal in- fection occurs around 20–​24 weeks’ gestation. At this stage the risk of severe neurological sequelae is approximately 10%. Toxoplasmosis is encountered in pregnancy either as part of in- vestigations for abnormal fetal ultrasound appearances, or as a result of screening. Toxoplasmosis screening is imprecise: IgM may not be detected with proven disease, and it may also persist for months after infection. Infection is nevertheless unlikely in the previous three months if IgM is negative, or there is high-​avidity IgG. Maternal in- fection is confirmed by a change from negative to positive IgG, or low to high levels of IgM. Mothers infected in pregnancy are treated with spiramycin with the aim of reducing vertical transmission, this being diagnosed or excluded using PCR on amniotic fluid taken after 18 weeks. Combination therapy of pyrimethamine and sulfadiazine with folinic acid is used if fetal infection is detected. Although re- versal of ultrasound abnormalities has been recorded after therapy, there is no consistent evidence that treatment is effective when ver- tical transmission has occurred. In the neonate, diagnosis requires IgA or IgM testing because maternal IgG will persist for up to one year. Neonatal infection is treated for one year. Because of the per- ceived effectiveness of therapy in preventing vertical transmission, screening is widely practised in Europe, but is not recommended in the United Kingdom. Malaria Plasmodium falciparum (75%), P. vivax, P. malariae, and P. ovale are transmitted by the bite of a sporozoite-​bearing female anopheline mosquito. In sub-​Saharan Africa, up to 8% of infant mortality is at- tributable to malaria in pregnancy, and malaria accounts for 100 000 neonatal deaths annually worldwide. Severe malarial anaemia of pregnancy causes spontaneous miscarriage, premature birth, intra- uterine growth restriction, and stillbirth. Characteristically the intervillous space is filled with fibrin. Congenital malaria from transplacental spread occurs in approximately 10% of infected preg- nancies. The newborns have fever, respiratory distress, pallor, an- aemia, hepatomegaly, jaundice, and diarrhoea. Fig 14.16.3  MRI head of a 20-​day-​old baby with congenital toxoplasmosis, showing severe ventriculomegaly from hydrocephalus.

14.16  Fetal effects of maternal infection 2685 Antimalarial drugs reduce parasitaemia, placental malaria, low birth weight and, depending on their timing, perinatal death. Drugs used depend on the sensitivity of the relevant plasmodium locally and include proguanil, chloroquine, mefloquine, and artemisinin compounds. Most falciparum malaria is now resistant to mefloquine and chloroquine. Primaquine is not used in pregnancy. Treatment of malaria in pregnancy is discussed in Chapter 14.15. Artemisinin combination therapy is increasingly used for febrile malaria be- cause of resistance to other drugs and lower frequency of few side effects, although there are less safety data, particularly for the first trimester. Sulfadoxine–​pyrimethamine is most commonly used as intermittent preventive treatment, this chemoprophylaxis involving two doses at least one month apart for all pregnant women in stable transmission areas. A third dose is recommended where HIV in- fection is common. Following malaria infection, surveillance for growth restriction is advised. Trypanosomiasis Infection in pregnancy can cause miscarriage, intrauterine growth restriction, and preterm delivery. Congenital infection occurs in about 10% and may be initially asymptomatic, but jaundice, an- aemia, hepatosplenomegaly, encephalitis, and pneumonitis can then develop. Diagnosis is through placental histology, blood smear examination for parasitaemia, and enzyme-​linked immuno- sorbent assay (ELISA). There is no safe and reliable treatment in pregnancy. Other conditions Notes on other infections in pregnancy are given in Table 14.16.1 FURTHER READING American College of Obstetricians and Gynecologists Committee on Obstetric Practice (2011). ACOG Committee Opinion No. 485: pre- vention of early-​onset group B streptococcal disease in newborns. Obstet Gynecol, 117, 1019–​27. British Association for Sexual Health (BASSH) and the Royal College of Obstetricians and Gynaecologists (RCOG) (2014). Management of Genital Herpes in Pregnancy. October 2014. https://​www.rcog. org.uk/​globalassets/​documents/​guidelines/​management-​genital-​ herpes.pdf British HIV Association (2014). British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). Updated guidelines: https://www.bhiva.org/ guidelines Doroshenko A, Sherrard J, Pollard AJ (2006). Syphilis in pregnancy and the neonatal period. Int J STD AIDS, 17, 221–​7. Lamberth J, et al. (2015). Chronic hepatitis B infection in pregnancy. World J Hepatol, 7, 1233–​7. Lamont R, et al. (2011). Parvovirus B19 infection in human pregnancy. BJOG, 118, 175–​86. Paquet C, et  al. (2013). Toxoplasmosis in Pregnancy:  Prevention, Screening, and Treatment (SOGC Clinical Practice Guideline
No. 285), January 2013. http://​sogc.org/​wp-​content/​uploads/​2013/​02/​ gui285CPG1301E-​Toxoplasmosis.pdf Petersen LR, et al. (2016). Zika virus. N Engl J Med, 374, 1552–​63. Rours G, et al. (2011). Chlamydia trachomatis infection during preg- nancy associated with preterm delivery: a population-​based pro- spective cohort study. Eur J Epidemiol, 26, 493–​502. Royal College of Obstetricians and Gynaecologists (RCOG) (2010). Malaria in Pregnancy, Diagnosis and Treatment (Green-​top Guideline No. 54B). https://​www.rcog.org.uk/​globalassets/​documents/​guide- lines/​gtg54bdiagnosistreatmentmalariapregnancy0810.pdf Table 14.16.1  Notes on other infections in pregnancy Infection Notes Escherichia Coli An unusual cause of chorioamnionitis and neonatal sepsis particularly of preterm neonates Staphylococcus aureus An unusual cause of chorioamnionitis and neonatal sepsis particularly of preterm neonates HHV6 Transplacental transfer occurs, probably without any effect on the fetus HPV Vertical transmission has been reported rarely; if vaginal warts are massive they may obstruct delivery Enteroviruses 50% have a mild respiratory or gastrointestinal illness; some have severe cramping abdominal pains simulating placental abruption that can lead to unnecessary emergency caesarean section; newborns with vertically acquired echoviral infections may have fulminant hepatic necrosis, severe coagulopathy from disseminated intravascular coagulopathy, and meningitis or myocarditis Japanese B encephalitis virus Particularly high mortality rates with fetal death have been reported in pregnancy Lassa fever Increased mortality for women in pregnancy, survival is improved by termination and ribavirin Trichomonas vaginalis Infections are common in pregnancy, associated with preterm delivery, can be transmitted to the newborn around birth, but there are no adverse effects on the fetus Mycoplasma hominis A commensal of the lower female genital tract; controversial disease role in newborns Ureaplasma urealyticum As for M. hominis Lyme disease Borrelia burgdorferi in gestation has a good prognosis if recognized early and treated aggressively; fetal death or disease, including meningoencephalitis, occurs without maternal treatment Schistosomiasis Placental infection occurs in up to 25% in bilharzia infested areas, but there is no effect on gestational age or birth weight Candida The incidence of vaginal thrush increases with each trimester; rarely, vaginal thrush in pregnancy predisposes to congenital candidiasis

Section 14  Medical disorders in pregnancy 2686 Royal College of Obstetricians and Gynaecologists (RCOG) (2012). The Prevention of Early-​onset Neonatal Group B Streptococcal Disease (Green-​top Guideline No. 36), 2nd edition, July 2012. http://​www. rcog.org.uk/​globalassets/​documents/​guidelines/​gtg_​36.pdf Royal College of Obstetricians and Gynaecologists (RCOG) (2015). Chickenpox in Pregnancy (Green-​top Guideline No. 13). January 2015, Royal College of Obstetricians and Gynaecologists, London. https://​ www.rcog.org.uk/​globalassets/​documents/​guidelines/​gtg13.pdf Witkin S (2015). The vaginal microbiome, vaginal anti-​microbial de- fence mechanisms and the clinical challenge of reducing infection-​ related preterm birth. BJOG, 122, 213–​8. World Health Organization. Standards for Maternal and Neonatal Care. Prevention of congenital rubella syndrome (CRS). Department of Making Pregnancy Safer, World Health Organization. http://​ www.who.int/​reproductivehealth/​publications/​maternal_​peri- natal_​health/​prevention_​crs.pdf Yeung C, et  al. (2014). Vertical transmission of hepatitis C virus:  current knowledge and perspectives. World J Hepatol,
6, 643–​51. Yinon Y, Farine D, Yudin M (2010). Screening, diagnosis, and man- agement of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv, 65, 736–​43.

14.17 Blood disorders in pregnancy 2687

14.17 Blood disorders in pregnancy 2687

ESSENTIALS Plasma volume increases by more during pregnancy than does red cell mass, leading to haemodilution and a fall in the haematocrit from about 40% to 33%, with a nadir usually reached at 24–​32 weeks’ gestation. Anaemia during pregnancy is defined as a haemoglobin concentration of below 105 g/litre during the second and third tri- mesters and below 110 g/​litre in the first trimester. Anaemias and haemoglobinopathies The commonest haematological problem encountered in preg- nancy is iron-​deficiency anaemia. Routine iron supplementation in all pregnant women is probably not justified in developed countries, but if iron deficiency is detected it is advisable to treat as early as possible. Folic acid—​the requirement for folic acid doubles in pregnancy and dietary folate deficiency is the most frequent cause of gestational megaloblastic anaemia. This can be prevented by supplementation with 300 μg folic acid daily, although higher doses of folate (up to 5 mg daily) are recommended to prevent neural tube defects. Haemoglobinopathies—​the diagnosis of variant haemoglobins and the thalassaemia syndromes before pregnancy or early in ges- tation is important. Screening is usually performed on a blood sample taken at booking. If a haemoglobin variant or thalassaemic indices are detected, then the partner should be tested to determine the risk of having an affected fetus and allowing informed prenatal counselling. Haemostatic disorders Normal pregnancy is associated with marked changes in all aspects of haemostasis, the overall effect of which is to generate a state of hypercoagulability. These changes in haemostasis, while reducing the risks of excessive blood loss at delivery, significantly increase the risk of venous thromboembolic disease in pregnancy. Gestational thrombocytopenia—​seen in about 8% of all preg- nancies and accounts for more than 70% of cases of thrombo- cytopenia in pregnancy: its main differential diagnosis is immune thrombocytopenic purpura. Disseminated intravascular coagulation—​can be caused by intra- uterine death with a retained fetus, severe pre-​eclampsia, pre- mature separation of the placenta (placental abruption), retained placenta, amniotic fluid embolism, haemorrhagic shock, and trans- fusion reaction. Inherited haemostatic disorders (e.g. haemophilia, von Willebrand disease)—​women with these conditions require specialist manage- ment during pregnancy. Anaemia Physiology Hormonal changes in pregnancy can significantly alter haemato- logical parameters. An understanding of these changes can avoid misinterpreting them as abnormal. During pregnancy the total blood volume will increase by about 1.5 litres. This is mainly due to an expansion of the plasma volume by 25–​80%. This increase occurs mainly after the first trimester and peaks at 34–​36 weeks’ gestation. The increase is greater in multip- arous women with larger babies and in multiple pregnancies. The red cell mass also increases by 10–​20%, again after the first trimester. This can increase further in women taking iron supplementation. The consequence of the greater relative increase in the plasma volume leads to haemodilution and a fall in the haemoglobin by 10–​20 g/​litre. The nadir is usually reached at 24–​32 weeks’ gestation, with the haemoglobin then starting to rise again towards term. The degree of haemodilution shows considerable variation between women, which means that haemoglobin alone is not a valid marker of iron status. The World Health Organization (WHO) defines anaemia in pregnancy as a haemoglobin below 110 g/​litre at any time during pregnancy and below 100 g/​litre following delivery. There is, how- ever, significant variation in haemoglobin levels and in the United Kingdom a level of 110 g/​litre or greater appears adequate in the first trimester and 105 g/​litre or greater in the second and third trimesters. During pregnancy the mean cell volume will increase by about 5–​10 fl in iron replete women, independent of the vitamin B12 and folate levels. There is also a gradual increase in erythropoietin levels with increasing gestation. In pregnancy it is unusual to have haemoglobin levels of more than 135 g/​litre. When this does occur, it may be due to inadequate plasma volume expansion and can be associated with pregnancy-​ related problems (e.g. pre-​eclampsia, poor fetal growth). 14.17 Blood disorders in pregnancy David J. Perry and Katharine Lowndes

Section 14  Medical disorders in pregnancy 2688 Iron-​deficiency anaemia During pregnancy the daily requirements for iron increase from 0.8 to 7.5 mg/​day between the first and third trimesters. Iron is needed to expand the maternal red cell mass, fulfil fetal requirements, and to prepare the mother for blood loss at delivery. There is also an in- creased iron requirement during lactation. This increased require- ment is met by increased absorption, which is most pronounced after 20 weeks’ gestation. Iron-​deficiency anaemia is the commonest haematological problem encountered in pregnancy. Worldwide it affects about 20% of women and is a significant cause of morbidity and mor- tality. In non​pregnant individuals iron deficiency frequently mani- fests as a hypochromic, microcytic anaemia, but in the pregnant woman, owing to a relative increase in the number of larger im- mature red cells, the mean cell volume may remain unchanged. The red cell distribution width, however, increases. A serum fer- ritin below 30 μg/​l reflects a loss of storage iron and indicates iron deficiency, and this occurs before the haemoglobin falls, which is a relatively late manifestation. Mothers that enter pregnancy iron deficient will have no stores remaining at term, and it takes about two years of normal dietary iron to replace the iron lost with each pregnancy. The level of transferrin, the iron binding protein in plasma, doubles during the course of pregnancy leading to a fall in per- centage transferrin saturation. Transferrin receptors are present on the surface of young erythrocytes and also circulate within the blood as soluble transferrin receptors (sTfR). These increase in number during iron deficiency and are independent of total body iron stores. They can, therefore, be a helpful measure of iron defi- ciency in women with a raised ferritin for other reasons. Mild iron-​deficiency anaemia is unlikely to have any harmful ef- fects on the mother, although it has been associated with irritability and poor concentration. Severe iron deficiency is associated with pallor, glossitis, angular chelitis, and koilonychia. The symptoms of anaemia can make the last few weeks of pregnancy difficult to tol- erate. Women that are iron deficient are unlikely to tolerate signifi- cant blood loss at delivery and may, in fact, have increased blood loss due to impaired neuromuscular transmission. An uncorrected an- aemia may be associated with placental enlargement, which in turn leads to a higher incidence of fetal abnormalities, low birth weight, and increased preterm births. Iron deficiency can also affect cellular immunity and phagocytosis making those affected more susceptible to infection. Iron replacement Routine iron supplementation in all pregnant women is probably not justified in developed countries. However, if iron deficiency is detected it is advisable to treat as early as possible as the demands for iron will increase as the pregnancy progresses. The recom- mended dose of oral elemental iron is 100–​200 mg daily. Once the haemoglobin has reached the normal range the supplementation should be continued for three months to replenish iron stores. Side effects are experienced by 10–​20% of patients due to nausea, ab- dominal discomfort, and altered bowel habit. In these situations, liquid preparations that have lower iron doses can be given and then titrated up according to symptoms. Alternatively, the iron can be given parenterally, although most parenteral iron preparations are relatively contraindicated in the first trimester of pregnancy. A maximal increase in haemoglobin of approximately 0.8 g/​week can be expected. Pregnancy can have a profound effect on a woman’s iron stores, with nulliparous women having higher serum ferritin levels than multiparous women. These differences can persist even into meno- pause. However, if iron supplementation is given, the haemoglobin will reach pre-​pregnancy levels within five to seven days of delivery assuming there has not been excessive blood loss. Vitamin B12 and folate deficiency Vitamin B12 and folate are required in pregnancy for the growing uterus, fetus, and the expanding red cell mass. The requirement for folic acid doubles in pregnancy and dietary folate deficiency is the most frequent cause of gestational megaloblastic anaemia. Megaloblastic anaemia secondary to a deficiency of either vitamin B12 and/​or folate is most common in those countries with inad- equate nutrition. Folate deficiency is more frequent in multiple preg- nancies and multiparous women, with most cases presenting in the third trimester and post-​partum. Folate deficiency is known to be associated with an increase in neural tube defects but can also lead to an increased incidence of prematurity and low birth weight infants. In most women the diagnosis of folate deficiency is made in the last four weeks of pregnancy, usually as a failure to respond to iron supplementation. Few symptoms may be present. An earlier presen- tation in the second trimester should prompt a search for another cause of folate deficiency such as chronic haemolysis, malabsorption, or anticonvulsant therapy. Folate supplementation is recommended prior to conception and during the first trimester to prevent neural tube defects. The current recommendation is 400 μg daily which will reduce the risk of neural tube defects by 36%, but there is a linear dose response, and a dose of 5 mg daily improves this reduction to 85%. Megaloblastic anaemia due to poor dietary folate intake is prevented by 300 μg daily, but if the folate deficiency is due to malabsorption it will need to be given parenterally. Initial concerns that folate supplementation would mask an underlying B12 deficiency, allowing continued neurological deteri- oration, have not been borne out. This is probably because severe B12 deficiency due to Addisonian pernicious anaemia and of sufficient severity to cause megaloblastosis is likely to be associated with in- fertility. Vitamin B12 stores are large (about 3000 μg) and therefore more or less unaffected by pregnancy. The daily requirements for vitamin B12 are increased in pregnancy (1.4 µg/​day in pregnancy vs. 1.0 µg/​day in the non​pregnant female) but this is easily met by a diet containing animal products. Dietary deficiency of vitamin B12 is rare in pregnancy, but can occur and was previously termed the ‘perni- cious anaemia of pregnancy’. However, it responds to oral vitamin B12 supplementation and is not associated with an autoimmune aeti- ology. The exception is those patients that have had bariatric sur- gery or a partial gastrectomy and are therefore deficient in intrinsic factor. These patients will require intramuscular B12 replacement. B12 levels can fall up to 50% during pregnancy, particularly in the third trimester. This is normal and represents a dilutional effect and increasing binding to the B12 biding proteins, and it does not re- quire replacement. The reference ranges stated are for non​pregnant individuals.

14.17  Blood disorders in pregnancy 2689 Haemoglobinopathies Genetic defects in the structure, function, and production of haemo- globin can be divided into two clinically significant groups: variant haemoglobins and the thalassaemia syndromes. Diagnosis prior to, or early in, pregnancy is important so that obstetric management can be tailored appropriately. It is also possible to offer prenatal diagnosis, which can shape parental decisions with regards to ter- mination of the pregnancy or can direct materno-​fetal management prior to delivery. Screening is usually performed on the blood sample taken at booking. This can be directed at high-​risk populations; however, with the increased migration of people from varied racial back- grounds it can be difficult to isolate this population accurately, and therefore it is prudent to offer the screening to all mothers. An al- gorithm for screening blood tests is outlined in Fig. 14.17.1. If a haemoglobin variant or thalassaemic indices are detected, then the partner should be tested to determine the risk of having an affected fetus and allowing informed prenatal counselling. Variant haemoglobins and sickle cell syndromes Clinically the important haemoglobin variants are those that are as- sociated with red cell sickling. The sickle cell syndromes with major clinical symptoms include sickle cell anaemia (HbSS), sickle cell haemoglobin C (HbSC) disease, and sickle cell β-thalassaemia (HbS β-​Thal). Other haemoglobin variants in combination with HbS (e.g. HbSE and HbSD are in general associated with a milder disorder, but vasocclusive crises may occur in pregnancy). Mothers with sickle cell trait (i.e. heterozygotes for haemoglobin A and S; HbAS) have no increased risk of sickle cell crises during normal pregnancy, but they do have an increased incidence of some infections (e.g. pyelonephritis). Caution should also be exercised if a general anaesthetic is required in these women as they have an in- creased risk of placental infarction and pre-​eclampsia if exposed to severe dehydration or shock. Outcome data in pregnancy for women with sickle cell disease (i.e. HbSS, HbSC and HbS β-​thal), is based upon retrospective case series; overall maternal mortality is below 2% and neonatal mor- tality is below 5%. There is an increased tendency to pre-​eclampsia, preterm labour, and low birth weight babies. The main medical problems facing a pregnant woman with sickle cell disease are those of increased sickle cell crises causing tissue infarction, severe an- aemia, and an increased risk of infection. The crises are predomin- antly vaso-​occlusive in nature and can be triggered by infection, or the pregnancy alone. If this is associated with a parvovirus infec- tion, then the crisis can become aplastic resulting in a rapid drop in haemoglobin. Painful vaso-​occlusive crises can occur in any organ leading to infarction and dysfunction, however the lungs are par- ticularly susceptible and can progress to a life-​threatening chest crisis. Treatment of a sickle crisis in pregnancy is the same as for the non-​ pregnant female; namely oxygen, fluids, and analgesia with the add- ition of antibiotics if an infective trigger is suspected. There should be a low threshold for proceeding to red cell exchange transfusion if the mother is not improving. It is particularly important that preg- nant women with sickle cell disease are on continuous folic acid supplementation due to the high erythrocyte turnover rate. Also, as most adults with sickle cell disease have functional hyposplenism, they should receive pneumococcal vaccination and twice daily peni- cillin prophylaxis. In the sickle cell syndromes, no correlation has been shown be- tween the degree of anaemia and obstetric or perinatal complica- tions. In addition, no benefit has been shown by prophylactic red cell transfusion to keep the haemoglobin at 100–​110 g/​litre, rather than transfusing when indications arise. In addition to the issues of cost and availability, prophylactic transfusion exposes the mother to the hazards of blood transfusion including infection and not- ably the risk of alloimmunization of the mother to minor red blood cell antigens. This can lead to severe, delayed, and sometimes fatal haemolytic reactions in the mother and haemolytic disease of the fetus and newborn. Indications for transfusion in sickle cell disease women during pregnancy are: anaemia associated with cardiac or respiratory compromise, severe sickle cell disease-​related complica- tions (e.g. acute chest syndrome); preparation for caesarean section or refractory pre-​eclampsia in previous pregnancies. More contro- versial indications are: increasing frequency of painful crises; sickle cell disease-​related complications during a previous pregnancy; and multiple gestation pregnancy. The increased risk of intrauterine growth restriction is probably due to the decreased oxygen supply from the maternal anaemia and some placental infarction. Fetal growth should therefore be moni- tored with regular ultrasound scans. The method of delivery is based on obstetric considerations. For the infant, the first two years of life are particularly hazardous with an increased risk of death due to in- fection and splenic sequestration. Therefore, if the diagnosis is not made antenatally, then it needs to be made as soon as possible after birth so that the parents can be aware of the need to investigate and treat any new symptoms early. Most pregnancies have a successful outcome, but early collabor- ation between obstetric and haematology teams is strongly recom- mended if there are any concerns. Thalassaemias Alpha(α) Thalassaemia There are four clinical syndromes dependent on the number of α- genes that have been deleted.

  1. Four gene deletion α-thalassaemia (-​-​/​-​-​) (i.e. a complete ab- sence of all four α-globin genes), results in a fetus that cannot make any α-chains and therefore no fetal or adult haemoglobin can be synthesized. The remaining γ-chains form tetramers known as haemoglobin Barts (Hb Barts—​γ4). Hb Barts has a high oxygen affinity, which restricts oxygen delivery to the tissues resulting in a hydropic fetus that usually dies in utero or shortly after birth. Pregnancy with an α-thalassaemia hydrops fetus is associated with severe hypertension and proteinuria early in pregnancy, along with a high risk of antepartum and post-​partum haemorrhage in addition to other obstetric complications secondary to a large fetus and bulky placenta. Routine antenatal screening can detect women at risk of carrying an affected fetus. Parents should be referred for counselling and offered prenatal diagnosis as termination of the pregnancy may be required to avoid serious obstetric complications. Most cases of Hb Barts hydrops fetalis are seen in the Far East. However, with migra- tion, this disorder will become more prevalent in Western countries.

Section 14  Medical disorders in pregnancy 2690 Transfusion in utero has been performed and has been successful in a few cases. 2) Haemoglobin H (-​-​/​-​α) is the result of the deletion of three α-globin genes. The fetus can, therefore, make some α-chains, so although most of the haemoglobin will be Hb Barts there will be some fetal Hb (HbF (α2γ2)) production. The neonate appears healthy at birth but soon develops a severe haemolytic anaemia as HbF levels fall. The Hb Barts (γ4) is replaced with HbH (β4), which FBC Raised HbF Normal: iron deficiency; α thal trait; normal A2 - β thal trait Raised: β thal trait Borderline: β thal trait,

14.17  Blood disorders in pregnancy 2691 results in a lifelong anaemia. This varies in severity and will worsen during pregnancy. 3) Mothers with one (-​α/​αα) or two gene deletion α-thalassaemia (-​-​/​αα or -​α/​-​α) can range from being asymptomatic to having a mild hypochromic microcytic anaemia. In all women with sus- pected two gene deletion α-thalassaemia, their partner should be screened and if necessary they should be referred for gen- etic counselling. Two gene deletion α-thalassaemia does not affect the pregnancy, but if both parents possess two gene dele­tion α-thalassaemia and the deletion occurs on the same al- lele (i.e. -​-​/​αα) then there is a 1:4 chance of having a Hb Barts hydropic fetus. β-Thalassaemia The β-thalassaemias are due to point mutations in the β-globin genes that cause varying degrees of reduction in the amount of β- chains produced.

  1. In β-thalassaemia major, the production of β-globin chains is severely impaired, because both β-globin genes are mutated. The severe imbalance of globin chain synthesis results in ineffective erythropoiesis and a severe microcytic hypochromic anaemia. The excess unpaired α-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular haem- olysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. This is not ap- parent in the fetus until the HbF production switches to HbA when the infant will become anaemic. Women with transfusion-​dependent β-thalassaemia major have historically been infertile however with improving iron chelation the number of successful pregnancies is increasing. There are also an increasing number of women with thalassaemia intermedia pro- ceeding to pregnancy. Both groups of women have an increased incidence of antepartum and post-​partum complications with intra- uterine growth restriction, recurrent infections, and hypersplenism. They need to continue with regular transfusions throughout preg- nancy with the incumbent risks and complications. Iron chelation therapy is not recommended in pregnancy, therefore consideration should be given to aggressive preconception chelation therapy.
  2. In β-thalassaemia minor (β-thalassaemia trait), one of the two β-globin genes is defective. The defect can be a complete ab- sence of the β-globin protein or a reduced synthesis of the β-globin protein. Women with β-thalassaemia minor are either asymp- tomatic or have a mild hypochromic microcytic anaemia with a raised proportion of HbA2 which does not affect the pregnancy. However, it is important to identify such women and screen their partners to see if they are similarly affected and if necessary to offer prenatal diagnosis. In cases in which both partners have β-thalassaemia minor, there is a 1:4 chance of having a child with severe β-thalassaemia major. Other anaemias Aplastic anaemia Coincidental aplastic anaemia can occur in pregnancy in the same way as acute leukaemia, however, there does appear to be a rare form of aplasia that develops due to the hormonal influences of pregnancy and may resolve following delivery. Diagnosis is often made in the second and third trimesters, and treatment depends on the severity of the aplasia. Haemolytic anaemia Pregnancy-​related autoimmune haemolytic anaemia is a rare dis- order, but pregnancy can act as a trigger. Secondary causes include lymphoproliferative disorders, connective tissue disorders, and infections. If triggered by pregnancy it usually occurs in the third trimester and remits spontaneously following delivery. Treatment aims to maintain the haemoglobin at an adequate level for placental perfusion and minimal symptomatic anaemia. Corticosteroids and intravenous immunoglobulin are often used but may not always be effective. Red cell transfusions may be required. Disorders of haemostasis in pregnancy Physiology Normal pregnancy is associated with marked changes in all aspects of haemostasis the overall effect of which is to generate a state of hypercoagulability (Table 14.17.1). The reason for this is clear when one considers that at the time of delivery, placental separation pro- vokes an acute massive blood loss in the region of 700 ml/​minute, which must be stopped immediately. Three weeks after delivery most of the changes in clotting factors have returned to normal. Table 14.17.1  Haemostatic changes in normal pregnancy Haemostatic factor Effect of pregnancy Platelet count Decreases during pregnancy Factor XIII, V Increase in early pregnancy but returns to the pre-​pregnancy state by the 3rd trimester Factors XII, X, VIII, VII, VWF, and fibrinogen Increase throughout pregnancy Factor IX No change Factor XI Either no change or a slight fall Protein C and Antithrombin No change Protein S Progressive decrease during pregnancy Activated Protein C resistance (APCr) Gradual fall during pregnancy PAI-​1, TAFI Increases throughout pregnancy PAI-​2 Appears during pregnancy PAI, plasminogen activator inhibitor; TAF, thrombin-​activatable fibrinolysis; VWF, von Willebrand factor.

Section 14  Medical disorders in pregnancy 2692 These changes in haemostasis, while reducing the risks of exces- sive blood loss at delivery, significantly increase the risk of venous thromboembolic disease in pregnancy. Increasingly it is recognized that disordered haemostasis has a role in intrauterine growth re- striction, pre-​eclampsia, early and late pregnancy loss, and placental abruption. Thrombocytopenia in pregnancy Thrombocytopenia is a common finding in pregnancy and may be due to a variety of causes (Table 14.17.2). Gestational thrombocytopenia Gestational thrombocytopenia is seen in approximately 8% of all pregnancies and accounts for more than 70% of cases of thrombo- cytopenia in pregnancy. The aetiology is unknown but probably represents increased peripheral destruction. The platelet count is, in general, only mildly reduced, and in 95% of women is between 100 and 150 × 109/​litre. Rarely does the count fall below 80 × 109/​litre. The major differential diagnosis is between gestational thrombo- cytopenia and immune thrombocytopenic purpura. Immune thrombocytopenic purpura Immune thrombocytopenic purpura has a prevalence of 1–​5 cases per 10 000 pregnancies (i.e. approximately 100 times less common than gestational thrombocytopenia). Chronic immune thrombocytopenic purpura, characterized by immunologically me- diated platelet destruction, is two to three times more common in women than men. The diagnosis of immune thrombocytopenic purpura is largely one of exclusion as there is no confirmatory la- boratory test. In pregnancy immune thrombocytopenic purpura has implications for both the mother and the fetus. All women with platelet counts below 100 × 109/​litre should be screened for clinical or laboratory evidence of pre-​eclampsia, a coagulopathy, or autoimmune disease. A screen for antinuclear anti- bodies should be performed and if positive it is essential to screen for anti-​Ro and anti-​La antibodies. Anti-​Ro and anti-​La antibodies can result in congenital heart block in approximately 2% of infants born to mothers with such antibodies. Asymptomatic women with platelet counts more than 20 × 109/​ litre do not require treatment until within a few weeks of delivery but should be carefully monitored, both clinically and haematologically. Platelet counts of more than 50 × 109/​litre are regarded as safe for normal vaginal delivery and for caesarean section but would pre- clude the use of spinal anaesthesia for which the platelet count should be more than 80 × 109/​litre. Because of the theoretical risk of haematoma formation and neurological damage, spinal or epi- dural anaesthesia is not recommended if the platelet count is below 80 × 109/​litre. Therapies aimed at increasing the platelet count during preg- nancy or prior to delivery include the use of oral prednisolone or intravenous immunoglobulin. Splenectomy is rarely performed during pregnancy. The mode of delivery for women with immune thrombocytopenic purpura is dictated by obstetric reasons rather than the platelet count. There is no good evidence that caesarean section is less traumatic than an uncomplicated vaginal delivery. The major risk to the fetus is of neonatal thrombocytopenia. The platelet count may be low at birth but reaches a nadir on day 3 following delivery. The risk of neonatal thrombocytopenia does not correlate with the maternal platelet count, although a previous splenectomy for immune thrombocytopenic purpura or a previ- ously affected infant with significant thrombocytopenia may in- crease the risk of significant fetal thrombocytopenia in subsequent pregnancies. Alloimmune thrombocytopaenia In this disorder the maternal platelet count is normal, but the mother is sensitized to paternally derived fetal platelet antigens the most common of which is HPA-​1. This can result in severe fetal and neo- natal thrombocytopenia beginning early in pregnancy. Women at risk can be tested for the presence of platelet alloantibodies during gesta- tion. In neonates with severe thrombocytopenia, the most common presentations are petechiae, purpura, or cephalohaematoma at birth, associated with major risk of intracranial haemorrhage (up to 20% of reported cases), which leads to death or neurological sequelae. The treatment of affected infants involves the transfusion of compat- ible platelets and washed maternal platelets are often used. Antenatal management is controversial but can include a combination of ma- ternal intravenous γ-globulin administration, intrauterine platelet transfusions, and corticosteroid therapy, while monitoring fetal platelet counts closely throughout the pregnancy. HELLP The HELLP syndrome comprises a haemolytic anaemia, elevated liver enzymes, and a low platelet count. It occurs in 0.2–​0.6% of all Table 14.17.2  Causes of thrombocytopenia in pregnancy Increased destruction or utilization • Immunologic Immune thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE) • Consumption Disseminated intravascular coagulation (DIC) • Microangiopathies

14.17  Blood disorders in pregnancy 2693 pregnancies and about 4–5% of pregnant women with pre-​eclampsia or eclampsia. Pregnancy-​induced hypertension, pre-​eclampsia, and the HELLP syndrome are related and overlap in their presentations. The syndrome is a subtype of severe pre-eclampsia and appears to be secondary to microvascular endothelial damage and intravascular platelet activation. The haemolysis in the HELLP syndrome is a microangiopathic haemolytic anaemia. Red blood cells become fragmented as they pass through small blood vessels with endothelial damage and fi- brin deposits. The elevated liver enzyme levels in the syndrome are thought to be secondary to obstruction of hepatic blood flow by fi- brin deposits in the sinusoids. The thrombocytopenia has been at- tributed to increased consumption and/​or destruction of platelets. Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura is a life-​threatening multi­ system disorder characterized by a pentad comprising: • Microangiopathic haemolytic anaemia • Thrombocytopenia • Neurological abnormalities • Fever • Renal dysfunction In most cases of acquired thrombotic thrombocytopenic purpura in pregnancy, women develop an autoantibody directed against ADAMTS13 and as a consequence cannot break down the ultra large von Willebrand factor multimers that are secreted from endothelial cells. The absence of this cleavage and the presence of ultra large von Willebrand factor multimers in the circulation is believed to lead to platelet activation and the generation of platelet microthrombi. Congenital thrombotic thrombocytopenic purpura is a rare dis- order due to a mutation within the gene encoding ADAMTS13 that results in a deficiency or functional abnormality of the protein. Although congenital thrombotic thrombocytopenic purpura usu- ally presents in childhood, there are cases in which the presentation is in adulthood. The diagnosis of thrombotic thrombocytopenic purpura is a clin- ical one, although assays for ADAMTS13 are available and can be helpful in distinguishing thrombotic thrombocytopenic purpura from other disorders. The mainstay of treatment for thrombotic thrombocytopenic purpura is early plasma exchange to remove the autoantibody and to increase ADAMTS13 levels, and with the intro- duction of this treatment the survival rate has improved from ap- proximately 3% prior to the 1960s to 82%. Steroids may also be helpful in thrombotic thrombocytopenic purpura in addition to plasma exchange. Patients also have an increased risk of venous thrombo- embolic disease and are therefore maintained on low-​dose aspirin. In the non​pregnant setting, there is extensive use of the anti-​CD20 monoclonal antibody Rituximab. This has been used successfully in some pregnancies, but pregnancy remains a relative contraindication. Disseminated intravascular coagulation Disseminated intravascular coagulation is an acquired syndrome characterized by the intravascular activation of coagulation. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction. Disseminated intravascular coagulation is not confined to pregnancy and can arise for a variety of reasons including sepsis, major trauma, and an incompatible blood transfusion. In pregnancy, disseminated intra- vascular coagulation may occur secondary to: • Intrauterine death with a retained fetus • Severe pre-​eclampsia • Premature separation of the placenta (placental abruption) • Retained placenta • Amniotic fluid embolism • Haemorrhagic shock • Transfusion reaction Systemic activation of the clotting cascade leads to depletion of pro- coagulant clotting factors, consumption of the natural anticoagu- lants that regulate the activity of clotting cascade (antithrombin, protein C, and protein S), activation of the fibrinolytic system leading to hyperfibrinolysis, and consumption of platelets leading to thrombocytopenia The main clinical manifestation of disseminated intravascular coagulation is haemorrhage secondary to the consumption of clot- ting factors and platelets. Treatment of disseminated intravascular coagulation involves identifying and removing the trigger and re- placing the missing clotting factors with fresh frozen plasma, re- storing fibrinogen with cryoprecipitate or fibrinogen concentrate, and correcting the thrombocytopenia with platelet transfusions. Inherited disorders of haemostasis Haemophilia A and B in pregnancy Haemophilia A and B are uncommon X-​linked disorders due to mutations within the genes for factor VIII (F8) and factor IX (F9), respectively. Female carriers of haemophilia A or B may have low levels of factor VIII (FVIII) or factor IX (FIX) as a consequence of Lyonization. Rarely women who are carriers may have severe haemophilia either because of extreme Lyonization or because they have a second mutation in the other F8 or F9 gene. Counselling should be offered to all potential carriers of haemo- philia to discuss prenatal diagnosis and other aspects of pregnancy management. Their carrier status should be established by DNA analysis. Women who may require blood product therapy should be immunized against hepatitis B. Initial fetal sexing is performed by cell-​free fetal DNA (cffDNA) analysis of maternal plasma. This can be undertaken at seven to nine weeks of pregnancy and if it indicates a male then prenatal diag- nosis by chorionic villus sampling or amniocentesis can then be performed to allow identification of an affected male fetus. Direct mutation analysis has now almost entirely replaced the use of linkage analysis in both carrier detection and prenatal diagnosis. Factor VIII levels increase significantly during pregnancy, but this rise is unpredictable and a few women may still have low levels at the time of delivery. FVIII and FIX levels should be checked at booking, at 28 weeks, and again at 34 weeks. If the levels are low (<0.50 IU/​ ml) at 34 weeks they are unlikely to rise into the normal range by delivery and treatment to prevent haemorrhage will be required. Factor IX levels do not rise during pregnancy. Women who undergo any form of invasive prenatal diagnostic procedure or who have a spontaneous abortion, or a termination of pregnancy will require prophylactic replacement therapy if their factor levels are below 0.50 IU/​ml. Women who require clotting factor replacement should receive recombinant products.

Section 14  Medical disorders in pregnancy 2694 Epidural anaesthesia may be safely used in haemophilia carriers providing a coagulation screen (including the platelet count) is normal and the factor level is 0.50 IU/​ml or greater. Von Willebrand disease in pregnancy Von Willebrand disease is due to a deficiency or functional abnor- mality of von Willebrand factor (VWF). Von Willebrand factor has two main functions, first as a carrier protein for factor VIII, and secondly as an adhesive protein involved in vessel wall–​platelet interaction. Its function as an adhesive protein is most important in situations of high shear stress. Inherited defects in von Willebrand factor may, therefore, cause bleeding by impairing either platelet ad- hesion or fibrin clot formation. Von Willebrand disease is the most common of the inherited dis- orders of coagulation and is classified into types 1, 2, and 3. Type 1 accounts for 80% of cases and is a partial quantitative defect. Type 3 is rare and represents a complete absence of von Willebrand factor in plasma. Type 2 (subclassified into types 2A, 2B, 2M, and 2N) rep- resents qualitative defects in von Willebrand factor. In women with type 1 von Willebrand disease, the levels of von Willebrand factor increase during pregnancy and usually normalize by delivery. In type 2 von Willebrand disease, while levels may in- crease, this increase is of a functionally abnormal protein and re- placement therapy may be required at the time of delivery. In women with type 1 or 2 von Willebrand disease, von Willebrand factor levels should be checked at 34–​36 weeks. Vaginal delivery is generally regarded as safe in types 1 and 3 if von Willebrand factor activity (VWF:RCo) is more than 0.50 IU/​ml. Von Willebrand factor activity should be more than 0.50 IU/​ml for caesarean section. In type 3, the levels will remain low and replacement therapy with a von Willebrand factor-​containing concentrate will be needed at the time of delivery. In women with type 1 von Willebrand disease, von Willebrand factor levels may fall rapidly following delivery although the rate of fall is unpredictable. In some women a rapid fall in von Willebrand factor levels may lead to a delayed post-​partum haemorrhage and women should be made aware of this possibility. Desmopressin is widely used in the treatment of type 1 von Willebrand disease, tended to be avoided in pregnancy because of concerns that it may cause vasoconstriction with subsequent pla- cental insufficiency, increase the risk of premature labour due to the drug’s potential oxytocic effect and increases the risk of maternal and neonatal hyponatraemia. However, desmopressin increases the levels of factor VIII and von Willebrand factor via its action on V2 receptors and its potential for vasoconstriction and uterus con- traction is negligible because the compound is practically devoid of these biologic activities related to the activation of V1 vasopressin receptors. Factor XI deficiency Factor XI deficiency is a recessively inherited disorder that is rare ex- cept in Ashkenazi Jews, where the frequency of heterozygosity may approach 10%. There is a poor correlation between absolute Factor XI levels and the risk of bleeding but individuals with levels below 0.30 IU/​ml tend to have a positive bleeding history. Observations of FXI levels in pregnancy are contradictory but changes are gen- erally not clinically significant. Women with FXI levels in the het- erozygous range may bleed at delivery. In women with FXI levels between about 0.15 IU/​ml and 0.70 IU/​ml and no bleeding history but previous haemostatic challenges, a policy of ‘watch and wait’ is justified. For women with FXI levels between about 0.15 IU/​ml and 0.70 IU/​ml and a significant bleeding history or no previous haemo- static challenges, tranexamic acid is often used for 3 days, with the first dose being administered during labour. For women with severe FXI deficiency (FXI:C <0.10–​0.20 IU/​ml), FXI concentrate should be given during labour. Rarer clotting factor Deficiencies Inherited deficiencies of all of the clotting factors have been reported and these may result in haemorrhage at the time of delivery. These rare inherited coagulation disorders affect between 1:500 000—​ 1:2 000 000 of the population, although because they are recessively inherited they are significantly more common in countries where consanguineous relationships are found. Guidelines on the investi- gation and treatment of these rare disorders are available, including the management of delivery. Acquired FVIII inhibitors Acquired haemophilia is a rare disorder with an incidence of 1.5 per million per year. It is due to the formation of an autoantibody (‘in- hibitor’) that results in the depletion or inhibition of a coagulation factor, most commonly factor VIII, but antibodies to all of the co- agulation factors have been described. Acquired haemophilia A leads to a potentially severe bleeding diathesis, often of sudden onset. Although acquired haemophilia A presents most commonly in older people with a median age of 70–​80 years, it can present in a younger age group and pregnancy is a recognized risk factor for the development of this disorder. The clinical features of acquired haemophilia A differ from those of congenital haemophilia in that bruising, soft tissue, muscle bleeding, gastrointestinal and urogenital bleeding are common manifestations, whereas haemarthroses are rare. Severe and life-​ threatening bleeding is common, but no haemostatic treatment is required in 25–​33% of cases. The mortality associated with acquired haemophilia A has been reported to be between 7.9% and 42%. In women who are actively bleeding secondary to an auto-​FVIII antibody, options for treatment include recombinant FVIIa and ac- tivated prothrombin complex concentrates. Elimination of the in- hibitor should be attempted using immunosuppression, which is initiated as soon as the diagnosis has been established. Where suc- cessful, this restores haemostasis to normal. Relapse of pregnancy-​related acquired haemophilia appears to be relatively rare, but may occur and women should be warned of this possibility. The antibody may affect the factor VIII level of the fetus and this must be considered at the time of delivery. Miscellaneous haematological conditions Autoimmune neutropenia This is a rare disorder, most cases of which are mild. It can be pri- mary or secondary (in association with autoimmune disorders, sys- temic lupus erythematosus, or rheumatoid arthritis, viral infections, drugs). Symptomatic neutropenia (recurrent infections) occurs at neutrophil counts of below 0.5 × 109/​litre. The main two risks during

14.17  Blood disorders in pregnancy 2695 pregnancy are maternal sepsis, which can precipitate miscarriage or preterm labour, and neonatal neutropenia. Steroids are usually the first line of treatment. Intravenous im- munoglobulin can be given if there is no response. Granulocyte-​ colony stimulating factor is used widely in the non​pregnant setting. There are concerns that it may be associated with increased preterm birth and a small increase in the incidence of venous thrombo-​ embolism, but there are case reports of its safe use in pregnancy. Myeloproliferative diseases Thrombosis and haemorrhage are the main cause of morbidity in pregnant patients with essential thrombocythemia and polycy- themia vera. There are limited data, but these conditions are dif- ficult to manage during pregnancy and are associated with a high fetal mortality. The live birth rate is approximately 60% in both essential thrombocythemia and polycythemia vera, with spontan- eous miscarriage during the first trimester being the most common complication and occurring in about 20–​30% of all pregnancies. Intrauterine growth restriction, preterm delivery, and increased neonatal deaths have all been described. Major maternal complica- tions are more frequent, including major thromboses, post-​partum haemorrhage, pre-​eclampsia, and disseminated intravascular co- agulation. These are reduced with low-​dose aspirin treatment. In high-​risk pregnancies, the additional use of low molecular weight heparin and/​or interferon α has also been beneficial. Such cases re- quire the close collaboration of obstetricians and haematologists, with attention to management of the thrombotic risk and increased fetal monitoring. FURTHER READING Collins P, et al. (2013). Diagnosis and management of acquired coagu- lation inhibitors: a guideline from UKHCDO. Br J Haematol, 162, 758–​73. Franchini M (2006). Haemostasis and pregnancy. Thromb Haemost, 95, 401–​13. Frenkel EP, Yardley DA (2000). Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12
(cobalamin) in pregnancy and gynecology. Hematol Oncol Clin North Am, 14, 1079–​100. Greig AJ, et al. (2013). Iron deficiency, cognition, mental health and fatigue in women of childbearing age: a systematic review. J Nutr Sci, 2, e14. Griesshammer M, Struve S, Harrison CM (2006). Essential thrombo- cythemia/​polycythemia vera and pregnancy: the need for an obser- vational study in Europe. Semin Thromb Hemost, 32(4 Pt 2), 422–​9. Kadir RA, et al. (2006). Screening for factor XI deficiency amongst pregnant women of Ashkenazi Jewish origin. Haemophilia, 12, 625–​8. Ladipo OA (2000). Nutrition in pregnancy: mineral and vitamin sup- plements. Am J Clin Nutr, 72(1 Suppl), 280S–​90S. Laffan MA, et  al. (2014). The diagnosis and management of von Willebrand disease:  a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol, 167, 453–​65. Letsky EA (1985). Haematological disorders in pregnancy. In: Letsky EA (ed) Clinics in haematology. Oxford University Press, New York, NY. Lottenberg R, Hassell KL (2005). An evidence-​based approach to the treatment of adults with sickle cell disease. Hematology Am Soc Hematol Educ Program, pp. 58–​65. McMullin MF, et al. (2005). Guidelines for the diagnosis, investigation and management of polycythaemia/​erythrocytosis. Br J Haematol, 130, 174–​95. Milman N (2006). Iron and pregnancy—​a delicate balance. Ann Hematol, 85, 559–​65. Mumford AD, et  al. (2014). Guideline for the diagnosis and man- agement of the rare coagulation disorders:  a United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol, 167, 304–​26. Nassar AH, et al. (2006). Pregnancy in patients with beta-​thalassemia intermedia: outcome of mothers and newborns. Am J Hematol, 81, 499–​502. Nugent DJ (2006). Immune thrombocytopenic purpura of childhood. Hematology Am Soc Hematol Educ Program, pp. 97–​103. Pavord S, et al. (2012). UK guidelines on the management of iron defi- ciency in pregnancy. Br J Haematol, 156, 588–​600. Scully M, et al. (2012). Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol, 158, 323–​35. Trent RJ (2006). Diagnosis of the haemoglobinopathies. Clin Biocem Rev, 27, 27–​38. Wald NJ (2004). Folic acid and the prevention of neural-​tube defects. N Engl J Med, 350, 101–​3. World Health Organization (WHO) (2007). Standards for Maternal and Neonatal Care. http://​www.who.int/​making_​pregnancy_​safer/​ publications/​standards/​en/​index.html

14.18 Malignant disease in pregnancy 2696

14.18 Malignant disease in pregnancy 2696

ESSENTIALS Cancer in pregnancy is rare, affecting less than 1 in 1000 live births. It may be specific to pregnancy (gestational trophoblastic disease) or incidental to it, the less infrequent conditions being melanoma, lymphoma, breast and cervical malignancy. Malignant disease particular to pregnancy Gestational trophoblastic disease—​a group of conditions that arise in the fetal chorion during various types of pregnancy: histologically they are categorized as (1) partial or complete hydatidiform mole, (2) gestational choriocarcinoma, or (3) placental site trophoblastic tumour. The most common of these conditions is molar pregnancy, when villi are present in association with malignant trophoblast in gestational choriocarcinoma. Any woman of reproductive age who has an undiagnosed tu- mour or unexplained bleeding from any organ other than the uterus should have a human chorionic gonadotrophin estimation to ex- clude highly treatable gestational trophoblastic disease. General aspects of management during pregnancy Consideration must be given both to the mother who is affected and the unborn fetus, with the balance of care favouring the mother’s well-​being. Anaesthesia and extra-​abdominal surgery—​ rarely carries risks in the second trimester. Ionizing radiation—​exposure during the first trimester increases the risk of fetal abnormalities and childhood cancers. Chemotherapy—​administration during the first trimester increases risk of miscarriage and congenital abnormalities, but administration after organogenesis may be appropriate. Introduction Cancer is rare during pregnancy, occurring in only about 1 per 1000 live births. Most malignancies affecting this age group have been seen during pregnancy. Tumours of the uterine cervix, ovary, breast, or thyroid can metastasize to the placenta, but not to the fetus. Gestational trophoblastic disease arises from fetal chorion and is a malignant transformation of the placenta. Melanoma and haematological tumours, which also can invade the placenta, may cross into the fetal circulation. Pregnancy may cause enlargement of a pituitary tumour and a previously silent tumour may present with symptoms in pregnancy. Rare cases of colonic and neurological can- cers developing in pregnancy have been reported. Concurrence of pregnancy and cancer raises complex therapeutic and ethical dilemmas because the most appropriate and timely treat- ment for the mother may not be in the best interests of the fetus. Anaesthesia and extra-​abdominal surgery during pregnancy rarely carry any risks to the fetus, and intra-​abdominal surgery may be safely carried out in the second trimester. However, fetal cells divide and differentiate rapidly during the first trimester, hence radiation and chemotherapy carry well-​recognized risks to the fetus, including the risk of miscarriage, congenital abnormalities, or preterm birth. As a result, physicians may be reluctant to treat the mother aggres- sively at the time of initial diagnosis, preferring to defer treatment for several weeks or months until the fetal lungs have matured, a delay which may substantially reduce the mother’s chance of sur- viving the disease. It is impossible to establish a threshold dose of ionizing radiation below which such treatment is safe for the fetus, inasmuch as exposure during the first trimester to a dose as low as 10 cGy appears to increase the risk of fetal abnormalities and exposure to 3–​5 cGy increases the risk of childhood cancers. The risk is negligible if exposure to the fetus is less than 1 cGy. The dose of radiation, the gestational age of the fetus, and the practicability of shielding the fetus from radiation must be balanced against potential benefits to the mother. Chemotherapy administered to the mother during the first tri- mester carries well-​recognized risks that include miscarriage or congenital abnormalities. Drugs that preferentially interfere with rapidly growing tissues (e.g. methotrexate), can harm the fetus. Use of antagonists of folate, purine, or pyrimidine synthesis during organogenesis result in congenital malformations in up to 25% of fetuses, although this figure is much lower if the mother only re- ceives therapy with a single agent. Treatment after the first trimester, when structural development is largely complete, is reasonably safe in many diseases and more appropriate than postponement of treatment. Chemotherapy after the first trimester has been asso- ciated with slight increases in the incidence of preterm birth and fetal growth restriction and, when administered shortly before de- livery, with transient neonatal myelosuppression. Nevertheless, the 14.18 Malignant disease in pregnancy Robin A.F. Crawford

14.18  Malignant disease in pregnancy 2697 long-​term outcomes of the children of women who received chemo- therapy during the second or third trimester are generally good. In practical terms, acute leukaemia is virtually the only condition requiring immediate chemotherapy in a pregnant woman. When faced with cancer in the first trimester, the available information should be explained to the woman and her partner, who should give informed, unhurried consent before treatment starts. In most situ- ations a consensus decision to proceed with chemotherapy can be reached between the woman, her partner, and the responsible phys- ician, but the ethical issues are very complex, and decisions must be made on an individual basis. Increasing success with the treatment of childhood cancers means that more women are entering the reproductive age group having survived cancer treatment. An increased incidence of spontaneous miscarriage, low birth weight babies, and neonatal deaths has been described in women with Wilms’ tumour who had received at least 20 Gy abdominal radiation. Survivors of Hodgkin’s disease treated with both radiation and chemotherapy (but not either alone) also appear to be at increased risk of spontaneous miscarriage. However, based on series of several thousand children there appears to be no overall increased risk of either congenital malformations or child- hood cancers in the offspring of cancer survivors. Malignant diseases specific to pregnancy Gestational trophoblastic disease Gestational trophoblastic disease is a group of diseases that arise in the fetal chorion during various types of pregnancy. Histologically they are categorized as one of two types of hydatidiform mole (par- tial or complete), gestational choriocarcinoma, or placental site trophoblastic tumour (Table 14.18.1). Gestational trophoblastic disease is notable for several reasons. First, the tumours are genetically different from the host, having antigens derived from the male partner. Secondly, apart from pla- cental site tumour, they secrete human chorionic gonadotrophin (hCG) in amounts proportional to the viable tumour volume, al- lowing hCG to be used as an ideal tumour marker. Thirdly, even metastatic disease can be cured with chemotherapy, the use of methotrexate in the early 1950s having shown reproducible results. Complete and partial hydatidiform moles present as abnormal pregnancies ending in first or second trimester miscarriages. Gestational choriocarcinoma is a highly malignant tumour derived from syncytial and cytotrophoblastic cells. When villi are present in association with malignant trophoblasts, it is classified as a molar pregnancy. If there is diagnostic doubt about the possibility of com- bined molar pregnancy with a viable fetus, then ultrasound scan- ning should be repeated before intervention. If a twin pregnancy is associated with a partial mole, it should be allowed to proceed; if a twin pregnancy is associated with a complete mole, it may proceed after appropriate counselling. These pregnancies are associated with a reduced live birth rate of 25% and are at risk of pre-​eclampsia and haemorrhage. The subsequent need for chemotherapy in these rare cases is about 20% and is the same whether the pregnancy is termin- ated spontaneously or therapeutically, or allowed to proceed to term. Gestational trophoblastic disease arises in various types of preg- nancy, most of which are clinically recognized as abnormal. The in- cidence is 1.54 per 1000 live births. The most common are molar pregnancies, but gestational trophoblastic disease can also arise fol- lowing miscarriages, ectopic pregnancies, or even normal full-​term pregnancies. Clinical surveillance of patients who have had a molar pregnancy is the only practical method of detecting and preventing gestational trophoblastic disease. In the United Kingdom all patients with a histological diagnosis of a molar pregnancy are registered and followed up at one of three screening centres (Charing Cross Hospital in London, Sheffield, and Dundee). Only 7.5% of women with hydatidiform mole require chemotherapy, and more than half of the patients who require chemotherapy for gestational tropho- blastic disease have a preceding molar pregnancy. Patients who develop gestational trophoblastic disease after a miscarriage or full-​term pregnancy are more difficult to detect. They present with symptoms attributable to metastases, the sites of initial metastasis being (in order of frequency) lung, vagina, brain, liver, gastrointestinal tract, and kidney. The interval between preg- nancy and the development of metastatic gestational trophoblastic disease may be years. Because these tumours are rare, many clin- icians are unfamiliar with them and do not consider gestational trophoblastic disease as part of any differential diagnosis. Any woman of reproductive age who has an undiagnosed tumour or un- explained bleeding from any organ other than the uterus should have an hCG estimation to exclude highly treatable gestational trophoblastic disease. Patients with gestational trophoblastic disease are classified as having a low or high risk depending on a scoring system devised at Charing Cross Hospital and now modified by the World Health Organization. The score relies on factors such as age, the antecedent pregnancy, the interval between presentation and the previous preg- nancy, the hCG level, the blood group, the size of the largest tumour, site, and number of metastases, and whether the patient had previ- ously received chemotherapy. In the United Kingdom the low-​risk group will be offered methotrexate with folinic acid rescue. The high-​risk group and those low-​risk patients who have resistant or persistent disease will be offered combination chemotherapy. The initial diagnosis may be made by surgical excision or biopsy of a sus- picious lesion, but surgery otherwise has little role, excepting rarely to remove a cerebral metastasis to prevent a cerebral bleed. The overall survival for patients with gestational trophoblastic disease is now about 94%. Women should be advised not to con- ceive for six months after a negative hCG reading. The risk of further molar pregnancy is low (1 in 74). Table 14.18.1  Types of hydatidiform mole Type of hydatidiform mole Genetic basis Clinical presentation Partial mole Triploid with paternal, maternal, and fetal elements Usually diagnosed on products of conception pathologically Complete mole Diploid (parental origin) with no fetal elements Commonly diagnosed on ultrasound

Section 14  Medical disorders in pregnancy 2698 Malignant diseases not specific to pregnancy The cancers observed in pregnancy are similar to those seen in the non​pregnant woman (Table 14.18.2). Fewer cancers are diagnosed during pregnancy than might other- wise be expected, most markedly so in breast, cervix, and ovary. Melanoma Melanoma in pregnancy is unusual in that it can metastasize to the placenta and to the fetus. As this is a rare phenomenon, therapeutic abortion is not indicated, but careful examination and follow-​up of the baby is warranted. Current evidence suggests that the clinical outcome for pregnant patients is similar to that of those who are not pregnant. Early detection and biopsy are performed as usual, and the surgical management is the same. Since most recurrences of melanoma occur in the first three years following initial diagnosis, it may be appropriate to delay further pregnancies until this time period has elapsed. Gynaecological cancers Cancer of the cervix The incidence of cervical cancer during pregnancy may be falling in those countries that have introduced effective cervical screening programmes. Pregnant women with cervical cancer generally pre- sent with early stage disease, their prognosis being similar to that of patients who are not pregnant. The presenting symptom is usually vaginal bleeding, hence it is important to check the cervix with a visual examination when pregnant women present with irregular vaginal bleeding. There is a tendency to assume that vaginal bleeding in early pregnancy is re- lated to miscarriage, organize an ultrasound scan to check for fetal viability, and forget vaginal examination. In the case of an obvious cancer, a wedge biopsy under general anaesthetic is appropriate for diagnosis and staging. If there is any doubt, colposcopy can be used to assess the cervix. There is an increased risk of bleeding when taking a biopsy from the pregnant cervix, but there is no increased rate of fetal loss. Patients with cervical intraepithelial neoplasia can be managed expectantly until after delivery. There is no contraindication to a vaginal delivery for women with cervical intraepithelial neoplasia; indeed, there are several series which suggest that vaginal delivery is associated with a higher rate of regression of severe dysplasia than is usually seen. Standard practice would be to review with colposcopy at about three months after delivery. Management of women with microinvasion of the cervix is usually via cone biopsy under a gen- eral anaesthetic, allowing the pregnancy to continue. When cervical cancer is diagnosed in early pregnancy, treatment options include immediate radical hysterectomy or delaying treat- ment until the fetus is viable, followed by classical caesarean section (scar in the upper segment of the uterus) and radical hysterectomy. This is appropriate for stage 1B cases, where the tumour is confined to the cervix and is less than 4 cm in diameter. In one series there was no difference in survival between the two modes of treatment. Typically, women diagnosed in the first trimester will be offered im- mediate surgery. Women diagnosed after 24–​28 weeks’ gestation are usually managed expectantly until after 32 weeks’ gestation and then delivered by caesarean radical hysterectomy. Steroids are usually given to accelerate fetal lung maturity. The outlook may be worse for patients who deliver vaginally across a cervical cancer, but this has not been substantiated. Cancer of the ovary The incidence of adnexal masses occurring in pregnant women has been reported as being as rare as 1 in 2500 to as frequent as 1 in 81 live births. With the use of routine early ultrasound, the true inci- dence of adnexal masses is closer to the latter figure. Most of these (>95%) are benign. Complications of a benign adnexal mass include pain due to torsion, rupture, or haemorrhage; obstruction of the pelvic outlet; and infection. Most cysts are managed conservatively, avoiding surgery, but when necessary surgery to remove cysts is usually performed in the second trimester. The advantage of waiting until the second trimester is that most cysts resolve spontaneously and that the rate of fetal loss is reduced. The rationale for removing a persistent adnexal mass is to exclude malignancy, but ovarian cancer in pregnancy is rare because the Table 14.18.2  Incidence of cancer during pregnancy Type of cancer Number of cases during pregnancy of women aged 15–​44 years
in Sweden, 1963–​2007 Incidence rate of pregnancy-​associated cancer in
New South Wales (Australia), 1994–​2008 Total number Rate per 100 000 live births Rate per 100 000 maternities Melanoma 232 5.1 15.1 Breast 139 3.0   7.3 Cervix 139 3.0   1.8 Ovary 54 1.2   1.5 Colon 44 1.0   0.8 Endocrine glands 43 0.9   3.2 (combined endocrine and thyroid) Nervous system 42 0.9   0.9 Thyroid 37 0.8   –​ Hodgkin disease 35 0.8   4.0 (lymphohaematopoietic) Leukaemia 20 0.4   –​ From Andersson TM, et al. Cancer 2015; 121: 2072–​7. From Lee YY, et al. BJOG, 2012; 119: 1572–​82.

14.18  Malignant disease in pregnancy 2699 usual age of childbirth is greater than the peak incidence of germ cell tumours and substantially less than the usual age of those with epithelial cancer. In addition, pregnancy protects against ovarian cancer. Two-​thirds of the cancers detected are epithelial and the remaining are germ cell (usually dysgerminoma) and stromal cell types. Cysts that are simple on ultrasound scan and less than 5 cm in diameter have almost no malignant potential: larger cysts with nodules, septa, or rapid growth are more likely to be malignant. Tumour markers are not helpful in pregnancy: CA-​125 can be raised by pregnancy, as can α-​fetoprotein and hCG. The management of the ovarian cancer is similar to that in the non​pregnant woman. Appropriate surgical staging is required, the author’s preference being removal of the cyst, taking of peritoneal washings for cytology, biopsy of the contralateral ovary, and biop- sies of any abnormal areas are sufficient at the primary operation. It is also preferable to wait 48 h for a definitive diagnosis from paraffin sections, rather than expect the pathologist to give an immediate result from frozen section. This delay also allows the woman and her partner to consider the implications of the diagnosis. Most of the women seen with a malignant diagnosis in pregnancy will have early stage epithelial cancer: FIGO stage 1A or B, meaning a well or moderately differentiated tumour confined to one or both ovaries, or will have borderline histology. No further therapy would then be necessary. Therapeutic termination is not required and preg- nancy per se does not worsen outcome. Fuller staging may be con- sidered 6–​12 weeks after delivery. The decision to use chemotherapy postoperatively depends on the stage and differentiation of the tu- mour, the gestational age of the fetus, and the wishes of the mother. The treatment of malignant germ cell tumours can be carried out without affecting the pregnancy in the second two trimesters, espe- cially if alkylating agents are avoided. Other gynaecological cancers Other gynaecological cancers are rarely seen. Cancer of the endo- metrium is associated with infertility in the reproductive age group and cancer of the vulva is predominantly a disease of older women. Cancer of the breast Gestational breast cancer is defined as a breast cancer presenting ei- ther during pregnancy or up to one year postpartum. It was originally thought that pregnancy-​related cancer carried a worse prognosis, but this has not been substantiated. Although breast cancer is re- garded as a hormone-​dependent tumour, termination of pregnancy and oophorectomy do not provide a better outcome for the woman. Women becoming pregnant after treatment for breast cancer have a similar or better survival when controlled for age and stage. Breast cancer is often diagnosed at a late stage as breast lumps may be difficult to detect against a background of pregnancy-​related hypertrophy. Consequently, investigation of masses is often de- layed. Mammography is not harmful to the fetus with appropriate shielding. When a breast mass is found, the most important step is to make a histological diagnosis. If the diagnosis of breast cancer is made, treatment is the same as for the non​pregnant woman. Chemotherapy in the first trimester is associated with risks for the developing fetus but may be given after the first trimester and evi- dence supports treating with chemotherapy and continuing the pregnancy until term as the best option for the baby. Suppression of lactation as a therapeutic manoeuvre is not neces- sary, with two exceptions. Firstly, if breast surgery is required during the puerperium, suppression of lactation can decrease the size and vascularity of the breast and allow a safer surgical procedure. Secondly, suppression of lactation is recommended in women re- ceiving chemotherapy as some of the drugs can reach the breast milk and cause neonatal neutropenia. Cancer of the colon The reported incidence of colorectal cancer in pregnancy may now be an underestimate as a reflection of the trend for women to delay pregnancy until later in life. By contrast, with increased awareness of inherited genetic traits and the availability of genetic testing, more and more patients at risk (e.g. those with familial adenoma- tous polyposis and hereditary non​polyposis coli) are undergoing screening, which may reduce the numbers of pregnant women diag- nosed with colon cancer. Colorectal cancer in pregnancy is particularly common in the rectal region, below the peritoneal reflection. The importance of this is that 88% of tumours are within reach of the flexible sigmoido- scope, allowing detection with a minimum of inconvenience to the patient and no risk to the fetus. Presenting symptoms are similar to those in non​pregnant women. However, the combination of altered bowel habit, abdom- inal pain/​swelling, and anaemia is common in pregnancy, such that these symptoms are frequently ascribed to the pregnancy itself. Assessment of the pregnant patient with colorectal cancer is similar to that of the non​pregnant patient. Radiological imaging is avoided in the first trimester. Carcinoembryonic antigen is not affected sig- nificantly by pregnancy and so can be used as a marker. Patients younger than 40 years generally have a poorer prognosis because of delayed diagnosis and advanced stage at presentation. Pregnant women are no different in this respect. The overall fetal prognosis is relatively favourable as the diagnosis is usually made close to term and the fetus can be delivered coincident with the sur- gery for the colon cancer. Thyroid and other endocrine cancers It is not uncommon to find thyroid nodules that require further in- vestigation during pregnancy. Most cancers are well differentiated, with a very good prognosis. When a diagnosis is made, treatment proceeds as normal, with the exception that radio-​iodine is contra- indicated. Cancers discovered early in the pregnancy can be treated surgically in the second trimester. Tumours discovered in later preg- nancy can be investigated and treated after delivery. Thyroxine is given to reduce the level of thyroid-​stimulating hormone. There is no evidence to suggest that pregnancy alters the outcome for thy- roid cancer. Thyroid cancer is not an indication for termination of pregnancy. Phaeochromocytoma is rare in pregnancy but has been described. It is difficult to diagnose because elevation of blood pressure is al- most invariably attributed to pregnancy-​induced hypertension, which is very much more common. Lymphoma Hodgkin’s disease is a disease of young adults (mean age 32 years), hence it is not surprising that there are more cases diagnosed in

Section 14  Medical disorders in pregnancy 2700 pregnancy than there are of non-​Hodgkin’s lymphoma (mean age of diagnosis 42 years). Although it was historically believed to be exacerbated by preg- nancy, there does not seem to be any influence of pregnancy on the outcome for Hodgkin’s disease. If treatment is required, most patients can be managed without compromise to mother or fetus. Patients presenting with localized Hodgkin’s disease relatively late in pregnancy may be observed with limited staging and not treated until after delivery. By contrast, in non-​Hodgkin’s lymphoma, pa- tients with Burkitt’s lymphoma in pregnancy appear to have a highly aggressive disease involving the breast or ovary. A recent study of 39 cases (31 Hodgkin, 8 non-​Hodgkin) reported overall survival 82% and progression free survival 75% at five years. Leukaemia Leukaemia in pregnancy is rare. This may be because most cases of acute lymphoblastic leukaemia occur before reproductive age and most cases of acute myeloid leukaemia occur afterwards. Chronic lymphocytic leukaemia is a disease of older people, hence chronic myeloid leukaemia constitutes 90% of the cases of chronic leu- kaemia seen in pregnancy. Since the introduction of intensive chemotherapy, the survival of pregnant women with leukaemia is similar to that of non-​ pregnant women. It does not appear that intrauterine exposure to antileukaemic chemotherapy produces detrimental late effects on the resulting children. Women treated with non​alkylating agents have no apparent decrease in fertility, although this is reduced by one-​third when alkylating agents are used. FURTHER READING Amant F, et al. (2012). Breast cancer in pregnancy. Lancet, 379, 570–​9. Barnea ER, Jauniaux E, Schwartz PE (eds) (2001). Cancer and preg- nancy. Springer, London. Charing Cross Hospital Trophoblast Disease Service. Hydatidiform Mole and Choriocarcinoma UK Information and Support Service. http://​www.hmole-​chorio.org.uk Morice P, et al. (2012). Gynaecological cancers in pregnancy. Lancet, 379, 558–​69. Ngan S, Seckl MJ (2007). Gestational trophoblastic neoplasia manage- ment: an update. Curr Opin Oncol, 19, 486–​91. Royal College of Obstetricians and Gynaecologists (RCOG) (2011). Pregnancy and Breast Cancer (Green-​top Guideline No. 12). https://​www.rcog.org.uk/​globalassets/​documents/​guidelines/ ​gtg_​12.pdf Wright TC Jr, et al. (2007). 2006 consensus guidelines for the manage- ment of women with cervical intraepithelial neoplasia or adenocar- cinoma in situ. Am J Obstet Gynecol, 197, 340–​5.

14.19 Maternal critical care 2701

14.19 Maternal critical care 2701

ESSENTIALS Critical illness during pregnancy or after giving birth is rare: in the United Kingdom 0.29% of maternities involve admission to a critical care unit, and the maternal death rate is 0.01%. Over 80% of obstetric admissions to critical care occur in the post-​ partum phase, mainly due to complications of massive haemorrhage. Other pregnancy specific conditions that may require critical care support include pre-​eclampsia (typically when diagnosis and treat- ment have been delayed), amniotic fluid embolism, peri-​partum cardiomyopathy and acute fatty liver of pregnancy. Puerperal sepsis remains a major problem in resource-​poor parts of the world. Pregnant women who survive critical illness may be particularly prone to long-​term psychological morbidity. It is vital that, once physiological stability has been achieved, no time is wasted before a mother is reunited with her baby. Introduction When a pregnant woman or new mother requires admission to the critical care unit it is a cause of grave anxiety to all involved. Women and their partners usually envisage a normal labour and childbirth with minimal medical intervention. An admission to intensive care, with mechanical and pharmacological organ support, is an unwel- come departure from this agenda. For the medical teams involved, obstetric admissions to the critical care unit occur infrequently and it is difficult to accrue sufficient clinical experience in this area to feel at ease. A genuine commitment to multidisciplinary working is essen- tial to achieve the best outcome for mothers. Obstetricians and midwives who have only limited experience of the critical care en- vironment need to remain closely involved to advise on aspects of antenatal, intra-partum and postnatal care. Specialist physicians and surgeons from other disciplines may be required, and the crit- ical care physician must listen carefully to all these viewpoints and integrate them into a coherent treatment plan. Early warning scores with thresholds specifically modified for the obstetric population are now widely used in an effort to detect developing critical illness. Their utility is compromised by the ability of young fit women to compensate for deteriorating physiology until a point of catastrophic deterioration, and data on normal values may not reflect today’s obstetric population. Epidemiology Critical illness during pregnancy or after giving birth is rare. In the United Kingdom, 290/​100 000 maternities involve admission to a critical care unit (for comparison the maternal death rate is now 10/​100 000). A far higher number of women will become sick and require a period of enhanced care, single organ support, and close monitoring. The incidence of a short period of morbidity may be as high as 1200/​100 000 maternities. Over 80% of obstetric admissions to critical care occur in the post-​partum phase and complications relating to massive haemor- rhage are by far the commonest reasons for admission. By contrast, admission during the antenatal period is almost always as a result of a non​obstetric condition. Severe infections (particularly pneu- monia) predominate, but the full range of critical illness that occurs in women of reproductive age can present, and the pregnancy may be an incidental feature. Short lived antenatal problems are often managed on the labour ward by obstetricians and obstetric anaesthetists. This can be par- ticularly appropriate if giving birth is an important part of the man- agement of the condition (e.g. pre-​eclampsia or acute fatty liver of pregnancy). Critical care severity scores and models of predicted mortality overestimate the death rate in the maternity population. The critical care unit mortality for obstetric admissions is less than 2%. General issues in maternal critical care Location of care In an emergency situation, critical care support can be provided almost anywhere. Vital equipment and staff can be moved faster and more safely than an unstable patient. Obstetric complications can develop and resolve rapidly and may only require a brief period of organ support. In some units this can be provided within the 14.19 Maternal critical care Rupert Gauntlett

Section 14  Medical disorders in pregnancy 2702 labour ward; in others transfer to a critical care facility is more ap- propriate. Women should receive high quality care by healthcare professionals with the appropriate skills and experience to manage their problems, the exact location where this is provided, and the designation of the staff involved is of secondary importance. For women who require prolonged or advanced organ support, safe transfer to a critical care facility should be immediately avail- able. Pregnant women admitted to a critical care unit should be reviewed daily by an obstetrician. There must be a clearly docu- mented plan for monitoring the pregnancy and robust arrange- ments for emergency delivery. Pregnancy monitoring will vary according to gestational age and fetal viability but may include cardiotocography and serial ultrasound scans to assess growth and placental circulation. Monitoring Frequent or continuous monitoring of physiological parameters is a universal feature of higher levels of care. Arterial lines may be easier to place during pregnancy because of the hyperdynamic cir- culation, but central venous line insertion can be more difficult. It is unpleasant and potentially harmful to position a pregnant woman supine and head-​down. Tissue oedema can complicate both land- mark and ultrasound vessel location. Femoral vessels may be dif- ficult to access and maintain due to the gravid uterus. Pulmonary artery catheters are now rarely used in favour of less invasive cardiac output monitoring techniques (such as arterial pulse contour ana- lysis). Experiences of using a variety of cardiac output monitoring devices on pregnant women have been reported. Point of care echo- cardiography for assessment of volume status and myocardial func- tion is becoming routine in critical care, but lack of familiarity with normal echo findings in pregnancy can complicate the interpret- ation of images. Respiratory support The growing uterus has a visible mechanical effect on respiratory function. A fall in functional residual capacity as pregnancy pro- gresses causes rapid hypoxaemia during induction of anaesthesia, particularly if there is a delay to intubation or intercurrent respira- tory disease. High-​flow nasal cannulae and other forms of non​invasive venti- latory support can be used in pregnancy when they are indicated. Gastric distension in a woman who is already suffering from re- flux as a result of increased intra-​abdominal pressure and reduced sphincter tone associated with progesterone can be a significant problem. Intubation of obstetric patients is associated with a high risk of failure. No mode of mechanical ventilation has been demonstrated to be superior in providing respiratory support. When blood gases are used to assess the adequacy of gas exchange the physiological respiratory alkalosis of pregnancy and normal values of pCO2 must be considered. Circulatory support The cardiovascular changes in pregnancy occur very early in gesta- tion, with increase in cardiac output and decrease in systemic vas- cular resistance occurring before 14 weeks. These changes must be kept in mind when assessing a woman in shock. There are no preg- nancy specific data to inform the choice of vasopressors or inotropes. The effect on the fetal circulation of high dose or potent vasopressors cannot be beneficial. Acute renal replacement therapy in pregnancy Renal function (including glomerular filtration rate and creatinine clearance) is upregulated from early pregnancy. Assessment for acute kidney injury must be made against expected pregnancy values of creatinine, or else the early stages of renal dysfunction may be over- looked. Severe acute kidney injury is rare in the obstetric patient. Vascular access for dialysis/​haemofiltration is usually by the sub- clavian or internal jugular veins. The femoral veins may be difficult to access, and vascular catheters may be kinked or compressed by a pregnant abdomen. There are no specific recommendations about the mode of renal replacement therapy used in pregnancy, but ex- perience from managing chronic dialysis patients in pregnancy sug- gests that the dose should be increased to mimic rates of clearance expected in pregnancy. Decision to deliver in antenatal critical illness The decision on whether to end a pregnancy (by planned birth or termination) in order to improve the chance of maternal survival is a clinical and ethical dilemma. There is conflicting clinical practice and outcome data for mothers and infants are often incomplete or inconsistent. Miscarriage is common in antenatal patients who be- come critically ill in early pregnancy, and it is hard to imagine that utero-​placental function in a critically sick mother at any stage of pregnancy remains conducive to normal fetal development and growth. By contrast, the risks of premature birth are well quantified. A managed birth is usually less traumatic than a precipitous labour and unanticipated birth on a critical care unit. Criteria that have been suggested for ending the pregnancy are included in Table 14.19.1. Recent experience of managing women with severe H1N1 infection (including those who received extracorporeal membrane oxygen- ation) guides against delivering the woman, but follow-​up studies of childhood growth and development are not available. Psychological sequelae and breastfeeding There is growing awareness of the long-​term psychological mor- bidity among survivors of critical illness. Anecdotal evidence suggests that pregnant women may be particularly prone to these problems, perhaps because of the gap between expectation and reality in their maternity experience or linked to a sense of missing out on the baby’s first hours or days of life. It is vital that, once physiological stability has been achieved, no time is wasted before a mother is reunited with her baby. Table 14.19.1  When to offer planned childbirth to a critically sick woman Obstetric conditions which improve after the pregnancy has ended (severe pre-​eclampsia, AFLP) Inadequate gas exchange/​severe respiratory compromise Severe bacterial sepsis Rapidly deteriorating maternal condition despite organ support/​treatment Multiorgan failure Fetal compromise AFLP, acute fatty liver of pregnancy.

14.19  Maternal critical care 2703 Women who have suffered a period of critical illness should not be denied the chance to breast feed. Milk can be expressed manu- ally or by breast pumps, and a review of maternal medication (in conjunction with advice from a neonatologist) can inform a deci- sion about whether breast milk can be given to the baby or should be discarded. Pregnancy specific conditions Obstetric major haemorrhage Complications arising from major haemorrhage and massive trans- fusion are the most common reasons for a woman to be admitted to intensive care around the time of childbirth. The common causes of severe obstetric bleeding are listed in Table 14.19.2. The blood supply to the uterus and placenta at term is usually estimated to be over 500 ml per minute, and the remainder of the genital tract is well vascularized and can contribute to rapid blood loss. The initial management of bleeding is in the domain of the obstetrician and obstetric anaesthetist. They must work together to control the blood loss by a combination of surgical and pharmacological techniques. In some centres interventional radiology may also be involved. It is important to utilize blood products early (rather than large volumes of clear intravenous fluids) in a major bleed. In addition to red cell replacement the use of other clotting products is vital to promote haemostasis. Pregnancy is a hypercoagulable state with up regulation of fibrinogen and most clotting factors. A low fibrinogen level heralds major obstetric haemorrhage and the early replace- ment of fibrinogen (with cryoprecipitate or fibrinogen concentrates) is increasingly recommended. Fresh frozen plasma has low levels of fibrinogen and administration of large volumes of fresh frozen plasma before fibrinogen replacement may be unhelpful. Platelet transfusion may also be indicated. Near patient tests of coagula- tion (e.g. thromboelastography), can be used to guide transfusion. Haemodilution, hypothermia, and acidaemia must be avoided or reversed as they can impede clot formation and stability. In the setting of a major bleed, most women will have been anaes- thetised and ventilated. At the end of a definitive surgical procedure, even if the clinicians are confident about haemorrhage control, a period of stabilization and observation may be indicated. Rapid blood loss and massive transfusion are a major physiological insult and there may be legitimate concern about immediate waking and extubation. The priorities in critical care management following ob- stetric major haemorrhage are • Careful review of the total quantities of blood products and fluid administered against the estimated blood loss • Administration of additional blood, clotting products, or antifibrinolytic agents as indicated by the post-​haemorrhage full blood count and coagulation screen • Measurement and replacement of critical electrolytes including calcium • Temperature monitoring with active warming if indicated • Close monitoring for signs of further haemorrhage or haemostatic complications • On-​going management of specific surgical and radiological inter- vention (e.g. removal of balloons or vascular catheter sheaths) • Monitoring for the complications of massive transfusion including transfusion related acute lung injury • Provision of adequate analgesia • Thromboprophylaxis should be prescribed as early as practic- able. A rebound hypercoagulable state has been described in the recovery phase of massive obstetric haemorrhage and low mo- lecular weight heparin should be administered soon after control of haemorrhage has been achieved Admission to the intensive care unit (ICU) after major blood loss is often brief and straightforward. Once stability has been achieved and organ function restored, a high priority should be given to waking, weaning, and extubation. An early return to the labour ward and as much participation as possible in the care of a newborn infant is a powerful motivator toward recovery. Complications of pre-​eclampsia The range of hypertensive disease encountered in pregnancy is de- scribed in Chapters 14.4 and 14.5. Almost all pre-​eclampsia is man- aged by obstetricians using practice guidelines and evidence-​based recommendations. Key principles include aggressive control of hyper- tension, fluid restriction to avoid pulmonary oedema, magnesium sul- phate to prevent eclampsia and early induction of labour or caesarean section. When these principles are followed, very few women pro- gress to serious complications of pre-​eclampsia. Admission to critical care more frequently involves women whose diagnosis and treatment has been delayed, or who present with fulminant disease or a serious complication. Complications of severe pre-​eclampsia that necessitate critical care admission are listed in Table 14.19.3. The central import- ance of bringing the pregnancy to an end in the management of severe pre-​eclampsia mandates that women are often cared for on the labour ward rather than on a critical care unit. Invasive blood pressure monitoring is indicated if women re- quire continuous infusions (or frequent intravenous boluses) of antihypertensive agents. Titration of vasoactive agents should be aimed at achieving consistent systolic blood pressure of less than 150 mm Hg and diastolic pressures of 80–​100 mm Hg. Intravenous drugs used by infusion in the management of severe pre-​eclampsia in- clude labetalol, hydralazine, nicardipine, and sodium nitroprusside. When a woman is admitted to the critical care unit with a severe complication of pre-​eclampsia it is important that a firm focus on the underlying management strategies (strict blood pressure control, cau- tious fluid balance and use of magnesium sulphate) are continued. Ignorance of the blood pressure treatment targets for pre-​eclampsia or insufficient appreciation of the susceptibility of the lung to pulmonary oedema must not be overlooked. Fluid management decisions in pre-​ eclampsia can be difficult. Central venous pressure does not predict fluid responsiveness or volume dependent pulmonary oedema. Post-​partum pre-​eclampsia, particularly where symptoms worsen in the period 24–​48 hours after childbirth, is associated with a higher risk of severe complications. Table 14.19.2  Common causes of obstetric major haemorrhage Antepartum Postpartum Placental abruption Atonic uterus Placenta previa Retained placenta Ruptured uterus Trauma to the genital tract

Section 14  Medical disorders in pregnancy 2704 Maternal susceptibility to neurological complications (including intracerebral bleeding, posterior reversible encephalopathy syn- drome and hypertensive encephalopathy) is believed to be higher in pregnancy than at the same levels of hypertension in the non​pregnant state. Amniotic fluid embolism Amniotic fluid embolism is a rare, poorly understood condition that is characterized by the abrupt development of shock during labour or after childbirth, which cannot be explained by other pathologies. There are several associations (e.g. rapid labour and cervical lacer- ations), but the precise aetiology remains unclear. The clinical picture usually consists of maternal collapse with hypotension, hypoxaemia, and severe coagulopathy. The term anaphylactoid syndrome of pregnancy has been used to explain some features of the condition; others prefer the name sudden obstetric collapse syndrome. There are no specific therapies for amniotic fluid embolism and management depends on the rapid initiation of organ support. Intubation with positive pressure ventilation and circulatory support with fluids and vasopressors can be lifesaving. Severe coagulopathy is a near universal feature of the condition and should be treated with rapid blood product infusion. Case reports in the literature de- scribe the use of extracorporeal membrane oxygenation, mechanical assist devices for the right ventricle, and nitric oxide in the successful management of women with the condition. Peri-​partum cardiomyopathy This condition is described in Chapter 14.6. Critical care therapy is similar to other causes of severe cardiac failure. Arrhythmias are more common than in other causes of heart failure and thromboprophylaxis is important. Critical care support in the most severe cases has included the use of ventricular assist devices, aortic balloon pumps, and cardiac transplantation. Acute fatty liver of pregnancy This condition is described in Chapter 14.9. Critical care will be re- quired if a woman develops fulminant hepatic failure or encephal- opathy. Ending the pregnancy is curative but can be complicated by haemorrhage as a result of coagulopathy. A very few women reach a level of disease severity where transplantation is indicated. The criteria for liver transplant are the same as for other causes of acute liver failure. Other specific conditions requiring critical care in pregnancy Cardiac arrest in pregnancy International guidelines describe the recommended management of cardiac arrest, with two important additions for the special circum- stance of a cardiac arrest during pregnancy. • Manual displacement of the uterus • Peri-​mortem caesarean section Compression of the vena cava, reducing venous return, is a well described feature of late pregnancy and it is vital that resuscitation efforts are not compromised by this effect. The preferred technique to avoid this complication is manual displacement of the uterus. The use of a steep left lateral tilt during resuscitation may reduce the quality of cardiac compressions. A plan to empty the uterus by peri-mortem caesarean section (also known as a resuscitative hysterotomy) must be enacted as soon as cardiac arrest is diagnosed. Resuscitation guidelines suggest a target of knife to skin at four minutes and extraction of the fetus within five minutes of maternal cardiac arrest. The recommendation to empty the uterus is not to salvage the fetus but to enhance resus- citation of the mother. Peri-​mortem caesarean section is generally recommended in women who are more than 20 weeks’ gestation. A check-​list of potentially treatable causes of maternal car- diac arrest has been promoted by the American heart association (Table 14.19.4). Severe sepsis in pregnancy Puerperal sepsis remains a major cause of maternal mortality around the world. In countries with well-​resourced healthcare systems the incidence of severe maternal sepsis is lower, but still occurs with a prevalence of at least 45 per 100 000 maternities. Infection rates may also be influenced by the community prevalence of streptococcal in- fection, patterns of antibiotic usage and outbreaks of influenza. Table 14.19.3  Complications of pre-​eclampsia leading to critical care admission Neurological Intracerebral bleeding Ischaemic stroke Cerebral oedema Posterior reversible encephalopathy syndrome Recurrent seizures Respiratory Pulmonary oedema Adult respiratory distress syndrome Cardiac Left ventricular failure Renal Acute kidney injury caused by cortical or tubular necrosis Hyperkalaemia Severe oliguria Abdominal Liver capsular rupture Hepatic infarction Massive blood loss secondary to low platelets (HELLP)
or disseminated intravascular coagulation Intractable hypertension requiring prolonged intravenous agents Table 14.19.4  Causes of cardiac arrest in pregnancy (American Heart Association) BEAU-​CHOPS Bleeding/​DIC Embolism—​pulmonary, amniotic fluid, coronary Anaesthesia complications—​including local anaesthetic toxicity Uterine atony Cardiac disease—​myocardial infarction, cardiomyopathy, coronary or aortic dissection Hypertension—​eclampsia or other complications Other unusual differentials Placental abruption/​previa Sepsis DIC, disseminated intravascular coagulation.

14.19  Maternal critical care 2705 The susceptibility to a variety of infections and the severity of the illness produced is due in part to the modulation of the immune system that occurs during pregnancy. Physical changes in pregnancy also predispose women to some infections. Stasis and decreased ureteric sphincter tone cause increased susceptibility to ascending urinary tract infection. Chemical changes and physical damage to the mucosa of the genital tract may also compromise the barrier to infection. In identified bacterial infection two organisms are particularly important. Group A streptococcus, which has a high attack rate during pregnancy, and E.  coli infections of the urogenital tract. Pregnant women are more susceptible to influenza and its compli- cations at all stages of pregnancy. Early detection of sepsis can be a particular problem during la- bour when mild degrees of pyrexia and a leucocytosis are normal. Clinical trials in sepsis almost always exclude pregnant women, but general sepsis care recommendations are still applied to maternity cases. Management priorities are: • High clinical suspicion and early identification using obstetric specific early warning systems • Measurement of serum lactate, blood culture, and early adminis- tration of appropriate antibiotics in a sepsis care bundle • Source control (this may need to include evacuation of the uterus) • Low threshold to end the pregnancy when sepsis has progressed to multiorgan failure FURTHER READING American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—​Obstetrics (2016). Practice bulletin No. 170: Critical care in pregnancy. Obstet Gynecol, 128(4), e147–​54. Gauntlett R on behalf of the MBRRACE-​UK critical care chapter-​ writing group (2016). Messages for critical care. In: Knight M, Nour M, Tuffnell D, Kenyon S, Shakespear J, Brocklehurst P, Kurinczuk JJ (eds.) on behalf of MBRRACE-​UK. Saving lives, improving mothers’ care—​surveillance of maternal deaths in the UK 2012–​2014 and lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–​2014, pp. 83–​95. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Honiden S, Abdel-​Razeq S, Siegel, MD (2013). The management of the critically ill obstetric patient. J Intensive Care Med, 28, 93–​106. Neligan PJ, Laffey JG (2011). Clinical review: special populations—​ critical illness and pregnancy. Crit Care, 15, 227.

14.2 Nutrition in pregnancy 2568

14.2 Nutrition in pregnancy 2568

ESSENTIALS Nutritional requirements for healthy pregnancy vary according to a woman’s pre-​pregnancy nutritional state and her access to food during pregnancy: there is no unifying nutritional advice that is appro- priate for all pregnant women throughout the world, or even within nations. The well-​nourished mother—​does not need to ‘eat for two’ during pregnancy. Gestational metabolic adaptations allow a pregnant woman to provide energy for fetal and maternal development while making few dietary changes. Supplemental folic acid (400 µg–​1 mg/​ day) from peri-​conception until the end of the first trimester re- duces the risk of neural tube and congenital heart defects. No other extra vitamins or micronutrients are necessary for healthy pregnant women who eat a balanced diet. Excessive vitamins and micronu- trients can be harmful to mother and fetus. The undernourished mother—​needs a balanced diet that is sup- plemented with (1) vitamins, including folic acid and vitamin D, and (2) micronutrients, including iron and zinc to ensure that the fetus fulfils its growth potential. Protein and energy supplements to undernour- ished women of small stature and pelvis size improve fetal growth, but can lead to obstructed labour, a significant cause of maternal and perinatal death in low-​income and middle-​income countries. Around the world, obesity and excessive gestational weight gain are now more common risk factors for pregnancy complications than undernutrition. Compared with mothers who have a normal body mass index (18.5–​24.9  kg/​m2), obese mothers have an in- creased risk of gestational diabetes, pre-​eclampsia, caesarean de- livery, stillbirth, congenital malformations and large for gestational age babies. Underweight mothers have an increased risk of small for gestational age babies, and preterm birth. Paternal obesity has a negative effect on fetal growth, probably mediated by inheritance of insulin resistance. Both low birth weight and high birth weight babies have an increased risk of obesity in later life. Introduction There is no unifying nutritional advice that is appropriate for all pregnant women throughout the world, or even within nations. Nutritional advice must take account of maternal body size, lifestyle, and availability of food. In high resource nations where food is gen- erally plentiful and obesity prevalent, dietary recommendations for a healthy pregnancy are targeted to reduce excessive weight gain and associated pregnancy complications. By contrast, in nations where food is scarce, undernourishment compromises maternal adaptation to pregnancy and leads to suboptimal fetal growth and development. Micronutrients and vitamin supplements are given with good ef- fect to chronically undernourished pregnant women, but with few exceptions are unnecessary and can be harmful to well-​nourished pregnant women. The ability of pregnant women to adapt to different environ- mental and nutritional conditions is a key requirement for repro- ductive success. Gestational metabolic adaptations minimize extra nutritional requirements and optimize fetal growth. However, millions of pregnant women are unable to provide enough nu- trition for their fetus to thrive despite these adaptations. Poor prenatal nutrition not only affects perinatal outcome, but also dictates susceptibility to adult diseases and even the health of the next generation. Maternal overweight and obesity Since the early 1970s in the United States, the prevalence of obesity (BMI >30  kg/​m2) among all women aged 20–​39  years has increased from less than 10% to more than 35% and is par- ticularly prevalent among non-​Hispanic black women, affecting more than 55%. A similar picture is seen in the United Kingdom and to varying degrees across Europe (Fig. 14.2.1). Even in low-​ income and middle-​income countries (LMICs), overweight/​ obesity is now more prevalent than underweight. In the Americas and Caribbean, Oceania, and Europe, between 50% and 75% of all women of reproductive age are either overweight (BMI >25 kg/​m2) or obese. Maternal obesity is associated with an increased risk of gestational diabetes and pre-​eclampsia. During labour obese women are at in- creased risk of maternal death, haemorrhage, infection, and cae- sarean delivery. Their offspring are at greater risk of macrosomia, birth trauma, neonatal, and infant death compared with women of normal body mass index. 14.2 Nutrition in pregnancy David J. Williams

14.2  Nutrition in pregnancy 2569 Postpartum, obese mothers have greater difficulty with breast- feeding and are predisposed to postpartum weight retention. Women who had gestational diabetes are predisposed to future type-​2 diabetes, and those who had pre-​eclampsia are predisposed to future cardiovascular disease. The children of overweight and obese mothers are themselves pre- disposed to obesity in later life. It is therefore important for mothers to understand nutritional energy requirements before and during pregnancy to diminish the risk of transmitting obesity between generations. Maternal undernutrition Over the last 20 years in LMICs, maternal undernutrition has de- clined, such that now approximately 10% of women have a BMI less than 18.5 kg/​m2 in Asia and Africa. Maternal undernutrition be- fore and during pregnancy contributes to fetal growth restriction. Low birth weight babies are at risk of perinatal and early childhood morbidity and mortality, with longer-​term stunting of growth and development. Maternal and child undernutrition is the underlying cause of 3.5 million deaths around the world each year, mainly of chil- dren. Ninety per cent of the world’s undernourished children live in just 34 countries, mainly in sub-​Saharan Africa, and south-​ central and Southeastern Asia (Fig. 14.2.2). Chronically under- nourished women are often of short stature, which increases their risk of an operative delivery due to cephalopelvic disproportion, and perioperative comorbidity is high even if caesarean section is available. In these low-​income countries, 16% of babies are of low birth weight (<2500 g), of which more than two-​thirds are due to fetal growth restriction and less than one-​third are due to prematurity. In comparison, in high-​income nations only 5% of babies are of low birth weight, of which most (55%) are premature. Low birth weight increases an individual’s risk of morbidity and mortality during all phases of life: neonatal, childhood, and adult. Weight gain in pregnancy During pregnancy, well-​nourished mothers with free access to food gain up to 30% of their pre-​pregnancy weight, of which only 25% is fetal. By contrast, mothers with limited access to food gain as little as 10% of their pre-​pregnancy weight, of which up to 60% is fetal. Excessive and insufficient gestational weight gain is associated with an increased risk of adverse pregnancy outcome. In 2009, the National Academy of Medicine in the United States refined earlier guidelines for weight gain in pregnancy, adjusted according to pre-​pregnancy maternal weight (Table 14.2.1). A subsequent review and meta-​analysis of 1.3 million pregnant women found that almost 50% had gestational weight gain greater than these recommendations, and 23% had less. Gestational weight gain above recommendations is associated with an increased risk of large for gestational age and macrosomic offspring, preterm birth, caesarean section, gestational diabetes mellitus, pre-​eclampsia, United Kingdom* Ireland* Spain* Hungary* Portugal* Austria* Greece* Italy* Germany BE: Wallonia Malta Denmark France Slovenia Poland 0.0 5.0 10.0 15.0 20.0 25.0 30.0 BE: Brussels Switzerland* Finland Norway BE: Flanders Sweden Netherlands* UK: Scotland Fig. 14.2.1  Distribution of maternal obesity (percentage of women delivering live or stillbirths with
pre-​pregnancy BMI ≥ 30 kg/​m2) from the Euro-​Peristat database and the World Health Organization (WHO). Reprinted from Devlieger R et al. (2016) Maternal obesity in Europe: where do we stand and how to move forward? A scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG). European Journal of Obstetrics & Gynecology and Reproductive Biology, 201: 203–20​8. Copyright © 2016, with permission from Elsevier. *From WHO database (2009) (globally higher rates due to general female population aged 20 or older). Source: http://​www.europeristat.com/​our-​indicators/​euro-​peristat-​perinatal-​health-​indicators-​2010.html.

Section 14  Medical disorders in pregnancy 2570 Fig. 14.2.2  Thirty-​four countries that account for 90% of the global burden of malnutrition and 90% of children with stunted growth. Reprinted from Bhutta ZA et al. Lancet, 2013; 382: 452–​77. Copyright © 2013, with permission from Elsevier.

14.2  Nutrition in pregnancy 2571 and postpartum weight retention. Women who retain weight after their first pregnancy have an increased risk of all these complications in a subsequent pregnancy. Furthermore, obesity during pregnancy fuels obesity in the next generation: about one-​ third of infants of obese mothers are in the ninetieth centile for their age, and a child of an overweight mother is three times more likely to be overweight by age seven years. Gestational weight gain below the National Academy of Medicine recommenda- tions increases the risk of small for gestational age offspring and preterm birth. Energy requirements during pregnancy The rate of human fetal growth is slow, and the daily incremental en- ergy stress of human pregnancy is relatively low compared with that in other species (Fig. 14.2.3). This allows a mother time to adapt her metabolism and energy expenditure to diverse nutritional condi- tions and the fetus to develop a complex brain. Energy requirements increase gradually as pregnancy progresses. In the first trimester an estimated 375 kJ (90 kcal)/​day is required, in the second trimester 1200 kJ (287 kcal)/​day, and in the third 1950 kJ (466 kcal)/​day. The total energy cost of pregnancy for a woman with a mean weight gain of 12 kg is 325 MJ (77 000 kcal). Energy requirements during lacta- tion are similar to those of the third trimester. The three major components of energy expenditure in an average well-​nourished pregnant woman are growth of the fetus and re- productive tissues (c.18%), new maternal fat stores (c.38%), and increased maternal metabolism (c.44%). Poorly nourished women try to maintain fetal growth by depressing their basal metabolic rate until late pregnancy and by laying down less fat. Although such adaptations usually result in successful reproduction, they are inev- itably a compromise with regards to perinatal health. However, at- tempts to quantify minimal energy requirements for good perinatal health will always be confounded by huge individual variability and the practical difficulties of attributing a single nutritional compo- nent to morbidity, which is a multifaceted problem. Well-​nourished women increase their basal metabolic rate most rapidly after 16 weeks’ gestation until term. During the middle trimester large amounts of maternal fat are laid down as energy stores, although women with the highest cumulative rise in basal metabolic rate lay down the least fat. If food intake becomes limited during late pregnancy, maternal fat can be mobilized to support the period of most rapid fetal growth. A similar strategy of fat storage before anticipated energy expenditure is used by birds before they migrate and by mammals before they hibernate. Well-​ nourished women with free access to food rarely need to utilize all their fat stores to support late fetal growth, and excess fat remains difficult to lose postpartum. Even poorly nourished women with low gestational weight gain lay down some extra fat, but they also suppress their basal metabolic rate until late in pregnancy in order to support fetal growth. Maternal energy intake during pregnancy actually increases by little more than 25% of that required to fulfil energy needs. It is likely that some of the estimated shortfall is due to under-​reporting 600 500 400 300 Energy cost (MJ) 200 100 0 Sweden England Netherlands Netherlands Scotland India, middle and upper class women Thailand Philippines The Gambia The Gambia, supplemented The Gambia, unsupplemented −100 Conceptus Fat deposition Maintenance Fig. 14.2.3  Estimated total energy costs of pregnancy in different nutritional environments. The ‘supplemented’ women from the Gambia were given a balanced protein–​energy diet. Reproduced from Prentice AM, Goldberg GR (2000). Energy adaptations in human pregnancy: limits and long-​ term consequences. Am J Clin Nutr, 71 Suppl, 1226–​32S, with permission from Oxford University Press. Table 14.2.1  Guidelines for gestational weight gain (recommendations of the National Academy of Medicine,
United States, 2009) Maternal
pre-​pregnancy
BMI (kg/​m2) Recommended weight gain at term (kg) Rate of weight gain in
second and third trimester, mean (range) kg/​wk Underweight (<18.5) 12.5–​18 0.51 (0.44–​0.58) Normal weight (18.5–​24.9) 11.5–​16 0.42 (0.35–​0.50) Overweight (25.0–​29.9) 7–​11 0.28 (0.23–​0.33) Obese (>30.0) 5–​9 0.22 (0.17–​0.27) BMI, body mass index.

Section 14  Medical disorders in pregnancy 2572 of nutritional intake and some due to an economy of energy ex- penditure, including reduced physical activity and diet-​induced thermogenesis. Metabolic changes in pregnancy Carbohydrate and fat metabolism during pregnancy During the first half of pregnancy women produce more insulin in response to a glucose load and are more sensitive to exogenous in- sulin than in the non​pregnant state. These changes affect carbohydrate and lipid metabolism to favour increased fat production and storage. During the second half of pregnancy a woman becomes resistant to insulin, so that at term the action of a particular circulating concen- tration of insulin is up to 70% lower than in the non​gravid state. As a consequence, the fat stores laid down in the first half of pregnancy are mobilized and postprandial blood glucose levels remain higher for longer. Circulating levels of fatty acids and glycerol increase and are used in the maternal liver to generate energy in preference to glucose and amino acids, which are left for the fetus and placenta. Therefore, fasting pregnant women produce ketones from fatty acid oxidation far earlier than they do when not pregnant. Women with a defect in fatty acid oxidation and who fast during pregnancy have limited ketogenesis and are vulnerable to multiorgan energy failure, including ‘acute fatty liver’ and hypoglycaemia. Other pregnant women with an exaggerated peripheral resistance to insulin are at risk of gestational diabetes mellitus. Protein metabolism Pregnancy is an anabolic state. Protein and nitrogen metabolism adapt early and gradually throughout healthy pregnancy to provide for tissue growth. Well-​nourished women are estimated to accumu- late an extra 500 g to 1 kg of protein during pregnancy, almost half of which is maternal lean body mass, while the rest lies within the fetus and reproductive tissues. In the United Kingdom the advised increment of dietary protein has been calculated to increase gradually throughout pregnancy to 8.5 g/​day at term, but this does not consider reduced hepatic metab- olism of branched chain amino acids and hence reduced urea syn- thesis. The rate of urea synthesis declines by 30% during the first trimester and by 45% during the third trimester, providing more nitrogen for protein synthesis. Consequently, maternal serum urea concentration continues to fall in the third trimester, despite a fall in glomerular filtration rate that raises the serum creatinine levels. Vitamins and micronutrients In many parts of the developing world, micronutrient deficiencies are endemic and have serious consequences for fetal, neonatal, and maternal well-​being (e.g. hypothyroidism due to iodine deficiency and night blindness due to vitamin A deficiency). Such deficiencies are rare in developed countries. Calculated increments in the recommended daily allowance of specific nutrients are derived from estimates of the cost of fetal growth and increased maternal metabolism. However, these calcula- tions do not usually take account of maternal metabolic adaptations aimed to minimize the need for extra nutrients. For example, intes- tinal absorption of calcium increases in well-​nourished women and the need for an increase in dietary calcium diminishes. Conversely, increased folic acid excretion leads to an underestimate of folic acid requirements. Furthermore, individual micronutrients interact with each other and changes to one may have a detrimental effect on the activity of another. Folic acid Supplemental folic acid (400 µg to 1.0 mg/​day) or folic acid food for- tification during the first trimester reduces the risk of fetal neural tube defects (NTD) and congenital heart defects (CHD). Women who have previously had a pregnancy affected by NTD or CHD, or who smoke, are obese, diabetic, or who take antifolate medica- tion should take a higher dose of folic acid, up to 5 mg folic acid daily. With this exception, extra vitamins and micronutrients are not necessary for well-​nourished, healthy pregnant women who eat a balanced diet. Indeed, excessive amounts of certain micronutrients can be harmful to the fetus. The situation is quite different for under- nourished women in LMICs. Iron During pregnancy, expansion in plasma volume exceeds the in- crease in red cell mass, causing a fall in haemoglobin concentration. Healthy pregnant women not taking iron supplements drop their haemoglobin from 133 g/​litre to 110 g/​litre by 36 weeks’ gestation. The minimum incidence of low birth weight (<2500 g at term) and preterm labour is associated with maternal haemoglobin in the range 95–​105 g/​litre, which in the non​gravid state would indicate an- aemia. A meta-​analysis of randomized controlled trials examining the benefit of supplemental iron found a significant reduction in the proportion of women with haemoglobin levels less than 100 g/​litre, but no effect—​beneficial or harmful—​on maternal or fetal outcome. In otherwise well-​nourished women in the United Kingdom, rou- tine supplemental iron is not recommended. Anaemia of multiple causes is endemic in many LMICs, and the risk of maternal death is increased with severe anaemia (haemo- globin <70 g/​litre), a condition where supplemental iron is unlikely to have much effect. However, in such countries mild to moderate anaemia can be prevented with iron (60 mg daily) and folate sup- plementation, which improve birth weight without increasing the maternal risk of Plasmodium infection. Many LMICs therefore ad- vocate a policy of iron and folic acid supplementation for all preg- nant women. More studies are necessary to monitor the effects of this policy on maternal and perinatal outcome. Anaemia in preg- nancy is discussed in more detail in Chapter 14.17. Vitamin A Vitamin A is a lipid-​soluble vitamin essential for healthy embryogen- esis and fetal growth. Preformed vitamin A is found in dairy prod- ucts and liver. Vitamin A deficiency is endemic in some parts of the world and associated with night blindness. In these circumstances, maternal vitamin A supplements may result in a small increase in birth weight. However, excessive doses of vitamin A (>15 000 IU/​day or 5000 mcg/​day) are teratogenic, and drugs that are derived from vitamin A, such as the retinoids, are associated with an estimated 25-​fold increased risk of fetal malformation. The National Institute for Health and Care Excellence (NICE) in the United Kingdom re- commends up to 700 mcg vitamin A daily to preserve health and re- duce the risk of teratogenesis. In general, vitamin A supplements are

14.2  Nutrition in pregnancy 2573 unnecessary for well-​nourished women, potentially harmful to the fetus, and of unproven benefit to safely improve fetal growth. Breast milk is rich in vitamin A and is important for neonatal immunity. Thiamine (vitamin B1) Thiamine deficiency is endemic in some developing countries but is also a global problem in women with hyperemesis gravidarum. Severe and persistent vomiting during pregnancy leads to thiamine deficiency and rarely causes Wernicke’s encephalopathy, hence thia- mine replacement is recommended for women with this condition. Vitamins C and E Serum vitamin C levels fall by about 50% during pregnancy, hence it was previously recommended that this was supplemented. Furthermore, the antioxidant properties of vitamins C and E were thought to reduce the risk of pre-​eclampsia, but this is not the case. Indeed, at high doses (vitamin C 1 g/​day and vitamin E 400 IU/​day) these vitamins increase the risk of babies being born with a low birth weight and their supplementation is not justified in pregnancy. Calcium and vitamin D The growing fetus gains about 50 mg calcium per day by mid preg- nancy and about 300 mg/​day at term, and the breastfed infant receives about 250 mg of calcium in breast milk each day. The re- commended daily allowance of calcium during pregnancy and lacta- tion is 1.2 g/​day, but women with much less dietary calcium undergo metabolic adaptations to meet the demands of pregnancy and lacta- tion without any detriment to their health or that of the fetus. During pregnancy, maternal calcium absorption increases two- fold, stimulated by increased 1,25-​dihydroxyvitamin D (calcitriol) activity due to placental synthesis and increased renal 1α-​ hydroxylase activity. Although urinary calcium excretion doubles during pregnancy, fasting urinary calcium excretion, corrected for increased creatinine clearance is unchanged. The concentration of parathyroid hormone falls during pregnancy, suggesting that the pregnant woman receives enough calcium for her growing fetus. There are two caveats: one is the pregnant adolescent who needs to meet the demands of her own bone growth as well as that of the fetus; the other is the benefit of supplemental calcium for women on a low-​calcium diet to prevent pre-​eclampsia. Following delivery, circulating calcitriol concentrations return to non​pregnant levels. During the first six months of breastfeeding mineralization of the maternal axial skeleton declines by about 3–​ 5%, recovering after six months whether or not breastfeeding con- tinues. Calcium supplements of 1 g/​day given to lactating women do not prevent bone demineralization or improve the calcium concen- tration of breast milk, even if the woman is on a low-​calcium diet. Furthermore, repeated long periods of breastfeeding in women with a low calcium intake do not contribute to osteoporosis in later life. Vitamin D deficiency is prevalent around the world, but is par- ticularly common among women who are obese, dark-​skinned, avoid sun exposure, and who have a sedentary lifestyle. However, there is little consensus among international organizations on the recommended plasma level of 25(OH)vitamin D levels for a healthy pregnancy outcome, these ranging between over 30 to more than 75 nmol/​litre. Similarly, the recommended dose of vitamin D sup- plementation for women with vitamin D deficiency ranges between 200 to 2000 IU daily. These wide ranges reflect a lack of good quality clinical trial data. We still need to define harmful vitamin D defi- ciency in pregnancy and what dose and dose-​frequency of vitamin D supplementation (if any) can safely and effectively correct it. Polyunsaturated fatty acids Maternal consumption of supplements containing n–​3 long-​ chain polyunsaturated fatty acid may reduce the risk of preterm birth (<34 weeks) and childhood allergy but have no proven benefit on neurocognitive and retinal development in the fetus. Supplementation with more than 200 mg of docosahexaenoic acid per day, which can be achieved with the consumption of one or two portions of sea fish per week, may protect against preterm birth. Limiting fish intake to smaller oily fish such as herring, mackerel, and salmon will diminish the overstated concern that large predator fish contaminated by neurotoxic levels of methylmercury might be harmful to the fetus. Iodine Almost two billion people have at least mild iodine deficiency from living in iodine-​deficient areas. Inadequate dietary iodine leads to maternal hypothyroidism, which in turn is detrimental to fetal growth and development. Supplemental iodine, which is added to salt in most developed countries, can prevent these consequences. Zinc Zinc deficiency is associated with intrauterine growth restriction and teratogenesis. Maternal zinc levels remain stable during preg- nancy through increased intestinal absorption. Excess iron supple- ments, smoking, alcohol abuse, or subsistence cereal diets high in phytate can all inhibit zinc absorption. Under such conditions, preg- nant women may benefit from 25 mg zinc daily. Other dietary matters Foods to avoid during pregnancy Acute maternal infection with Toxoplasma gondii can cross the pla- centa to the fetus. Congenital infection is least likely during early pregnancy, but more severe when it occurs. The risk of congenital in- fection can be kept to a minimum by not eating undercooked meat, taking care while handling raw meat, and avoiding contact with cat faeces. The risk of Listeriosis infection can be reduced by eating and drinking only pasteurized dairy products. The risk of salmonella in- fection can be reduced by avoiding uncooked eggs, or meat. Food cravings during pregnancy Common food cravings during pregnancy are for dairy products and occasionally for non​organic material such as soil (pica). Common aversions are to alcohol, caffeine, and meats. Fetal programming—​the influence of fetal nutrition on adult disease Epidemiological studies have found that low birth weight due to fetal growth restriction, rather than prematurity, is associated with an increased risk of cardiovascular disease in adulthood. It is

Section 14  Medical disorders in pregnancy 2574 hypothesized that a poorly growing fetus makes metabolic adapta- tions in utero to optimize growth and development. Despite these physiological adaptations, driven in part by insulin-​like growth fac- tors, birth weight remains low, and because of them the individual is programmed to insulin-​resistance syndromes including future car- diovascular disease. Animal studies have shown that the composition of maternal diet can influence fetal growth and consequently blood pressure in her offspring. At present not enough is known about the mechan- isms that control human fetal growth to give a mother nutritional advice that might eventually reduce the risk of cardiovascular dis- ease in her children. Inheritance of insulin resistance from father to fetus tempers insulin-​mediated fetal growth and may be another explanation for the association between low birth weight and future type-​2 diabetes/​metabolic syndrome. Understanding these mech- anisms may help to ameliorate the global epidemic of cardiovas- cular disease. FURTHER READING Bhutta ZA, et al. (2013). Evidence-​based interventions for improve- ment of maternal and child nutrition: what can be done and at what cost? Lancet, 382, 452–​77. Black RE, et al. (2013). Maternal and child undernutrition and over- weight in low-​income and middle-​income countries. Lancet, 382, 427–​51. Chitayat D, et  al. (2016). Folic acid supplementation for pregnant women and those planning pregnancy: 2015 update. J Clin Pharm, 56, 170–​5. Devlieger R, et al. (2016). Maternal obesity in Europe: where do we stand and how to move forward?: a scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG). Eur J Obstet Gynaecol Reprod Biol, 201, 203–​8. Goldstein RF et  al. (2017). Association of gestational weight gain with maternal and infant outcomes: a systematic review and meta-​ analysis. JAMA, 317, 2207–​25. Koletzko B, et al. (2014). Current information and Asian perspectives on long-​chain polyunsaturated fatty acids in pregnancy, lactation and infancy: systematic review and practice recommendations from an early nutrition academy workshop. Annals Nutrit Metab, 65, 49–​80. Kominiarek MA, Peaceman AM (2017). Gestational weight gain. Am J Obstet Gynecol, 217, 642–​51. Mousa A, et al. (2016). Vitamin D in reproductive health and preg- nancy. Semin Reprod Med, 34, e1–​e13. National Institute for Health and Care Excellence (NICE) (2017). Antenatal Care for Uncomplicated Pregnancies (CG62). Updated January 2017. https://​www.nice.org.uk/​guidance/​cg62 Poston L, et  al. (2016). Preconceptional and maternal obesity:  epi- demiology and health consequences. Lancet Diabetes Endocrinol, 4, 1025–​36. Prentice AM, Goldberg GR (2000). Energy adaptations in human pregnancy: limits and long-​term consequences. Am J Clin Nutr, 71 Suppl, 1226–​32S.

14.20 Prescribing in pregnancy 2706

14.20 Prescribing in pregnancy 2706

ESSENTIALS Many clinicians feel uncertain about prescribing for pregnant women. Despite well-​known examples of drugs that have caused serious adverse effects to the developing fetus, most medications can be used safely and effectively in this setting, provided some simple principles are followed. The first of these is that the health of the mother is the most important factor in determining the health of the fetus. Inappropriate cessation of existing medication, or failure to initiate new agents when clearly indicated, can be more harmful than the judicious use of selected medication to maintain maternal health. A medication should be prescribed in pregnancy if the benefit to the mother, and therefore indirectly to the fetus, outweighs the potential risk of fetal exposure. It may be preferable to use medications that have been in clinical use for many years ra- ther than newer agents, which have not yet been used in a sufficient number of women over an adequate period of time for potential adverse events to become apparent. Introduction Prescribing for the pregnant patient is a source of anxiety even for the experienced physician. Well-​known examples from history of ser- ious adverse events such as the association of antenatal thalidomide and phocomelia, and that of antenatal diethylstilbestrol and clear cell carcinoma of the vagina, mean the potential hazards of medica- tion use in pregnancy are familiar to both patients and physicians. Unfortunately, such is the level of anxiety surrounding prescribing in pregnancy, that appropriate medications may be withheld be- cause theoretical risks of fetal exposure are prioritized over the real risks of treatment cessation in the mother. This may not be in the best interests of either mother or fetus. One of the challenges with prescribing medications in pregnancy is that pregnant women are typically excluded from drug trials and understandably pharmaceutical companies do not perform large randomized controlled trials of new drugs during pregnancy. However, the absence of data does not equate to the medication being unsafe. Instead it means that each prescription must be made on an individual basis, after the benefits and risks of treatment to both mother and fetus have been carefully weighed up. Who is at risk? A recent study in the United States showed that almost 50% of non​pregnant women of childbearing age (defined as 15–​44 years) and almost 25% of pregnant women questioned reported use of prescription medication in the preceding 30 days. At least one in six pregnancies in the United Kingdom is unplanned, so it must be the case that physicians see women with inadvertent medication exposure in pregnancy on a regular basis. A recent MBRRACE-​UK (Mothers and babies:  reducing risk through audit and confidential enquiries across the United Kingdom) report demonstrated that between 2009 and 2012, 75% of the pregnant women who died in the United Kingdom had a med- ical or mental health diagnosis prior to pregnancy. These diag- noses often mandate medication prior to conception and during pregnancy. A  wide variety of healthcare professionals may be involved in their medical and obstetric care, and all require a good working knowledge of the appropriate use of medication in pregnancy. Discontinuation of medication or the inappropriate failure to institute appropriate pharmacological therapy may be life-​threatening. Medical disorders arise in pregnancy on a regular basis. Hyper­ tensive disorders are particularly common, complicating approxi- mately 10% of pregnancies, so knowledge of the appropriate use of antihypertensives in pregnancy is essential for general practi- tioners, hospital physicians, and obstetricians. The approach to antihypertensive use in pregnancy differs to that used in the non-​ pregnant population, as evidence of safety is available for those agents that have been used for many years in the obstetric popu- lation, for example methyldopa. Although rarely used outside of pregnancy, labetalol is first line in the UK National Institute for Health and Care Excellence (NICE) guidelines for the manage- ment of hypertension in pregnancy because it is the only agent with a licence for use in pregnancy. Other agents included in these guidelines such as nifedipine and methyldopa, although widely prescribed and effective, are used ‘off-​licence’. 14.20 Prescribing in pregnancy Lucy MacKillop and Charlotte Frise

14.20  Prescribing in pregnancy 2707 Effects of medication in pregnancy Knowledge of the stages of embryonic and fetal development is crucial in understanding the effects a medication may have. The key embryonic structures are formed between 5 and 10 weeks of gestation (3–​8 weeks following conception) and from then on, the conceptus is known as a fetus. Teratogenesis is the term used to describe abnormal development of the embryo during this period, which results in structural abnormalities (Fig. 14.20.1). After 10 weeks of gestation, the fetus may still be affected by medications, potentially resulting in altered growth of the fetus, or altered devel- opment of the immature organ systems. Medications can therefore be fetotoxic but not teratogenic, and vice versa. This distinction is illustrated by the effects of two particular medications:  warfarin and angiotensin-​converting enzyme (ACE) inhibitors. Both these medications are, with few excep- tions, avoided throughout pregnancy. Warfarin use in the em- bryonic period can result in specific abnormalities, including neurological, facial, ocular, and skeletal defects. After the em- bryonic period, warfarin does not affect the structural develop- ment of organ systems, but as it crosses the placenta it inhibits fetal vitamin K-​dependent clotting factors. Vitamin K is pre- sent in smaller amounts in the fetal circulation compared with the maternal circulation, hence the fetus is anticoagulated to a greater degree than the mother at any given dose of warfarin. This substantially increases the risk of fetal bleeding, with intracranial bleeding being of particular concern. ACE inhibitors are another group of medications commonly encountered peri-​conception as a result of NICE and other guidelines that advocate their use as first line agents in hypertensive individuals less than 55 years of age. Concerns have been raised about the teratogenicity of ACE inhibitors when used in the first trimester. It is not clear from cur- rent data whether the reported abnormalities are due to the medi- cation itself, or other factors such as hypertension, coprescribed medication, or comorbidities such as obesity. Use of ACE inhibi- tors later in pregnancy is associated with complications including oligohydramnios, intrauterine growth restriction, and persistence of a patent ductus arteriosus. There are fewer data on angiotensin receptor blockers, but the same advice is usually given. It is im- portant to remember that the background risk of all congenital malformations in the normal population is approximately 3%, so quoted risks associated with specific medications should be inter- preted with this in mind. Effects of pregnancy on medication The physiological changes of pregnancy affect every organ system. Drug metabolism is likely to be affected and this needs to be taken into consideration when prescribing. Drug levels in pregnancy are affected by the increase in blood volume (approximately 50% greater at 34 weeks of gestation compared to non​pregnant), an in- crease in renal clearance, changes in hepatic metabolism, reduced absorption from the gastrointestinal tract, or vomiting. Alteration in the proportion of free drug and protein-​bound drug may also occur. This can have an impact on the dose and frequency of a medication required. Lamotrigine is an important example; the level of circulating drug decreases in pregnancy by up to 50%. A larger dose is thus required to achieve the same serum concentra- tion and therapeutic effect as that outside pregnancy. Regular dose review and measurement of serum lamotrigine level should be con- sidered to reduce the likelihood of seizures occurring as a result of subtherapeutic levels. There is some evidence that a similar effect occurs with levetiracetam. Aside from the pharmacokinetic and pharmacodynamic changes that are associated with pregnancy, a woman’s concordance with medication may also be affected and this should not be overlooked. Treatment indications Maternal pre-​existing medical conditions Discussion about medication use for an existing medical condition would ideally occur prior to conception. The implications for preg- nancy should be discussed when prescribing any medication to a woman of childbearing age. If a pregnancy is being considered, pre-​ pregnancy counselling is essential, to ensure that a plan is in place for continuation or adjustment of medication in view of a likely fu- ture conception. Immunosuppression in women with solid organ transplants is a good example. Medications such as mycophenolate mofetil, which are teratogenic, should be substituted with medica- tions such as azathioprine, ensuring that an optimized and stable drug regime is found prior to conception. The commonly used antiepileptic and mood stabilizer, sodium valproate, is recognized—​as are all antiepileptic medications—​to be associated with congenital malformations including neural tube, cardiac, limb, and facial abnormalities. A  wide variety of factors influence the teratogenicity of valproate, but it has been shown in several large registries to be associated with increased risks of con- genital malformations and developmental delay in the offspring compared to other antiepileptics such as carbamazepine, phenytoin, and lamotrigine. It is also associated with an increased risk of atten- tion deficit disorder and autism spectrum disorder in the offspring. This has led to a recent call from the European Medicines Agency to stop the prescription of sodium valproate in all girls and women of childbearing age. It appears that the probability of a fetal anomaly increases with dose and when other antiepileptic agents are used alongside valproate, hence careful preconception counselling is re- quired to minimize harm in women who are unable or unwilling to discontinue sodium valproate in pregnancy. Though pre-​pregnancy counselling is the standard to aim for, many women only come to medical attention when already preg- nant. The booking visit may occur towards the end of the period of embryonic development, and so the crucial window of embryonic exposure to a potential teratogen may already have closed. A full medication history as well as a discussion about concordance is im- portant at this time, as the woman may already have discontinued medication after a positive pregnancy test for fear of potential fetal harm, without any involvement of a medical professional. Maternal medical conditions arising in pregnancy The initiation of a medication in pregnancy should take into consid- eration the factors already discussed, including the gestational age of the fetus, and a risk-​benefit analysis to both mother and fetus.

Section 14  Medical disorders in pregnancy 2708 Embryonic disc Morula Amnion Blastocyst Embryonic disc Death of embryo and spontaneous abortion common Major congenital anomalies Masculinization of female genitalia External genitalia Palate Cleft palate Enamel hypoplasia and staining Teeth Eyes Ears Upper lip Cleft lip Lower limb Amelia/Meromelia Amelia/Meromelia TA, ASD, and VSD Neural tube defects (NTDs) 3 4 5 6 7 8 9 16 32 38 Fetal Period (in weeks) Main Embryonic Period (in weeks) 2 1 Upper limb Heart Mental rehardation CNS Microphthalmia, cataracts, glaucomo Low-set malformed ears and deafness Functional defects and minor anomalies Highly sensitive period Less sensitive period Common site(s) of action of teralogens Not susceptible to teralogenesis TA—Truncus arteriosus; ASD—Atrial septal defect; VSD—Ventricular septal defect Period of dividing zygote, implantation and bilaminar embryo Fig. 14.20.1  Schematic illustration of critical periods of development before birth, showing the timing of vulnerability to teratogens. Reproduced from Moore KL, Persaud TVN and Torchia MG (2012). The Developing Human: Clinically Oriented Embryology (page 489), Philadelphia: Saunders, with permission from Elsevier.

14.20  Prescribing in pregnancy 2709 Fetal medical conditions arising in pregnancy Occasionally medication may be required to treat a medical condi- tion that has arisen in the fetus. An example is fetal supraventricular tachycardia, for which oral maternal antiarrhythmic agents can be used with good effect, for example digoxin, flecainide or (occasion- ally) amiodarone. The use of these agents requires care as side effects can arise in both mother and fetus. For example, regular maternal electrocardiogram monitoring is required, as well as therapeutic drug monitoring in the case of digoxin, to avoid maternal toxicity. Amiodarone use can result in maternal thyroid dysfunction and, less commonly, thyroid dysfunction in the neonate, so thyroid function testing should be performed in both individuals. Fetal thyrotoxicosis can occur as a result of transplacental transfer of thyroid stimulatory antibodies in a euthyroid mother who has previously had either surgical treatment for Graves’ disease or radio-​ iodine. In this case, maternal carbimazole treatment is required, the dose of which is titrated to the fetal heart rate. Thyroxine is added if the mother becomes hypothyroid due to this treatment, as very little thyroxine crosses the placenta. Paternal medical conditions The use of medication in men of childbearing age is less frequently considered, but some medications can have important effects on spermatogenesis and so their use prior to conception should be con- sidered and discussed. Sulfasalazine, for example, causes qualitative and quantitative abnormalities of sperm in over 80% of men, which is reversed on treatment cessation. Research into the use of metho- trexate in men prior to conception has yielded conflicting results: it has been reported to impair spermatogenesis in animal studies and in one human study, but in other studies there appeared to be no as- sociation of paternal methotrexate use with adverse pregnancy out- comes, including congenital malformations. At present, evidence does not support stopping treatment prior to conception. Prescribing in breastfeeding When prescribing for a lactating mother, there are two main issues to consider. First, will the medication have an effect on lactation, a process dependent on a variety of hormonal and neurological in- fluences? Secondly, is there potential for harm to the infant? As an example of the former, cabergoline, a dopamine receptor antagonist, has been shown in animal studies to have a direct inhibitory effect on prolactin secretion from lactotroph cells in the pituitary. When considering the risk of harm to the infant, several factors are important. Maternal pharmacokinetics and lipid solubility of the drug determines the amount of drug or active metabolite which enters the milk, and therefore the amount that is delivered to the gastrointestinal tract of the infant. Next, the absorption, metab- olism, and excretion of the medication by the infant determine the amount of circulating drug or active metabolite in the infant. The effect of the drug on the infant is the next consideration. If a medica- tion is known to have an effect on the infant, it does not automatic- ally follow that this will occur if the mother is given the medication. The amount of drug that enters breast milk may be small, and the absorption from the gastrointestinal tract of the infant also min- imal, so that even if the mother is given the medication, the amount reaching the infant could be of no clinical significance. Anti-​TNFα medications such as infliximab, for example, exhibit limited transfer into breast milk, and negligible transfer across the neonatal gut. An interesting example of a drug which interferes with breast- feeding by an action on the neonate is phenobarbital, which may impair the infant’s sucking reflex. Approach to inadvertent exposure in pregnancy When counselling a woman about inadvertent exposure to a medi- cation, a careful assessment needs to be undertaken, including the doses taken, and the exact gestation at which this occurred. If there is uncertainty about dates, ultrasound should be used to clarify the gestational age. It is then advisable to seek up-​to-​date information about the exact risks of exposure in pregnancy, to provide the woman with sufficient information to make a decision about continuation of the pregnancy. Several online resources are available, including those provided by national teratology information services in the United States and the United Kingdom. Approach to initiation or continuation of medications in pregnancy The main threat to the health and well-​being of the developing fetus is maternal ill health. A medication should be prescribed in preg- nancy if the benefit to the mother, and therefore indirectly to the fetus, outweighs the potential risk of fetal exposure. It may be pref- erable to use medications that have been in clinical use for many years rather than newer agents, which have not yet been used in a sufficient number of women over an adequate period of time for po- tential adverse events to become apparent. Practice points • Decisions about medical therapy should ideally be made prior to conception for women with existing medical conditions. • The prescription of any medication to a woman of childbearing age should prompt discussion about contraception, whether they could be pregnant, and what the potential implications for preg- nancy would be. • In the pregnant woman inadvertently exposed to a potential ter- atogen, counselling by specialists should be offered at the earliest opportunity. • When initiating a new medication in a pregnant woman, the risks and benefits should be weighed up, but it must be remembered that inappropriate withholding of medications that would im- prove maternal well-​being is a significant risk to the fetus in itself. Case 1 A 33-​year-​old woman with a long history of ankylosing spondyl- itis presents with increasing, disabling joint pain at 16 weeks of

Section 14  Medical disorders in pregnancy 2710 gestation in her first pregnancy. She has previously taken non-​ steroidal anti-​inflammatory agents with good effect. Previous trials of steroids have made no difference to her symptoms. Paracetamol and codeine now fail to make an appreciable difference to her pain and discomfort. What treatment options should be advised? There are limited other treatment options for ankylosing spondyl- itis and non​steroidal agents are a mainstay of treatment outside pregnancy. Steroids may be of use in some individuals. Non-​ steroidal anti-​inflammatory drug use in the third trimester is asso- ciated with oligohydramnios and premature closure of the ductus arteriosus. She could therefore use a non​steroidal agent such as ibuprofen until 28 weeks of gestation. Biological agents such as anti TNFα medications are increasingly used in ankylosing spondylitis and are an option in this case. Transplacental transfer increases from the second trimester onwards, and it has been shown that infliximab can be detected in infants exposed in utero for several months after birth, although the effect of this on response to vac- cinations or infections in the infant is not clear. These medications are often therefore stopped in the third trimester to enable fetal clearance prior to delivery. Case 2 A 25-​year-​old woman presents with an unplanned pregnancy at approximately nine weeks of gestation and is taking warfarin as she has metallic aortic and mitral valves (having had previous rheumatic fever). Should her warfarin be stopped? More information is required before a decision can be made se- curely about the warfarin. Ultrasound confirmation of a viable fetus should be undertaken urgently, as well as assessment of gestational age. The period that the embryo is most at risk (4–​10 weeks after conception) may have already passed so immediate cessation of warfarin to avoid embryopathy may be unhelpful. A decision then needs to be made as to whether heparin should be substituted for warfarin. This depends on the overall risk of thromboembolism, which is influenced by factors such as the type of valves, the overall risk of bleeding to mother and fetus, and the views of the mother. Warfarin is superior to low-​molecular-​weight heparin for reducing the risk of maternal valve thrombosis, but for the reasons described earlier, increases the risk of fetal bleeding. Case 3 A 28-​year-​old woman presents for pre-​pregnancy counselling. She was diagnosed with Graves’ disease a year after her first pregnancy and is taking carbimazole. Should the carbimazole be continued? Carbimazole is the preferred antithyroid medication in non​pregnant individuals because of the association of propylthiouracil with a slower recovery of normal thyroid function, and the risk of idiosyn- cratic liver injury with propylthiouracil use (reported rate 1:10 000 individuals). Propylthiouracil has traditionally been recommended over carbimazole in pregnancy due to a small number of cases of aplasia cutis attributed to carbimazole or methimazole use during the first trimester. However, larger studies of antithyroid drugs in pregnancy have not confirmed this effect. In cases where hyperthy- roidism is diagnosed in the first trimester, use of propylthiouracil is advised, but carbimazole may be used in cases diagnosed from the second trimester onwards. If a woman’s condition is well-​controlled on carbimazole prior to pregnancy, then it is generally accepted that there is no need to switch to propylthiouracil if pregnancy is being planned. The priority is to maintain normal thyroid function with as low a dose of antithyroid medication as possible, since thyroid dys- function is undoubtedly harmful to the fetus. FURTHER READING Briggs GG, Freeman RK, Yaffe SJ (2008). Drugs in pregnancy and lac- tation, 8th edition. Lippincott Williams and Wilkins Publishing, Chicago, IL. Knight M, et  al. on behalf of MBRRACE-​UK (2014). Saving lives, improving mothers’ care: lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–​2012. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Rubin P, Ramsay M (eds) (2008). Prescribing in pregnancy, 4th edition. BMJ Books, Blackwell Publishing, London. Online resourcesBest Use of Medicines in Pregnancy. http://​www. medicinesinpregnancy.org LactMed Drugs and Lactation database. http://​toxnet.nlm.nih.gov/​ lactmed (Mobile app also available.) Medications and mothers’ milk. Hale Publishing, London. http://​www. medsmilk.com (Subscription required.) Organisation of Teratology Information Specialists http://​www. mothertobaby.org and http://​www.teratology.org

14.21 Contraception for women with medical disease

14.21 Contraception for women with medical diseases 2711

ESSENTIALS All women with underlying medical disorders should be given cor- rect advice regarding adequate contraception so that they can make informed choices regarding potential future pregnancies. There are several important factors to consider when deciding upon the most appropriate form of contraception to use. These include the risk of pregnancy for the woman, the effect of the contraceptive method on the medical disease, the failure rates associated with the contra- ceptive method, the consequences of an unplanned pregnancy, and the compliance and preferences of the individual woman. There are a small number of very high-​risk conditions where pregnancy is not recommended due to high mortality rates, and the most reliable contraceptive methods should be recommended for these women. Introduction All women with underlying medical conditions should be given advice regarding adequate contraception so that informed choices regarding potential future pregnancies can be made. All special- ists involved in the care of women with medical disorders should have an understanding of the methods of contraception that are best suited for the needs of their patients and should be adequately trained in advising their patients regarding the most effective and safe contraception for them. It is the responsibility of the doctor seeing a woman for pre-​conception or postpartum counselling to discuss the issue of contraception with her. Pre-​conception counselling should optimize the woman’s medical condition(s) prior to pregnancy, ensure current drug treatment is compatible with pregnancy, and gain access to healthcare profes- sionals who have expertise in managing women with medical dis- eases in pregnancy. In the most recent Mothers and Babies: Reducing Risks through Audits and Confidential Enquiries (MBRRACE)-​UK Reports, two-​thirds of women died from indirect causes (not preg- nancy specific) and almost three-​quarters of all women who died had co-​existing medical complications. As in previous reports, car- diac disease remains the single largest cause of indirect maternal deaths. There was a lack of pre-​pregnancy counselling for many of the women who died who had medical problems in pregnancy. It is important to disseminate accurate information regarding contraception to all healthcare professionals responsible for looking after women with medical conditions. This is to avoid un- planned pregnancies in women receiving teratogenic medication, and in those for whom pregnancy carries an extremely high risk of maternal mortality or severe morbidity, as well as to avoid in- accurate advice to terminate pregnancy in women whose medical risk associated with pregnancy is low. For women who have more complex medical conditions, a multidisciplinary meeting involving specialist physicians and sexual and reproductive health specialists is advised. There are a small number of very high-​risk conditions where pregnancy is not recommended due to a high risk of ma- ternal mortality or significant morbidity. These women should be counselled at length regarding the most reliable forms of contra- ception to use. There are several important factors to consider when deciding upon the most appropriate form of contraception in women with medical disorders. These include the risk of pregnancy for the woman, the effect of the contraceptive method on the medical dis- ease, the failure rates associated with the contraceptive method, the consequences of an unplanned pregnancy, and the compliance and preferences of the individual woman. In 2010, the World Health Organization (WHO) published the 4th edition of the Medical Eligibility Criteria for contraceptive use, which provides recommendations for the safety of various methods of contraception in women with a range of health conditions. There are four categories, ranging from category 1, where there is no re- striction for the use of the contraceptive method, to category 4 where the condition represents an unacceptable health risk if the contra- ceptive method is used (Table 14.21.1). Contraceptive agents There is a variety of contraceptive agents available. They can be divided into hormonal and non​hormonal methods. The decision regarding contraception should be based on a risk–​benefit analysis of the contraceptive method (Table 14.21.2). The individual patient’s risks of the contraceptive method adversely affecting the medical condition should be balanced against the risks of an unwanted pregnancy and its subsequent health implications for the woman. 14.21 Contraception for women
with medical diseases Aarthi R. Mohan

Section 14  Medical disorders in pregnancy 2712 The most reliable contraceptive methods should be recommended for those women with the highest risk of mortality if pregnant. Hormonal methods Combined oestrogen-​progesterone contraception These combinations of oestradiol (an oestrogen) and a progestogen (synthetic progesterone) inhibit ovulation and are very effective contraceptives. They include the combined oral contraceptive pill, the combined transdermal patch, and the combined vaginal ring. Relative and absolute contraindications for using combined hor- monal contraception are shown in Tables 14.21.3 and 14.21.4. The oestrogen component carries an increased thrombotic risk due to an increase in the circulating vitamin K-​dependent clotting factors, an increase in plasminogen, a decrease in antithrombin, and an increase in platelet adhesion. Due to an increase in circulating volume, the risk of hypertension increases, and dyslipidaemia may worsen. Combined hormonal contraceptives should be avoided in women with a personal history of thromboembolic disease (WHO Class 4). Combined hormonal contraceptives containing levonorgestrel may carry a slightly lower risk of thromboembolic disease compared with other combined hormonal contraceptives. Combined hormonal contraceptives are associated with an in- creased risk of hypertension (risk ratio of 1.8), especially in women who have used them for more than five years. There is a very small absolute increase in the risk of ischaemic stroke in non​smoking, normotensive women, and combined oral contraceptives are contraindicated in women with ischaemic heart disease, as there is Table 14.21.1  Meaning of category 1–​4 recommendations in the WHO medical eligibility criteria (MEC) for contraceptive use Category Meaning of category 1 A condition for which there is no restriction for the use of the contraceptive method 2 A condition where the advantages of using the method generally outweigh the theoretical or proven risks 3 A condition where the theoretical or proven risks usually outweigh the advantages of using the method 4 A condition which represents an unacceptable health risk if the contraceptive method is used Table 14.21.2  Points to be considered when deciding on the most appropriate contraceptive agent Points to be considered when deciding on the most appropriate contraceptive agent Efficacy Thrombotic risk (oestrogen-​containing contraceptives) Arterial risks (oestrogen-​containing contraceptives) Infection risk (e.g. insertion of an IUD) Vagal stimulation (e.g. insertion of an IUD/​IUS, ESSURE®) Bleeding risks (e.g. with patients on anticoagulants) Interaction with concomitant drugs Effects of anaesthesia Ease of use/​acceptability IUD, intrauterine device; IUS, intrauterine system. Table 14.21.3  Relative contraindications for using combined hormonal contraception (WHO Class 3) System Disease Arterial • Adequately controlled hypertension • Moderate hypertension untreated: SBP <160 mm Hg or DPB <95 mm Hg • Multiple risk factors for arterial disease Venous • First degree relative age <45 years with VTE • Immobility unrelated to surgery Endocrine • Diabetes mellitus with mild/​moderate vascular disease/​nephropathy/​retinopathy/​neuropathy Breast • Not breastfeeding <3 weeks postpartum • Fully breastfeeding ≥6 weeks to 6 months postpartum • Breast cancer >5 years ago without recurrence • Carriers of known gene mutations associated with breast cancer (e.g. BRCA1 and BRCA2) Metabolic • Some known hyperlipidaemias • Obesity 35–​39 kg/​m2 BMI Neurological • Previous migraine with aura at any age • Migraine with aura ≤35 years (continuation of contraceptive) • Migraine without aura ≥35 years (initiation of contraceptive) Liver • Current or medically treated gallbladder disease • Previous cholestasis due to combined oral contraceptives • Obstetric cholestasis Drugs • Liver enzyme inducers • Ritonavir-​boosted protease inhibitors • Lamotrigine • Smoking <15 cigarettes/​day and age ≥35 years • Stopped smoking <1 year ago BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; VTE, venous thromboembolism.

14.21  Contraception for women with medical diseases 2713 a dose-​related increased risk of myocardial infarction (odds ratio of 2.5). This risk increases almost 10-​fold in women who are hyperten- sive, who smoke, or who have hyperlipidaemia. Due to the throm- botic risk, combined oral contraceptives are contraindicated in women with pulmonary hypertension. They should also be avoided in women with uncontrolled hypertension. Oestrogens and progestogens are metabolized by the liver and their use may adversely affect women who have abnormal liver func- tion. They also interact with warfarin metabolism so more frequent monitoring of the international normalized ratio is necessary when initiating treatment and adjustment of dose. It is also important to remember that liver enzyme inducers (Table 14.21.5) may result in reduced contraceptive efficacy of combined hormonal contra- ceptives. If combined hormonal contraceptives are used by women taking liver enzyme inducers, then the preparation should contain at least 50 µg of ethinyl oestradiol and barrier contraception should be used for up to four weeks following discontinuation of the liver enzyme inducer. Progestogen-​only contraceptives Progestogens cause no significant changes in blood pressure, throm- botic risk, or lipid profile and are therefore suitable for most women with medical disorders where oestrogens are contraindicated, such as in cardiac disease or women at significant risk of thromboses. However, progestogen-​only oral contraceptives have a higher failure rate than combined hormonal contraceptives. The contraceptive ef- fect relies on strict patient compliance, as etynodiol, norethisterone, and levonorgestrel must be taken within the same three-​hour window each day in order to maintain contraceptive protection. Unlike other progestogen-​only oral contraceptives, desogestrel in- hibits ovulation, and the missed pill window is extended to 12 hours. Desogestrel (e.g. Cerazette®) may therefore benefit women who are suitable for progestogen-​only oral contraceptives but have difficulty with compliance. Relative contraindications for using progestogen-​ only methods of contraception are shown in Table 14.21.6. Women with pulmonary arterial hypertension receiving bosentan need an increased dose of desogestrel, as bosentan induces the cyto- chrome P450 enzymes CYP2C9 and CYP3A4. They should also be advised to use a supplementary form of contraception, like condoms, as the risks associated with contraceptive failure in women with pul- monary hypertension are extremely serious. Progestogen-​only oral contraceptives are a suitable form of contraception for women on long-​term anticoagulation therapy, for example, those with metallic prosthetic cardiac valves. It is contraindicated in women with cur- rent breast cancer. Table 14.21.4  Absolute contraindications for using combined hormonal contraception (WHO Class 4) System Disease Arterial • Severe hypertension untreated: SBP ≥160 mm Hg or DPB ≥95 mm Hg • Hypertension with vascular disease (e.g. coronary heart disease, peripheral vascular disease, hypertensive retinopathy,
transient ischaemic attacks) • Ischaemic heart disease • Cerebrovascular accident • Complicated valvular and congenital heart disease (e.g. with pulmonary hypertension, atrial fibrillation, history of bacterial endocarditis) • Multiple risk factors for cardiovascular disease (e.g. age, smoking, diabetes mellitus, hypertension, hyperlipidaemia) Venous • Thrombosis (deep vein thrombosis, pulmonary embolism, or cerebral venous thrombosis) • Major surgery with prolonged immobilization • Known thrombophilia Endocrine • Diabetes mellitus >20 years • Diabetes mellitus with severe vascular disease or severe nephropathy, retinopathy, or neuropathy Breast • Breastfeeding <6 weeks post-​partum • Current breast cancer Metabolic • Obesity ≥40 kg/​m2 BMI Neurological • Migraine with aura • Migraine without aura and age ≥35 years (continuation of contraceptive) Liver • Active viral hepatitis • Severe (decompensated) cirrhosis • Benign or malignant liver tumours Connective Tissue • Systemic lupus erythematosus with anticardiolipin antibodies/​lupus anticoagulant Drugs • Smoking ≥15 cigarettes/​day and age ≥35 years Table 14.21.5  Examples of enzyme inducers that can result in reduced contraceptive efficacy of combined hormonal contraceptives Liver enzyme inducers Rifampicin Rifabutin Griseofulvin Phenytoin Carbamazepine Oxcarbamazepine Primadone Barbiturates St John’s Wort

Section 14  Medical disorders in pregnancy 2714 The newer long-​acting progestogen-​only oral contraceptives (levonorgestrel-​releasing intrauterine system, LNG-​IUS; Mirena®, and the progesterone implant, Nexplanon®) are the most effica- cious contraceptives available, providing contraceptive protection comparable to that of sterilization. The LNG-​IUS system requires replacement every five years and works by releasing 20 µg of levo- norgestrel directly into the uterus, causing endometrial shedding and subsequently light periods. Most women with a LNG-​IUS be- come oligoamenorrhoeic, which is a major advantage in women receiving long-​term anticoagulation therapy who may suffer from menorrhagia, as well as those women with cyanotic heart disease who would not tolerate anaemia from heavy periods. Women with pulmonary arterial hypertension or a Fontan circulation may not tolerate a bradycardiac response to cervical instrumentation. So in these women, LNG-​IUS insertion should be performed in a hos- pital setting with anaesthetic support. Women should be screened for sexually transmitted infections or empirically covered with anti- biotics, and those at risk of infective endocarditis should be given appropriate antibiotic prophylaxis for insertion. Women with puer- peral sepsis, following a septic abortion or with current pelvic in- flammatory disease should not have an intrauterine device inserted. In women with ischaemic heart disease and hyperlipidaemia, the LNG-​IUS provides the safest lipid profile, as levels of high-​density lipoprotein are increased. Depot medroxyprogesterone acetate (DMPA) is an effective contraceptive injection that has no cardiac contraindications. Good compliance with 12-​weekly injections is important for contraceptive effectiveness. However, deep intramuscular injections may cause significant haematomas in those receiving anticoagulation therapy. Amenorrhoea is a common side effect and may be an advantage in women with cyanotic heart disease, many of whom suffer from men- orrhagia. In women with ischaemic heart disease there is a small the- oretical concern that DMPA may cause a moderately unfavourable alteration in lipid metabolism. In women taking enzyme-​inducing drugs such as bosentan, or in women with significantly raised BMI, additional supplemental progestogen may be required. Fertility re- turns to normal within six months of cessation of treatment. Nexplanon® is a radio-​opaque etonogestrel-​releasing implant. It has replaced Implanon® and has no cardiac contraindications. Nexplanon® is as effective as sterilization and produces steadier blood levels, and fewer side effects, than injectable contraceptives. There is much less risk of haematoma formation, as the implant is subdermal and only needs replacing every three years. The inter- national normalized ratio should be checked prior to insertion in women taking warfarin. The efficacy of contraceptive implants is affected by bosentan, so an additional method of contraception should be used in order to provide reliable contraception for women with pulmonary hypertension. Copper intrauterine contraceptive device The copper-​releasing intrauterine device (IUD) works by inhibiting fertilization, as well as implantation, without the need for exogenous hormones. As with the LNG-​IUS, it is recommended that prophy- lactic antibiotics be administered at the time of insertion of the intrauterine device, if the woman has not been screened for sexually transmitted infections. In all women, the risks of intrauterine contraception include uterine perforation, infection, and displacement of the IUD. It should, therefore, be avoided in women with previous infective endocarditis, and used with caution in the presence of complicated valvular disease or in those who are anticoagulated. IUDs are not re- commended in immunosuppressed women, for example, those who have undergone heart or kidney transplantation, due to the risk of infection, and it should be avoided in cases of puerperal sepsis. Emergency hormonal contraception The first choice of oral emergency hormonal contraception is 1.5 mg of levonorgestrel, taken as a single dose. This should ideally be taken within 12 hours of intercourse but no later than 72 hours for best ef- fect. An alternative form of emergency contraception, if the woman exceeds the 72-​hour window, is 30 mg of ulipristal acetate, a selective progesterone receptor modulator, which is licensed for administra- tion up to 120 hours after intercourse. Alternatively, a copper IUD may be inserted up to 120 hours after intercourse. Insertion, how- ever, carries risks of vagal reaction and infection, as previously dis- cussed. In women who are treated with warfarin, the international normalized ratio should also be monitored after emergency oral contraception, as this can be affected. Table 14.21.6  Relative contraindications for using progestogen-​only methods of contraception (WHO Class 3): All methods unless specified System Disease Arterial • Hypertension with vascular disease (injectables) • Multiple risk factors for cardiovascular disease (e.g. age, smoking, diabetes mellitus, hypertension, hyperlipidaemia) (injectables) • Ischaemic heart disease (injectables; POP/​IMP initiation or continuation of contraceptive) • Cerebrovascular accident (injectables; POP/​IMP initiation or continuation of contraceptive) Endocrine • Diabetes mellitus >20 years (injectables) • Diabetes mellitus with vascular disease (i.e. nephropathy, retinopathy, or neuropathy, injectables) Breast • Breastfeeding <6 weeks postpartum • Breast cancer >5 years ago without recurrence Neurological • Migraine with aura (all methods: continuation of contraceptive) Liver • Active viral hepatitis • Severe (decompensated) liver cirrhosis • Tumours: benign/​malignant liver tumours Drugs • Liver enzyme inducers (POP/​IMP) IMP, implant; POP, progesterone-​only pill.

14.21  Contraception for women with medical diseases 2715 Non​hormonal methods Female sterilization Female sterilization carries a 10-​year failure rate of 2–​3/​1000 when performed laparoscopically with Filshie clips, and a lifetime failure rate of 5/​1000. If the sterilization is performed at the same time as a caesarean section, the 10-​year failure rate is higher (approximately 7.5/​1000). Laparoscopic sterilization is usually performed under general anaesthesia. A carbon dioxide (CO2) pneumoperitoneum is created, which reduces venous return and has the potential for the CO2 to be systemically absorbed. This can result in paradoxical em- boli in women with right to left shunts. Laparoscopic sterilization can usually be performed without instrumentation of the cervix, but if instrumentation is essential in order to manipulate the uterus to gain better access to the fallopian tubes, it can result in a vasovagal response, which may not be tolerated in those with pulmonary vas- cular disease. ESSURE® is a new sterilization method in which intratubal stents are hysteroscopically inserted into the proximal section of the fal- lopian tubes using oral analgesia or light sedation. Tubal occlusion occurs by three months due to mechanical obstruction and inflam- mation causing fibrosis. The incidence of vasovagal attacks from the insertion of the hysteroscope is 1.85%. Male sterilization Vasectomy is more efficacious than female sterilization and has the added benefit of involving no risk to the woman. It is performed under local anaesthetic but should be a very considered choice if it is to be used as contraception in the partner of a woman with severe medical disease whose lifespan may be significantly reduced, as he may wish to father children in the future with a new partner. Barrier methods Neither male nor female condoms are very effective methods for prevention of pregnancy but should be used to prevent sexually transmitted infections. They should be used with a more reliable contraceptive method. Termination of pregnancy If a woman with a high-​risk medical condition becomes pregnant and the continuation of the pregnancy carries with it a high risk of maternal mortality or severe morbidity, termination of pregnancy should be discussed with the woman and facilities made available. Medical termination of pregnancy can be performed at any gesta- tion and is usually carried out by administering oral mifepristone, followed two days later by a prostaglandin, misoprostol. Surgical termination of pregnancy is performed by suction, or dilatation and evacuation at more advanced gestations up to 24 weeks. Cervical priming with prostaglandins may be required. Specific medical conditions Hypertension Combined oral contraceptives with low-​dose oestrogen formu- lations increase ambulatory blood pressure in normotensive and mildly hypertensive women by 6–​8 mm Hg compared with users of the copper IUD. The risk is highest among women who have used combined oral contraceptives for six or more years and the risk decreases shortly after the combined oral contraceptive has been stopped. Progestogen-​only oral contraceptives do not in- crease blood pressure and so are considered safe contraceptives in hypertensive women. Arterial disease Combined hormonal contraceptives should not be used in women with a history of ischaemic heart disease or stroke. The risk of stroke and myocardial infarction are thought to be related to the dose of oestrogen, with those taking the lower dose oestrogen preparation at lower risk. Users of low-​dose combined oral contraceptives with second-​generation progestogens have a higher risk of stroke than those using third-​generation progestogens. Smoking and hyperten- sion further increases the risk of stroke and myocardial infarction in combined oral contraceptive users by up to 10-​fold. There is no increased risk of stroke or myocardial infarction in users of the progestogen-​only oral contraceptives. However, in- jectable and implantable progestogens should be used with cau- tion in those with a history of ischaemic heart disease or stroke, as studies have shown a reduction in high-​density lipoprotein and an increase in low-​density lipoprotein in those on DMPA, and a reduction in high-​density lipoprotein and low-​density lipopro- tein and an increase in triglyceride levels in those women using Nexplanon®. LNG-​IUS has been shown to have a better lipid profile with an increase in high-​density lipoprotein levels, so if a woman using Nexplanon®, DMPA or the progesterone-​only pill develops ischaemic heart disease or a stroke, she should consider changing to LNG-​IUS or the copper IUD. Thrombosis There is a three to fivefold increased risk of venous thrombo- embolism in women taking oestrogen-​containing contraceptives compared with non​users, as oestrogen is pro-​thrombotic due to increases in the hepatic production of some clotting factors (Table 14.21.7). However, pregnancy itself carries a 12-​fold increased risk of venous thromboembolism. Desogestrel and gestodene, which are third-​generation progestogens, are twice as thrombotic as second-​generation progestogens, and the overall risk increases with age and obesity. The WHO recommends that combined hormonal contraceptives should not be used in women who have had an idiopathic venous thromboembolism or a venous thromboembolism associated with pregnancy or previous use. Women with known thrombophilias should not use combined hormonal contraceptives as they have an Table 14.21.7  Risks of venothrombolic events with combined oral contraceptives and pregnancy Category Risk of VTE per 100 000 women Healthy non​pregnant, non​users of COC   5 Second-​generation COC 15 Third-​generation COC 25 Pregnancy 60 COC, combined oral contraceptive; VTE, venous thromboembolism.

Section 14  Medical disorders in pregnancy 2716 increased risk of venous thromboembolism, which is further in- creased by 2–​20-​fold if they start combined oral contraceptives. The copper IUD and progestogen-​only oral contraceptives are thought to be safer than the combined hormonal contraceptives for women at risk of venous thromboembolism, although caution should be used as there is an increased risk of haematoma formation with injectables or Nexplanon®, and with bleeding at the time of in- sertion of LNG-​IUS in women on anticoagulants. Pulmonary arterial hypertension Pulmonary arterial hypertension is associated with maternal mor- tality rates of up to 25%. Nexplanon® is the most suitable method of contraception in women with pulmonary hypertension as it is highly efficacious and avoids the complications of injectables and IUDs. Injectables are unsuitable, as most patients with pulmonary arterial hypertension are anticoagulated with warfarin. IUD inser- tion results in a vasovagal episode in at least 1.2% of women due to cervical dilatation, and the incidence is greater with the LNG-​IUS insertion than with copper IUDs due to the larger width of the LNG-​IUS. Bradycardias are poorly tolerated in pulmonary arterial hypertension and can lead to circulatory collapse. If IUD use is considered necessary, it should be inserted in hospital with an an- aesthetist present and atropine at hand. Combined hormonal contraceptives are contraindicated due to their thrombotic risk. As previously mentioned, female sterilization may be performed without instrumenting the uterus, but vasectomy is not usually recommended as the male partner will usually outlive the woman. Migraine The combined oral contraceptive increases the risk of stroke in women with migraine by 2–​4-​fold. Aura occurs before a headache and specifically relates to focal symptoms indicating ischaemia and includes unilateral sensory or motor symptoms and speech disturb- ance. Aura is also considered to increase the risk of stroke, and the mechanism is thought to be due to a reduction in cerebral blood flow to certain areas and increased platelet activity. The combined oral contraceptive is WHO Class 3 in women with migraine without aura, and WHO Class 4 in those with aura. Progestogen-​only oral contraceptives have been given WHO Class 2 and the copper IUD is Class 1 for women with migraine with aura. Diabetes Women with diabetes should have their glucose control optimized around the time of conception, as the risk of major congenital ab- normalities is directly related to glycaemic control, so effective contraception for women with diabetes is especially important. Women with poorly controlled diabetes are also at risk of miscar- riage, macrosomia, pre-​eclampsia, and intrauterine growth restric- tion and intrauterine fetal death. The copper IUD is recommended (WHO Category 1) for women with diabetes, although as previously mentioned, there is a risk of infection with this method. Reports that have suggested that carbohydrate and lipid metab- olism are affected by hormonal contraception, especially glucose metabolism with high-​dose combined oral contraceptives, but the studies involved are small. There are no long-​term studies on the progression of vascular complications in women with diabetes who are on hormonal contraceptives, but the threat of arterial events limits the use of combined hormonal contraceptives to non​smokers under the age of 35 years who are normotensive, without any vas- cular complications. Epilepsy Epilepsy affects approximately 0.5–​1% of women of childbearing age and is the commonest neurological disorder seen in preg- nancy. Women with epilepsy should ideally be referred to a neur- ologist before getting pregnant. A re-​evaluation of the need for and choice of antiepileptic drug treatment, including whether the diagnosis is correct and whether the epilepsy has spontaneously remitted, is important. The aim is to treat with one antiepileptic drug at the lowest effective dose. If one antiepileptic drug is re- placed with another felt to be more suitable for pregnancy, this may involve a period of overlap of two antiepileptic drugs, which increases the risk of congenital malformations. Contraception counselling is vital to avoid unplanned pregnancy in women taking antiepileptic drugs. The enzyme-​inducing antiepileptic drugs, which include phenytoin, carbamazepine, phenobarbital, and topiramate, can accelerate the metabolism of oral steroids, and so high-​dose oestrogen preparations may be needed to suppress ovulation. Lamotrigine is not an enzyme inducer, but its clearance may be accelerated when used with combined hormonal contraceptives which should be used with caution in women taking lamotrigine (WHO Class 3). As mentioned earlier, enzyme-​inducing antiepileptic drugs decrease serum concentrations of both ethinyl oestradiol and progestogens. Because progesterone-​only pills generally con- tain lower doses of progestin than doses found in combined oral contraceptives, there is a potentially high failure rate when taken in combination with enzyme-​inducing antiepileptic drugs. As a result, progesterone-​only pills should be prescribed with cau- tion (WHO Category 3). DMPA is WHO Category 1 for women using antiepileptic drugs. Contraceptive failure has been reported with the implant in women taking enzyme-​inducing antiepileptic drugs. In contrast to combined oral contraceptives, progestogen-​ only oral contraceptives do not lower serum lamotrigine levels, so in women taking lamotrigine, progesterone-​only pills, DMPA, and implants are WHO Category 1.  Both the LNG-​IUS and copper IUD can be used without restriction in women with epilepsy, and both enzyme-​inducing antiepileptic drug and lamotrigine users can use them without restriction (WHO Category 1). Liver disease Women with a history of obstetric cholestasis or previous cholestasis while using combined hormonal contraceptives may develop cholestasis with subsequent use. This is also possible with progestogen-​only oral contraceptive use, hence if hormonal contraception is used the patient should be monitored carefully for pruritus and abnormal liver function tests. Oestrogens and progestogens are metabolized by the liver, and their use may ad- versely affect those with active viral hepatitis, severe cirrhosis, and liver tumours where liver function is compromised. Combined hormonal contraceptive use is regarded as WHO Category 4 in these patients, whereas progestogen-​only oral contraceptive use is

14.21  Contraception for women with medical diseases 2717 graded WHO Category 3. The copper IUD can be safely used in women with liver disease. Sickle cell disease Advice regarding combined hormonal contraceptive use in women with homozygous sickle cell disease remains uncertain, with theor- etical concerns of promoting thromboses. DMPA reduces the in- cidence of painful crises in women with sickle cell disease, which makes it an attractive option for these women. Systemic lupus erythematosus Combined hormonal contraceptives should be avoided in those with any evidence of vascular disease, lupus nephritis, or anti­ phospholipid antibodies, due to an increased risk of increased dis- ease activity and thrombosis. Progestogen-​only oral contraceptives and the copper IUD are suitable and effective contraceptives in women with varying lupus disease severity. FURTHER READING Knight M, Nair M, Tuffnell D, Shakespeare J, Kenyon S, Kurinczuk JJ
(Eds.) on behalf of MBRRACE-UK (2017). Saving Lives, Improving Mothers’ Care - Lessons learned to inform maternity care from the
UK and Ireland Confidential Enquiries into Maternal Deaths and
Morbidity 2013–15. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Mohan AR, Nelson-​Piercy C (2014). Drugs and therapeutics, including contraception, for women with heart disease. Best Pract Res Clin Obstet Gynaecol, 28, 471–​82. Nelson-​Piercy C (2015). Handbook of obstetric medicine, 5th edition. CRC Press, Boca Raton. World Health Organization (WHO) (2010). Medical Eligibility Criteria for Contraceptive Use, 4th edition. Department of Reproductive Health and Research, World Health Organization, Geneva. http://​ whqlibdoc.who.int/​publications/​2010/​9789241563888_​eng.pdf

SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav 15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward 15.3 Methods for investigation of gastroenterological disease  2734 15.3.1 Colonoscopy and flexible sigmoidoscopy  2734 James E. East and Brian P. Saunders 15.3.2 Upper gastrointestinal endoscopy  2740 James E. East and George J. Webster 15.3.3 Radiology of the gastrointestinal tract  2748 Fiachra Moloney and Michael Maher 15.3.4 Investigation of gastrointestinal function  2757 Jervoise Andreyev 15.4 Common acute abdominal presentations  2765 15.4.1 The acute abdomen  2765 Simon J.A. Buczacki and R. Justin Davies 15.4.2 Gastrointestinal bleeding  2771 Vanessa Brown and T.A. Rockall 15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser 15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson 15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro 15.8 Peptic ulcer disease  2849 Joseph Sung 15.9 Hormones and the gastrointestinal tract  2862 15.9.1 Hormones and the gastrointestinal tract  2862 Rebecca Scott, T.M. Tan, and S.R. Bloom 15.9.2 Carcinoid syndrome  2870 B. Khoo, T.M. Tan, and S.R. Bloom 15.10 Malabsorption  2875 15.10.1 Differential diagnosis and investigation
of malabsorption  2875 Alastair Forbes and Victoria Mulcahy 15.10.2 Bacterial overgrowth of the small
intestine  2879 Stephen J. Middleton and Raymond J. Playford 15.10.3 Coeliac disease  2884 Peter D. Mooney and David S. Sanders 15.10.4 Gastrointestinal lymphomas  2892 Kikkeri N. Naresh 15.10.5 Disaccharidase deficiency  2902 Timothy M. Cox 15.10.6 Whipple’s disease  2909 Florence Fenollar and Didier Raoult 15.10.7 Effects of massive bowel resection  2911 Stephen J. Middleton, Simon M. Gabe,
and Raymond J. Playford 15.10.8 Malabsorption syndromes in the tropics  2916 Vineet Ahuja and Govind K. Makharia 15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine 15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving 15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz 15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf,
and Neil J.McC. Mortensen 15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig 15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira

15.17	 Vascular disorders of the gastrointestinal

tract  2997 Ray Boyapati 15.18 Gastrointestinal infections  3008 Sarah O’Brien 15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson 15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson 15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal 15.22 Presentations and management of liver disease  3049 15.22.1 Investigation and management of jaundice  3049 Jane Collier 15.22.2 Cirrhosis and ascites  3058 Javier Fernández and Vicente Arroyo 15.22.3 Portal hypertension and variceal
bleeding  3068 Marcus Robertson and Peter Hayes 15.22.4 Hepatic encephalopathy  3080 Paul K. Middleton and Debbie L. Shawcross 15.22.5 Liver failure  3089 Jane Macnaughtan and Rajiv Jalan 15.22.6 Liver transplantation  3100 John G. O’Grady 15.23 Hepatitis and autoimmune liver disease  3108 15.23.1 Hepatitis A to E  3108 Graeme J.M. Alexander and Kate Nash 15.23.2 Autoimmune hepatitis  3119 G.J. Webb and Gideon M. Hirschfield 15.23.3 Primary biliary cholangitis  3127 Jessica K. Dyson and David E.J. Jones 15.23.4 Primary sclerosing cholangitis  3135 Kate D. Lynch and Roger W. Chapman 15.24 Other liver diseases  3142 15.24.1 Alcoholic liver disease  3142 Ewan Forrest 15.24.2 Nonalcoholic fatty liver disease  3147 Quentin M. Anstee and Christopher P. Day 15.24.3 Drug-​induced liver disease  3155 Guruprasad P. Aithal 15.24.4 Vascular disorders of the liver  3166 Alexander Gimson 15.24.5 The liver in systemic disease  3169 James Neuberger 15.24.6 Primary and secondary liver tumours  3178 Graeme J.M. Alexander, David J. Lomas,
William J.H. Griffiths, Simon M. Rushbrook,
and Michael E.D. Allison 15.24.7 Liver and biliary diseases in infancy and childhood  3191 Richard J. Thompson 15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright 15.26 Diseases of the pancreas  3209 15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay 15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen 15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira SECTION 15  Gastroenterological disorders

14.3 Medical management of normal pregnancy 2575

14.3 Medical management of normal pregnancy 2575

ESSENTIALS The global maternal mortality ratio fell by almost 50% between 1990 and 2015. In resource-​poor nations, provision of basic antenatal facilities with community healthcare workers, improved transport, communications, and education are largely responsible. Yet despite this progress maternal deaths are still common, particularly in sub-​ Saharan Africa, usually from readily preventable causes that would not occur in the presence of a skilled birth attendant. In wealthy nations, new challenges to maternal health include obesity, older age, and a growing number of pregnancies in women with chronic diseases through in vitro fertilization. Pregnancy can be accurately diagnosed within a day of missing a menstrual bleed by identifying a rise in urinary human chorionic gonadotropin concentration. Antenatal checks—​at the first antenatal visit, a medical and ob- stetric history is combined with (1)  cardiovascular examination; (2)  urinalysis—​proteinuria, bacteriuria; and (3)  laboratory tests—​ HIV, hepatitis B, and syphilis; screening for sickle cell disease, thalassaemias, and rhesus antibodies. A first-​time pregnant mother should be offered 10 antenatal appointments to check fetal well-​ being, blood pressure, urinalysis, and (at 26–​28 weeks) glucose tolerance. Clinical features of healthy pregnancy—​aside from an enlarging abdomen due to a growing fetus, symptoms can include fa- tigue, palpitations, dizziness, syncope, dyspnoea, nausea, vomiting, headaches, and oedema, and signs include full and bounding arterial pulses, an ejection systolic flow murmur, signs of raised intra-​abdominal pressure such as varicose veins and haemorrhoids. General management—​pregnant women require nutritional advice and should be advised to take regular exercise, stop smoking, and limit alcohol consumption to one to two units of alcohol once or twice a week. Clinical priorities—​when managing medical disorders in pregnancy, the clinician’s priority is to treat the maternal condition, sometimes at the risk of fetal well-​being. Introduction Since 1930, the maternal mortality rate (MMR) in the United Kingdom has fallen from approximately 1 in 100 pregnancies in the worst maternity hospitals to almost 1 in 12 000 pregnancies in 2014. Since 1990, lessons learnt from antenatal care in high-​resource na- tions have been introduced as a priority to low-​resource nations. Consequently, the global MMR has fallen by almost 50% to 1:463 maternities in 2015. In sub-​Saharan Africa however, pregnancy-​ related maternal deaths still occur in approximately 1:183 maternities. The tragedy is that maternal deaths in resource-​poor nations are frequently due to common complications that could be readily cor- rected by a skilled birth attendant with minimal equipment. HIV/​ AIDS and health systems disrupted by war and poor government exacerbate the problem. Furthermore, for every maternal death there are at least 20 additional women who suffer serious pregnancy-​ related conditions that cause lifelong disabilities. In high-​resource nations, new challenges for the medical manage- ment of pregnant women have emerged. The increased prevalence of maternal obesity has led to an increased incidence of gestational syn- dromes, particularly diabetes and hypertension, but also acquired heart disease and obstetric/​anaesthetic complications at the time of childbirth. In vitro fertilization (IVF) offers women who have passed through the menopause an opportunity to become pregnant, but in associ- ation with an increased incidence of multiple pregnancies that in- crease the physiological burden on (often) older mothers less able to cope with the physical stress of pregnancy. Similarly, women with serious chronic or congenital diseases who have an assisted con- ception, struggle to meet the physiological demands of pregnancy. Consequently, fetal development and pregnancy outcome are com- promised, and the mother’s health is put at risk. Maternal morbidity could also be reduced if physicians showed less reticence about their management of otherwise familiar medical conditions during pregnancy. Well-​intended, but misplaced concern about fetal welfare is often wrongly prioritized over life-​saving inves- tigations and treatment for the mother. By contrast, the general phys- ician must be aware of the symptoms and signs of normal pregnancy 14.3 Medical management
of normal pregnancy David J. Williams

Section 14  Medical disorders in pregnancy 2576 to avoid meddlesome and sometimes harmful intervention when a doctor is presented with a healthy, but symptomatic pregnant woman. Maternal factors that influence pregnancy outcome Maternal age Since the mid-​1970s, the mean age of first-​time mothers in the United Kingdom has increased gradually by almost 4 years to 28.6 years in 2015. The physiological adaptations necessary for optimal preg- nancy outcome are compromised by increasing maternal age, al- though biological age is more important than chronological age. The risk of fetal aneuploidy, most notably trisomy 21 (Down’s syndrome), also increases with maternal age. At 25 years, the risk is 1:1250, at 35 years 1:385, and at 45 years 1:30. These risks can be refined between 11 and 14 weeks’ gestation by the ‘combined test’ (nuchal translucency, which is an ultrasound measurement of skin-​ fold thickness at the back of the fetal neck, combined with a ma- ternal serum measure of β-​human chorionic gonadotropin, and pregnancy-​associated plasma protein A). Serum screening for fetal aneuploidy can be carried out between 14 and 20 weeks but is less ac- curate than the combined test. Women at high risk of chromosomal abnormality (usually >1:250), can be offered a diagnostic test that re- quires obtaining cells from the fetus or placenta using amniocentesis or chorionic villus sampling, which carry a 0.5 to 1.0% risk of mis- carriage. Although not yet in widespread use, non​invasive prenatal testing that examines fetal DNA isolated from the maternal circula- tion is showing great promise as a diagnostic test that will hopefully reduce the need for invasive diagnostic sampling. Maternal weight A mother’s body mass index (BMI) should be calculated at the first antenatal appointment. In high-​resource nations, approximately half of women of childbearing age are overweight and 20% are obese. Overweight or obese mothers are at increased risk of gestational hypertension and diabetes, neonatal macrosomia, and late fetal death. Conversely, underweight women (BMI <19 kg/​m2) are prone to have babies with lower birth weights. However, maternal weight gain correlates poorly with fetal growth, which is most accurately assessed by serial ultrasound measurements. Healthy women with a normal BMI (19–25 kg/m2) in the first tri- mester, have an average gestational weight gain of 13.7 kg (SD 4.5 kg) by 40 weeks’ gestation, irrespective of ethnic background. Lean, nul- liparous, healthy, pregnant women who eat to appetite gain 0.65 kg to 1.1 kg during the first 10 weeks of pregnancy, about 0.45 kg/​week during the second trimester, and about 0.36 kg/​week during the last trimester. Unless the mother is underweight, or has hyperemesis gravidarum, conditions that often coexist, regular antenatal meas- urements of maternal weight are not helpful. Past medical history Pregnancy is a medical stress for women. This is particularly evi- dent in women with chronic medical disorders. A diseased ma- ternal organ system may transiently lose residual function in attempting to accommodate the physiological demands of preg- nancy. For example, women with classic risk factors for hyperten- sion are more likely to develop pre-​eclampsia, and women with subclinical insulin resistance are at increased risk of gestational dia- betes. Similarly, women with inherited thrombophilias may develop thrombosis only in combination with the hypercoagulable environ- ment of healthy pregnancy. These gestational syndromes are likely to be associated with an adverse fetal outcome, but the physiological changes of pregnancy are not always damaging: some conditions im- prove, while others deteriorate (Box 14.3.1). Box 14.3.1  Effect of pregnancy on pre-​existing conditions Conditions that tend to improve during pregnancy • Mitral and aortic regurgitation • Raynaud’s phenomenon • Mild hypertension (but worsens towards term) • Hyperthyroidism (may transiently worsen in first trimester) • Sarcoid • Rheumatoid arthritis • Multiple sclerosis (may relapse postpartum) • Peptic ulceration • Migraines Conditions that are unpredictable during pregnancy • Asthma • Systemic lupus erythematosus (may relapse postpartum) • Inflammatory bowel disease Conditions that tend to deteriorate during pregnancy Cardiovascular system • Mitral and aortic stenosis • Pulmonary hypertension (10–​30% risk of maternal mortality) • Congenital cyanotic heart disease • Supraventricular arrhythmias (in third trimester) • Vascular aneurysms • Haemolytic–​uraemic syndrome/​thrombotic thrombocytopenic purpura • Epistaxis • Varicose veins and haemorrhoids • Venous thrombosis • Antiphospholipid syndrome (deep vein thrombosis and recurrent miscarriage) Respiratory system • Viral pneumonia, in particular influenza Gastrointestinal system • Gastro-​oesophageadl reflux (especially in third trimester) • Cholestatic liver disease (in third trimester) • Constipation Genitourinary system • Upper urinary tract infections (pyelonephritis) • Reflux nephropathy • Renal impairment (if glomerular filtration rate <30 ml/​min) Musculoskeletal system • Osteoporosis • Osteoarthritis • Back pain • Hypermobility syndromes Endocrine system • Diabetes mellitus • Central diabetes insipidus (continued)

14.3  Medical management of normal pregnancy 2577 Family history Gestational conditions tend to run in families. Pre-​eclampsia, gestational diabetes mellitus, obstetric cholestasis, hyperemesis gravidarum, and postnatal depression have genetic components. Inherited thrombophilias may be associated with early onset pre-​ eclampsia and fetal growth restriction. Infertility and multiple pregnancies In 1978 the first baby was born by IVF, and she herself has now given birth to a healthy child following natural conception. Since then, it is estimated over five million babies have been born world- wide using IVF technology. One-​quarter of these pregnancies have resulted in multiple births, compared with 11 per 1000 preg- nancies following natural conception. In the United Kingdom this has led to a 66% increase in twin births, which itself has increased the frequency of maternal complications in often older mothers. The cause of infertility may also lead to problems in pregnancy. For example, women with polycystic ovary syndrome are at in- creased risk of pregnancy-​induced hypertension and gestational diabetes. Ovarian hyperstimulation syndrome Women undergoing IVF are often treated with gonadotropins to stimulate their ovaries and increase the yield of eggs. In about 10% of women receiving this treatment, multiple follicles each develop into a corpus luteum, resulting in massive ovarian enlargement produ- cing excessive amounts of progesterone. Increased vascular perme- ability allows protein-​rich fluid to shift into serous cavities, causing ascites, and in more severe cases pleural and pericardial effusions. Haemoconcentration and hypotension result, increasing the risk of thrombosis and reduced renal perfusion. This phenomenon is known as ovarian hyperstimulation syndrome. Most cases are mild and self-​limiting, but death has followed acute respiratory distress, hepatorenal failure, thromboembolism, and rupture of grossly en- larged ovaries. Management is mainly supportive, including careful fluid balance, thromboprophylaxis, analgesia, and adjustment of luteal stimulation under the guidance of a specialist in assisted conception. In some cases, paracentesis can transiently relieve ab- dominal pressure symptoms. Diagnosis of pregnancy Pregnancy can be diagnosed within a day of missing a menstrual bleed by identifying a rise in concentration of urinary human chorionic gonadotropin (hCG). At this time the embryo is two weeks old, but obstetric convention dictates that the gestation of pregnancy is calculated from the first day of the last menstrual period (i.e. two weeks earlier than embryonic age). Teratogenic drugs interfere with organ development in the two to eight weeks postconception (embryonic period). After nine weeks and until delivery, the conceptus is known as a fetus, but its development can still be harmed by drugs given to the mother, or indeed ma- ternal illness itself. Screening of maternal health during pregnancy Pregnancy is an opportunity for women to be screened for occult disease. In the United Kingdom, healthy women are encouraged to register with an antenatal clinic by 10 weeks’ gestation. However, by this time they will have missed the opportunity to take folic acid prophylaxis against neural tube defects and may not recognize the need to adjust social behaviour, or regular medications. At the first antenatal visit, a medical and obstetric history is combined with cardiovascular examination, urinalysis, and la- boratory tests. Identification of maternal infection with HIV, hepa- titis B, or syphilis is necessary for the appropriate management of the mother and her partner, and to minimize the risk of ver- tical transmission to the infant. All women should be screened for sickle cell disease and thalassaemias as early as possible in preg- nancy, and the father of the pregnancy should be strongly encour- aged to undergo screening if a woman is found to be a carrier of a significant haemoglobinopathy. Rhesus antibody screening allows prophylactic measures to prevent haemolytic disease of the fetus. Further antenatal checks are usually performed around 16 weeks to discuss the results of screening tests, following a 20-​week fetal scan, at 26–​28 weeks to assess maternal serum glucose check in those at high risk of gestational diabetes mellitus, and a full blood count, 31, 34, 36, 38, and 40 weeks, then weekly until delivery. At each visit, obstetric assessment is combined with a check of blood pressure and urinalysis. Parous women who have had an uneventful pregnancy need fewer antenatal visits (NICE CG62; 2016). Screening and treatment of asymptomatic bacteriuria during healthy pregnancy reduces the risk of maternal pyelonephritis and fetal morbidity. The cost-​effectiveness of such screening depends on the prevalence of asymptomatic bacteriuria in the pregnant population. If this is less than 5%, as it is in most healthy women, then screening is not cost-​effective, but in women with renal dis- ease and diabetes mellitus, asymptomatic bacteriuria is far more common and screening is worthwhile. As the recurrence rate of asymptomatic bacteriuria is about 30%, women identified with an occult infection should be screened every four to six weeks throughout the remainder of their pregnancy. See Chapter 14.5 for further discussion. Box 14.3.1  Continued • Hypothyroidism • Hyperlipidaemia • Pituitary macroadenoma (not microadenoma) Neurological system • Epilepsy • Cerebrovascular accidents, especially postpartum • Depression (antenatal and postnatal) • Headache, in first and second trimester • Carpal tunnel syndrome, third trimester Haematological system • Anaemia and thrombocytopenia • Sickle cell disease • Thrombophilias Infections and allergies • Intracellular pathogens (viruses, malaria, listeria, and tuberculosis postpartum) • Skin allergies

Section 14  Medical disorders in pregnancy 2578 Symptoms and signs of healthy pregnancy Fatigue Fatigue is a common gestational symptom. It often begins early in healthy pregnancy, improves in the second trimester, and reappears again in the third trimester. Insomnia in the third trimester can be caused by changes in maternal size and shape as well as nocturia and acid-​reflux. Anaemia or hypothyroidism should be excluded if daily living is significantly compromised. Cardiovascular system The hyperdynamic circulation of pregnancy causes cardiovas- cular symptoms that can mimic heart disease (see Chapter 14.6). Palpitations, dizziness, syncope, and dyspnoea are common symp- toms of healthy pregnancy. Failure to recognize benign physiological change leads to anxiety and unnecessary investigations. However, is- chaemic heart disease is the most common cause of maternal death from cardiac disease in the United Kingdom. Older, obese women who smoke and who have symptoms suggestive of ischaemic heart disease should be investigated promptly as if not pregnant, espe- cially in the third trimester and immediately postpartum. Palpitations Transient sinus tachycardia up to 130 beats/​min, and premature atrial and ventricular ectopic beats are common features of healthy pregnancy, especially in women who complain of palpitations. Low dose β-blockers reduce the frequency of ventricular ectopics and provide symptomatic relief. As pregnancy may expose previ- ously asymptomatic abnormalities of cardiac conducting tissue, investigations should include a 12-​lead electrocardiogram (ECG). During healthy pregnancy, the QRS axis moves to the left as the dia- phragm becomes elevated, and Q waves and inverted T waves are frequently seen in leads III and aVR. Pregnant women with syncope or presyncope coinciding with palpitations require further investi- gation with a 24-​hour ECG Holter monitor and echocardiogram. Thyrotoxicosis, anaemia, and hypokalaemia should be excluded. Oedema By the end of pregnancy 80% of healthy women will have some de- gree of dependent oedema. This is associated with a fall in plasma al- bumin concentration by 5–​10 g/​litre and reduced venous return due to compression of the inferior vena cava by the gravid uterus. Unless peripheral oedema is very severe, or is associated with pulmonary oedema, diuretics should be avoided as they attenuate the plasma volume expansion of healthy pregnancy and are associated with fetal growth restriction. Severe and rapid onset of oedema, especially af- fecting hands and face, may herald pre-​eclampsia and warrants fur- ther assessment for hypertension and proteinuria. Blood pressure Peripheral vasodilatation leads to a significant fall in diastolic blood pressure by six weeks of conception, reaching a nadir at 16–​20 weeks. Pre-​pregnancy hypertension may therefore be masked by the early gestational fall in blood pressure. Maternal blood pressure returns to non​pregnant values during the third trimester. Hypertension be- fore 20 weeks’ gestation suggests pre-​existing hypertension, while new onset hypertension after 20 weeks suggests gestational hyper- tension or pre-​eclampsia. Clinical examination During healthy pregnancy the peripheral pulses are full, bounding, and often collapsing, suggesting aortic regurgitation. From mid-​ gestation onwards, the jugular venous pressure becomes more ob- vious and may be raised due to increased intra-​abdominal pressure. The apex beat is more forceful and mildly displaced because of the increase in cardiac output, suggesting cardiomegaly in healthy preg- nant women. An apex beat more than 2 cm outside the midclavicular line should be considered abnormal. On auscultation an ejection systolic flow murmur can be heard in up to 90% of healthy preg- nant women. Increased mammary blood flow in the third trimester occasionally produces a bruit that varies with the pressure of the stethoscope. In countries with established healthcare systems, it is rare for new heart lesions to be identified during pregnancy as most women with congenital heart disease are diagnosed in early life. By contrast, women from low-​income countries are more likely to present with previously unrecognized cardiac abnormalities such as rheumatic heart disease. Respiratory system Dyspnoea The physiological hyperventilation of pregnancy leads to a sub- jective feeling of breathlessness in about 70% of women. The max- imum prevalence of breathlessness is between 28 and 31 weeks’ gestation, but about 50% of women will feel breathless before 20 weeks. The early onset of dyspnoea and improvement towards term suggests that the gravid uterus has little influence on this physio- logical symptom. Women with gestational dyspnoea are more sen- sitive to CO2 and hypoxia than asymptomatic women and respond with excessive ventilation. However, physiological dyspnoea should not usually interfere with daily activities: further investigations are only necessary if symptoms or signs suggest cardiorespiratory dis- ease (e.g. chest infection, pulmonary embolus, or heart failure). Acid-​reflux, especially at night, can cause bronchoconstriction, dyspnoea, and cough. A proton pump inhibitor or H2 antagonist can control this cause of dyspnoea. Radiological imaging in pregnancy In general, the management of sick pregnant women should con- sider the health of the mother before that of the fetus. Nowhere is this consideration ignored more than with the use of X-​rays. Although ionizing radiation is a known carcinogen, there is very little, if any increased risk of childhood cancer following prenatal exposure to X-​rays. Radiation from a chest radiograph is minimal (0.02 mSv), equivalent to 10 days of background radiation or a transatlantic air flight. During healthy pregnancy the chest radiograph shows an in- creased cardiothoracic ratio and pulmonary vascular markings. If pulmonary embolus is suspected and the chest radiograph is normal, then a pregnant woman should have a ventilation–​perfusion scan (1.3 mSv). If the chest radiograph is abnormal and pulmonary em- bolism is still suspected, a computed tomography pulmonary angio- gram should be carried out (see Chapter 14.7).

14.3  Medical management of normal pregnancy 2579 Gastrointestinal system Nausea and vomiting About 75% of all healthy women will feel nauseated and up to 50% will vomit during early pregnancy. Nausea usually begins around the fifth week and usually resolves by 16 weeks. Approximately 10% of healthy pregnant women will still feel occasional nausea throughout pregnancy. Contrary to popular belief, nausea is not usually confined to the mornings, but affects 80% of sufferers all day. Beneficial measures for mild symptoms include rest, carbohy- drate, carbonated drinks, ginger, pyridoxine, antihistamines, and metoclopramide. Vomiting is severe and persistent in 1–​2% of pregnant women. Hyperemesis gravidarum is associated with dehydration, weight loss, and ketonuria (see Chapter 14.9). Ptyalism is a frequent accompani- ment, due to an inability to swallow excessive saliva. Biochemical changes include a transient elevation of liver transaminases and biochemical thyrotoxicosis. A suppressed thyroid-​stimulating hor- mone (TSH) level coincides with the rise and fall of serum hCG, which has mild TSH-​like activity. Resolution of hyperemesis, not treatment of biochemical thyrotoxicosis, corrects the abnormal thy- roid biochemistry. Most antiemetics have not been fully evaluated in early pregnancy. As with all prescribing in pregnancy the clinician must balance the potential risks to the fetus of maternal drug use against the risks of leaving the mother untreated. With regard to hyperemesis gravidarum, a woman is at risk of malnourishment, dehydration, and thrombosis, and most antiemetics have been used effectively during pregnancy for decades without apparent fetal harm. These include antihistamines, phenothiazines, and metoclopramide. More severe cases require hospital admission and intravenous re- hydration, which often provides immediate relief from nausea. Additional treatment with serotonin (5-​HT3) antagonists such as Ondansetron is of proven benefit. Steroid treatment with prednis- olone 30–​40 mg daily may also provide relief. Thiamine (vitamin B1) supplementation will reduce the risk of Wernicke’s encephalopathy and prophylactic low molecular weight heparin will reduce the risk of thrombosis. Parenteral nutrition is rarely necessary. New onset of nausea and vomiting during the second half of preg- nancy suggests pathology unrelated to hyperemesis and may herald pre-​eclampsia or acute fatty liver of pregnancy. Gastro-​oesophageal reflux is a common problem of late pregnancy that usually improves with antacids or a change in diet. Persistent symptoms can be safely treated with H2-​receptor antagonists or proton pump inhibitors. Increased circulating progesterone levels relax intestinal smooth muscle and commonly provoke constipation, for which increased dietary fibre, lactulose, and avoidance of unnecessary iron supple- ments provide symptomatic relief. Neurological system Headaches are common in healthy pregnancy, and many pregnant women develop migrainous-​type headaches for the first time in early pregnancy. Overall however, migraines have been found to be less frequent and severe during pregnancy. If headaches are recurrent, or do not respond to occasional paracetamol, then regular aspirin 75 mg each evening, or propranolol 10–​20 mg three times daily, or amitryptiline 10–​25 mg nocte can be used as prophylactic meas- ures. Severe, persistent headache that presents for the first time in pregnancy, or is accompanied by focal neurological signs, requires investigation with MRI (see Chapter 14.12). An epidural catheter introduced during labour can lead to acci- dental puncture of the dura and a cerebrospinal fluid leak, which may lead to a postural headache that improves when lying flat. If there is no improvement within 24 hours, then injection of 2–​3 ml of autologous blood at the site of dural puncture (blood patch) usually resolves the headache. Carpal tunnel syndrome affects about 20% of women with healthy pregnancies. It begins during the second half of pregnancy and is more common in women who have excessive weight gain and oe- dema. Pain and numbness in the distribution of the median nerve, affecting the first three fingers can be particularly severe at night and on waking. Wrist splints alleviate symptoms, usually making sur- gical intervention inappropriate as most cases recover within weeks of delivery. Musculoskeletal system Low back and pelvic pain affect about 50% of all pregnancies. A com- bination of mechanical stress on the lumbar spine and pelvis and the effects of relaxin, a hormone produced by the corpus luteum to relax ligaments in anticipation of childbirth, are likely to be responsible. Some women develop radicular symptoms affecting nerve roots and the lumbar sacral plexus, but only 1% develop true sciatica with a dermatomal distribution. Progressive neurological symptoms ne- cessitate further investigations, often with MRI. Some relief can be gained from massage, exercises, or a maternity cushion. Others can obtain relief from transcutaneous electrical nerve stimulation or a trochanteric support belt. Non​steroidal anti-​inflammatory drugs are safe and often effective until 32 weeks’ gestation. Pubic-​symphysis dysfunction due to local joint inflammation and causing intense tenderness develops in up to 5% of pregnant women. Ultrasound guided intra-​articular local anaesthetic with hydrocor- tisone and a lumbosacral support can provide relief, but the condi- tion can persist postpartum, requiring longer-​term orthopaedic and rheumatological follow up. Skin Pruritus is a common symptom of late pregnancy, thought to re- late to increased cutaneous blood flow and dryness. If there is an associated rash, then gestational skin conditions need to be con- sidered (see Chapter 14.13). If itch persists without a rash, then liver function should be checked to exclude intrahepatic cholestasis (see Chapter 14.9). Dietary modification and vitamin/​ mineral supplementation during pregnancy Folic acid In the United Kingdom and the United States of America spina bifida or anencephaly (neural tube defects) affect about 1 in 1000 preg­ nancies. The neural tube develops and then closes within 28 days of conception. Women who take 400 µg folic acid daily around the time of conception and for the first 12 weeks of pregnancy reduce their risk of a pregnancy complicated by neural tube defects by

Section 14  Medical disorders in pregnancy 2580 approximately 70%. In some countries the fortification of food with folic acid provides an extra 100 µg/​day of folic acid, which is also ef- fective in lowering rates of neural tube defects and congenital heart defects. Women who have had a baby affected by spina bifida are advised to take a higher dose of folic acid (5 mg/​day). Multivitamins and other supplements Multivitamin preparations without folic acid do not reduce the risk of neural tube defects. Multivitamins taken periconceptually may reduce the risk of some congenital heart defects, but beyond the first trimester are of no proven benefit for healthy women on a balanced diet. Antioxidant vitamins (vitamin C 1000 mg and vitamin E 400 IU daily) taken from mid-​pregnancy do not reduce the incidence of pre-​eclampsia and have been associated with an increased incidence of low birth weight babies. Women should keep up adequate stores of vitamin  D during pregnancy and when breastfeeding. Women at high risk of vitamin D deficiency should be encouraged to take supplemental vitamin D (10 µg/​day). Supplemental vitamin D may reduce the risk of pre-​eclampsia, low birth weight, and preterm birth. However, the optimal dose of vitamin D, the target concentration of serum 25-​ hydroxyvitamin D and any adverse effects remain to be determined. Certain liver products and vitamin A  supplementation above 700 µg daily increase the risk of embryonic teratogenesis and should be avoided. In the developing world where diet is poor, vitamin A supplements, and zinc improve fetal outcome. See Chapter 14.2 for further discussion. In the developed world, supplemental iron should not be offered routinely, but reserved for those who have a haemoglobin of less than 95 g/litre and a mean corpuscular volume of less than 84 fl in the third trimester. In resource-​poor nations, malnutrition and chronic infection diminish iron stores that are further exhausted during pregnancy. Under these conditions, routine supplemental iron and folate improve maternal and neonatal outcome. See Chapter 14.2 for further discussion. Sea food, fish oils, and long-​chain polyunsaturated fatty acids Women should be encouraged to eat two to three portions of white fish or cooked shellfish each week during pregnancy and breastfeeding. Such a maternal diet is associated with improved neurocognitive development in their offspring. However, ingestion of large fish such as tuna should be avoided, as they retain neuro- toxic heavy metals like mercury. Because of this latter observation many women take supplemental n-​3 long chain polyunsaturated fatty acids (n-​3 LCPUFAs). Current evidence has shown that women who take supplemental n-3 LCPUFAs from 24 weeks’ gestation re- duce the risk of asthma and respiratory infections in their children. N-3 LCPUFA supplements taken during pregnancy may also reduce the risk of preterm birth, but contrary to popular belief, they do not improve a child’s intelligence. Prophylaxis against pre-​eclampsia Pre-​eclampsia is discussed in Chapter  14.4. Low-​dose aspirin 60–​150 mg taken each evening by women at increased risk of pre-eclampsia from 12 weeks’ gestation until childbirth, reduces the incidence of pre-eclampsia by up to 50%. Calcium supplementation (1.5–​2.0 g elemental calcium daily) also reduces the incidence of pre-​eclampsia in women with a low dietary intake of calcium who are at high risk of the condition. However, the dose and timing of calcium prophylaxis and any interaction with vitamin D has yet to be determined. Antioxidant vitamins (vitamin C and vitamin E) should not be used to prevent pre-​eclampsia. Our ability to prevent or treat pre-​eclampsia effectively will remain inadequate until our understanding of its pathophysiology improves. Asymptomatic thyroid disease Neurodevelopment of the fetus depends on maternal thyroid hormone until week 18–​20 of pregnancy, when the fetal thyroid gland becomes functional. Untreated overt maternal hypothyroidism is associated with impaired childhood neurocognitive development, but if treated promptly with thyroxine then pregnancy and childhood outcome is normal. Subclinical maternal hypothyroidism (low T4, normal TSH) has also been associated with reduced child IQ, but so too has subclin- ical maternal hyperthyroidism (high T4, normal TSH). This observa- tion may explain why treating subclinical hypothyroidism has had no impact on childhood neurocognitive performance. Screening for sub- clinical hypothyroidism cannot be recommended, although screening for overt maternal hypothyroidism has clinical merit. Neonates are currently screened for congenital hypothyroidism, a condition far rarer than overt maternal hypothyroidism (see Chapter 14.11). Behavioural habits during pregnancy Exercise Pregnancy outcome is improved by regular exercise throughout pregnancy. The gestational increases in both cardiac output and re- spiratory work are enhanced further by exercise, but the intensity of exercise should not exceed levels to which a woman is accustomed. In late pregnancy non​weight-​bearing exercises such as swimming become easier. Exercise may be harmful to women with impaired cardiac or respiratory function who struggle to fulfil the physio- logical demands of pregnancy alone. Alcohol Heavy alcohol consumption during pregnancy leads to the ‘fetal al- cohol syndrome’ in approximately one-​third of offspring. The sus- ceptibility of the fetus to alcohol depends on genetic vulnerability, the nutritional status of the woman, and her abuse of other drugs. The developmental and neurological abnormalities that make up fetal alcohol syndrome affect approximately one to two per 1000 live births, but there is a spectrum of fetal alcohol disorder that includes infants with less marked neurological impairment, which is likely to be associated with lower levels of maternal alcohol consumption. It is not known whether there is a safe level of alcohol consumption in pregnancy, but evidence suggests that one or two units of alcohol once or twice a week is not harmful to the fetus. Tobacco Women should stop smoking during pregnancy as it impairs fetal growth and increases the risk of poor obstetric outcome. Nicotine gum contains less nicotine than cigarettes and none of the other toxins, making it preferable to smoking during pregnancy. Nicotine patches provide a constant release of nicotine throughout the day that exceeds that of periodic nicotine gum. Pregnant women are

14.3  Medical management of normal pregnancy 2581 advised to remove nicotine patches before they go to bed. Electronic vapour products that deliver nicotine may be less harmful than cig- arette smoking, but their use in pregnancy has not yet been assessed and therefore they cannot be recommended. Caffeine Moderate caffeine consumption is not associated with harm in preg- nancy, but more than six cups of coffee a day increases the risk of miscarriage. Travel Aircraft are pressurized to a maximum oxygen partial pressure equivalent to an altitude of 2440  m (8000  ft) above sea level. During a routine commercial flight, healthy pregnant women (32–​38 weeks’ gestation) increase their heart rate and blood pres- sure and drop their oxygen saturation, but fetal heart rate remains unchanged. Long-​haul flights further increase a pregnant woman’s risk of deep vein thrombosis. Simple thromboprophylaxis with antiembolic stockings, hydration, and mobility, including calf muscle exercise are sufficient for most pregnant women. Low dose aspirin is safe in pregnancy and may have an as-​yet unproven role in reducing the risk of thrombosis in pregnant women during travel. Airlines are reluctant to carry women after 36 weeks’ gestation for the obvious and sensible practical reason that they do not want to deliver a baby in flight. Events after delivery Lactation Breastfeeding is beneficial to the infant. However, the mother who breastfeeds for six months or longer transiently loses 4–​5% of bone density in her lumbar spine. Calcium supplementation does not prevent this transient loss of bone mineral density, which recovers spontaneously six months after delivery whether or not the mother continues to breastfeed. Calcium supplementation does not increase the concentration of calcium in breast milk or the bone mineral status of the infant in the first year of life. Postnatal depression Almost half of all women develop the ‘maternity blues’. This is char- acterized by tearfulness, anxiety, and irritability, starting around the third to fifth postpartum days and usually resolving by the tenth day. About 10% of women develop non​psychotic postnatal depression four to six weeks postpartum, with a maximum incidence at three months postpartum. The depression is similar to that occurring at other times, but is often accompanied by thoughts of harming the baby. Although most women recover without treatment within three to six months, recovery can be hastened by counselling. Women who fail to respond to counselling or who have severe depression may benefit from antidepressant treatment. Although small amounts of tricyclic Fig. 14.3.1  Risk of type 2 diabetes mellitus (T2DM) after gestational diabetes mellitus (GDM). Note that the x-​axis is a log scale. Each solid square represents a relative risk. Horizontal lines indicate 95% CIs. Reprinted from The Lancet, 373(9677), L. Bellamy et al., Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-​analysis, 1773–​9. Copyright © 2009, with permission from Elsevier.

Section 14  Medical disorders in pregnancy 2582 antidepressants and selective serotonin reuptake inhibitors appear in breast milk, breastfeeding should be encouraged. Nonetheless, the in- fant should be watched for possible unwanted effects. Future maternal health Gestational syndromes unmask a woman’s future vulnerability to dis- ease. For example, insulin resistance underlying gestational diabetes mellitus returns to pre-​pregnancy levels immediately postpartum, but affected women have a sevenfold relative risk of future type 2 diabetes in later life compared with women who had a normogly- caemic pregnancy (Fig. 14.3.1). Similarly, both pregnancy-​induced hypertension and pre-​eclampsia are associated with an almost fourfold risk of future hypertension and a twofold relative risk of maternal cardiovascular disease in later life. Proteinuria related to pre-​eclampsia can take up to 12 months to disappear but may be the first sign of previously subclinical renal disease. Similarly, elevated liver transaminases associated with intrahepatic cholestasis of preg- nancy may be the first sign of hepatitis C or other cholestatic liver disease. Women who have had postpartum depression are more likely to suffer depression in later life. Despite the physical demands of pregnancy, most women com- plete an uncomplicated pregnancy and have a healthy baby. This bodes well for maternal health during subsequent pregnancies and for the mother and her offspring in future life. FURTHER READING Alkema L, et al. on behalf of the United Nations Maternal Mortality Estimation Inter-​Agency Group collaborators and technical ad- visory group (2016). Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-​based projections to 2030:  a systematic analysis by the UN Maternal Mortality Estimation Inter-​Agency Group. Lancet, 387, 462–​74. Bellamy L, et al. (2007). Pre-​eclampsia and risk of cardiovascular dis- ease and cancer in later life: systematic review and meta-​analysis. BMJ, 335, 974–​77. Bellamy L, et al. (2009). Type 2 diabetes mellitus after gestational dia- betes: a systematic review and meta-​analysis. Lancet, 373, 1773–​9. Chaiworapongsa T, et al. (2014). Pre-​eclampsia part 2: prediction, pre- vention and management. Nat Rev Nephrol, 10, 531–​40. de-​Regil LM, et al. (2016). Vitamin D supplementation for women during pregnancy (Review). Cochrane Database of Systematic Reviews, 1, CD008873. Garcia-​Rio F, et al. (1996). Regulation of breathing and perception of dyspnoea in healthy pregnant women. Chest, 110, 446–​53. Haines N (2016). Births by Parents’ Characteristics in England and Wales:  2015 Office for National Statistics. https://​www.ons.gov. uk/​peoplepopulationandcommunity/​birthsdeathsandmarriages/​ livebirths/​bulletins/​birthsbyparentscharacteristicsinenglandandwa les/​2016 Knight M, et  al. on behalf of MBRRACE-​UK (2016). Saving Lives, Improving Mothers’ Care—​Surveillance of Maternal Deaths in the UK 2012–​14 and Lessons Learned to Inform Maternity Care from the UK and Ireland: Confidential Enquiries into Maternal Deaths and Morbidity 2009–​14. National Perinatal Epidemiology Unit, University of Oxford, Oxford. https://​www.npeu.ox.ac.uk/​downloads/​files/​ mbrrace-​uk/​reports/​MBRRACE-​UK%20Maternal%20Report%20 2016%20-​%20website.pdf Korevaar TIM, et al. (2016). Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-​based prospective cohort study. Lancet Diabetes Endocrinol, 4, 35–​43. Laurberg P, et al. (2013). Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. Clin Endocrinol, 79, 297–​304. Magnussen EB, et al. (2007). Pre-​pregnancy cardiovascular risk factors as predictors of pre-​eclampsia: population-​based cohort study. BMJ, 335, 978–​82. McParlin C, et al. (2016). Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review. JAMA, 316, 1392–​401. National Institute for Health and Care Excellence (NICE) (2016). Antenatal Care for Uncomplicated Pregnancies. Clinical care guide- line [CG62]. https://​www.nice.org.uk/​guidance/​cg62 Powrie R, Greene M, Camann W (eds) (2010). De Swiet’s ­medical ­disorders in obstetric practice, 5th edition. Wiley-​Blackwell, Oxford. Reece EA (2008). Perspectives on obesity, pregnancy and birth out- comes in the United States: the scope of the problem. Am J Obstet Gynecol, 198, 23–​7. Starling P, et  al. (2015). Fish intake during pregnancy and foetal neurodevelopment—​a systematic review of the evidence. Nutrients, 7, 2001–​14. Williams DJ (2003). Pregnancy: a stress test for life. Curr Opin Obstet Gynecol, 15, 465–​71. World Health Organization (WHO) (2011). Recommendations for pre- vention and treatment of pre-​eclampsia and eclampsia, p. 38. World Health Organization, Geneva.

14.4 Hypertension in pregnancy 2583

14.4 Hypertension in pregnancy 2583

ESSENTIALS High blood pressure (BP >140/​90 mm Hg) complicates approximately 10% of pregnancies and may be due to white coat hypertension, chronic hypertension, gestational hypertension, or pre-​eclampsia (de novo or superimposed on chronic hypertension). Pre-​eclampsia occurs in 2–​8% of pregnancies and remains a common cause of fetal and maternal death in developing countries. Maternal symptoms include headache/​visual disturbances, breath- lessness, epigastric pain, and seizures (eclampsia); signs include pulmonary oedema, liver tenderness, hyper-​reflexia/​clonus, and papilloedema. Treatment of pre-​eclampsia is by timely delivery of the fetus (and placenta) to minimize maternal complications and maxi- mize fetal gestational age, while avoiding morbidity and mortality. Pharmacological treatment to control hypertension is generally given when BP consistently exceeds 150 mm Hg (systolic) or 90 mm Hg (diastolic). Commonly used agents include labetalol, nifedipine, amlodipine, and α-​methyldopa. ACEi, ARBs, and diuretics should not be used in pregnancy. Intravenous magnesium sulphate is given to women at risk of eclampsia. Introduction Hypertensive disorders in pregnancy are the commonest medical disorder complicating approximately 10% of pregnancies. These fig- ures are expected to rise with increasing maternal age and maternal co-​morbidities such as obesity. Hypertension in pregnancy may be classified into white coat hypertension, chronic hypertension, gestational (or pregnancy-​induced) hypertension or pre-​eclampsia; de novo or superimposed on chronic hypertension (see Table 14.4.1). Pre-​eclampsia, a pregnancy-​specific condition associated with hypertension and proteinuria, complicates 2–8% of pregnancies. Over the past few decades within the United Kingdom, maternal deaths from hypertensive disorders in pregnancy have consistently declined. Nonetheless, worldwide they continue to contribute to maternal and perinatal morbidity and mortality. Hypertensive conditions are responsible for approximately one-​ third of severe maternal morbidity in pregnancy. Up to 5% of patients with severe pre-​eclampsia require admission to intensive care and 8–​10% of all preterm deliveries occur as a result of iatrogenic de- livery secondary to pre-​eclampsia. More extreme prematurity (de- fined as delivery <34 weeks’ gestation) occurs in approximately 1 in 250 (0.4%) women with pre-​eclampsia—​and fetal growth restriction as a result of pre-​eclampsia occurs in a quarter of preterm births and up to 20% of term births. Epidemiology Around 2–​8% of pregnancies are complicated by pre-​eclampsia, which occurs in nearly all cases during the second half of preg- nancy. Worldwide, approximately 10 million women develop pre-​ eclampsia annually. According to the World Health Organization, approximately 76 000 women die each year from hypertensive-​ related disorders in pregnancy. Although overall rates of pre-​ eclampsia remain static, rates of severe pre-​eclampsia appear to have increased over recent decades. In the United Kingdom and Ireland in 2010–​2012, pre-​eclampsia was responsible for nine ma- ternal deaths giving a maternal mortality rate of 0.38 per 100 000 maternities. Worldwide, severe pre-​eclampsia is commoner ran- ging from 4% of all deliveries up to 18% of all deliveries in some African countries. In Latin America, pre-​eclampsia remains the leading cause of maternal death. In developing countries, women are seven times more likely to have a pregnancy complicated by pre-​eclampsia compared with women in developed countries. Around 10–​25% of these cases will result in maternal death. Furthermore, the condition increases perinatal mortality fivefold, largely through iatrogenic prematurity. Approximately 500 000 babies are thought to die annually as a result of hypertensive dis- orders. Post-​partum, pre-​eclampsia and its complications are a common reason for post-​partum admission to high dependency or critical care. Aetiology • Pre-​eclampsia occurs from impaired trophoblast differentiation and invasion in early pregnancy. This stimulates a sustained oxi- dative stress and a systemic inflammatory response. 14.4 Hypertension in pregnancy Fergus McCarthy

Section 14  Medical disorders in pregnancy 2584 • These processes are widely accepted to be influenced by both maternal and fetal genetic composition and environmental factors. • Risk factors for pre-​eclampsia include advanced maternal age (greater than 40  years), a family history of pre-​eclampsia, first pregnancy, previous hypertensive disease in pregnancy, chronic hypertension, chronic kidney disease, autoimmune diseases such as systemic lupus erythematosus, or antiphospholipid syndrome and diabetes. Pre-​eclampsia results from impaired trophoblast differentiation and invasion in the first trimester. As a result of this impaired invasion trophoblast cells are unable to break down the muscularis layer of the spiral arterioles and this results in the development of a poorly formed and ultimately poorly perfused placenta. The uterine spiral artery invasion is limited to the proximal decidua and there is no endovascular trophoblast remodelling in 30–​50% of the spiral ar- teries in the placental bed. This prevents the normal adaptation of spiral arteries to pregnancy and leads to a reduction in blood flow to the intervillous space and both placental hypoxia and ischaemia. The development of pre-​eclampsia is thought to require additional maternal factors. These include environmental (such as obesity and diet) and genetic factors. All these contribute to widespread endothelial dysfunction, which is thought to cause proteinuria and hypertension. Many other factors have been shown to potentially contribute to the development of the syndrome of pre-​eclampsia. Oxygen is a major regulator of trophoblast invasion and altered oxygen tension has been shown to control trophoblast differentiation down the extravillous trophoblast pathway. Most cases of pre-​eclampsia are sporadic but genetic factors also play a role in disease development. Primigravid women with a family history of pre-​eclampsia have a two-​ to fivefold increased risk of developing the disease com- pared with primigravid women with no history of pre-​eclampsia. Placental hypoxia, which may result from the impaired tropho- blast invasion that occurs in pre-​eclampsia, results in an imbal- ance between pro-​angiogenic and antiangiogenic factors due to the excessive secretion of antiangiogenic factors such as soluble fms-​like tyrosine kinase-​1 (sFlt-​1) and a reduction in the release of the pro-​angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). In pre-​eclampsia there is an increase in the levels of placental oxidative stress, and this oxidative stress may mediate endothelial cell dysfunction con- tributing to the pathophysiology of pre-​eclampsia. Other systems/​ molecules implicated in the pathogenesis of pre-​eclampsia include altered plasma levels of cell adhesion molecules (VCAM-​1, ICAM-​ 1, and E-​selectin), which are also significantly elevated in women with pre-​eclampsia; altered plasma levels of nitric oxide; and re- duced prostacyclin (PGI2), a potent antiplatelet and vasodilator compound. Pathogenesis/​Pathology The clinical presentation of pre-​eclampsia is varied but all of its fea- tures can be explained as responses to generalized endothelial dys- function. Headaches, seizures, visual symptoms, epigastric pain, and fetal growth restriction are the sequelae of endothelial dysfunction in the vasculature of target organs, such as the brain, liver, kidney, and placenta. In the cardiovascular system there is an increase in peripheral resistance, resulting in vasospasm and hypertension. Intravascular volume becomes reduced in pre-​eclampsia. This is worsened by the endothelial damage which leads to increased vascular permeability, oedema, and a decrease in central venous/​pulmonary wedge pres- sures. Haematologically, pre-​eclampsia may result in a decrease in platelet count secondary to immunologically mediated consump- tion, but an increase in platelet aggregation and adhesion to vascular endothelial cells occurs. Activation of these cells causes the produc- tion of both inflammatory and oxidative mediators which further augment vascular dysfunction. It is rare for clotting problems to occur in the absence of thrombo- cytopenia. The levels of antithrombin, protein C, and protein S fall in pre-​eclampsia as a result of increased consumption of clotting factors. In the hepatic bed vasoconstriction occurs which may lead to periportal fibrin deposition, haemorrhage, and hepatocellular ne- crosis. This may occur as part of the HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count). Rarely, hepatic in- farction with rupture of the liver capsule may occur. Enhanced vascular sensitivity to angiotensin II and norepineph- rine, resulting in vasoconstriction and hypertension occurs in pre-​ eclampsia. The enhanced sensitivity to angiotensin II may be secondary to increased bradykinin upregulation seen in pre-​eclamptic patients. In pre-​eclampsia there is a reduction in uric acid clearance due to impair- ment of tubular function. Proteinuria of intermediate selectivity occurs as a result of impaired glomerular filtration. The characteristic renal lesion of pre-​eclampsia is glomerular endotheliosis, which involves Table 14.4.1  Classification of hypertension in pregnancy White coat hypertension Blood pressure readings ≥140/​90 mm Hg but only when in a medical setting Chronic hypertension Blood pressure readings ≥140/​90 mm Hg which predate the pregnancy or discovered at <20 weeks’ gestation Gestational (or pregnancy induced) hypertension Blood pressure readings ≥140/​90 mm Hg occurring after 20 weeks’ gestation without proteinuria Pre-​eclampsia; de novo or superimposed
on chronic hypertension Gestational hypertension (≥140/​90 mm Hg on two separate occasions) at least four hours apart and associated with one of: • Proteinuria >300 mg in a 24-​hour collection of urine or a protein creatinine ratio ≥30 mg/​mmol on a spot urine or at least 1 g/​litre (2+ on urine dipstick) • Other maternal organ dysfunction including renal impairment (creatinine >90 µmol/​litre), hepatic involvement (elevated liver transaminases of at least twice upper value of normal), neurological complications (seizure) or haematological complications such as thrombocytopenia. • Uteroplacental dysfunction manifested by fetal growth restriction

14.4  Hypertension in pregnancy 2585 swelling of the glomerular endothelial cells and subendothelial fi- brinoid deposits, which may occlude capillary lumens. Cerebral vasoconstriction may occur in the brain resulting in focal ischaemia and abnormal electrical activity, which may trigger seizures (eclampsia). Eclampsia is the occurrence of one or more convulsions, not attributable to other pathology in a patient with pre-​eclampsia. Previously pulmonary oedema, mainly as a result of iatrogenic fluid administration, was the main cause of mortality in women with pre-​eclampsia. Intracranial haemorrhage is now the leading cause of death in women with pre-​eclampsia. Blindness which may be retinal or cortical in origin is a rare, but usually tem- porary complication of pre-​eclampsia. Clinical features The clinical presentation of pre-​eclampsia can vary; from the asymptomatic patient with incidental findings of hypertension and proteinuria, to the patient presenting with eclamptic seizures. Maternal symptoms and signs of pre-​eclampsia may include: • severe headache and visual disturbances • epigastric pain • hyper-​reflexia and/​or clonus • papilloedema • pulmonary oedema • seizures • placental abruption (1–​4%) • liver (right upper quadrant) tenderness • platelets under 100 × 109/litre • alanine amino transferase more than twice upper value of normal • creatinine more than 90 umol/​litre Fetal effects include oligohydramnios and fetal growth restriction (up to 30%). Differential diagnosis Secondary causes of hypertension should be considered particularly if hypertension is diagnosed in the first half of pregnancy and appro- priate investigations performed if necessary as detailed in Table 14.4.2. In those women with pre-​existing disease it may be extremely difficult to differentiate pre-​eclampsia from worsening renal disease due to pre-​ existing hypertension and proteinuria. A low placental growth factor may help in this differentiation. Clinical investigations • Full blood count may show an elevated haematocrit occurring due to haemoconcentration and/​or thrombocytopenia. • Urea and electrolytes may demonstrate elevated creatinine and/​or uric acid. • Liver function tests may show elevated transaminases which may be part of a HELLP syndrome. Table 14.4.2  Secondary causes of hypertension (see Chapter 16.17.3) System Disease Key diagnostic test/​clinical clues Vascular disorders Renovascular hypertension Renal bruit; renal ultrasound/CT angiography/MR angiography Aortic coarctation Hypertension in upper limbs/​diminished or delayed femoral pulses; echocardiography Endocrine disorders Hyperparathyroidism Hypercalcaemia: abdominal pain, renal stones, nausea vomiting Hyperthyroidism Palpitations, weakness, sweating, anxiety, tremor, intolerance of heat; thyroid function tests Hypothyroidism Weight gain, lethargy; thyroid function tests Phaeochromocytoma Headache, palpitations, sweating; measurement of 24-​hour urine fractionated catecholamines and metanephrines Acromegaly Macrognathia, enlargement of hands and feet; measurement of serum insulin-​like growth factor-​1 Cushing’s syndrome Central obesity, ecchymoses Cushingoid facies, proximal muscle weakness; initially measurement of ACTH Primary hyperaldosteronism Hypokalaemia, metabolic alkalosis; measurement of plasma renin and aldosterone concentrations Renal disorders Diabetic nephropathy Reflux nephropathy History of urinary tract infections Chronic glomerulonephritis Nephritic and nephrotic syndrome Nephrotic syndrome: heavy proteinuria (>3.5 g/​day). Nephritic syndrome: variable degrees of proteinuria with the presence of red cells and/​or white blood cells Polycystic kidney Family history, renal ultrasound Connective tissue disorders Systemic lupus erythematosus Oral ulcers, malar rash, arthritis discoid rash, photosensitivity, raised protein creatinine ratio, presence of ANA, anti-​dsDNA, anti-​Sm, and/​or other extractable nuclear antigens Systemic sclerosis Skin thickening; anti-​topoisomerase I, anticentromere, anti-​RNA polymerase III antibodies Polyarteritis nodosa General symptoms including weakness, fever, arthralgia, fatigue, weight loss, and skin lesions. Systemic signs such as hypertension, renal insufficiency, or neurologic dysfunction

Section 14  Medical disorders in pregnancy 2586 • A coagulation screen (prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR)) is indicated if platelet count and/​or liver function tests are abnormal. • Urine analysis should be performed using either a 24-​hour urine collection or protein creatinine ratio. A protein creatinine ratio greater than 30 mg/​mmol is equivalent to a 24-​hour urine excre- tion greater than 300 mg. • Ultrasound should be performed to estimate fetal weight (and outrule fetal growth restriction) and calculate liquor volume and Doppler indices. This should be performed at the time of diagnosis and then fortnightly depending on the findings. In the presence of intrauterine growth restriction, increased frequency of surveillance is recommended with additional Doppler studies of middle cerebral artery and ductus venosus in addition to umbilical artery Dopplers. Prediction of pre-​eclampsia The National Institute for Clinical Excellence (NICE) guidelines advise that none of the screening methods for pre-​eclampsia have sufficient sensitivity and specificity to be used in clinical practice. Nonetheless, many assays are currently in use in clinical practice. Impedance to flow in the maternal uterine arteries normally de- creases as pregnancy progresses. Increased impedance in the uterine arteries is an early feature of pre-​eclampsia detectable on ultrasound. This increased resistance is thought to reflect high downstream re- sistance due to defective invasion of spiral arteries and failure of these vessels to transform into low resistance vessels. In low-​risk women, the risk of severe pre-​eclampsia is best predicted by eleva- tion of the pulsatility index in the second trimester (sensitivity 78%, specificity 95%). In women at high risk of pre-​eclampsia, the risk is best predicted by elevated resistance index in the second trimester (sensitivity 80%, specificity 78%). Placental growth factor (PIGF), one of the vascular endothelial growth factor family, is an angiogenic, proinflammatory factor pro- duced by trophoblast cells. It is involved in the regulation of vascular endothelial growth factor dependent angiogenesis and is thought to be a secondary marker for placental dysfunction. PlGF levels less than the fifth centile had high sensitivity (0.96; 95% CI 0.89–​0.99) and negative predictive value (0.98; 0.93–​0.99) for the need for de- livery due to the development of pre-​eclampsia in the following two weeks; specificity was lower (0.55; 0.48–​0.61). Other methods used to screen for pre-​eclampsia include meas- urement of pregnancy-​associated plasma protein A at 11–​13 weeks’ gestation. The ASPRE study used an algorithm that combines ma- ternal factors, mean arterial pressure, uterine artery pulsatility index and maternal serum pregnancy-associated plasma protein-A and placental growth factor at 11–13 weeks’ gestation. This combined screening detected 76.6% of cases of preterm pre-eclampsia and 38.3% of term pre-eclampsia at a FPR of 10%. Treatment The treatment for pre-​eclampsia remains timely delivery of the fetus (and placenta) to minimize maternal complications and maxi- mize fetal gestational age while avoiding morbidity and mortality. Pharmacological treatment is aimed at the control of hypertension. No disease-​modifying drugs are currently available that target the placenta or pathophysiological processes causing pre-​eclampsia. The risk of pre-​eclampsia may be reduced by optimization of pre-​ pregnancy health. This may include adjustment of medications to optimize medical morbidities including renal disease, blood pres- sure control in those with chronic hypertension, weight loss, and cessation of potentially teratogenic agents such as warfarin and angiotensin-​converting enzyme inhibitors. Low-dose (60–150 mg) aspirin has been shown to reduce the risk of development of pre-eclampsia in moderate to high-risk woman by approximately 10–15%. The ASPRE study was a multicenter, double- blind, placebo-controlled trial in which 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia were randomly assigned to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Calcium supplementation (≥1 g/​day) in women with low calcium diets has been shown to reduce the chances of having a pregnancy complicated by pre-​eclampsia. Recommendations regarding timing of delivery for women with pre-​eclampsia are based largely around the HYPITAT studies. HYPITAT I, a randomized controlled trial, recruited patients with gestational hypertension or mild pre-​eclampsia with a singleton pregnancy between 36 and 41 weeks’ gestation. The primary out- come was a composite measure of maternal morbidity and mortality. The trial randomized 756 patients to either induction of labour (n = 377 patients) or expectant management (n = 379). 117 (31%) women in the induction group developed poor maternal outcome com- pared with 166 (44%) women in the expectant group (relative risk 0.71, 95% CI 0.59–​0.86, p <0.0001). As a result of this trial, induction of labour is advocated beyond 37 weeks’ gestation in women with pre-​eclampsia. The HYPITAT II trial, an open-​label, randomized controlled trial, focused on women with non​severe hypertensive disorders of preg- nancy between 34 and 37 weeks of gestation. Women were randomly allocated to delivery (induction of labour or caesarean section) within 24 hours (immediate delivery) or expectant management until 37 weeks’ gestation or deterioration of the mother or fetus. The primary outcomes were a composite of adverse maternal outcomes and neo- natal respiratory distress syndrome. The trial recruited 703 women and demonstrated that the composite adverse maternal outcome oc- curred in four (1.1%) of 352 women allocated to immediate delivery versus 11 (3.1%) of 351 women allocated to expectant monitoring (relative risk 0.36, 95% CI 0.12–​1.11; p = 0·069). Respiratory distress syndrome was diagnosed in 20 (5.7%) of 352 neonates in the imme- diate delivery group versus six (1.7%) of 351 neonates in the expect- antly managed group (relative risk 3.3, 95% CI 1.4–​8.2; p = 0·005). This trial demonstrated that the absolute risk of maternal morbidity under 37 weeks’ gestation was low and earlier delivery significantly increased the risk of neonatal respiratory distress syndrome. As a re- sult, most would continue to advocate expectant management with monitoring until the clinical situation deteriorates. Generally, when blood pressure consistently exceeds 150 mm Hg systolic or 90 mm Hg diastolic treatment with antihypertensives is advocated but treatment should be individualized depending on the clinical picture. A systolic blood pressure over 160 mm Hg is a med- ical emergency requiring an immediate response due to the risk of haemorrhagic stroke.

14.4  Hypertension in pregnancy 2587 Commonly used antihypertensive agents in pregnancy are as follows; • Labetolol is a combined β- and α-adrenoceptor blocker. It may be used throughout pregnancy and in the postpartum period. Doses typically range from 100 mg twice daily to 400 mg four times daily. Labetolol is contraindicated in women with asthma. • Nifedipine is a calcium channel blocker. The main side effect is headache which is often most severe after starting the medication. Long-​acting once-​daily preparations may reduce the incidence of headache and help with compliance. The concomitant use of nifedi- pine and magnesium sulphate must be with caution due to the po- tential risk of serious adverse maternal effects such as hypotension. • Amlodipine is another calcium channel blocker which has the advantage of a once-​daily dosage to help improve compliance. Its side effect profile is similar to nifedipine. • α-​Methyldopa, a central acting α-​adrenergic agonist, is a safe medication for use in pregnancy. However, it has a slow onset of action and at higher doses causes sedation and irritability. It should be stopped postnatally as it may cause postnatal depression. Angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, and diuretics should not be used in pregnancy. Angiotensin converting enzyme inhibitors may result in fetal hypocalvaria and renal defects. These drugs have also been associated with growth restriction, prematurity, persistent patent ductus arteriosus, and neonatal anuria. Therefore, patients with pre-​existing hypertension should be commenced on safe alternatives ideally preconception. In the case of severe hypertension, or when oral treatment is not possible, intravenous antihypertensives may also be used. The com- monest intravenous regimens are: • Labetolol given as a bolus of 50 mg over a minimum of five min- utes. This may be repeated to a maximum of 200 mg, at 10-​minute intervals. A labetolol infusion can then be commenced to control blood pressure until oral medication can be administered or has had sufficient time to act. The maintenance rate is 5 mg/​ml at 4 ml/​ hr via a syringe pump, which can be doubled every 30 minutes, up to a maximum of 32 ml (160 mg)/​hour until the blood pressure has dropped and stabilized at an acceptable level. • Hydralazine is an alternative intravenous agent given by bolus in- fusion. The recommended dose is 5–​20 mg over 10–​20 minutes. This may be followed by a maintenance infusion, which runs at 40 mg hydralazine in 40 ml normal saline at a rate of 1–​5 ml/​hour (1–​5 mg/​hour). The Control of Hypertension in Pregnancy Study (CHIPS) was a ran- domized controlled trial in which women with hypertension in preg- nancy (pre-​existing or pregnancy-​induced but not pre-​eclampsia) were randomized to either ‘less tight’ control (aiming for diastolic blood pressure of 100–​105 mm Hg) or ‘tight’ control (aiming for a dia- stolic blood pressure of 80–​85 mm Hg) of their hypertension. The trial demonstrated that women in ‘less tight’ compared with ‘tight’ con- trol groups had similar rates of adverse perinatal (31.4% vs. 30.7%) and maternal outcomes (3.7% vs. 2.0%), despite higher mean diastolic blood pressures by 4.6 mm Hg. However, severe hypertension (≥160/​ 110 mm Hg) developed more frequently in ‘less tight’ (vs. ‘tight’) con- trol (40.6% vs. 27.5%). As a result, tight control of blood pressure is advocated to prevent potential adverse maternal outcomes. When a patient is at risk of eclampsia, magnesium sulphate is the pharmacological agent of choice. Initial treatment is with a loading dose of 4 grams. This is followed by a maintenance infusion of 1 g/​hour continued for up to 24 hours after delivery. Signs of toxicity with mag- nesium sulphate include motor paralysis, absent reflexes, respiratory depression, and cardiac arrhythmia. If signs of toxicity occur magne- sium sulphate should be discontinued, and consideration given to ad- ministration of 10 ml 10% calcium gluconate slowly intravenously to counteract the toxicity. Ninety-​seven per cent (97%) of magnesium sul- phate is excreted in the urine. As a result, when oliguria or acute kidney injury occur, the maintenance dose should be reduced or withheld. Prognosis/​outcome While the severity of clinical presentation of pre-​eclampsia is highly variable, outcomes are usually favourable when pre-​eclampsia de- velops after 36 weeks’ gestation. When preterm pre-​eclampsia occurs (<34 weeks’ gestation), the risk of adverse maternal and peri- natal outcome increases significantly. Outcomes are less favourable in women living in developing countries, regardless of gestation or severity of clinical presentation. With eclampsia 38% of fits occur antenatally, 18% intrapartum, and the remaining 44% postpartum, usually in the first 24–​48 hours. Eclampsia has a high maternal and perinatal morbidity. Nearly one in 50 women with eclampsia die and the rate of stillbirths and neonatal deaths is 22.2/​1000 and 34.1/​1000, respectively. The most common cause of death in women dying with eclampsia is cerebral haemorrhage. The risk of progression from gestational hypertension to pre-​ eclampsia is approximately 20–​30% and increased if the hyperten- sion appears at earlier gestations. Therefore, closer monitoring of these patients is essential. Women with chronic hypertension who become pregnant are at significantly increased risk of adverse pregnancy outcomes. A sys- tematic review demonstrated that women with chronic hyperten- sion had higher pooled incidences of multiple adverse pregnancy outcomes. As a result, heightened antenatal surveillance is required. Increased risks included: • superimposed pre-​eclampsia (26%) • Caesarean section (41%) • preterm delivery less than 37 weeks’ gestation (28%) • birth weight less than 2500 g (17%) • neonatal unit admission (21%) • perinatal death (4%) Those who have been diagnosed with severe pre-​eclampsia are more likely to experience recurrence in their next preg- nancy. However, this is typically less severe with clinical presen- tation usually approximately two to three weeks later in gestation. Women who have experienced severe early onset pre-​eclampsia necessitating delivery at less than 34 weeks, especially if complicated by growth restriction or late fetal loss, should undergo testing for antiphospholipid syndrome. It may be necessary to discuss the im- plications of these results on future pregnancies. Special circumstances Women with pre-​eclampsia are at high risk of fluid overload and subsequent pulmonary oedema. Fluid management should be

Section 14  Medical disorders in pregnancy 2588 closely monitored, and total input should not exceed 80 ml/​hour (approximately 1 ml/​kg/​hr). Oxytocin, if required, should be used at high concentrations, and included as part of the total fluid input. When oliguria occurs, caution should be exercised, and boluses of fluid and diuretics avoided if possible. Most of these patients re- cover spontaneously, provided delivery is expedited. Following delivery and resolution of symptoms, women should be reviewed six to eight weeks postpartum to ensure resolution of hypertension and blood abnormalities. Women should also be debriefed in the case of complicated deliveries, educated re- garding modifiable risk factors, and counselled regarding their increased risk of later hypertension (3.7 times higher risk), cor- onary heart disease (2.2 times increased risk) and stroke (1.8 times higher risk). Areas of uncertainty, controversy,
and future developments The prediction of pre-​eclampsia remains elusive with established assays having poor sensitivity and specificity. To date, no pharma- cological therapies exist for the prevention or treatment of pre-​ eclampsia. Statins for the treatment of pre-​eclampsia are currently being trialled in randomized trials in the United States and United Kingdom. An increasing body of evidence supports the association of pre-​eclampsia with long-​term adverse cardiovascular health. It is unclear whether women with pre-​eclampsia should be offered any interventions such as angiotensin-​converting-​enzyme (ACE) inhibitors, statins, or low-​dose aspirin in the postpartum period to reduce these long-​term risks. FURTHER READING Bramham K, et al. (2013). Postpartum management of hypertension. BMJ, 346, f894. Bramham K, et al. (2014). Chronic hypertension and pregnancy out- comes: systematic review and meta-​analysis. BMJ, 348, g2301. Broekhuijsen K, et  al. (2015). Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-​II): an open-​label, random- ised controlled trial. Lancet, 385, 2492–​501. Brown MA, Magee LA, Kenny LC, et al. (2018). Hypertensive dis- orders of pregnancy: ISSHP classification, diagnosis, and manage- ment recommendations for international practice. Hypertension, 72(1), 24–43. Koopmans CM, et al. (2009). HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension or mild
pre-​eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-​label randomised controlled trial. Lancet, 374, 979–​88. Magee LA, et al. (2015). Less-​tight versus tight control of hypertension in pregnancy. N Engl J Med, 372, 407–​17. National Institute for Health and Clinical Excellence (NICE) (2010). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. https://​www.nice.org.uk/​guidance/​CG107 Rolnik DL, Wright D, Poon LC, et al. (2017). Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med, 377(7), 613–22.

14.5 Renal disease in pregnancy 2589

14.5 Renal disease in pregnancy 2589

ESSENTIALS Pregnancy leads to extensive and complex physiological change in the kidney and renal system. Acute kidney injury—​The causes of acute kidney injury in preg- nancy are as those in the non​pregnant patient, but additional pregnancy-​related pathologies need to be considered including pre-​eclampsia and HELLP syndrome. Microangiopathic haemo- lytic anaemias (haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura) are rare but can be triggered by preg- nancy or the post-​partum state. Chronic kidney disease—​Failure of the renal system to adapt to pregnancy is hypothesized to lead to the increase in adverse ma- ternal and fetal outcomes seen in women with chronic kidney dis- ease. Chronic kidney disease severity, hypertension, proteinuria, and underlying systemic disease all contribute to pregnancy outcome. All women with chronic kidney disease should take low dose aspirin for prophylaxis of pre-​eclampsia. Pre-​existing hypertension and pro- teinuria complicate the diagnosis of pre-​eclampsia in pregnancy and there is no consensus definition for superimposed pre-​eclampsia. In the absence of obstetric indications for surgical delivery, vaginal delivery is the optimum mode of delivery in chronic kidney disease. Angiotensin-​converting enzyme inhibitors, angiotensin receptor antagonists, and mycophenolate mofetil are fetotoxic/teratogenic and should not be used in pregnancy. Urinary tract infection—​Asymptomatic bacteriuria affects 2–​10% of pregnant women and is associated with increased risks of symp- tomatic infection, preterm birth, low birth weight, and perinatal mortality. Antibiotic treatment mitigates these risks. Renal physiology in pregnancy The physiological adaptation to pregnancy includes gestational changes to the morphology and function of the kidney and renal system. The complexity of the renal response to pregnancy is shown in Table 14.5.1. Women with chronic kidney disease (CKD) are known to have an increased risk of adverse pregnancy outcomes compared to women without kidney disease. Although maladaptation of the kidney in one or more of the elements listed in Table 14.5.1 is hypothesized, the pathological mechanisms by which chronic kidney disease im- pacts pregnancy remain poorly understood. Acute kidney injury in pregnancy Epidemiology The incidence of acute kidney injury (AKI) in pregnancy is affected by the socioeconomic status of the population studied. In low-​ and middle-​income countries, acute kidney injury in pregnancy consti- tutes 25% of referrals for renal replacement therapy. In contrast, in the developed world acute kidney injury is estimated to complicate 1–​2% of obstetric hospital admissions; but when it develops, it is as- sociated with increased morbidity and mortality. Diagnosis and causes Diagnosis of acute kidney injury in pregnancy is difficult given the physiological changes to glomerular filtration and serum cre- atinine (see Table 14.5.1). The fall in serum creatinine in pregnancy means that a ‘normal’ laboratory value can mask kidney injury. A new serum creatinine of greater than 90 µmol/​litre in pregnancy should trigger investigation for acute kidney injury. For women with chronic kidney disease, there is no diagnostic definition for superimposed acute kidney injury. However, the physiological changes of pregnancy should lead to a fall in creatinine (see Table 14.5.1) and creatinine values that are higher than those measured pre-​pregnancy should be investigated. In addition, urine output parameters are changed by pregnancy, particularly in the context of pre-​eclampsia when oliguria is common. A post-​partum diuresis is also normal, likely mediated by atrial natriuretic peptide (ADH) (see Table 14.5.1). Causes of acute kidney injury in pregnancy mirror those outside of pregnancy with the addition of pregnancy-​specific aetiologies (see Table 14.5.2). The most common causes for acute kidney injury in pregnancy are pre-​eclampsia, sepsis, haemorrhage, and the use of nonsteroidal anti-​inflammatory drugs, which are commonplace in post-​partum analgesic protocols. Clinical approach The clinical approach to a pregnant woman with acute kidney injury is outlined in Table 14.5.3. 14.5 Renal disease in pregnancy Kate Wiles

Section 14  Medical disorders in pregnancy 2590 Acute kidney injury develops in 1–​2% of pre-​eclampsia, but the incidence of pre-​eclampsia means that pre-​eclampsia is the com- monest glomerular disease in the world. Pre-​eclampsia leads to endothelial swelling termed ‘glomerular endotheliosis’, which is pro- portional to the severity of the underlying disease. Reduced perme- ability of the glomerular capillary is hypothesized to lead to reduced glomerular filtration and acute kidney injury. Fluid balance assessment is complicated by the presence of pre-​eclampsia. Oliguria is common and may not indicate volume depletion. In addition, a fluid challenge cannot be used to im- prove uteroplacental perfusion and intravenous hydration in pre-​ eclampsia is associated with pulmonary oedema and maternal morbidity and mortality. Oliguria should not be aggressively man- aged, as there is no evidence that this prevents severe acute kidney Table 14.5.1  The renal response to pregnancy Renal system changes in pregnancy Effect Details Morphology Kidney size Increase in renal size 1–​2 cm. Ureters Physiological dilatation of 8 mm (left) and 20 mm (right). Bladder Distention limited by fetus. Plasma flow Increased by up to 80%. Glomerular filtration Creatinine clearance Increased by 25% at four weeks and by 50% by 16 weeks’ gestation. Fall towards pre-​pregnancy values at term. Serum creatinine Lower in pregnancy due to increased clearance. Average value in pregnancy 53 µmol/​litre. eGFR Creatinine based formulae are not valid in pregnancy. MDRD and CKD-​EPI underestimate, Cockcroft-​ Gault overestimates GFR in pregnancy. Cystatin Concentrations increased in second trimester, not useful as a marker of GFR in pregnancy. Endocrine changes Relaxin Secreted by the corpus luteum, temporal association with the pregnancy rise in GFR. Progesterone Hypothesized as a placental mediator of renal adaptation in pregnancy. Nitric oxide Hypothesized role in renal pregnancy adaptation in animal models. Endothelin Endothelin type B receptor hypothesized as a mediator of relaxin and nitric oxide induced vasodilatation in pregnancy. ADH Increased production and secretion at lower blood pressure leads to water retention in pregnancy. ANP Attenuated response to volume expansion in pregnancy. Increased post-​partum causing natriuresis. Renin-​angiotensin-​ aldosterone Systemic activation in normal pregnancy. Paradoxical suppression in pre-​eclampsia therefore activating antibodies hypothesized as a driver of pre-​eclamptic hypertension. Protein handling Change in glomerular ionic charge and saturation of tubular reabsorption leads to increased protein excretion up to 300 mg/​24 hours or PCR 30 mg/​mmol. Tubular function Glucose Increased filtered load and reduced tubular reabsorption lead to glycosuria. Potassium Reduced excretion due to anti-​mineralocorticoid action of progesterone. But serum levels same/​lower as non​pregnant. Acid-​Base Increased ventilation leads to a respiratory alkalosis. Fall in serum bicarbonate to 18–​20 mmol/​litre compensates. Uric acid Decreased tubular reabsorption leads to fall in serum levels. Increased in pre-​eclampsia but not diagnostic. Calcium Increased excretion and urine saturation. Simultaneous increase in glycoprotein excretion protects against stone formation. CKD, chronic kidney disease; GFR = glomerular filtration rate; eGFR = estimated glomerular filtration rate; ADH = antidiuretic hormone; ANP = atrial natriuretic peptide; MDRD, modification of diet in renal disease. Table 14.5.2  Aetiology of AKI in pregnancy Gestation Early Mid-​Late Post-​partum Any Hyperemesis Pre-​eclampsia and HELLP Post-​partum haemorrhage Drugs Septic abortion/​miscarriage Placental abruption Chorioamionitis Sepsis Ureteric obstruction NSAIDs Intravascular volume depletion Acute fatty liver of pregnancy Ureteric injury New primary renal disease: lupus, glomerulonephritis HUS/​TTP HUS/​TTP Interstitial nephritis HELLP, haemolysis, elevated liver enzymes, low platelets; TTP, thrombotic thrombocytopenic purpura; HUS, haemolytic uraemic syndrome; NSAIDs, non​steroidal anti-​inflammatory drugs.

14.5  Renal disease in pregnancy 2591 injury and chronic kidney disease, both of which are rare. Fluid restriction to 80 ml/​hour is therefore advised in the peri-​partum period. The presence of acute kidney injury does not change the obstetric management of pre-​eclampsia (see Chapter  14.4), al- though the presence of acute kidney injury in pre-​eclampsia is an indicator of severe disease. Magnesium sulphate can be used for both maternal and fetal indications at the same loading dose of 4 g, although there needs to be a reduction in the maintenance infu- sion from 1 g/​hour to 0.5 g/​hour or less when oliguria and/​or acute kidney injury are present. Particular causes HELLP HELLP is the combination of haemolysis, elevated liver enzymes, and low platelets and is a variant of severe pre-​eclampsia. The in- cidence of acute kidney injury in HELLP is 3–​15% with the risk of acute kidney injury increasing if there are superadded complications such as haemorrhage, abruption, disseminated intravascular coagu- lation, or sepsis. Both glomerular endotheliosis and thrombotic microangiopathy are seen on renal biopsy. Treatment of both severe pre-​eclampsia and HELLP is by delivery of the baby and recovery of laboratory parameters should be anticipated post-​partum. Where recovery is delayed, and platelet consumption and acute kidney in- jury predominate, the possibility a thrombotic microangiopathy such as thrombotic thrombocytopenic purpura (TTP) or haemo- lytic uraemic syndrome (HUS) should be considered. Features that distinguish HELLP from thrombocytopenic purpura and haemo- lytic uraemic syndrome are included in Table 14.5.4. Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura is caused by a con- genital or acquired deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thombospondin type I motif member 13). In pregnancy there is a physiological reduction in ADAMTS13 levels such that thrombotic thrombocytopenic purpura can manifest for the first time, usually in the second or third trimester or during the post-​partum period. The constellation of signs and symptoms include haemolysis with fragments on blood film microscopy, an elevated lac- tate dehydrogenase (LDH), severe thrombocytopenia, neurological dysfunction/​seizures, and fever. In addition, renal impairment is more prevalent in pregnancy-​associated thrombotic thrombocytopenic purpura compared to thrombotic thrombocytopenic purpura out- side of pregnancy, with acute kidney injury rates of up to 80%. Urgent treatment with plasma infusion and/​or plasma exchange is required for thrombotic thrombocytopenic purpura as both maternal and fetal morbidity and mortality are significant. Treatment should not be de- layed in suspected thrombotic thrombocytopenic purpura, but com- menced while serological confirmation is awaited. Haemolytic uraemic syndrome Pregnancy-​associated haemolytic uraemic syndrome tends to pre- sent in the post-​partum period when placental expression of com- plement regulatory proteins is lost. It is classified as an ‘atypical’ Table 14.5.3  The clinical approach to acute kidney injury in pregnancy Assessment Considerations in pregnancy Assessment and treatment of complications of AKI • ECG if K >6.0 mmol/​litre and consider continuous monitoring in a high dependency setting • Intravenous calcium salts and insulin/​dextrose are safe in pregnancy • Normal serum bicarbonate level in pregnancy 18–​20 mmol/​litre • Urea >17 mmol/​litre despite medical management may be an indication for renal replacement due to fetal toxicity Assessment and optimization
of fluid balance • Physiological hypotension in pregnancy, refer to booking BP • Physiological reduction in oncotic pressure • Oliguria common in pre-​eclampsia in the absence of hypovolaemia • Post-​partum diuresis common • Late decompensation of physiological parameters • Heart rate >100/​min and respiratory rate >20/min should be considered significant Medication review Discontinue nephrotoxic medications including post-​partum NSAID analgesia Diagnose aetiology of AKI Consider differential diagnosis of AKI (see Table 14.5.2) and target investigations appropriately Expert opinion Early involvement of a nephrologist/​critical care if: • Fails to respond to initial management • Underlying diagnosis is unclear • Presentation is atypical • Fluid resuscitation >20 ml/​kg needed AKI, acute kidney injury; NSAID, non​steroidal anti-​inflammatory drug; ECG, electrocardiogram; BP, blood pressure. Table 14.5.4  Clinical features of HELLP vs. TTP/​HUS Feature HELLP TTP/​HUS Incidence 1% pregnancies 1 in 25 000 pregnancies Platelets <10 × 109/​litre rare Usually <20 ×109/litre Liver function Transaminitis Pre-​hepatic hyperbilirubinaemia AKI 3–​15% Pregnancy associated TTP: 30–​80% HUS: 100% AKI and end-​stage renal failure common Coagulopathy 20% None ADAMTS13 Normal/​mildly reduced TTP: Circulating antibodies and/​ or deficiency (activity <10%) Complement abnormalities Described HUS: Detected in >80% of women Presentation After
20 weeks TTP: second trimester to post-​partum HUS: Usually post-​partum HELLP, haemolysis, elevated liver enzymes, and low platelets; HUS, haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura.

Section 14  Medical disorders in pregnancy 2592 (non​diarrhoea-​associated) haemolytic uraemic syndrome (aHUS). It is driven by pathological complement overactivity with comple- ment abnormalities detected in most women. The clinical pheno- type is a triad of haemolysis, platelet consumption, and significant acute kidney injury which, in the absence of treatment, progresses to end-​stage renal failure. Eculizumab is an anti-​C5 antibody licensed outside of pregnancy for aHUS. Data in pregnancy are limited but comparable biological agents are used without evidence of terato- genicity, and the benefits of aHUS treatment in pregnancy are likely to exceed risk, although long term outcomes remain unknown. Acute fatty liver of pregnancy Acute fatty liver of pregnancy is a rare obstetric emergency charac- terized by microvesicular hepatic steatosis. Acute kidney injury is a common complication with tubular free fatty acid deposition seen on renal biopsy. Around 3–​4% of women with AFLP require tem- porary renal replacement therapy. Clinical presentation is predom- inantly in the third trimester with prodromal vomiting, impaired liver function, hypoglycaemia, coagulopathy, diabetes insipidus and raised serum ammonia. Management includes supportive care, and recovery of acute kidney injury should be anticipated. Systemic lupus erythematosus Lupus nephritis is a disease of childbearing age and can present de novo or flare during pregnancy. The clinical presentation of acute kidney injury, proteinuria, and hypertension can be difficult to dis- tinguish from pre-​eclampsia and clinical assessment should include careful questioning about systemic symptoms of lupus in addition to other serological markers. Renal biopsy may be indicated in preg- nancy in order to diagnose and manage lupus nephritis, despite an increased bleeding risk during pregnancy (7% vs. 1%). Urinary obstruction Obstructive nephropathy is rare in pregnancy but should be considered, especially in women with a single functioning kidney (including renal transplant), polyhydramnios, or multiple pregnancy, and in those with risk factors for autonomic neuropathy, including women with multiple sclerosis and diabetes with microvascular complications. Diagnosis is complicated by a physiological dilatation of the renal tract in pregnancy (see Table 14.5.1). However, pathological obstruction is suggested on ultrasound imaging if ureteric dilatation is seen distal to the pelvic brim, no decompression is seen with the patient lying prone, and/​or there is an absence of visible ureteric jets. Post-​partum urinary retention is esti- mated to occur in 15% of women. Drugs Drugs should always be considered in the differential of acute kidney injury and establishing a temporal relationship between drug ex- posure and acute kidney injury is important. Proton-​pump inhibi- tors, H2 antagonists, and antibiotics may all be newly prescribed in pregnancy and are recognized causes of acute interstitial nephritis. Chronic kidney disease in pregnancy Chronic kidney disease is estimated to complicate 3% of pregnancies in the United Kingdom, but an increasing prevalence is anticipated in the future due to both increasing maternal age and obesity. Pre-​ pregnancy chronic kidney disease is associated with an increased risk of adverse pregnancy outcomes for both mother and baby. Predictors of adverse outcome in women with chronic kidney dis- ease are given in Table 14.5.5. The interplay between chronic kidney disease, proteinuria, and hypertension is complex and the individual contribution and interaction between these different factors in determining preg- nancy outcome can be difficult to predict. However, women with stage 1 chronic kidney disease have an increased rate of adverse pregnancy outcome even when those with pre-​existing hyper- tension, proteinuria, and systemic disease are removed from the statistical analysis. This suggests that there is a risk conferred by chronic kidney disease per se, although pathogenic mechanisms and potential disease modulators remain elusive. Cohort studies and systematic review data demonstrate a clear, proportional effect of pre-​pregnancy chronic kidney disease severity on pregnancy outcome (see Table 14.5.6). The generic management and the safe use of medication in women with chronic kidney disease during pregnancy are outlined in Tables 14.5.7 and 14.5.8. Table 14.5.5  Predictors of adverse pregnancy outcome in women with chronic kidney disease Factors affecting pregnancy outcome in CKD Details Severity of renal disease (see Table 14.5.6) • Proportional increased risk of adverse pregnancy outcome with increasing stage of pre-pregnancy CKD • Increased risk in pregnancy even with CKD stage 1 • Urea is teratogenic. Consider renal replacement at >17 mmol/​litre Proteinuria • Physiological increase in proteinuria in pregnancy • Increases thromboembolic risk • >1 g/24hr pre-​pregnancy increases risk of preterm delivery and post-​partum decline in renal function, corrected for GFR Hypertension • Common in CKD • Increase in superimposed pre-​eclampsia, preterm delivery, low birth weight, neonatal unit admission, and perinatal death Superimposed pre-​eclampsia • CKD and chronic hypertension both increase risk • Diagnosis complicated by pre-​pregnancy hypertension and proteinuria • Development at preterm gestation increases adverse outcome Previous obstetric history • May predict risk of subsequent pregnancies • Previous pre-​eclampsia increases the risk of future pre-​eclampsia, particularly if it developed at an early gestation CKD, chronic kidney disease; GFR, glomerular filtration rate.

14.5  Renal disease in pregnancy 2593 Specific causes of chronic kidney disease Certain aetiologies of chronic kidney disease warrant specific consideration. Systemic lupus erythematosus Women with lupus nephritis have more complicated pregnancies than women with alternative aetiologies of CKD, despite a matched level of renal impairment. Pre-​existing hypertension, proteinuria, active disease, low serum complement levels at conception, and the presence of antiphospholipid antibodies have all been found to increase adverse pregnancy outcomes. Women are therefore ad- vised to delay conception until six months of disease quiescence on pregnancy safe medication. Women who are positive for SSA(Ro) and SSB(La) antibodies should be counselled regarding congenital Table 14.5.6  Pre-​pregnancy chronic kidney disease and maternal and fetal outcomes (data are % of women affected) Outcome Control* Pre-​pregnancy CKD stage (eGFR ml/​min/​1.73 m2) 1 (>90) 2 (60–​89) 3 (30–​59) 4–​5 (<30) Pre-​eclampsia** 3–8   8 18–​22 40–​47 50–​75 Preterm delivery (<37 weeks) 14 24 30–​51 60–​78

89 Early preterm delivery (<34 weeks)   2   7 21 38 44 Caesarean delivery 27 48 70 78 70 Small for gestational age   7 13 18–​25 19–​40 50-​>90 NICU   6 10 27 44 70 Perinatal death   1   5 10 CKD stage shift or 25% loss of function or need for renal replacement NA 0–​8 0–​13 16–​20 20–​50

Section 14  Medical disorders in pregnancy 2594 lupus syndromes. In 2% of cases the transfer of these antibodies to the fetus is associated with fibrosis of the fetal cardiac conduc- tion pathway leading to congenital heart block. Fetal cardiac scans should therefore be offered to pregnant women who are Ro/​La anti- body positive and the fetal heart rate should be checked at all ante- natal clinic reviews between 20 and 28 weeks. Hydroxychloroquine is safe to prescribe in pregnancy (see Table 14.5.8) and retro- spective data have shown a reduction in the incidence of congenital heart block in Ro antibody positive women with a previously af- fected infant. Neonatal cutaneous lupus is estimated to develop in 5% of infants born to women with Ro/​La antibodies. Women can be reassured that this is a benign, non​scarring rash which should spontaneously resolve, usually within six months. Diabetes mellitus Diabetic nephropathy increases pregnancy risk above that con- ferred by chronic kidney disease stage. Poor periconception diabetic control increases the risk of early pregnancy loss and car- diac, neural tube, and other congenital abnormalities. High dose (4–​5  mg) folic acid should be prescribed for at least 12 weeks prior to conception. Polyhydramnios may be a result of ma- ternal hyperglycaemia or uraemia. Assessment of fetal growth parameters is complicated by the combination of macrosomia due to hyperglycaemia and fetal growth restriction in association with chronic kidney disease and pre-​eclampsia. Maternal mor- bidity due to both microvascular and macrovascular complica- tions needs to be remembered during pregnancy. Proteinuria can Table 14.5.8  Medication use in women with chronic kidney disease in preparation for and during pregnancy and lactation Medication class Drug Advice Antihypertensives Angiotensin-​converting enzyme inhibitors/​angiotensin receptor antagonists • If used for hypertension convert to alternative agent in advance of pregnancy • If used to manage proteinuria consider continuing until positive pregnancy test • Enalapril and captopril: safe in breastfeeding α-/β-blockers • Labetalol: licensed for use in pregnancy and safe in breastfeeding • Bisoprolol and doxazosin: use in pregnancy described, limited safety data Calcium channel blockers • Nifedipine: safe in pregnancy and breastfeeding • Amlodipine: use in pregnancy described, limited safety data in pregnancy, safe in breastfeeding Diuretics • Discontinue in pregnancy • Rare use under expert guidance where benefit outweighs risk Methyldopa • Safe in pregnancy • Discontinue post-​partum due to increased risk of postnatal depression Antiplatelets/​ Anticoagulants Aspirin • Safe in pregnancy and breastfeeding • Low dose (75–​150 mg) should be given to all women with CKD as pre-​eclampsia prophylaxis Low molecular weight heparin (LMWH) • Safe in pregnancy and breastfeeding • Given according to VTE risk (including proteinuria) Warfarin • Teratogenic, convert to LMWH in pregnancy Immunosuppressants Prednisolone • Safe in pregnancy and breastfeeding Calcineurin inhibitors (tacrolimus, ciclosporin) • Safe in pregnancy and breastfeeding • Serums levels fall in pregnancy and should be monitored Azathioprine • Safe in pregnancy and breastfeeding • Used as a non​teratogenic alternative to mycophenolate Hydroxychloroquine • Safe in pregnancy and breastfeeding, associated with a decrease in fetal growth restriction • May reduce congenital heart block in Ro/​La antibody positive women Mycophenolate • Teratogenic • Switch to azathioprine prior to pregnancy • Confirm disease/​transplant stability prior to conception (≥3 months) Cyclophosphamide • Teratogenic in first trimester Biologic agents • Data limited, no long-​term outcome data • No evidence of teratogenesis to date • Neonate may be immunosuppressed, and live vaccines should be avoided for
six months CKD complications Erythropoietin • Safe in pregnancy and breastfeeding • Monitor blood pressure • Anticipate increased requirements in pregnancy Vitamin D • Safe in pregnancy and breastfeeding Statins • Discontinue in pregnancy CKD, chronic kidney disease; LMWH, low molecular weight heparin; VTE, venous thromboembolism.

14.5  Renal disease in pregnancy 2595 increase dramatically and produce a maternal nephrotic syndrome during pregnancy. Low molecular weight heparin for prophylaxis of venous thromboembolism should be given to pregnant women with significant proteinuria (see Table 14.5.7). Reflux nephropathy An underlying diagnosis of reflux nephropathy also contributes to adverse outcomes. Historically, higher rates of fetal loss were seen for the degree of renal impairment, although there are limited contem- porary data. Rates of recurrent urinary tract infection are high, and it is advised that urine culture is performed at every antenatal appoint- ment. The heterogenous nature of studies examining both asymp- tomatic and symptomatic urine infection in pregnancy mean there is little consensus as to required length of treatment. Given the in- creased risk to pregnancy associated with urine tract infection, seven days of antibiotic treatment is advised although longer courses may be needed for pyelonephritis. Antibiotic prophylaxis in pregnancy should be considered for women with recurrent urinary tract infec- tions, after a single episode of pyelonephritis in pregnancy and for all women with a history of reconstructive bladder surgery. Given that a reflux nephropathy may have a genetic aetiology, women should be advised of the increased risk of reflux in their children, which may warrant specialist input if urinary tract infection occurs. Autosomal dominant polycystic kidney disease Most women with autosomal dominant polycystic kidney disease have either no measurable or mild renal disease during their child- bearing years. Without the complications of advanced chronic kidney disease, pregnancies tend to be successful, although an in- creased risk of pre-​eclampsia remains. Enlarged cystic kidneys do not affect fetal growth but both urinary tract and cyst infection are more common in pregnancy and surveillance should be undertaken. Women and their partners should be counselled pre-​pregnancy re- garding the 50% risk of disease inheritance in their offspring. Immunoglobulin (IgA) nephropathy IgA nephropathy is the most prevalent glomerular disorder in women of childbearing age. Although severity of chronic kidney disease, hypertension, and proteinuria will impact on pregnancy, IgA disease is usually associated with a good outcome. Retrospective cohort data suggest that pregnancy is not an independent risk factor for disease progression in women with IgA nephropathy. Pregnancy and dialysis End-​stage renal failure is associated with impaired fertility attrib- uted to low oestradiol and progesterone levels, an absent surge of lu- teinizing hormone, and increased prolactin levels. In addition, most women with end-​stage renal disease describe symptoms of sexual dysfunction. Pregnancy in women on dialysis is therefore rare, al- though case report data suggest that more intensive, nocturnal haemodialysis may be associated with an increase in fertility. Registry data gives an overall incidence of 3.3 pregnancies per 1000 person-​ years in more recent female dialysis cohorts, with the highest preg- nancy rates for women aged 20–​29. In general, pregnancy outcomes for women on dialysis continue along the spectrum of increasing adversity with more advanced renal impairment (see Table 14.5.6). However, data from a Canadian cohort that received intensified haemodialysis for 37–​56 hours per week during pregnancy resulted in a live birth rate of 85%, compared to 48% in women who received up to 20 hours per week. In addition, increasing time on dialysis during pregnancy is associated with a higher birth weight, more ad- vanced gestational age, and a reduction in hypertensive complica- tions during pregnancy. Pregnancy and renal transplantation In the United Kingdom, 200–​600/​million women of childbearing age have a renal transplant, and in the United States 5–​12% of trans- plants are performed in women of childbearing age. Pregnancy in renal transplant recipients is therefore increasingly common, and 30–​40 such pregnancies occur each year in the United Kingdom. Women with a renal transplant should have access to contracep- tive advice and pre-​pregnancy counselling to allow for informed decision-​making and to ensure graft stability and optimization of all relevant medical comorbidity prior to pregnancy. Conception is not advised within the first year following transplantation when both the risk of acute rejection and immune suppressant drug doses are higher, and confirmation of graft stability is more difficult. However, for women with stable renal transplants for more than one year and good graft function, there is no evidence that pregnancy will in- crease their risk of graft rejection or lead to a deterioration in graft function. The management of the renal transplant recipient and the safe use of medication in pregnancy mirror that of the chronic kidney disease population (see chronic kidney disease in pregnancy and Tables 14.5.7 and 14.5.8). Like women with any chronic kidney disease, the rates of ma- ternal and fetal complication in pregnancy are dependent upon pre-​pregnancy graft function, hypertension, and proteinuria (see Table 14.5.5). There are conflicting data about whether steroid and calcineurin inhibitor exposure increases the risk of gesta- tional diabetes due to both ethnicity and contemporary changes to immunosuppressant regimens complicating cohort data ana- lysis. However, screening for gestational diabetes is advocated for women with transplants. Although approximately one-​third of women will have a rise in their creatinine during pregnancy, the most common cause for this is pre-​eclampsia. The incidence of graft rejection during pregnancy in cohort and meta-​analysis studies is estimated to be 2–​5%. Although the available data pre- vent direct comparison with the background population, this rejection rate is thought to be comparable to that of the non-​ pregnant transplant population and is not increased by pregnancy or in the post-​partum period. Renal transplantation is not a contraindication to vaginal delivery. The risk of trauma to the renal graft during caesarean delivery is estimated to be 1–​2% and it is advised that all transplant recipients have access to a multidisciplinary assessment during pregnancy, including both obstetric and transplant surgical teams, in order to plan a delivery in the event of either elective or emergency caesarean delivery. Management of pregnancy in women who have undergone kidney-​pancreas (SPK) transplantation is more complex due to the need for surveillance of two grafts, and higher rates of infection, graft obstruction, and pre-​eclampsia compared to women with a single organ renal transplantation. The microvascular and macrovascular comorbidity of previous long-​standing diabetes must also be con- sidered and managed in pregnancy. Multidisciplinary care should be provided by a team with expertise in managing SPK and pregnancy.

Section 14  Medical disorders in pregnancy 2596 Urinary tract infection Asymptomatic bacteriuria The incidence of asymptomatic bacteriuria is 2–​10% in both preg- nant and non​pregnant young women, but it is two to three times more common in pregnant women with diabetes. It is associated with increased risks of preterm birth, low birth weight, and peri- natal mortality, and—​if not treated—​40% of women with asymp- tomatic bacteriuria will develop acute symptomatic infection during pregnancy, including acute pyelonephritis. A Cochrane review of 14 studies found that antibiotic treatment (compared to placebo or no treatment) is effective at reducing the risk of pyelonephritis (RR 0.23, 95% CI 0.13–​0.41), reducing the incidence of low birth weight (RR 0.64, 95% CI 0.45–​0.93) and preterm birth (RR 0.27, 95% CI 0.18–​0.53). Screening for asymptomatic bacteriuria should be performed at 12–​16 weeks’ gestation or at the first prenatal visit (if later). If this is negative, then no further screening is required, except in women thought to be at high risk of infection (e.g. urinary tract abnormal- ities, preterm labour, receiving immunosuppression). Escherichia coli is responsible for over 75% of cases of bacteriuria in pregnancy. If treatment is to be given, then the choice of anti- biotic should be determined by the sensitivity of the organism iso- lated. Amoxicillin and cephalosporins are safe in pregnancy, as is nitrofurantoin, except if close to delivery due to a rare association with neonatal haemolysis. Trimethoprim is contraindicated in the first trimester (folate antagonist) and quinolones are avoided in pregnancy (they cause arthropathy in animal studies). There is no good evidence to determine the first choice of antibiotic (pending culture results) or the duration of treatment. The United Kingdom Health Protection Agency guidelines recommend a one-​week course of antibiotic, but three-day and single-dose (fosfomycin) regimens are also described. Urine culture should be performed one week after treatment is stopped and monthly thereafter until delivery. About 25% of patients will suffer recurrent infection and require a second course of treatment, with 15% continuing to have positive cultures thereafter, for which suppressive therapy with a nocturnal dose of nitrofurantoin or cephalexin is often recom- mended, although there is no strong evidence that this is better than continued close surveillance with treatment of infection if detected. After delivery, there is no indication for urinary/​renal investiga- tion in women who were found to have asymptomatic bacteriuria, in the absence of other complicating factors. Symptomatic infection Acute cystitis affects about 1% of pregnant women. Treatment is as for asymptomatic bacteriuria, with the aim of abolishing symp- toms and preventing acute pyelonephritis. A  Cochrane review that included nine studies of antibiotic treatment of symptomatic urinary infection in pregnancy concluded that there were no signifi- cant differences between any of the treatments studied (except that cefuroxime was better than cephradine) and was unable to recom- mend any particular regimen. Acute pyelonephritis presents with the same symptoms as it does in patients who are not pregnant, including flank pain, nausea/​ vomiting, fever (>38 °C), tenderness in the renal angle, with or without symptoms of cystitis (see Chapter 21.13). However, the dif- ferential diagnosis in pregnancy includes uterine fibroid degener- ation and placental abruption, and distinction from appendicitis can be particularly difficult. Complications include anaemia (23%), bac- teraemia (17%), and respiratory failure due to adult respiratory dis- tress syndrome (7%, higher in severe cases). Preterm labour occurs in about 4% of mild cases and 20% of severe cases. Treatment is usually with intravenous antibiotics (choice as determined by likely local re- sistance patterns, typically co-​amoxiclav (amoxicillin–​clavulanate) or a third-​generation cephalosporin) in the first instance, switching to oral therapy after the patient has improved and been afebrile for 24 h, continuing to complete a 10-​ to 14-​day course. Pyelonephritis recurs in 5–​10% of women during pregnancy, hence it is important to continue close monitoring for evidence of recurrent urinary in- fection, with or without instigating prophylactic treatment with a single daily dose of nitrofurantoin or cephalexin. FURTHER READING Blom K, et al. (2017). Pregnancy and glomerular disease: a system- atic review of the literature with management guidelines. CJASN. doi: 10.2215/CJN.00130117. Bramham K, et al. (2013). Pregnancy in renal transplant recipients:
a UK national cohort study. CJASN, 8, 290–​8. Bramham K, Nelson-​Piercy C (2016). Pregnancy and renal physiology. In: Turner NN, et al. (eds) Oxford textbook of clinical nephrology, 4th edition, Chapter 294. Oxford University Press, Oxford. Deshpande NA, et al. (2011). Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-​analysis. Am J Transplant, 11, 2388–​404. Kendrick J, et al. (2015). Kidney disease and maternal and fetal out- comes in pregnancy. Am J Kidney Dis, 66, 55–​9. Nevis IF, et al. (2011). Pregnancy outcomes in chronic kidney dis- ease: a systematic review. CJASN, 6, 2587–​98. Piccoli GB, et  al. (2015). Risk of adverse pregnancy outcomes in women with CKD. J Am Soc Nephrol, 26, 2011–​22. Schneeberger C, Geerlings SE, Middleton P, Crowther CA (2015). Interventions for preventing recurrent urinary tract infection during pregnancy. Cochrane Database Syst Rev, 7, CD009279. Smaill FM, Vazquez JC (2015). Antibiotics for asymptomatic bacteri- uria in pregnancy. Cochrane Database Syst Rev, 8, CD000490. Vazquez JC, Abalos E (2011). Treatments for symptomatic urinary tract infections during pregnancy. Cochrane Database Syst Rev, 1, CD002256. Wiles K, Banerjee A (2016). Acute kidney injury (AKI) in pregnancy and the use of non-​steroidal anti-​inflammatory drugs (NSAIDs). Obstet Gynecol Clin North Am, 43, 747–​65. Wiles K, et al. (2018). Reproductive health and pregnancy in women with chronic kidney disease. Nat Rev Nephrol 14, 165–84.

14.6 Heart disease in pregnancy 2597

14.6 Heart disease in pregnancy 2597

ESSENTIALS Pregnancy is a vasodilator state in which plasma volume and car- diac output increase such that many symptoms and signs of cardiac disease can occur physiologically. Disproportionate symptoms or abnormal signs such as a diastolic murmur require investigation as usual; necessary radiological investigations should not be withheld as the risks to the fetus are generally low. Pre-​pregnancy risk assessment—​this is ideally based on data related to the specific cardiac abnormality, with pre-​pregnancy functional status an important predictor of outcome. Issues of particular note are (1) pregnancy is high risk in pulmonary hypertension or severe left ventricular dysfunction—​effective contraception and termination should be offered; (2) women at risk of aortic dissection are at in- creased risk during pregnancy—​pre-​pregnancy elective replacement of the aortic root should be considered if its diameter at its widest point is greater than 4.5–​5.0 cm, depending on the underlying aeti- ology; β-​blockers and regular echo monitoring should continue through pregnancy. Delivery of the baby—​vaginal delivery is recommended, other than in the presence of a dilated aortic root, aneurysm, or dissection, or if the fetal INR is elevated. Low-​dose infusions of epidural anaesthesia and oxytocic drugs are safe. Heart conditions arising in pregnancy Peripartum cardiomyopathy—​this should be considered in any woman presenting peripartum with dyspnoea or tachycardia. Myocardial infarction—​when occurring in pregnancy, this may be due to coronary dissection: immediate angiography with consider- ation of percutaneous coronary intervention is the management of choice, but thrombolysis is not contraindicated. Pregnancy in women with known cardiac disorders Valve diseases and cardiomyopathies—​(1) symptomatic mitral stenosis—​may be managed medically with diuretics, β-​blockade and maintenance of sinus rhythm; failing this, balloon valvuloplasty is usually successful; (2)  aortic stenosis—​women with satisfactory pre-​pregnancy haemodynamics are at low risk of problems in preg- nancy. (3) Hypertrophic cardiomyopathy—​patients generally tolerate pregnancy well. Congenital cardiac lesions—​low-​risk conditions include atrial septal defect, restrictive ventricular septal defect, and corrected tetralogy of Fallot in the absence of severe pulmonary regurgitation or aortic root dilatation. All cases other than those at low risk should be managed by a multidisciplinary team in a specialist centre. Anticoagulation—​the optimal anticoagulation management of a pregnant patient with a mechanical prosthetic valve is not known. Continued warfarin therapy carries the risk of warfarin embryopathy for the fetus but switching to heparin increases the maternal risk of thromboembolism, although current regimens using low-​ molecular-​weight heparin heparin with monitoring of anti-​Xa levels perform better than historical regimens using unfractionated heparin. Introduction Cardiac disease is the commonest cause of maternal death in the United Kingdom. Historically most of these women had rheumatic mitral stenosis, but in the developed world today the leading causes are sudden adult death syndrome, cardiomyopathy, aortic dissec- tion, and myocardial infarction, followed by congenital heart disease and pulmonary hypertension. Maternal death is fortunately rare, but the proportion of pregnant women who have cardiac disease is increasing, reflecting both the improved survival of adults with con- genital heart disease and changes in pregnancy demographics. Cardiovascular changes in pregnancy Early in gestation the up-​regulation of nitric oxide synthesis by oestradiol causes arterial vasodilatation and a reduction in both systemic and pulmonary vascular resistance. Simultaneously the normal fall in heart rate at the end of the menstrual cycle fails to occur, and the heart rate increases by 10–​20 beats/​min for the dur- ation of the pregnancy. The reduction in afterload and blood pres- sure stimulates an increase in plasma volume and hence preload by activation of the renin–​angiotensin–​aldosterone system. End dia- stolic volume, stroke volume and contractility increase such that 14.6 Heart disease in pregnancy Catherine E.G. Head

Section 14  Medical disorders in pregnancy 2598 cardiac output reaches about 140% of pre-​pregnancy level by mid gestation. These changes combined with the development of the low resistance uteroplacental circulation cause blood pressure (systolic and diastolic) to decline by around 10 mm Hg to a nadir at about 20 weeks, before returning to pre-​pregnancy levels by term (see Chapters 14.1 and 14.4). Although central venous pressure and pul- monary capillary wedge pressure remain unchanged, serum colloid osmotic pressure is reduced by plasma expansion and the pregnant woman is therefore at increased risk of pulmonary oedema. The 50% increase in plasma volume combined with the 25% increase in red cell mass accounts for a haemoglobin level of around 11 g/​dl: the physiological anaemia of pregnancy. Labour, particularly the second stage, is associated with a further increase in cardiac output as pain increases heart rate via the sympa- thetic response and stroke volume is augmented by autotransfusion during contractions and post-​partum. This means that the later stages of labour are a period of high risk for pulmonary oedema. Structural changes to the heart and great vessels occur. Orifice areas of all four valves increase, causing a higher incidence of valvular regurgitation. Changes in the extracellular matrix of the aortic media increase compliance but also, in combination with the increased cardiac output, the risk of dissection. Cardiac clinical features of normal pregnancy Fatigue, dizziness, palpitation, oedema, dyspnoea, and reduced exer- cise tolerance may occur in a normal pregnancy. Pressure of the uterus on the inferior vena cava when supine can significantly reduce pre- load and therefore cardiac output, causing presyncope. Symptoms are rapidly relieved by turning on one side. The increased cardiac output of pregnancy, together with the relative sinus tachycardia and the in- creased tendency to ectopy, may be experienced as palpitation, often particularly when at rest lying down. Physiological hyperventilation of pregnancy is perceived as breathlessness, particularly when speaking, by most women at some point during a normal pregnancy. Normal cardiovascular examination findings in pregnancy are: • increased volume ‘bounding’ peripheral pulses • third heart sound • soft ejection systolic murmur at the left sternal edge • peripheral oedema Abnormal findings that require further assessment include: • fourth heart sound • diastolic murmur Cardiovascular investigation in pregnancy Electrocardiogram The rotated position of the heart causes left axis deviation. Common findings also include the presence of a Q wave and T wave inver- sion in lead III, and inverted T waves in V1 and V2. Changes in autonomic control and ion channel expression result in an increase in corrected QT interval and QT dispersion. Exercise testing Maximal exercise testing is safe for both mother and fetus in a normal pregnancy, with maximal oxygen uptake the same as that of non​pregnant matched controls in non​weight-​bearing (static cycle) protocols. European Society of Cardiology guidelines rec- ommend submaximal testing to 80% of target heart rate in asymp- tomatic pregnant patients with suspected cardiovascular disease. Semi-​recumbent cycle ergometry is usually the most comfortable modality. There is no specific data on the use of exercise testing to diagnose ischaemic heart disease during pregnancy and so sens- ible extrapolation from the non​pregnant data should be used, remembering that non​specific T wave changes can be normal in pregnancy. Pre-​pregnancy testing is useful in risk stratification. Chest radiograph/​Computed tomography The fetal absorbed dose of ionizing radiation is less than 0.01 mGy from a chest radiograph and less than 1 mGy from a chest computed tomography (CT) scan. Maximum recommended total occupational exposure during pregnancy is 1 mGy, the mean annual dose received from background radiation. The threshold dose for fetal malforma- tion is 50–​100 mGy, and while there is no threshold associated with an increased rate of later malignancy, the relative risk is modest at ×1.4 for a dose of more than 10 mGy. Thus, a chest radiograph or CT necessary to make a diagnosis should not be withheld from a preg- nant woman, although lung scintigraphy may be preferred to CT pulmonary angiography in the investigation of possible pulmonary embolism if the chest radiograph was normal. Echocardiogram Echocardiography is safe and useful. Views are standard other than for the absence of a subcostal view in later pregnancy. Normal find- ings include a small increase in the size of all cardiac chambers, mild regurgitation of all four valves, and the presence of a small pericar- dial effusion. Cardiac catheterization Diagnostic cardiac catheterization is rarely indicated in pregnancy, but percutaneous intervention may be required for valvular or cor- onary disease. Most interventional cardiac procedures are asso- ciated with a total maternal exposure of less than 50 mGy (usually 1–​10 mGy), of which c.20% reaches the fetus. External shielding of the pelvis and abdomen is of limited protective value as most fetal exposure is caused by internally scattered radiation. However, fetal doses can be reduced by use of adjunctive imaging modalities such as transoesophageal echo, use of the transradial route for coronary intervention, and imaging of the woman in the first trimester with an empty bladder. A wedge should be placed under one hip during the procedure to prevent aortocaval compression. Magnetic resonance imaging (MRI) MRI avoids ionizing radiation and yields very high-​quality diag- nostic information but is associated with theoretical fetal risk from heat, noise, and electromagnetic fields. If MRI is necessary in

14.6  Heart disease in pregnancy 2599 pregnancy, often for imaging of the aorta, gadolinium contrast is avoided. Pre-​pregnancy assessment and risk stratification In all but the most straightforward cases a planned pregnancy is preferable to one that is unplanned. Prior to pregnancy a full clinical assessment should be made, including measurement of oxygen satur- ation, electrocardiogram (ECG), chest radiography, and echocardio- gram. Pre-​pregnancy functional capacity is an important predictor of a woman’s ability to tolerate pregnancy, with those in New York Heart Association (NYHA) classes I and II generally having a good outcome. Treadmill exercise testing can be useful to define this: achievement of a level of above 7 METS (multiples of resting oxygen consumption) being used empirically by some centres to predict a good outcome. Invasive investigation may also be necessary. An estimate of maternal and fetal risk can then be given, together with recommendations for any medical, interventional, or surgical treatment before conception (Tables 14.6.1 and 14.6.2). Although it is a difficult issue to discuss, it is also important that the prospective mother is fully aware of her expected lifespan and capacity. Maternal In parallel with the known lesion-​specific risks, generic scoring sys- tems can be used to predict the risk of an adverse maternal event, but these are highly population dependent and tend to overestimate risk. The best overall maternal risk predictor is probably the modified World Health Organization risk classification, which integrates all known ma- ternal cardiovascular risk factors, both lesion-​specific and generic. Fetal Maternal baseline NYHA III or IV, cyanosis, left heart obstruction, smoking, anticoagulation, and multiple pregnancy are adverse pre- dictors of fetal and neonatal outcome, especially prematurity and low birth weight. Recurrence risk of any non​monogenic congenital heart disease is 3–​6%, which is up to a 10-​fold increase over the gen- eral population. Affected women should be offered fetal echocardi- ography and families with multiple cases of congenital heart disease should be offered referral to a clinical geneticist. Management—​general principles Antenatal care Women in WHO class I can generally be managed locally, but in all other cases antenatal care should be multidisciplinary either in, or shared with, a specialist centre. Many cardiac drugs are relatively or ab- solutely contraindicated in pregnancy (see Chapter 14.20), and therapy should be reviewed before conception. In general warfarin should be changed to subcutaneous low-​molecular-​weight heparin (with anti-​Xa level monitoring) for the duration of pregnancy, except in the case of mechanical valve replacements discussed later in this chapter. Cardiac surgery during pregnancy Maternal mortality rates are similar to those reported for emergency procedures in non​pregnant patients, but rates of fetal loss associated with cardiopulmonary bypass are high at 15–​33%. Modifications to standard cardiopulmonary bypass may improve fetal outcome, but Table 14.6.1  Classification of maternal risk of pregnancy Risk class Risk of pregnancy by medical conditions I No detectable increased risk of maternal mortality and no/​mild increase in morbidity II Small increased risk of maternal mortality or moderate increase in morbidity III Significantly increased risk of maternal mortality or severe morbidity. Expert counselling required. If pregnancy is decided upon, intensive specialist cardiac and obstetric monitoring needed throughout pregnancy, childbirth, and the puerperium IV Extremely high risk of maternal mortality or severe morbidity; pregnancy contraindicated. If pregnancy occurs termination should be discussed. If pregnancy continues, care as for class III Table 14.6.2  Maternal risk of pregnancy for women with various cardiac conditions Conditions in which pregnancy risk is WHO I • Uncomplicated, small, or mild —​ pulmonary stenosis —​ patent ductus arteriosus —​ mitral valve prolapse • Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage) • Atrial or ventricular ectopic beats, isolated Conditions in which pregnancy risk is WHO II or III WHO II (if otherwise well and uncomplicated) • Unoperated atrial or ventricular septal defect • Repaired tetralogy of Fallot • Most arrhythmias WHO II–​III (depending on individual) • Mild left ventricular impairment • Hypertrophic cardiomyopathy • Native or tissue valvular heart disease not considered WHO I or IV • Marfan syndrome without aortic dilatation • Aorta <45 mm in aortic disease associated with bicuspid aortic valve • Repaired coarctation WHO III • Mechanical valve • Systemic right ventricle • Fontan circulation • Cyanotic heart disease (unrepaired) • Other complex congential heart disease • Aortic dilatation 40–​45 mm in Marfan syndrome • Aortic dilatation 45–​50 mm in aortic disease associated with bicuspid aortic valve Conditions in which pregnancy risk is WHO IV (pregnancy contraindicated) • Pulmonary arterial hypertension of any cause • Severe systemic ventricular dysfunction (LVEF <30%, NYHA III–​IV) • Previous peripartum cardiomyopathy with any residual impairment of left ventricular function • Severe mitral stenosis, severe symptomatic aortic stenosis • Marfan syndrome with aorta dilated >45 mm • Aortic dilatation >50 mm in aortic disease associated with bicuspid aortic valve • Native severe coarctation

Section 14  Medical disorders in pregnancy 2600 consideration should also be given to early delivery, balancing the risk of fetal loss against those of prematurity. Labour and delivery In women in risk classes WHO III and IV, delivery should occur at the tertiary centre with a written management plan in place. Awaiting spontaneous onset of labour is the norm, with induction indicated for the standard obstetric reasons, maternal cardiac decompensa- tion, or for practical reasons, for example when the mother lives far from the intended site of delivery. Current National Institute for Health and Care Excellence guidelines do not recommend antibiotic prophylaxis for delivery. Vaginal delivery is generally recommended. There is not complete consensus on cardiac indications for caesarean section, but these are generally agreed to be: • aortopathy with aortic root more than 4.5 cm or rapidly dilating • aortic dissection • warfarin therapy within the preceding two weeks (although the maternal INR may be normal, the fetus clears warfarin more slowly and may still be at risk of cerebral haemorrhage) Low-​dose epidural anaesthesia does not cause excessive vaso- dilatation, and with adequate volume expansion is the analgesia of choice. Invasive blood pressure monitoring is advisable in women with obstructive lesions (e.g. aortic stenosis), in whom large fluid shifts may be poorly tolerated. Observation and monitoring on a high-​dependency unit may be required for up to one week post-​partum. Specific cardiac conditions in pregnancy Cardiomyopathy Peripartum cardiomyopathy This is defined as an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction to- wards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. It is a diagnosis of exclusion. The left ventricle may not be dilated but the ejection fraction is nearly always reduced below 45%. Incidence in Western countries is 1 in 4000. Risk factors include multiple pregnancy, multiparity, hypertension, increased maternal age, and black ethnicity. The cause of peripartum cardiomyopathy is not known but may involve angiogenic imbalance in the heart due to systemic antiangiogenic signals in late pregnancy combined with inadequate local cardiac proangiogenic defences. It may be that activation of cathepsin D by oxidative stress is involved, leading to proteolytic cleavage of prolactin into a potent antiangiogenic, pro-​apoptotic, and pro-​inflammatory 16 kDa subfragment. Clinical features are those of left ventricular failure; the diagnosis should be suspected in any peripartum woman with dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, or tachycardia. The differential diagnosis in includes pre-​existing cardiomyopathy, valve disease or congenital heart disease, pregnancy associated myocar- dial infarction, pulmonary embolism/​amniotic fluid embolism, and myocarditis. Echocardiography is key in the diagnosis, both to establish left ventricular systolic dysfunction and to exclude other cardiac causes (Fig. 14.6.1). Left ventricular failure is managed conventionally, with oxygen, diuretics, vasodilators (angiotensin-​converting enzyme (ACE) in- hibitors post-​partum only), β-​blockers, and (occasionally) digoxin. There is a high risk of thromboembolism, necessitating the add- ition of a prophylactic or, in high-​risk cases, treatment dose of low-​ molecular-​weight heparin. There is some evidence to support the use of bromocriptine, an inhibitor of prolactin secretion. Patients with LVEF less than 35% are at increased risk of sudden cardiac death which may be temporarily mitigated by use of a wearable cardioverter-​defibrillator device. Patients with haemodynamic instability despite treatment should undergo urgent delivery. Cases refractory to standard medical therapy may require intensive care with inotropic support and con- sideration of a ventricular assist device Extracorporeal membrane oxygenation (ECMO) or cardiac transplantation. Mortality is 9–​15%, usually occurring within three months and predicted by poor NYHA class at presentation, larger left ventricle dimensions, lower ejection fraction (LVEF), and lack of contractile reserve on dobutamine stress echocardiography. Up to 60% of patients recover normal resting left ventricular function, which is crucial to the outcome of a future pregnancy (a) (b) Fig. 14.6.1  Left ventricular dimensions on M mode echocardiogram. (a) Dilated impaired ventricle in peripartum cardiomyopathy. (b) Normal ventricle.

14.6  Heart disease in pregnancy 2601 (Fig. 14.6.2). We counsel against subsequent pregnancy in women whose left ventricular function has not recovered and offer termination of unplanned pregnancy. In those who are NYHA I with a normal resting echocardiogram, we attempt to refine their risk by exercise stress echo- cardiography, judging empirically that women with a normal contractile reserve are less likely to deteriorate during a pregnancy. This, however, will not predict cases of recurrence of the original pathological process and hence a further pregnancy will always involve a degree of risk. Dilated cardiomyopathy DCM is defined by the presence of left ventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions (hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment. PPCM is a form of acquired DCM presenting later in pregnancy or postpartum. Women may present with a pre-​existing diagnosis or de novo in pregnancy when the haemo- dynamic load unmasks limited cardiac reserve. LVEF less than 40% is a predictor of adverse events in pregnancy and less than 30% or NYHA III/​IV clinical status is a contraindication. Management is largely as discussed for peripartum cardiomyopathy, with the important add- ition of consideration of termination of pregnancy for women with worsening symptoms or ventricular function prior to fetal viability. Hypertrophic cardiomyopathy Women with hypertrophic cardiomyopathy generally tolerate preg- nancy well, with outcome predicted by pre-​pregnancy functional status. An asymptomatic woman has a better than 90% chance of remaining so throughout her pregnancy. Reported mortality rates are 0–​1%, with the two deaths in a recent series both being high-​ risk cases who had been advised against pregnancy. Pre-​pregnancy assessment should include exercise testing, echocardiography, and standard assessment of sudden cardiac death risk. Women with a high outflow tract gradient are at increased risk and those with se- vere systolic or diastolic dysfunction should be advised against preg- nancy. Women with moderate diastolic dysfunction may require diuretic treatment if they do not cope with volume expansion. β-​ blockers should be continued and atrial fibrillation cardioverted if it occurs. An implantable cardioverter-​defibrillator is no bar to preg- nancy. During labour cardiac filling pressures should be maintained by fluid infusion, especially in the event of post-​partum haemor- rhage, and any epidural analgesia/​anaesthesia should be low dose and slowly titrated to avoid vasodilatation and hypotension. Ischaemic heart disease In the 10 years from 1994, a small decrease in the female prevalence of hypertension and smoking, combined with an increase in dia- betes and obesity, resulted in an unchanged prevalence of cardio- vascular disease in women. However, the proportion of live births occurring to women in their thirties or older has more than doubled over the last 30 years, such that the prevalence of coronary atheroma in pregnant women is increasing. Known ischaemic heart disease pre-​pregnancy is rare and should be assessed as if risk-​stratifying for non​cardiac surgery. Previous per- cutaneous coronary intervention or coronary artery bypass grafting is no bar to pregnancy if functional status is good and ventricular func- tion normal. Angina presenting in pregnancy should be managed with standard medical therapy, other than a statin as these are teratogenic. Percutaneous coronary intervention is feasible, as just described. Drug eluting stents should be avoided as their safety is unknown in pregnancy and their use would require prolonged dual antiplatelet therapy. Troponin I is unaffected by normal pregnancy and delivery. In the United States myocardial infarction occurs in 3–​6 in 100 000 deliveries, with mortality 5–​7%. Current UK incidence is 0.7/​100 000 pregnancies. Most cases occur in the third trimester, largely peripartum. Risk factors include thrombophilia, infection, twin pregnancy, pre-​eclampsia, and transfusion in addition to standard coronary risk factors. Coronary atheroma is present in ap- proximately half of cases (43–​60%), with the remainder caused by spontaneous dissection, thrombosis, or embolus. In 29% of cases, angiography is entirely normal and coronary spasm the presumed diagnosis; this has been reported following administration of the vasoconstrictor ergometrine to prevent post-​partum haemorrhage (transfusion, listed here as a risk factor, may be a surrogate marker for this). Immediate angiography is the management of choice as it allows percutaneous intervention and appropriate targeting of sec- ondary coronary prevention. Thrombolysis is not contraindicated, but best avoided two weeks peripartum because of the risk of post-​ partum haemorrhage. Aspirin is safe, but there is only case report evidence about other antiplatelet drugs. Aortopathy Dilated aortic root Aortic root dilatation secondary to cystic medial necrosis occurs in association with Marfan syndrome and related disorders, Turner syndrome, familial thoracic aneurysm, bicuspid aortic valve, and repaired tetralogy of Fallot, but has also been reported in healthy pregnant women. Together with hypertension, atherosclerosis, and infection it confers a risk of type A dissection, most commonly in the third trimester or peripartum—​the time of greatest haemodynamic shear stress to the aortic wall. Most of the literature concerns Marfan syndrome, with an overall pregnancy mortality of 1%. It is important to note that although pre-​pregnancy aortic root dimensions less than 4 cm tend to remain 50 40 44% 21% 21% 25% 31% 14% 19% 0% 30 20 10 0 HF symptoms Maternal mortality 1 2 1 2 1 Percentage of women 2 1 2

20% decreased LVEF 20% decreased LVEF at F/U Fig. 14.6.2  Maternal complications in subsequent pregnancy in patients with previous peripartum cardiomyopathy. Group 1, LVEF more than 50% prior to subsequent pregnancy; group 2, LVEF less than 50%. HF, heart failure. From Elkayam U (2002). Pregnant again after peripartum cardiomyopathy: to be or not to be? European Heart J, 23, 753–​6, with permission.

Section 14  Medical disorders in pregnancy 2602 stable during pregnancy, dissection can occur in a non​dilated root, especially if there is a family history. Although the number of re- ported cases is small, the risk in Marfan syndrome appears to in- crease significantly if the aortic root diameter is greater than 4.5 cm, in which case elective aortic root replacement before conception should be considered. The risk of dissection is lower in other conditions, such as bicuspid aortic valve and tetralogy of Fallot, and a pre-​pregnancy threshold of 5 cm is used for prophylactic surgery. In small women an indexed measurement of 2.7 cm/​m2 BSA is more useful. The aorta should be screened by echocardiography and MRI/​CT before conception and by echocardiogram every 4–​12 weeks during pregnancy and the puerperium (Fig. 14.6.3). It is recommended that, regardless of root diameter, all higher risk women are fully β-​ blocked throughout pregnancy. If despite these measures the root dilates rapidly or dissects, the management of choice is caesarean delivery of a viable fetus followed by root replacement. If the fetus is nonviable, surgery should proceed, accepting the risk of fetal loss. Low-​risk cases should have a normal delivery with consideration of an assisted second stage, but caesarean section should be considered when maximum aortic dimension exceeds 4.5 cm. Other obstetric complications of Marfan syndrome include recur- rent miscarriage, preterm rupture of membranes, and post-​partum haemorrhage. Ehlers–​Danlos type IV (associated with aortic in- volvement) confers a significant risk of uterine rupture and is there- fore a contraindication to pregnancy. Coarctation of the aorta Pregnancy is low risk in repaired coarctation as long as there is no aneurysm at the site of repair: MRI or CT should be performed be- fore conception to exclude this. Two recent series reported a single death, by type A dissection, in 104 women (20 unrepaired) under- going 244 pregnancies. The incidence of hypertension is fourfold higher than in the general pregnant population, particularly in those women with a residual or native gradient higher than 20 mm Hg. This should ideally be corrected prior to pregnancy. In the presence of a significant gradient the concerns are dual: maternal hyperten- sion, with risk of aortic dissection and stroke, and hypotension of the fetoplacental unit. Blood pressure should therefore be meas- ured in the right arm and either leg, using β-​blockers as the first line antihypertensive agent to achieve systolic pressures of less than 140 mm Hg in the arm and more than 70 mm Hg in the leg. Delivery should usually be vaginal, with consideration of assisted second stage in the presence of a significant gradient or hypertension, un- less an aneurysm is present. Angioplasty and stenting of coarctation during pregnancy and the puerperium is not recommended because of the increased predisposition to dissection during this period, al- though there are no series from which to estimate risk. Pulmonary hypertension Pulmonary hypertension (mPAP >25 mm Hg at rest or 30 mm Hg on exercise) of any cause is high risk for pregnancy, with maternal mor- tality up to 25%. Effective contraception or termination should be advised. Women who elect to continue should be monitored closely in a specialist centre and advised strongly to reconsider termination should they deteriorate in the first or second trimester. Suggested treatments include bed rest, oxygen, anticoagulation, and targeted pulmonary vascular therapies such as sildenafil, nitric oxide, and prostacyclin analogues, but the evidence is scant. Bosentan is not recommended as it has been associated with animal teratogenesis. One small series reported an improved maternal mor- tality with a regimen of oxygen, heparin before delivery, and war- farin after 48 h; 60% of infants were liveborn, with most premature. Early reports of the use of nebulized iloprost, intravenous prosta- cyclin, and oral sildenafil are optimistic, but numbers are small, and deaths still occur. In the presence of a right-​to-​left shunt (Eisenmenger syndrome), systemic vasodilatation should be avoided as it increases shunting and therefore cyanosis, and thromboembolic prophylaxis should be considered. Admission for bed rest and timing of delivery are determined by the clinical status of the woman. There is no evidence to support the choice of either vaginal or caesarean delivery for cardiac reasons: va- ginal delivery is associated with a lower average blood loss but also increased maternal effort. In practice, early caesarean delivery is often required because of intrauterine growth retardation. In either case regional is preferable to general anaesthesia, as positive pressure ventilation reduces preload. Invasive blood pressure monitoring is required, and oxytocic drugs should be given as a low-​dose infusion, rather than a bolus dose. Monitoring should continue for at least a week after delivery because the risk of sudden death post-​partum is high. Valvular lesions Mitral stenosis This is generally rheumatic in aetiology, occurring predominantly in those born outside the developed world. The volume expansion and tachycardia of pregnancy can unmask a previously clinically silent lesion. Death rates are low but pulmonary oedema or arrhythmia occur in one-​third, particularly those with valve area less than 1.5 cm2 or a history of cardiac events. Medical therapy includes β-​ blockade to increase time for diastolic filling, diuretics, and consid- eration of anticoagulation, as left atrial thrombus has been reported in pregnancy even in sinus rhythm. New atrial fibrillation should be cardioverted promptly. If NYHA III/​IV symptoms develop despite medical therapy, and the valve is morphologically suitable, balloon mitral valvuloplasty is the treatment of choice, being clinically suc- cessful in more than 95% with significantly lower rates of fetal loss than surgery. Aortic stenosis and bicuspid aortic valve Bicuspid aortic valve (Fig. 14.6.3) in the absence of any stenosis or aortic dilatation can be managed as a normal pregnancy. Aortic stenosis is well tolerated if before pregnancy the patient is asymptomatic, has a normal resting ECG, echocardiography shows normal left ventricle function with peak aortic valve gradient less than 80 mm Hg and mean less than 50 mm Hg, and a treadmill ex- ercise test to target heart rate (220 minus age) reveals no ST seg- ment change or arrhythmia and a normal haemodynamic response. Otherwise aortic stenosis should be relieved before conception using balloon dilatation or a tissue valve (if feasible) to avoid mech- anical valve replacement. A recent series reported a 10% complication rate in pregnant women with peak gradient more than 64 mm Hg or valve area less than 1 cm2, and no complications in those with less severe stenosis. The valve

14.6  Heart disease in pregnancy 2603 gradient increases as pregnancy progresses, and failure to do so is a warning sign of ventricular dysfunction. There is benefit in bed rest and β-​blockade if a pregnant woman presents or becomes severely symp- tomatic with dyspnoea, angina, or syncope, but balloon valvuloplasty may need to be considered. Valve replacement during pregnancy car- ries a maternal mortality of 1.5–​6%, and fetal mortality of 30%. Delivery should generally be vaginal, avoiding vasodilatation and fluid shifts, with consideration of caesarean under general an- aesthetic in severe symptomatic cases only. It is unknown whether pregnancy accelerates the progression of congenital aortic stenosis. Pulmonary stenosis This is generally well tolerated, although in severe cases may pre- cipitate right heart failure, tricuspid regurgitation, or atrial ar- rhythmia. Women with a pre-​pregnancy peak echo gradient of more than 64 mm Hg or symptoms should be considered for balloon valvuloplasty or surgery before conception. Balloon valvuloplasty is also possible during pregnancy if symptoms develop. It has been suggested that women with pulmonary stenosis are at increased risk of hypertensive disorders and preterm delivery, but this requires confirmation. Mitral and aortic regurgitation Left-​sided valve regurgitation is generally very well tolerated in pregnancy if ventricular function is normal. The offloading of the left ventricle caused by systemic vasodilatation is beneficial, but diuretics and vasodilators such as nitrates may be necessary in add- ition. ACE inhibitors are contraindicated in pregnancy. Small left-​to-​right shunts Atrial septal defect In the presence of a normal pulmonary vascular resistance an unre- paired atrial septal defect should be well tolerated. The pre-​existing tendency to atrial arrhythmia may increase with the increase in car- diac output. The potential to shunt right to left in combination with the hypercoagulable state of pregnancy increases the risk of para- doxical embolism, especially with increases in intrathoracic pres- sure during labour. There should therefore be a low threshold for the use of compression stockings and prophylactic heparin in the pres- ence of immobility or additional risk factors for venous thrombosis. This also applies to patients known to have a patent foramen ovale. Surgical or device closure of the atrial septal defect removes this risk and if planned should therefore be carried out before pregnancy, al- though there is no evidence to support the same recommendation for patent foramen ovale. Ventricular septal defect or patent ductus arteriosus A small defect with normal right-​sided pressures confers no added risk in pregnancy. Because of the large pressure gradient across the defect paradoxical embolism is extremely unlikely. Large defects causing pulmonary vascular disease (Eisenmenger’s syndrome) are high risk as discussed previously. Complex congenital heart disease For full descriptions of these lesions and their sequelae, see Chapter 16.12. Transposition of the great arteries—​post Mustard
or Senning atrial repair Successful tolerance of pregnancy depends largely on good function of the systemic right ventricle and its atrioventricular valve. In a total of 195 pregnancies reported in 104 women there were two deaths, one heart transplant, and seven women with a permanent reduction in ventricular function or functional class. Atrial arrhythmia occurs in 10–​20%, those with a previous history being at higher risk. There is an increased incidence of miscarriage, prematurity, and low birth weight. More recently, repair has been by the arterial switch oper- ation, following which pregnancy appears to be well tolerated, but the number reported remains relatively small. Congenitally corrected transposition of the great arteries Outcome of this rare condition (where the circulation is physio- logically ‘corrected’, with blood passing from the pulmonary veins to the left atrium, to the right ventricle, to the aorta) depends on systemic right ventricular function and the presence of associated lesions such as complete heart block, ventricular septal defect, or pulmonary stenosis. Fontan operation for univentricular circulation These patients have two separate circulations in series and are there- fore usually not cyanosed, but they experience a chronic low-​output state and are at risk of ventricular failure, atrial arrhythmia, and thrombosis. They are generally anticoagulated with warfarin, which should be converted to full dose low-​molecular-​weight heparin for (a) (b) Fig. 14.6.3  Bicuspid aortic valve (a) in short axis, (b) showing the aortic root measurements used in monitoring.

Section 14  Medical disorders in pregnancy 2604 the duration of pregnancy. Maternal outcome again depends on functional capacity and ventricular function. If these are satisfac- tory and the woman accepts the two to threefold increase in the rate of first trimester fetal loss, then there is no reason to advise against pregnancy, as any deterioration appears to be reversible. Surgically corrected tetralogy of Fallot Women with good functional capacity and no significant haemo- dynamic abnormality tolerate pregnancy well, although the pres- ence of severe pulmonary regurgitation may confer a 20–​30% risk of symptomatic heart failure. If the mother carries del22q11, the re- currence risk is 50%. Cyanotic heart disease without pulmonary hypertension Cyanosis is associated with a poorer outcome for both mother and fetus. The risk of paradoxical embolism should be reduced by appro- priate hydration, mobilization, use of compression stockings, and consideration of thromboprophylaxis. Because cyanosis also con- fers an increased bleeding tendency, full-​dose anticoagulation is not used routinely but only if there is an additional indication. Increased right-​to-​left shunting can occur with the systemic vasodilatation of pregnancy, causing worsening cyanosis. Fetal outcome is dependent on maternal saturation—​the chance of a live birth decreases from 92% with pre-​pregnancy maternal saturation over 90%, to 12% if maternal saturation is less than 85%, and many of these infants are premature or of low birth weight. Prosthetic valves Bioprosthetic valves do not confer increased risk if haemodynamics are normal, and they do not degenerate more rapidly in pregnancy as previously feared. The management of a mechanical prosthesis is far less straightforward because of a conflict of interest between the mother and fetus. Complication rates associated with the alternative anticoagulation regimens are shown in Table 14.6.3. The increased rate of fetal loss associated with all effective anticoagulation may re- flect retroplacental haemorrhage. A relatively safe option for the mother is to remain on war- farin for the duration of the pregnancy, changing to dose-​adjusted unfractionated or low-​molecular-​weight heparin at 36 weeks (to allow the fetus to clear the warfarin) if vaginal delivery is planned, or at 38 weeks for elective caesarean delivery. This strategy is associated with a risk of warfarin embryopathy, which is significantly reduced if the dose required to achieve target INR is less than 6 mg daily. Heparin does not cross the placenta, hence a strategy of sub- stituting heparin for warfarin during the period of organogenesis (6–​12 weeks) abolishes the risk of warfarin embryopathy, but it doubles the maternal thromboembolism rate. Heparin throughout pregnancy has historically been associated with a high risk of thromboembolism but has not always been appropriately dose-​ adjusted. With twice-​daily dosing of low-​molecular-​weight hep- arin and anti-​Xa levels monitored fortnightly, achieving a level of 1–​1.2 IU/​ml 4–​6 h post dose, the thromboembolism rate in one meta-​analysis was only 2%. Arrhythmia Ectopy occurs in most pregnancies, but sustained arrhythmia in less than 1%. A pre-​existing tachyarrhythmia confers a 50% chance of a recurrence of supraventricular tachycardia and 25% of ventricular tachycardia. The principles of diagnosis and management are the same as in the non​pregnant state—​only recurrent symptomatic or life-​threatening arrhythmia should be treated and underlying causes such as thyroid disease should be sought and corrected. Vagal manoeuvres are useful as a first line to diagnose or terminate a narrow complex tachycardia. Adenosine is safe in pregnancy, as is DC cardioversion with fetal monitoring. The risk/​benefit ratio of all drugs should be assessed: no drug is absolutely contraindicated, as maternal haemodynamic instability may result in worse fetal outcome. Bradyarrhythmia is rare; the presence of a permanent pacemaker or implantable cardioverter-​defibrillator is no problem, but the per- manent pacemaker may need to be reprogrammed for delivery. Equipment for temporary pacing during labour is recommended, though not usually needed, for non​paced women with complete heart block. Contraception Barrier methods These are safe for all cardiac patients and have the added benefit of protection against sexually transmitted infections, but reported failure rates are 2–​26 per 100 womanyears. Hormonal methods The oestrogen component of the combined oral contraceptive, whether oral or transdermal, confers an increased risk of thrombosis that is not completely abolished by warfarin. These preparations are therefore contraindicated in women who already have a high thrombotic risk (i.e. pulmonary hypertension, the Fontan circula- tion, older mechanical valves, dilated cardiac chambers with the risk Table 14.6.3  Complication rates (%) of anticoagulation regimens in pregnant women with mechanical heart valves Regimen Maternal thromboembolism Maternal death Fetal abnormality Fetal lossa Source Warfarin to 38/​40, then heparin 4 2 6 34 Chan et al. (2000) Heparin 6–​12/​40, warfarin otherwise 9 4 0b 16 Chan et al. (2000) Heparin throughout 25 7 0 44 Chan et al. (2000) Heparin anti-​Xa adjusted throughout 2 0 0 12c Oran et al. (2004) a Refers to miscarriage, stillbirth, or neonatal death. b If heparin instituted at or before 6/​40. c Miscarriage and stillbirth only.

14.6  Heart disease in pregnancy 2605 of atrial fibrillation, or in cyanosed patients in whom paradoxical embolism may occur). The standard progesterone-​only ‘mini pill’ is safe, but is less reliable than the combined oral contraceptive pill and therefore not the method of choice for women in whom avoidance of pregnancy is critical. Recommended progesterone-​only prepar- ations, more reliable as they act by suppression of ovulation, include daily oral desogestrel, 3-​monthly depot medroxyprogesterone, and a subcutaneous etonogestrel implant (Nexplanon), which is the method of choice for complex congenital heart disease. Women concurrently taking the endothelin antagonist bosentan require additional protection. Intrauterine devices These are not contraindicated, but insertion of the device can be as- sociated with bacteraemia and also a vasovagal response, which can be life-​threatening in a haemodynamically unstable patient such as those with a Fontan circulation or Eisenmenger’s syndrome. Sterilization Sterilization by tubal ligation may be appropriate for women in whom pregnancy would be high risk. However, failure may result in ectopic pregnancy and the surgery is not trivial, especially in women at risk of paradoxical embolism, as it includes a head-​down tilt and distension of the abdomen with CO2. Sterilization of the male partner is not generally advised if he has a much longer potential lifespan than his partner and may therefore wish to father children in a subsequent relationship. See Chapter 14.21 for further discussion of contraception for women with medical diseases. FURTHER READING Bates SM, et  al. (2008). Venous thromboembolism, thrombophilia, antithrombotic therapy, and Pregnancy:  ACCP Clinical Practice Guideline. Chest, 133, 844S–​66S. Bauersachs J, et al. (2016). Current management of patients with se- vere acute peripartum cardiomyopathy: practical guidance from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail, 18, 1096–​105. Beauchesne LM, et al. (2001). Coarctation of the aorta: outcome of pregnancy. J Am Coll Cardiol, 38, 1728–​33. Bush N, et  al. (2013). Myocardial Infarction in pregnancy and postpartum in the UK (UKOSS report). E J Prev Cardiol, 20, 12–​20. Chan WS, Anand S, Ginsberg JS (2000). Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med, 160, 191–​6. Gowda RM, et al. (2003). Cardiac arrhythmias in pregnancy: clinical and therapeutic considerations. Int J Cardiol, 88, 129–​33. Hilfiker-​Kleiner D, et al. (2015). Peripartum cardiomyopathy: current management and future perspectives. Eur Heart J, 36, 1090–​7. James AH, et al. (2006). Acute myocardial infarction in pregnancy: a United States population-​based study. Circulation, 113, 1564–​71. Meijboom LJ, et al. (2005). Pregnancy and aortic root growth in the Marfan syndrome: a prospective study. Eur Heart J, 26, 914–​20. Oran B, Lee-​Parritz A, Ansell J (2004). Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mech- anical heart valves during pregnancy. Thromb Haemost, 92, 747–​51. Presbitero P, et al. (1994). Pregnancy in cyanotic congenital heart dis- ease: outcome of mother and fetus. Circulation, 89, 2673–​6. Silversides CK, et al. (2003). Cardiac risk in pregnant women with rheumatic mitral stenosis. Am J Cardiol, 91, 1382–​5. Silversides CK, et al. (2003). Early and intermediate-​term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol, 91, 1386–​9. Siu SC, et al. (2001). Prospective multicenter study of pregnancy out- comes in women with heart disease. Circulation, 104, 515–​21. Sliwa K, et al. (2010). Current state of knowledge on aetiology, diag- nosis, management and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum car- diomyopathy. Eur J Heart Fail, 12, 767–​78. Sliwa K, et  al. (2017). Clinical characteristics of patients from the worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on PPCM. Eur J Heart Fail, 19, 1131–​41. Steer PJ, Gatzoulis MA, Baker P (eds) (2006). Heart disease and preg- nancy, RCOG Press, London. Task Force on the Management of Cardiovascular Diseases During Pregnancy of the European Society of Cardiology (2011). ESC Guidelines on the management of cardiovascular diseases during pregnancy. Eur Heart J, 32, 3147–​97. Thaman R, et al. (2003). Pregnancy associated complications in women with hypertrophic cardiomyopathy. Heart, 89, 752–​6. Thorne S, MacGregor A, Nelson-​Piercy C (2006). Risks of contracep- tion and pregnancy in heart disease. Heart, 92, 1520–​5. Thorne SA, et al. (2006). Pregnancy and contraception in heart disease and pulmonary arterial hypertension. J Fam Plann Reprod Health Care, 32, 75–​81. Veldtman GR, et al. (2004). Outcomes of pregnancy in women with tetralogy of Fallot. J Am Coll Cardiol, 44, 174–​80. Vitale N, et al. (1999). Dose-​dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol, 33, 1637–​41. Vriend JWJ, et al. (2005). Outcome of pregnancy in patients after re- pair of aortic coarctation. Eur Heart J, 26, 2173–​8. Walker F (2007). Pregnancy and the various forms of the Fontan circu- lation. Heart, 93, 152–​4. Weiss BM, Hess OM. (2000). Pulmonary vascular disease and preg- nancy: current controversies, management strategies, and perspec- tives. Eur Heart J, 21, 104–​15.

14.7 Thrombosis in pregnancy 2606

14.7 Thrombosis in pregnancy 2606

ESSENTIALS Pregnancy and the puerperium are associated with a 10-​fold ­increase in the risk of venous thromboembolism, comprising deep vein throm- bosis and pulmonary embolism, compared to the non​pregnant state. Pulmonary embolism has been the leading direct cause of maternal mortality in most of the United Kingdom’s triennial Confidential Enquiries into Maternal Deaths over the past 30 years, attesting to the importance of prevention and prompt diagnosis and treatment of venous thromboembolism during pregnancy and following delivery. The diagnosis of venous thromboembolism is challenging in preg- nancy because it can be difficult to distinguish features of venous thromboembolism, such as leg swelling and breathlessness, from those of normal pregnancy, and there are no validated clinical scoring sys- tems. It is therefore important to have a high index of suspicion and initiate treatment with low-​molecular-​weight heparin when the diag- nosis is considered, and to objectively confirm or exclude the diagnosis as soon as possible. Compression duplex ultrasonography is required when deep vein thrombosis is suspected. In those with suspected pul- monary embolism and no features of deep vein thrombosis, either ven- tilation/​perfusion lung scanning (provided a chest X-​ray is normal) or computerized tomography pulmonary angiography can be used. Treatment with low-​molecular-​weight heparin should continue for a minimum of three months and until at least six weeks post-​partum. Management around the time of labour and delivery requires close collaboration between obstetricians and anaesthetists, and is particu- larly important when regional anaesthesia is used. Warfarin and direct oral anticoagulants should not be used in pregnancy, but warfarin and heparin can be used in women who are breastfeeding. All women should undergo risk assessment for venous thrombo- embolism in early pregnancy, at the time of hospital admission or change in clinical condition, and after delivery. Women with identi- fied risk factors should be considered for thromboprophylaxis with low-​molecular-​weight heparin in line with national guidelines. Introduction Pregnancy and the puerperium are associated with a 10-​fold in- crease in the risk of venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, compared to the non-​ pregnant state. Pulmonary embolism has been the leading direct cause of maternal mortality in most of the United Kingdom’s tri- ennial Confidential Enquiries into Maternal Deaths over the past 30 years (Table 14.7.1). The prevention, diagnosis, and treatment of venous thromboembolism are therefore important concerns in obstetric practice. This is reflected in a series of guidelines on venous thromboembolism prevention and management from the Royal College of Obstetricians and Gynaecologists. Overall there has been a welcome reduction in the annual incidence of fatal pul- monary embolism in pregnancy and the puerperium in recent years despite an increase in the prevalence of common risk factors for venous thromboembolism such as increasing maternal age and ma- ternal comorbidities, body mass index, and caesarean section. This suggests that changes in obstetric care have been beneficial. Likely 14.7 Thrombosis in pregnancy Peter K. MacCallum and Louise Bowles Table 14.7.1  Direct deaths from thrombosis and thromboembolism and rates per 100 000 maternities (United Kingdom, 1985–​2013) Thrombosis and thromboembolism Number Rate 95% CI 1985–​1987 32 1.41 1.00 1.99 1988–​1990 33 1.40 1.00 1.96 1991–​1993 35 1.51 1.09 2.10 1994–​1996 48 2.18 1.65 2.90 1997–​1999 35 1.65 1.19 2.29 2000–​2002 30 1.50 1.05 2.14 2003–​2005 41 1.94 1.43 2.63 2006–​2008 18 0.79 0.49 1.25 2009–​2011 30 1.26 0.85 1.8 2010–​2012 26 1.08 0.71 1.59 2011–​2013 24 1.01 0.65 1.5 2012–2014 20 0.85 0.52 1.32 2013–2015 26 1.13 0.74 1.65 Data from Knight M, Nair M, Tuffnell D, Shakespeare J, Kenyon S, Kurinczuk JJ (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care - Lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2013–15. Oxford: National Perinatal Epidemiology Unit, University of Oxford 2017.

14.7  Thrombosis in pregnancy 2607 important improvements include: routine risk assessment of women during pregnancy and after delivery, and use of thromboprophylaxis with low-​molecular-​weight heparin (LMWH) in those perceived to be at increased risk of venous thromboembolism; a high index of clinical suspicion for venous thromboembolism in symptomatic women; adoption of LMWH as the preferred modality of treatment for venous thromboembolism; and advances in general obstetric care (e.g. early mobilization after delivery). Aetiology and pathogenesis The increased risk of venous thromboembolism in pregnancy is the result of alteration in the components of Virchow’s triad of venous stasis, prothrombotic changes in the blood, and vessel wall injury. Reduced blood flow in the veins of the lower limbs and pelvis arises from the vasodilator effects of progesterone and other pregnancy-​related hormones, also the obstruction resulting from the gravid uterus. Pregnancy itself is a prothrombotic state, pre- sumably arising as the body prepares for delivery and its attendant bleeding risks. Well described procoagulant changes (increases in fibrinogen, factor VII, factor VIII, and von Willebrand factor), re- duced fibrinolytic activity (elevated plasminogen activator inhibi- tors) and reduced protein S (a naturally occurring anticoagulant) occur during pregnancy and likely predispose to venous thrombo- embolism. These changes can take some weeks to fully correct postnatally, and the risk of venous thromboembolism is further enhanced in the puerperium by the injury to the pelvic veins that occurs during delivery. Many pregnancy-​related deep vein thromboses are ileofemoral, whereas in the non​pregnant setting most are thought to originate in the distal veins before extending to the popliteal and femoral veins. Deep vein thrombosis in pregnancy affects the left leg in 80–​90% of cases compared to around 50% in the non​pregnant state, and this likely reflects additional compression in pregnancy of the left common iliac vein by the right common iliac artery. Epidemiology The absolute risk of venous thromboembolism in pregnancy and the puerperium is approximately one event per 1000 pregnancies com- pared to the non​pregnant state where the risk of venous thrombo- embolism is approximately 1 in 10 000 annually. The risk of venous thromboembolism increases in early pregnancy (when UK maternal mortality data suggest fatal pulmonary embolism may be more fre- quent), increases further towards term, and peaks in the first three weeks post-​partum. The venous thromboembolism risk is increased around 5-​fold during pregnancy and 20-​fold or more during the puerperium. The risk per day is therefore higher in the puerperium, with up to 50% of events occurring post-​partum. Over the past 10 years, the number of maternal deaths from pulmonary embolism in the United Kingdom has ranged from around 5–​10 annually (Table 14.7.1). Taking account of the number of births per year in the UK (approximately 800 000) and therefore the number of expected episodes of venous thromboembolism (approximately 800), this sug- gests an overall case fatality rate for venous thromboembolism in pregnancy of around 1%. Risk factors for venous thromboembolism in pregnancy and the puerperium are shown in Table 14.7.2. Clinical features One of the difficulties with the diagnosis of deep vein throm- bosis or pulmonary embolism is that the characteristic features of these conditions (e.g. leg swelling, breathlessness), are common in normal pregnancy (Table 14.7.3). The standard predictive clinical tools widely used in the initial assessment of non​pregnant patients, such as the Wells scores for deep vein thrombosis and pulmonary embolism, have not been validated in pregnancy, and the clinical diagnosis of venous thromboembolism in pregnancy is particularly unreliable. The condition should be suspected with leg swelling that is unilateral (particularly if left-​sided) and associated with pain, Table 14.7.2  Risk factors for venous thromboembolism in pregnancy and the puerperium Pre-​existing New onset or transient Previous episode of VTE Age over 35 years Obesity (BMI >30 kg/​m2) either pre-​pregnancy or in early pregnancy Parity >3 Known thrombophilia or family history of unprovoked or oestrogen-​related VTE in a first-​degree relative Smoker Gross varicose veins with phlebitis Paraplegia Medical comorbidities, e.g. cancer, heart disease; metabolic, endocrine, or respiratory pathologies; inflammatory conditions (e.g. inflammatory bowel disease, active systemic lupus erythematosis); sickle cell disease; nephrotic syndrome; current intravenous drug user Caesarean section Surgical procedure in pregnancy or puerperium, except immediate repair of the perineum Hospital admission Hyperemesis Dehydration Ovarian hyperstimulation syndrome Multiple pregnancy or assisted conception Current systemic infection (e.g. pyelonephritis) Immobility (e.g. SPD, significantly reduced mobility for three or more days; long distance travel >4 hours during pregnancy and up to six weeks post-​partum) Preeclampsia in current pregnancy Post-​partum haemorrhage (>1 litre or transfusion) Prolonged labour (>24 hours) Stillbirth in current pregnancy Preterm delivery (<37 weeks in current pregnancy) Mid-​cavity instrumental delivery Immobility after delivery Critical care admission PPH >1 litre or blood transfusion SPD, symphysis pubis dysfunction; VTE, venous thromboembolism.

Section 14  Medical disorders in pregnancy 2608 lower abdominal pain, or back pain (especially if unilateral), or sudden onset of breathlessness, chest pain, haemoptysis, dizziness or collapse. Low grade pyrexia may be present. Differential diagnosis Some of the features of deep vein thrombosis and pulmonary em- bolism described here may occur in normal pregnancy. In common with the non​pregnant state, other conditions that may present with similar features to deep vein thrombosis include superficial vein thrombosis, a ruptured Baker’s cyst, and muscle tears. The differ- ential diagnosis of pulmonary embolism includes musculoskel- etal pain, chest infection (particularly pneumonia with pleurisy), pneumothorax, acute coronary syndrome, and heart failure. Clinical investigations Because the clinical diagnosis of venous thromboembolism is unre- liable and anticoagulant treatment carries significant risks, it is very Table 14.7.3  Symptoms and signs of venous thromboembolism in pregnancy Deep vein thrombosis Painful swollen leg (lower leg or whole leg) Redness/​oedema of leg Left iliac fossa/​groin/​buttock pain Non​specific lower abdominal pain Pulmonary embolism Chest pain (sudden onset) Breathlessness (sudden onset) Dizziness Syncope or collapse Haemoptysis Tachypnoea Tachycardia Hypoxia Raised jugular venous pressure

  1. Investigations should be completed within 24 hours of admission with suspected pulmonary embolism (PE).
  2. Chest X-ray signs of PE may include small effusion, prominent pulmonary vasculature and regional oligemia, but the chest X-ray is most often normal in PE. Clinical assessment and initial investigations. Chest X-ray, ECG, and arterial blood gas. FBC, U&E, LFTs Do not perform a D-dimer test CXR Normal Commence LMWH if suspect PE1 Abnormal Treat LMWH High probability of PE V/Q scan Treat other disorder CTPA Other diagnosis likely based on chest X-ray and initial investigations PE remains likely diagnosis2 No further investigations necessary (if good quality scan and clear report) Stop LMWH Demonstrates PE Normal Low/ intermediate probability of PE Stop LMWH Does not demonstrate PE Treat LMWH Fig. 14.7.1  Algorithm for the investigation and initial management of suspected pulmonary embolism in pregnancy and the puerperium (from Royal College of Obstetricians and Gynaecologists (RCOG) green-​top guideline 37b) in haemodynamically stable women without symptoms or signs of deep vein thrombosis.

14.7  Thrombosis in pregnancy 2609 important that the diagnosis of venous thromboembolism is object- ively confirmed as expeditiously as possible. When deep vein thrombosis is suspected, compression duplex ultrasonography should be undertaken. If this is negative and there is a low index of clinical suspicion, treatment can be discontinued. If a high index of suspicion remains, treatment can be discontinued, and the ultrasound repeated on days 3 and 7. The diagnosis of iliac vein thrombosis should be considered in those with swelling of the en- tire leg plus associated back pain. Magnetic resonance (MR) or com- puted tomography (CT) venography may be required to confirm the diagnosis. If pulmonary embolism is suspected, a chest X-​ray and electrocar- diogram (ECG) should be performed to exclude other conditions in the differential diagnosis. In women who also have features of deep vein thrombosis, compression duplex ultrasonography should be performed and, if positive, treatment for venous thromboembolism should continue without further investigation for pulmonary em- bolism. If the Doppler is negative, imaging to exclude a pulmonary embolism should be undertaken. In women without features of deep vein thrombosis, a ventilation/​perfusion (V/​Q) lung scan or compu- terized tomography pulmonary angiogram (CTPA) should be per- formed (Fig. 14.7.1). The latter is particularly preferred in women with an abnormal chest X-​ray. There are potential drawbacks to both V/​Q scanning (slightly increased risk of childhood cancer) and CTPA (slightly increased risk of maternal breast cancer), but the absolute risk is very small in each case and outweighed by the risk incurred by failing to establish the diagnosis of pulmonary embolism object- ively. In the case of V/​Q scanning, the radiation dose can be further limited by avoiding a ventilation scan in those with a normal perfu- sion scan. Women should be involved in the decision to undergo V/​ Q scanning or CTPA and give informed consent before these tests are undertaken. The value of a negative D-​dimer test has not been validated in preg- nancy and it should not be used for venous thromboembolism diag- nosis. It is important, however, to perform a baseline full blood count, coagulation screen, urea and electrolytes, and liver function tests to iden- tify any comorbidities that might complicate anticoagulant treatment. Treatment Antenatal The optimal treatment of venous thromboembolism in pregnancy is with therapeutic doses of low-​molecular-​weight heparin based on booking or early pregnancy weight (Table 14.7.4a). Unless strongly contraindicated, treatment should commence when venous thrombo- embolism is clinically suspected and stopped if the diagnosis is ex- cluded by objective testing. In those in whom the diagnosis of venous thromboembolism is confirmed, low-​molecular-​weight heparin should continue for the remainder of the pregnancy and for at least six weeks postnatally and until at least three months of treatment has been given in total. It is not necessary to monitor low-molecular-weight heparin by measurement of anti-​Xa levels, except perhaps in women at extremes of body weight (less than 50 kg or more than 90 kg) or with renal im- pairment or recurrent venous thromboembolism. The risk of heparin-​ induced thrombocytopenia with low-​molecular-​weight heparin in pregnancy is low and it is not necessary to monitor the platelet count. Women should be taught to self-​inject low-​molecular-​weight heparin and arrangements made to ensure safe disposal of needles and syringes. Elevation of the leg may reduce swelling, and mobilization should be encouraged. Graduation compression stockings may reduce pain and swelling in the affected leg, but recent evidence suggests they do not prevent the post-​thrombotic syndrome. Warfarin and other vitamin K antagonists should not be used for antenatal venous thromboembolism treatment because they cross the placenta and have adverse effects on the fetus. Direct oral anti- coagulants are contraindicated in pregnancy. In women who present with massive pulmonary embolism with haemodynamic compromise characterized by systolic hypotension, a multidisciplinary team of senior clinicians including obstetricians, physicians and radiologists should be involved as a matter of ur- gency (Fig. 14.7.2). If possible an urgent portable echocardiogram or CTPA should be arranged to confirm the diagnosis. Women should be managed on an individual basis, taking account of the severity of the situation, the availability of resources such as echocardiography Table 14.7.4 (a)  Calculation of initial treatment doses of low-​molecular-​weight heparin by early pregnancy weight <50 kg 50–​69 kg 70–​89 kg 90–​109 kg 110–​125 kg

125 kg Enoxaparin 1 mg/​kg bd
(or 1.5 mg/​kg od) 40 mg bd
(60 mg od) 60 mg bd
(90 mg od) 80 mg bd
(120 mg od) 100 mg bd
(150 mg od) 120 mg bd
(180 mg od) Discuss with a haematologist Dalteparin 100 IU/​kg bd
(or 200 IU/​kg od) 5000 IU bd (10 000 IU od) 6000 IU bd
(12 000 IU od) 8000 IU bd (16 000 IU od) 10 000 IU bd
(20 000 IU od) 12 000 IU bd (24 000 IU od) Discuss with a haematologist Tinzaparin 175 units/​kg od od, once daily; bd, twice daily. Table 14.7.4 (b)  Suggested thromboprophylactic doses of low-​molecular-​weight heparin by early pregnancy weight <50 kg 50–​90 kg 91–​130 kg 131–​170 kg 170 kg Enoxaparin 20 mg od 40 mg od 60 mg oda 80 mg oda 0.6 mg/​kg/​daya Dalteparin 2500 IU od 5000 IU od 7500 IU od 10 000 IU od 75 IU/​kg/​ day Tinzaparin 3500 IU od 4500 IU od 7000 IU oda 9000 IU oda 75 IU/​kg/​daya a May be given in two divided doses. (a) and (b) Source data from Royal College of Obstetricians and Gynaecologists (2015). Reducing the risk of venous thromboembolism during pregnancy and the Puerperium (Green- top Guideline No. 37a). https://www.rcog.org and Royal College of Obstetricians and Gynaecologists (2015). Thromboembolic disease in pregnancy and the puerperium: acute management (Green-top Guideline No. 37b). https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37b.pdf

Section 14  Medical disorders in pregnancy 2610 or CTPA, and the bleeding risks. Treatment should commence with intravenous unfractionated heparin (Table 14.7.5). Systemic or catheter directed thrombolysis should be considered in women who are hypotensive. If this is contraindicated because of bleeding, then percutaneous catheter fragmentation or thoracotomy and surgical embolectomy should be considered. During labour and delivery Women who are established on low-​molecular-​weight heparin should be advised to stop further injections when they are in, or think they are in, labour. When delivery is planned, either by elective caesarean section or induction of labour, low-​molecular-​weight heparin should be discontinued 24 hours prior to planned delivery. Regional anaesthesia should not be undertaken until at least 24 hours after the last therapeutic dose of low-​molecular-​weight heparin. If delivery is by caesarean section, wound drains should be considered and the skin incision closed with interrupted sutures to allow drainage of any haematoma. Following delivery, a prophylactic dose of low-​molecular-​weight heparin can be administered at least four hours later, providing bleeding has settled, and a therapeutic dose recommenced 8–​12 hours later. At least four hours should pass after a spinal anaesthetic has been administered or after an epidural cath- eter has been removed before further low-​molecular-​weight heparin is given, and an epidural catheter should not be removed within 12 hours of the most recent injection. Postnatal As mentioned earlier, women who are diagnosed with venous thromboembolism antenatally need to continue treatment for at least six weeks postnatally and until at least three months of treatment has been given in total. Women who are diagnosed with venous thrombo- embolism post-​partum need to continue treatment for a minimum of three months. The continuing risk of thrombosis should be assessed before treatment is stopped. Postnatally, women should be offered the choice of low-​weight-​molecular heparin or warfarin after discus- sion about the need for regular blood tests for monitoring warfarin, particularly during the first 10 days of treatment. Warfarin should not be commenced until at least the fifth day post-​partum and after a longer delay in those at risk of post-​partum haemorrhage. Neither heparin (unfractionated or low-​molecular-​weight heparin) nor war- farin is contraindicated in breastfeeding. Direct oral anticoagulants should not be used in those who are breastfeeding. Prognosis/​outcome Anticoagulant treatment is very effective in most women with acute venous thromboembolism presenting during pregnancy or the puerperium. An overall case fatality rate of around 1% is supported by the data alluded to earlier. Although uncommon, the fatalities are more often the result of failure of diagnosis than of established treatment. The mortality rate is higher in patients presenting with pulmonary embolism and haemodynamic compromise, and thrombolytic therapy may be life-​saving in this group. Around 40% of women develop the post-​thrombotic syndrome after deep vein thrombosis in pregnancy. This is characterized by variable chronic swelling, pain, a feeling of heaviness, dependent cyanosis and chronic pigmentation in the leg affected by the throm- bosis, and may be a cause of considerable impairment of quality of life. Occasionally the post-​thrombotic syndrome can be sufficiently severe as to lead to venous ulceration. Chronic thromboembolic pulmonary hypertension should be considered in those with persistent breathlessness. It is relatively uncommon, but identification can lead to successful pulmonary endarterectomy in those where the persisting embolus is large and central. Individuals who have had an episode of venous thrombo- embolism are at greater risk of another event in the future. The abso- lute risk is thought to be around 1–​5% in the first year after stopping anticoagulant treatment and likely declines subsequently, although Multidisciplinary resuscitation team Oxygen, IV UFH, IV fluids, inotropic support Transfer to ITU Inform on call obstetric team immediately for consideration of early delivery Negative investigations –pursue other diagnoses Diagnosis of PE by emergency CTPA or echocardiogram (ECHO) If the patient becomes peri-arrest, consider thrombolysis without imaging CTPA confirms PE or ECHO confirms right ventricular dilatation/dysfunction If persistent hypotension (systolic BP < 90 mm Hg), consider thrombolysis If thrombolysis contraindicated, consider percutaneous catheter fragmentation or surgical embolectomy Fig. 14.7.2  Management of women with clinically suspected massive pulmonary embolism. UFH, unfractionated heparin; ITU, Intensive Therapy Unit; CTPA, computerized tomography pulmonary angiogram; PE, pulmonary embolism. Reproduced from Khalil A., Bowles L., O’Brien P., Cohen H. (2015) Systemic Thromboembolism in Pregnancy: Venous Thromboembolism. In: Cohen H., O’Brien P. (eds) Disorders of Thrombosis and Hemostasis in Pregnancy. Springer with permission from Springer Nature. Table 14.7.5  Adjustments in the infusion rate of unfractionated heparin (UFH) according to the activated partial thromboplastin time (APTT) with target APTT ratio 1.5–​2.5 APTT ratio Dose (units/​kg/​h) Additional action Next APTT (h) <1.2 +4 Re-​bolus 80 units/​kg   6 1.2–​1.5 +2 Re-​bolus 40 units/​kg   6 1.5–​2.5 No change 24 2.5–​3.0 −2   6

3.0 −3 Stop infusion for 1 h   6 Loading dose of 80 units/​kg followed by a continuous infusion of 18 units/​kg/​hour. Measure APTT 4–​6 hours after the loading dose. Source data from Royal College of Obstetricians and Gynaecologists (2015). Thrombo­ embolic disease in pregnancy and the puerperium: acute management (Green-top Guideline No. 37b). https://www.rcog.org.uk/globalassets/documents/guidelines/ gtg-37b.pdf

14.7  Thrombosis in pregnancy 2611 Appendix I: Obstetric thromboprophylaxis risk assessment and management Antenatal assessment and management (to be assessed at booking and repeated if admitted) Any previous VTE except a single event related to major surgery Hospital admission Single previous VTE related to major surgery High-risk thrombophilia + no VOTE Medical comorbidities e.g. cancer, heart failure, active SLE, IBD or inflammatory polyarthropathy, nephrotic syndrome, type I DM with nephropathy, sickle cell disease, current IVDU Any surgical procedure e.g. appendice to my OHSS (first trimester only) Obesity (BMI > 30 kg/m2) Age > 35 Parity ≥ 3 Smoker Gross varicose veins Current pre-eclampsia Immobility, e.g. paraplegia, PGP Family history of unprovoked or estrogen- provoked VTE in first-degree relative Low-risk thrombophilia Multiple pregnancy IVF/ART Transient risk factors: Dehydration/hyperemesis; current systemic infection; long-distance travel APL = antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, β2 -glycoprotein 1 antibodies); ART = assisted reproductive technology; BMI based on booking weight; DM = diabetes mellitus; FHx = family history; gross varicose veins = symptomatic, above knee or associated with phlebitis/oedema/skin changes; high-risk thrombophilia = antithrombin deficiency, protein C or S deficiency, compound or homozygous for low-risk thrombophilias; IBD = inflammatory bowel disease; immobility = ≥ 3 days; IVDU = intravenous drug user; IVF = in vitro fertilization; LMWH = low-molecular- weight heparin; long-distance travel = >4 hours; low-risk thrombophilia = heterozygous for factor V Leiden or prothrombin G20210A mutations; OHSS = ovarian hyperstimulation syndrome; PGP = pelvic girdle pain with reduced mobility; PPH = postpartum haemorrhage; thrombophilia = inherited or acquired; VTE = venous thromboembolism. Fewer than three risk factors LOWER RISK mobilization and avoidance of dehydration Four or more risk factors: prophylaxis from first trimester Three risk factors: prophylaxis from 28 weeks HIGH RISK Refer to trust-nominated thrombosis in pregnancy expert/team Requires antenatal prophylaxis with LMWH Postnatal assessment and management (to be assessed on delivery suite) Antenatal and postnatal prophylactic dose of LMWH Fewer than two risk factors Two or more risk factors NB If persisting or > 3 risk factors consider extending thromboprophylaxis with LMWH At least 10 days’ postnatal prophylactic LMWH INTERMEDIATE RISK HIGH RISk At least 6 weeks’ postnatal prophylactic LMWH LOWER RISK Early mobilization and avoidance of dehydration Weight > 170 kg = 0.6 mg/kg/day enoxaparin/75 u/kg/day dalteparin/ 75 u/kg/day tinzaparin Weight 131–170 kg = 80 mg enoxaparin/10000 units dalteparin/9000 units tinzaparin daily Weight 91–130 kg = 60 mg enoxaparin/7500 units dalteparin/7000 units tinzaparin daily Weight 50–90 kg = 40 mg enoxaparin/5000 units dalteparin/4500 units tinzaparin daily Weight < 50 kg = 20 mg enoxaparin/2500 units dalteparin/3500 units tinzaparin daily Any previous VTE Anyone requiring antenatal LMWH High-risk thrombophilia Low-risk thrombophilia + FHx Caesarean section in labour BMI ≥ 40 kg/m2 Readmission or prolonged admission (≥3 days in the puerperium Any surgical procedure in the puerperium except immediate repair of the perineum Medical comorbidities e.g. cancer, heart failure, active SLE, IBD or inflammatory polyarthro- pathy; nephrotic syndrome, type I DM with nephropathy, sickle cell disease, current IVDU Obesity (BMI ≥ 30 kg/m2) Parity ≥ 3 Smoker Elective caesarean section Family history of VTE Low-risk thrombophilia Gross varicose veins Current systemic infection Immobility, e.g. paraplegia, PGP, long- distance travel Current pre-eclampsia Multiple pregnancy Preterm delivery in this pregnancy (<37° weeks) Stillbirth in this pregnancy Mid-cavity rotational or operative delivery Prolonged labour (>24 hours) PPH > 1 litre or blood transfusion Age > 35 years INTERMEDIATE RISK Consider antenatal prophylaxis with LMWH Fig. 14.7.3  Obstetric venous thromboembolism risk assessment and thromboprophylaxis. Reproduced from: Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism during pregnancy. Green-​top Guideline No. 37a. London: RCOG; 2015, with the permission of the Royal College of Obstetricians and Gynaecologists.

Section 14  Medical disorders in pregnancy 2612 remaining higher than in those without a venous thromboembolism history. This size of risk is not thought to be sufficiently high to war- rant long-​term anticoagulation with its attendant risks, but short-​ term thromboprophylaxis should be considered in future high-​risk settings (e.g. surgery or prolonged immobility). The risk of venous thromboembolism is also higher during subsequent pregnancies and warrants postnatal thromboprophylaxis in all and antenatal thromboprophylaxis in most cases. Special circumstances/​complications Venous thromboembolism occurring near to or during labour and delivery presents particularly acute challenges because of the dif- ficulties with anticoagulation and the risk of peripartum haemor- rhage. If possible, it is preferable to complete at least two (and ideally four) weeks of anticoagulant treatment before delivery as the risk of recurrence is highest in this period. In this setting around the time of delivery, intravenous unfractionated heparin may have advantages because of its short half-​life and reversibility with protamine sul- phate. It needs to be monitored by the activated partial thrombo- plastin time (APTT) according to an approved algorithm, and this is challenging in pregnancy because of the naturally shortened APTT that occurs, which results in apparent heparin resistance. Intravenous heparin should be stopped six hours before delivery or regional anaesthesia. In those who have an operative delivery and are receiving intravenous unfractionated heparin, the platelet count should be monitored every two to three days from days 4 to 14, or until the heparin is stopped. Consideration should be given to the use of temporary inferior vena cava filters in the peripartum period where anticoagulation cannot be given, particularly for those with iliac vein thrombosis. Expert advice should be sought in this setting. In women who develop allergic skin reactions a switch in low- molecular-weight heparin may be tried. In those with heparin-​induced thrombocytopenia, low-​molecular-​weight heparin must be stopped and replaced by non​heparin alternatives such as danaparoid or fondaparinux. In this rare setting specialist advice should be sought. Prevention of venous thromboembolism in pregnancy and the puerperium Although pregnancy and the puerperium are associated with an in- creased risk of venous thromboembolism, the size of risk is insuffi- cient to warrant routine thromboprophylaxis. However, several risk factors for venous thromboembolism have been identified in obser- vational studies (Table 14.7.2) and women who have one or more of these factors may require consideration for thromboprophylaxis. Within the overall population of pregnant women, the most common risk factors are advanced maternal age (over 35 years), obesity (body mass index over 30 kg/​m2) and caesarean section, particularly when performed as an emergency. Other groups at increased risk include those with underlying medical comorbidities including acute sys- temic infections and inflammatory conditions. Admission to hos- pital for medical, surgical, or obstetric reasons poses an additional risk. One particularly important risk factor is a previous episode of venous thromboembolism (i.e. prior to the current pregnancy). A family history of venous thromboembolism, especially affecting a first-​degree relative, also indicates an increased risk whether or not a defined thrombophilic tendency is identified. It is therefore recom- mended that all women should undergo a documented assessment of risk factors for venous thromboembolism in early pregnancy and this should be repeated if a woman is admitted to hospital or de- velops intercurrent problems in pregnancy. It should be repeated again intrapartum or immediately post-​partum. Women with identified venous thromboembolism risk factors should be considered for thromboprophylaxis with low-​molecular-​ weight heparin and the risks and benefits discussed in each case. A  summary of the recommendations from the Royal College of Obstetricians and Gynaecologists is shown in Fig. 14.7.3. In most women who require low-​molecular-​weight heparin for venous thromboembolism prevention, prophylactic doses (weight-​adjusted as shown in Table  14.7.4b) should be used. In certain particu- larly high-​risk women; for example, those with a previous venous thromboembolism episode and heritable antithrombin deficiency or antiphospholipid syndrome—​intermediate or therapeutic doses are recommended. Women receiving antenatal thromboprophylaxis should be ad- vised to discontinue low-​molecular-​weight heparin if they have va- ginal bleeding or when labour begins. Regional anaesthesia should be avoided until at least 12 hours after the previous injection (and 24 hours for those on higher doses of low-​molecular-​weight hep- arin). Following delivery prophylactic low-​molecular-​weight hep- arin should be recommenced as outlined in the Treatment section earlier. Mechanical thromboprophylaxis (antiembolism stockings or intermittent pneumatic compression) should be considered in those whom low-​molecular-​weight heparin is contraindicated. After delivery thromboprophylaxis should be considered for 10 days in those at intermediate risk of venous thromboembolism and six weeks in those at high risk. Areas of uncertainty, controversy, and future developments Important unresolved issues include the optimal selection of women for thromboprophylaxis taking account of cost-​effectiveness, also the clinical criteria used to assess whether women with often non​specific symptoms warrant further investigation for venous thromboembolism. FURTHER READING Royal College of Obstetricians and Gynaecologists (2015). Reducing the Risk of Venus Thromboembolism during Pregnancy and the Puerperium (Green-​top Guideline No. 37a). https://​www.rcog.org. uk/​globalassets/​documents/​guidelines/​gtg-​37a.pdf Royal College of Obstetricians and Gynaecologists (2015). Thrombo­ embolic disease in Pregnancy and the Puerperium: Acute Management (Green-​top Guideline No. 37b). https://​www.rcog.org.uk/​globalassets/​ documents/​guidelines/​gtg-​37b.pdf

14.8 Chest diseases in pregnancy 2613

14.8 Chest diseases in pregnancy 2613

ESSENTIALS Respiratory changes in pregnancy include an increase in tidal volume and minute ventilation, leading to a primary respiratory alkalosis. During a normal and uncomplicated pregnancy many women ex- perience the sensation of dyspnoea, hence it is important—​but sometimes difficult—​for the clinician to distinguish breathlessness resulting from normal physiological changes from that caused by underlying medical diseases. Chest conditions arising in pregnancy—​these include (1) amniotic fluid embolism—​unique to pregnancy; (2) venous air embolism—​a rare condition that can occur in pregnancy; (3)  venous and pul- monary thromboembolism—​pregnancy is a risk factor; (4)  pul- monary oedema—​this can be caused by heart disease, as in the
non​pregnant state, but it can also be associated with pre-​eclampsia or HELLP syndrome and be induced by tocolysis; (5)  aspiration; (6) varicella pneumonia—​a potentially devastating complication of primary varicella-​zoster virus infection; (7) influenza—​associated with increased maternal morbidity. Pregnancy in women with known chest disorders—​(1) asthma—​ patients with a history of admission to an intensive care unit for asthma, prior mechanical ventilation, or frequent healthcare visits are at risk of developing severe or life-​threatening asthma exacerba- tions during pregnancy. The treatment of chronic asthma and acute asthma exacerbations during pregnancy is largely the same as in the non​pregnant state; (2) pulmonary arterial hypertension—​associated with high maternal mortality. Introduction Pregnancy is associated with increased minute ventilation and rela- tive hyperventilation, increase in thoracic diameter, pulmonary function changes, as well as cardiovascular and hormonal changes. Most women with mild pulmonary disease can have successful pregnancies, but some pre-​existing chest diseases can put women at risk during pregnancy and parturition. During a normal and uncomplicated pregnancy many women experience the sensation of dyspnoea, hence it is important—​but sometimes difficult—​for the clinician to distinguish breathlessness resulting from normal physiological changes from that caused by underlying medical dis- eases. In this chapter, we review chest conditions unique to preg- nancy as well as management principles for important pre-​existing chest diseases during pregnancy. Respiratory changes in pregnancy The respiratory system undergoes many changes during preg- nancy, in part as a result of elevated oestrogen and progesterone levels (Fig. 14.8.1). Chest wall and diaphragm Changes to the chest wall and diaphragm occur early in pregnancy in response to changing hormone levels and before the uterus is large enough to exert any mechanical effects. The diaphragm rises up to 4 cm into the chest, and the ligaments of the ribs relax and cause the subcostal angle of the rib cage to increase, resulting in in- creased circumference of the chest. Ventilation and gas exchange Very early in pregnancy, changes in respiratory drive, ventilation, and gas exchange occur secondary to the stimulatory response from increased progesterone levels. The mechanism by which pro- gesterone affects respiratory drive and ventilation is explained by alterations in the sensitivity of chemoreceptors in the medulla to CO2: even slight increases in arterial Pco2 will cause an increase in tidal volume. Tidal volume increases up to 40% during preg- nancy, resulting in increased minute ventilation. The arterial Pco2 falls from 40 mm Hg (5.3 kPa) in the non​gravid patient to approxi- mately 30 mm Hg (4.0 kPa) in the pregnant patient, resulting in a primary respiratory alkalosis. In response, the kidney excretes bi- carbonate to normalize the pH, hence it is usual to see bicarbonate levels of approximately 20 mEq/​litre during pregnancy. A second ef- fect of increased minute ventilation is a rise in alveolar and arterial oxygenation that produces arterial Po2 levels ranging from 100 to 110 mm Hg (13.3–​14.6 kPa). Lung volumes As tidal volume increases during pregnancy, the functional residual capacity decreases because the diaphragm rises up into the chest, 14.8 Chest diseases in pregnancy Meredith Pugh and Tina Hartert

Section 14  Medical disorders in pregnancy 2614 Fig. 14.8.1  Normal physiological changes of the upper airway, lung, and cardiovascular system during pregnancy that may result in dyspnoea or exacerbation of existing pulmonary disease. * (From Prowse CM, Gaensler EA (1965). Respiratory and acid-​base changes during pregnancy. Anesthesiology, 26, 381–​92. Top left and right insets duplicated, with permission.)

14.8  Chest diseases in pregnancy 2615 resulting in lower residual and expiratory reserve volumes. The forced expiratory volume in 1 s (FEV1), FEV1/​forced vital capacity (FVC) ratio, and peak expiratory flow rates are unchanged during pregnancy. Hence a reduction in FEV1 or FVC should prompt the clinician to seek out underlying pulmonary disease pathology to ex- plain the spirometric changes. Cardiovascular As outlined in Fig. 14.8.1, the cardiovascular changes that impact pulmonary physiology are observed as early as six to eight weeks’ gestation. There is a 50% increase in blood volume to meet the in- creased metabolic demands of pregnancy and an increase in cardiac output by 1–​2 litre/​min. Cardiac output increases further during delivery and the post-​partum period. Systemic and pulmonary vas- cular resistances are also reduced. Respiratory conditions in pregnancy Up to 70% of women experience the sensation of dyspnoea during a normal and uncomplicated pregnancy, hence it is important for the clinician to distinguish dyspnoea resulting from normal physio- logical changes of pregnancy from that caused by underlying med- ical diseases. The obstetric patient presenting with acute onset of shortness of breath requires a careful assessment to exclude life-​ threatening conditions detrimental to the mother or the fetus. Approach to dyspnoea in pregnancy Physiologic dyspnoea in pregnancy is common and due to hor- monal influences and physiologic changes described here. Physiologic dyspnoea has a gradual onset, often beginning in the first and second trimester, and lacks other associated symptoms or exam findings. Acute onset dyspnoea or the presence of wheezing, stridor, chest pain, fever, cough, and/​or abnormal physical examin- ation (i.e. crackles on lung auscultation) suggest cardiopulmonary disease and further evaluation may be indicated. Pulmonary func- tion testing and chest radiography (with abdominal shielding) are low-​risk and may identify concomitant lung disease in the setting of these symptoms and signs. Specific disease considerations and diag- nostic testing are discussed in the remainder of this chapter. Pregnancy-​associated rhinitis Upper airway mucosal oedema, hyperaemia, and hypersecretion occur during pregnancy and result in nasal congestion and/​or naso- pharyngeal obstruction that may significantly impact a patient’s ability to breathe comfortably. Treatment of this pregnancy-​ associated rhinitis includes raising the head of the bed 30–​45 de- grees, saline nasal spray washings to help clear secretions; nasal ipratropium bromide and corticosteroids have not been shown to be clearly beneficial. Nasal sprays containing phenylephrine or oxymetazoline may also be used. Embolic disease Venous thromboembolism Venous thromboembolism complicates approximately 1–​2 out of every 1000 pregnancies and is a leading cause of maternal mortality in the developed world. Diagnosing the condition during pregnancy may be challenging, since many of the symptoms in the non​gravid patient can be a part of the normal physiologic changes observed in pregnancy (e.g. tachycardia, dyspnoea, lower extremity oedema). The diagnostic evaluation of venous thromboembolism in pregnant patients is similar to non​pregnant patients. D-​dimer testing, widely used in low-​ and intermediate-​risk non​pregnant patients, has limited utility for venous thromboembolism diagnosis during pregnancy. Compression ultrasonography is frequently used as the first test in pa- tients with leg symptoms and avoids ionizing radiation. If pulmonary embolism is suspected and venous ultrasound is negative, or no leg symptoms are present, then a chest X-​ray followed by a ventilation-​ perfusion scan or computed tomography (CT) angiogram should be performed. CT angiography exposes the fetus to similar amounts of radiation as ventilation-​perfusion scanning and offers the potential to make other diagnoses, but it delivers more ionizing radiation to maternal breast tissue. Low molecular weight heparin is the agent of choice for prophylaxis or treatment for venous thromboembolism in most cases. See Chapter 14.7 for further discussion. Venous air embolism Venous air embolism, with air travelling through the placental venous sinuses into the venous circulation and through the right ventricle leading to obstruction of the right ventricular outflow tract, has been reported during labour and delivery (most com- monly during caesarean delivery). Presenting symptoms and signs are dyspnoea, hypotension, tachycardia, tachypnoea, a character- istic ‘millwheel murmur’, or sudden cardiac arrest. Treatment is supportive. Amniotic fluid embolism Amniotic fluid embolism is a rare disorder unique to pregnancy. It is thought to be a severe systemic inflammatory response to fetal tissue components entering the maternal circulation, most com- monly during labour and delivery, or in the immediate post-​partum period. The characteristic presentation is sudden onset of hypoxia, hypotension, and coagulopathy. The diagnosis of amniotic fluid em- bolism is a clinical one, and while detection of fetal elements may be found in maternal pulmonary artery aspirates, this finding is not exclusive to amniotic fluid embolism and there are no other proven laboratory markers specific to amniotic fluid embolism. Treatment is supportive, focusing on rapid cardiorespiratory stabilization and delivery of the fetus if necessary. Maternal mortality is very high (60–​90%). Acute pulmonary oedema Acute pulmonary oedema during pregnancy is uncommon, with an incidence of 0.08% in a large retrospective study from a single med- ical centre. In this series, half of all patients developed pulmonary oedema as a result of either cardiac disease or tocolytic therapy; pre-​eclampsia and iatrogenic volume overload were other common causes. Clinical signs and symptoms include dyspnoea, cough, orthopnoea, tachycardia, tachypnoea, crackles, and/​or wheezing on lung auscultation, and hypoxia. Chest radiography findings are similar to pulmonary oedema in non​pregnant patients, including interstitial or alveolar pulmonary infiltrates and Kerley B lines. While we review here specific causes of acute pulmonary oedema related to pregnancy, other causes of pulmonary oedema not related to preg- nancy must be considered in the appropriate context (i.e. acute re- spiratory distress syndrome, transfusion-​related acute lung injury).

Section 14  Medical disorders in pregnancy 2616 Cardiogenic pulmonary oedema Cardiogenic pulmonary oedema can result from established or newly diagnosed cardiac disease. Valvular heart disease and other structural cardiac diseases are common precipitants of cardiogenic pulmonary oedema, but with advancing maternal age and presence of maternal comorbid conditions including diabetes mellitus, sys- tolic and diastolic heart disease contribute to some cases. Antenatal diagnosis, multidisciplinary management, and meticulous fluid management can reduce risks. Peripartum cardiomyopathy, defined as the development of heart failure towards the end of pregnancy or in the months following delivery in the absence of other causes, is another important cause of pulmonary oedema in pregnancy. See Chapter 14.6 for further discussion. Pre-​eclampsia While uncommon (occurring in 3% of cases of pre-​eclampsia), the development of pulmonary oedema is a leading cause of death in women with pre-​eclampsia. The risk of developing pulmonary oe- dema is highest after delivery when plasma oncotic pressures drop to their lowest values and the distal air spaces of the lung fill with fluid. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets) can also result in pulmonary oedema. See Chapters 14.4 and 14.9 for further discussion. Tocolytic-​induced pulmonary oedema Tocolytic-​induced pulmonary oedema accounts for about 25% of all cases of pulmonary oedema during pregnancy. Most cases occur in the setting of systemic β2-​agonist use for refractory preterm labour. The mechanism is unclear, but it is suspected that changes in haemo- dynamics as a secondary effect of β-​receptor stimulation (i.e. tachy- cardia and increased stroke volume) accompanied by increased hydrostatic pressures and capillary leak lead to pulmonary oedema. Pulmonary oedema can be seen with the use of other tocolytics including magnesium sulfate and more recently used agents such as nifedipine and nicardipine, although believed to be less common. Treatment of tocolytic-​induced pulmonary oedema consists of oxygen, diuretics, and discontinuing the offending drug. Aspiration Aspiration pneumonitis occurring during pregnancy, also termed Mendelson’s syndrome, is an important cause of acute respiratory distress syndrome and maternal morbidity. During normal preg- nancy, hormonal changes and enlargement of the uterus lead to de- creased oesophageal sphincter tone, delayed gastric emptying, and increased abdominal pressures. These physiological changes place pregnant patients at risk for aspiration, particularly during labour and delivery. Preventive measures to reduce the risk of aspiration include the use of regional anaesthesia, gastric acid suppression, and limiting oral intake around the time of labour and delivery. Asthma Asthma is a common chest disease in pregnancy, occurring in up to 8% of pregnant women in the United States of America. Poorly controlled or severe maternal asthma during pregnancy is asso- ciated with increased risk of pre-​eclampsia, low birth weight in- fants, preterm delivery, and perinatal mortality. Patients with a history of admission to an intensive care unit for asthma, prior mechanical ventilation, and frequent healthcare visits are at risk of developing severe or life-​threatening asthma exacerbations during pregnancy. Several studies have demonstrated that optimal management of asthma is associated with improved maternal and infant outcomes. The principles of managing asthma during pregnancy are not different from those in non​gravid women, and management goals focus on avoidance of triggers, controlling symptoms, optimizing pulmonary function, and preventing and appropriately treating exacerbations. The treatment of chronic asthma and acute asthma exacerbations during pregnancy is largely the same as in the non-​ pregnant state. Short-​acting β agonists (salbutamol) are used as initial therapy and for rapid-​acting relief of bronchospasm. When asthma symptoms are persistent, use of a controller therapy, usually an inhaled corticosteroid, is initiated. Therapy can be ‘stepped up’ to achieve adequate control with addition of long-​acting β agonists (formoterol, salmeterol) when necessary. There is limited information regarding the safety and efficacy of asthma medications in pregnant women, primarily because preg- nant women are generally excluded from clinical studies, but ex- tensive clinical experience and registry studies inform clinicians regarding the safety of asthma therapy in pregnancy. β agonists are felt to be safe, with more evidence available for salbutamol than the newer longer acting β agonists. Inhaled corticosteroids have not been linked to adverse pregnancy outcomes, with most data avail- able for budesonide. In a large cohort, Schatz and colleagues did not identify a significant relationship between use of chronic asthma medications and perinatal adverse outcomes. Pulmonary arterial hypertension Pregnancy in patients with pulmonary arterial hypertension, a dis- ease of increased pulmonary vascular resistance and consequent right ventricular failure, is poorly tolerated due to the cardiopulmonary demands of pregnancy including increased cardiac output, stroke volume, and increased circulating blood volume. Deterioration is commonly related to right heart failure and can occur during early second and third trimester as well as during delivery and the post-​ partum period. Earlier series reported maternal mortality of 30–​50% in pulmonary arterial hypertension patients during pregnancy, and while recent reports show improved mortality (as low as 12% in one series), pregnancy-​related mortality remains unacceptably high even with best available treatments. Pregnancy is generally contra- indicated in pulmonary arterial hypertension because of the high maternal mortality, and pregnant patients with pulmonary arterial hypertension should be referred to a specialist centre. Pulmonary infections during pregnancy Despite new antibiotics and advances in respiratory support, pneu- monia during pregnancy is still a significant cause of maternal and fetal morbidity and mortality, even though the incidence is similar to the general population. Respiratory failure due to pneumonia is the leading cause of fatal non​obstetric infection and the third leading cause for intubation during pregnancy. Adverse fetal outcomes in- clude preterm labour, increased need for tocolytics, and lower birth weights. Here we highlight the common respiratory infections com- plicating pregnancy as well as some atypical pathogens for which pregnant patients are at higher risk.

14.8  Chest diseases in pregnancy 2617 Community-​acquired pneumonia The causative pathogens, presentation, and management of community-​acquired pneumonia during pregnancy are similar to that in the non​pregnant state. Evaluation of the pregnant patient with suspected community-​acquired pneumonia should include chest X-​ray (with abdominal shielding) and initial antimicrobial treatment should be directed at S. pneumonia, H. influenzae, and atypical pathogens. Vaccination with the 23-​valent pneumococcal polysaccharide vaccine (PPSV23, pneumococcal vaccine) has been shown to be effective in decreasing the prevalence of pneumococcal pneumonia in patient populations considered at high risk for mor- tality from pneumonia: it is recommended for patients considered immunosuppressed (e.g. diabetes mellitus, asthma, chronic ob- structive pulmonary disease) and may be given during pregnancy. Recently the Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Immunization Practices recommended ad- ministration of the pneumococcal conjugate vaccine (PCV13) for adults with certain immunocompromising conditions (asplenia, cochlear implant, cerebrospinal fluid leak, chronic kidney disease, HIV), but there is no consensus recommendation about timing of and safety of PCV13 immunization in pregnancy. Varicella pneumonia Varicella-​zoster virus infection in pregnancy is serious for both mother and fetus and is associated with high mortality (see Chapter 14.15). Signs and symptoms of varicella-​zoster virus in- clude vesicular rash, dyspnoea, cough, fever, malaise, and pleuritic chest pain. The risk of varicella pneumonia complicating primary varicella-​zoster virus infection during pregnancy occurs particu- larly in the second or third trimester. The diagnosis is usually made clinically; radiographic findings are non​specific. Mechanical ven- tilation may be required in about 50% of pregnant patients with varicella pneumonia (25% mortality in this group). Early treatment with aciclovir 10 mg/​kg every 8 h intravenously is recommended, and observational data suggest improved outcomes with aciclovir treatment. While rare, congenital varicella syndrome is a feared complication of maternal varicella-​zoster virus infection, with the greatest risk when maternal disease occurs before 20 weeks’ gestation. The best method for preventing maternal and fetal complica- tions of varicella-​zoster virus infection is preconception coun- selling and documentation of a history of varicella or presence of serum varicella antibodies (IgG). If either of these conditions is not met, then varicella vaccination is recommended before preg- nancy, preferably one to three months before conception. Varicella vaccination is not recommended for use during pregnancy as it is a live-​attenuated vaccine. Pregnant women without evidence of im- munity to varicella-​zoster virus who have been exposed to varicella-​ zoster virus are eligible to receive varicella-​zoster immune globulin as recommended by the United States Advisory Committee on Immunization Practices. Influenza Influenza A and B are common causes of respiratory illness, with influenza A  being the most virulent strain in humans. During the influenza season pregnant women have over fivefold higher influenza-​related morbidity compared to non​gravid women, and also increased mortality during pandemic years. During the in- fluenza A H1N1 pandemic in 2009–​2010, mortality among preg- nant women was high related to severe influenza pneumonia and acute respiratory distress syndrome, particularly during late preg- nancy (second and third trimester). While asthma and obesity were common comorbidities in pregnant patients with severe H1N1, nearly half of women with severe complications related to H1N1 had pregnancy as the only risk factor. Vaccination against influenza can reduce the risk of maternal and fetal influenza illness, and no adverse fetal outcomes have been identified in women who received the inactivated vaccine during pregnancy. The live-​attenuated intranasal spray vaccine should not be given to pregnant women. Influenza vaccine is recommended for all women pregnant during the influenza season, regardless of trimester. Antiviral medications (amantadine, oseltamivir, zanamivir) are effective in prophylaxis for influenza in high-​risk pregnant pa- tients and in treatment of influenza illness. While there are reports describing congenital malformations associated with amantadine and oseltamivir, the benefits of therapy may outweigh the risks depending on the clinical scenario. During the 2009 H1N1 epi- demics, use of antiviral therapy (oseltamivir, amantadine, or zanamivir, alone or in combination) resulted in fewer deaths. Fungal pneumonia Fungal pneumonia during pregnancy is rare, but in the setting of disseminated disease carries an increased risk of maternal mor- tality, preterm births, and perinatal mortality. Coccidioidomycosis is primarily found in semiarid areas in the western hemisphere, such as the south-​western portion of the United States, central and nor- thern areas of Mexico, and endemic pockets in Central and South America. Coccidioidomycosis pneumonia tends to occur in the third trimester of pregnancy. Other causes of fungal pneumonia including Cryptococcus neoformans, Histoplasma capsulatum, and Blastomyces dermatitidis can similarly complicate pregnancy but are more uncommon. For patients with severe fungal pneumonia or disseminated disease, amphotericin B is recommended, followed by oral antifungals such as fluconazole after delivery. In pregnant women without pre-​existing medical diseases, coccidioidomycosis pneumonia usually resolves on its own regardless of whether or not treatment is given. Acute respiratory failure during pregnancy Acute respiratory failure is a rare complication in pregnancy but needs to be promptly identified and treated to minimize maternal and fetal morbidity. Initial management is similar to management in the non​pregnant state, with support of oxygenation and ventila- tion, identification of the cause, and prompt initiation of directed therapy. Many of the major causes of acute respiratory failure are discussed earlier in this chapter. The physiological changes of preg- nancy need to be considered when optimizing pulmonary mech- anics and gas exchange during mechanical ventilation. Pregnant women normally exhibit a respiratory alkalosis with a mean baseline arterial pH of 7.44 and an arterial CO2 of approximately

Section 14  Medical disorders in pregnancy 2618 32 mm Hg (4.3 kPa), and this level of CO2 should be considered the target during mechanical ventilation. Animal studies suggest that overventilation to an arterial partial pressure of CO2 significantly below this level may compromise uterine blood flow and should be avoided. The strategy of low tidal volume ventilation with permis- sive hypercapnoea, proven to improve mortality in acute respira- tory distress syndrome, has not been rigorously studied in pregnant women but does not appear to have adverse effects on the fetus, at least to a CO2 level of 60 mm Hg (8 kPa). To optimize fetal oxy- genation, maternal oxygenation goals may be higher than in non-​ gravid patients, as adequate fetal oxygenation requires an arterial oxygen tension of at least 70 mm Hg (9.3 kPa), corresponding to a maternal oxygen saturation of 95%. FURTHER READING Physiology of pregnancy Gilroy RJ, Mangura BT, Lavietes MH (1988). Rib cage and abdominal volume displacements during breathing in pregnancy. Am Rev Resp Dis, 137, 668–​72. Lim VS, Katz AI, Lindheimer MD (1976). Acid-​base regulation in pregnancy. Am J Physiol, 231, 1764–​9. Pernoll ML, et al. (1975). Ventilation during rest and exercise in preg- nancy and postpartum. Resp Physiol, 25, 295–​310. Prowse CM, Gaensler EA (1965). Respiratory and acid-​base changes during pregnancy. Anesthesiology, 26, 381–​92. Embolic disease Bates SM, et  al. (2012). VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:  American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141 (Suppl), e691S–​e736S. Bourjeily G, et al. (2010). Pulmonary embolism in pregnancy. Lancet, 375, 500–​12. Clark SL (2014). Amniotic fluid embolism. Obstet Gynecol, 123, 337–​48. Leung AN, et  al. (2011). An Official American Thoracic Society/​ Society of Thoracic Radiology Clinical Practice Guideline: evalu- ation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med, 184, 1200–​8. Acute pulmonary oedema Dennis AT, Solnordal CB (2012). Acute pulmonary oedema in preg- nancy. Anaesthesia, 67, 646–​59. Pisani RJ, Rosenow EC, III (1989). Pulmonary edema associated with tocolytic therapy. Ann Inter Med, 110, 714–​18. Sciscione AC, et al. (2003). Acute pulmonary edema in pregnancy. Obstet Gynecol, 101, 511–​15. Asthma Asthma in pregnancy in: 2016 BTS/SIGN Guideline for the manage­ ment of asthma. https://www.brit-thoracic.org.uk/document-library/ clinical-information/asthma/btssign-asthma-guideline-2016/ Bonham CA, Patterson KC, Strek ME (2018). Asthma outcomes and management during pregnancy. Chest, 153, 515–27. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group (2005). J Allergy Clin Immunol, 115, 34–​46. Schatz M, et al. (2004). The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol, 113, 1040–​5. Pulmonary arterial hypertension Banerjee D, Ventetuolo C (2017). Pulmonary hypertension in preg- nancy. Semin Respir Crit Care Med, 38, 148–59. Jais X, et al. (2012). Pregnancy outcomes in pulmonary arterial hyper- tension in the modern management era. Eur Respir J, 40, 881–​5. Pulmonary infections during pregnancy Brito V, Niederman MS (2011). Pneumonia complicating pregnancy. Clin Chest Med, 32, 121–​32. Martin SR, Foley MR (2006). Intensive care in obstetrics: an evidence-​ based review. Am J Obstet Gynecol, 195, 673–​89. Pastuszak AL, et al. (1994). Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med, 330, 901–​5. Siston AM, et al. (2010). Pandemic 2009 influenza (H1N1) virus illness among pregnant women in the United States. JAMA, 303, 1517–​25. Zaman K, et al. (2008). Effectiveness of maternal influenza immuniza- tion in mothers and infants. N Engl J Med, 359, 1555–​64. Acute respiratory failure during pregnancy Ende H, Varelmann D (2016). Respiratory considerations including airway and ventilation issues in critical care obstetric patients. Obstet Gynecol Clin N Am, 43, 699–708. Munnur U, Bandi V, Guntupalli KK (2011). Management principles of the critically ill obstetric patient. Clin Chest Med, 32, 53–​60.

14.9 Liver and gastrointestinal diseases of pregna

14.9 Liver and gastrointestinal diseases of pregnancy 2619

ESSENTIALS Liver diseases Pregnancy-​specific disorders that cause de novo abnormal serum liver tests in pregnancy include: Hypertension-​related liver diseases and pregnancy—​including pre-​ eclampsia and HELLP (haemolysis, elevated liver enzymes, low plate­ lets) syndrome, also hepatic haematoma, infarction, and rupture Acute fatty liver of pregnancy—​a rare disorder, part of the mito- chondrial cytopathy spectrum, but one of the commoner causes of liver failure in pregnancy. Prompt delivery is essential. Intrahepatic cholestasis of pregnancy—​affects 0.67% of pregnancies in the United Kingdom; presents typically with pruritis and com- monly treated with ursodeoxycholic acid. Hyperemesis gravidarum—​affects 0.3–​2% of all pregnancies; treat- ment is supportive, with thiamine supplementation mandatory to prevent Wernicke’s encephalopathy. Viral hepatitis is probably the most commonly recognized cause of jaundice occurring during pregnancy worldwide. There is no specific change in the presentation, clinical features, or general outcome for hepatitis A virus, hepatitis B, hepatitis C, cytomegalovirus, or Epstein–​ Barr virus infection in pregnancy. By contrast, hepatitis E is worse in preg- nancy, with high mortality from acute liver failure in the third trimester. Gastrointestinal diseases Inflammatory bowel disease—​does not generally affect fertility. Can flare, be stable, or improve during pregnancy. Women should be en- couraged to continue to take drugs that maintain disease remission. Gallstones and gallbladder sludge—​occur more commonly in preg- nant women and are generally asymptomatic. Acute cholecystitis usually requires surgery, preferably laparoscopic. Gastro-​oesophageal reflux disease—​affects approximately 40%
of pregnant women; simple treatments are often effective, but both H2-​antagonists and proton pump inhibitors have good safety data for use in pregnancy. Introduction Pregnant women can have hepatic diseases that are specific to pregnancy or incidental to pregnancy (Table 14.9.1). In contrast, most gastrointestinal diseases encountered in pregnant women are not specific to pregnancy, although some occur more commonly in pregnant women (e.g. gastro-​oesophageal reflux disease). This chapter will describe the influence of pregnancy on pre-​existing diseases, the effect of these diseases on pregnancy outcome, the impact of specific drugs used to treat women with liver and gastro- intestinal disorders on the fetus, and it will describe gestational disorders that cause hepatic impairment, including hyperemesis gravidarum, pre-​eclampsia, acute fatty liver of pregnancy, and cholestasis. Pregnancy-​specific liver diseases When evaluating pregnant women with hepatic disease, it is im- portant to know the normal range of the laboratory tests that are used (Table 14.9.2). The commonest disorders that cause de novo abnormal serum liver tests in pregnancy are pre-​eclampsia, the HELLP (haemolysis, elevated liver enzymes, low platelets) syn- drome, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy and hyperemesis gravidarum. Typical patterns of change in serum liver tests in each of these pregnancy-​specific liver dis- orders are shown in Table 14.9.3. Hypertension-​related liver disease and pregnancy Hypertension in pregnancy is defined as a blood pressure greater than 140/​90  mmHg on at least two occasions. Pre-​eclampsia, eclampsia, HELLP syndrome, hepatic infarction, and rupture are all part of this spectrum. Pre-​eclampsia and eclampsia Pre-​eclampsia represents a multisystem disorder occurring in ap- proximately 5% of all pregnancies. It may involve the liver, kidneys, central nervous system, and bone marrow. Pre-​eclampsia is defined by the presence of new onset hypertension and proteinuria (greater than 300 mg in a 24-​hour period) occurring after 20 weeks’ gestation and/​or within 48 hours of delivery. The presence of seizures differen- tiates eclampsia from pre-​eclampsia. Risk factors include pre-​existing hypertension, family history, ex- tremes of maternal age, primiparity, and occurrence in a previous pregnancy. Endothelial dysfunction from placental ischaemia is thought to play a critical role. 14.9 Liver and gastrointestinal diseases of pregnancy Michael Heneghan and Catherine Williamson

Section 14  Medical disorders in pregnancy 2620 The clinical features include abdominal pain, headache, nausea, and vomiting. Abnormal liver enzymes occur in 20–​30% of pa- tients and this is thought to be secondary to vasoconstriction of the hepatic vascular bed. Aspartate transferase (AST) and alanine aminotransferase (ALT) maybe as high as 10 times normal range, but bilirubin levels are rarely elevated (Table 14.9.3). Liver biopsy is not indicated although identifiable sinusoidal fibrin thrombi, haem- orrhage, and hepatocellular necrosis may be seen. Tight control of blood pressure is essential. Liver involvement, albeit infrequent, always suggests severe disease, and in that con- text immediate delivery is usually necessary. Complications include maternal hypertensive crises, renal dysfunction, hepatic rupture or Table 14.9.1  Liver diseases most commonly encountered in pregnant women Liver diseases specific to pregnancy Liver diseases incidental to pregnancy Pre-​eclampsia with hepatic impairment HELLP syndrome Hyperemesis gravidarum Intrahepatic cholestasis of pregnancy Autoimmune hepatitis Viral hepatitis Primary biliary cholangitis Primary sclerosing cholangitis Budd Chiari syndrome Cirrhosis Portal hypertension Metabolic diseases Gallstone disease Drug-​induced liver injury Table 14.9.2  Normal ranges for the laboratory tests used to investigate women with hepatic disorders of pregnancy Liver enzyme Non​pregnant Pregnant 1st trimester 2nd trimester 3rd trimester ALT (IU/​litre) 0–​40 -​ 6–​32 6–​32 6–​32 AST (IU/litre) 7–​40 -​ 10–​28 11–​29 11–​30 Bilirubin (µmol/​litre) 0–​17 -​ 4–​16 3–​13 3–​14 γGT (IU/​litre) 11–​50 -​ 5–​37 5–​43 3–​41 ALP (IU/litre) 30–​130 -​ 32–​100 43–​135 133–​418 Albumin (g/litre) 35–​46 28–​37 -​ -​ -​ Bile acids (µmol/litre) 0–​14 0–​14 -​ -​ -​ Haemoglobin (g/​litre) -​ 110–​135 103–​130 100–​130 Platelets (103/​ml) 135–​212 -​ -​ -​ Adapted by permission from BMJ Publishing Group Limited. I Walker, LC Chappell, C Williamson (2013). Abnormal liver function tests in pregnancy. BMJ, 25, 347. Table 14.9.3  Typical elevations of liver enzymes in pregnancy-​specific liver disorders Pattern of LFT changes Likely diagnosis Trimester at onset of symptoms and abnormal serum liver tests Estimated proportion of pregnant women with abnormal LFTs that have each diagnosisa Recommended additional investigations ↑ALT (1.5–​8 fold) ↑tBA (1.5–​15 fold) tBil usually normal Intrahepatic
Cholestasis of Pregnancy (also known as Obstetric Cholestasis) 3rd, but may present as
early as 7 weeks’ gestation 17% Viral serology Antimitochondrial and antismooth muscle antibodies Abdominal USS ↑ALT (2–​5 fold) tBA usually normal tBil usually normal Pre-​eclampsia with
hepatic impairment 3rd, but may present
from 20 weeks’ gestation 49% ↑BP in most Urinalysis for protein U&E, creatinine ↓Platelets ↑ALT (2–​30 fold) tBA usually normal ↑tBil (1.5–​10 fold) HELLP syndrome (haemolysis, elevated
liver enzymes, & low platelets) 3rd, but may present
from 20 weeks’ gestation 22% ↑BP in most Proteinuria in most ↑Creatinine ↓Platelets in all ↑LDH ↑ALT (3–​15 fold) tBA usually normal ↑tBil (4–​15 fold) Acute fatty liver of pregnancy (AFLP) 3rd 4% ↑BP in most Proteinuria in most ↑Creatinine ↓Platelets ↑WBC ↓ plasma glucose ↑ALT (2–​5 fold) tBA usually normal tBil usually normal Hyperemesis
gravidarum 1st If new vomiting later in pregnancy, an underlying
cause must be sought 8% ↑Thyroxine, ↓↓TSHb Hyponatraemia Hypokalaemia ALT, alanine transaminase; tBA, total serum bile acids; tBil, total bilirubin; LFT, liver function test; TSH, thyroid-​stimulating hormone. a During a 15-​month study period, out of a total of 4377 deliveries, 142 women (3%) with 206 diagnoses were found to have abnormal LFTs; of these, 138 diagnoses were pregnancy-​specific liver disease. One additional woman had hepatic infarct/​haematoma. b Symptoms of thyrotoxicosis are rarely seen. TSH is normally suppressed during the first trimester but it is detectable in uncomplicated pregnancy. Adapted by permission from BMJ Publishing Group Limited. I Walker, LC Chappell, C Williamson (2013). Abnormal liver function tests in pregnancy. BMJ, 25, 347.

14.9  Liver and gastrointestinal diseases of pregnancy 2621 infarction, seizures, and increased peri-​natal morbidity and mor- tality. Liver biochemistry typically recovers within two weeks of delivery. HELLP syndrome The combination of haemolysis with a micro-​angiopathic blood smear, elevated liver enzymes and low platelets (HELLP) in preg- nancy was first described in 1982 and affects 6/​1000 pregnancies. Up to 10% of women with pre-​eclampsia develop HELLP. Considered to be a part of the spectrum of pre-​eclampsia, it is one of the cri- teria that can define severe pre-​eclampsia. HELLP may develop in isolation and a peri-​natal infant mortality rate ranging from 6.7 to 70% has been reported. HELLP usually arises in the second or third trimester but can deteriorate or occur following delivery. Risk fac- tors include increased maternal age, multiparity, and white ethnicity. Clinical features and diagnosis Patients with HELLP syndrome maybe asymptomatic, or present with nausea, vomiting, malaise, or right upper quadrant/​epigastric pain. Hypertension and proteinuria is evident in up to 85% of cases. Liver injury is precipitated by intravascular fibrin deposition, low blood volume, and increased sinusoidal pressure. This results in mild to moderate elevation of the AST/​ALT and mild elevation of bilirubin. Recognized classification systems of HELLP include the Tennessee and the Mississippi systems (Table 14.9.4). The prothrombin time or international normalized ratio (INR) remains normal unless there is evidence of disseminated intravas- cular coagulation or severe liver injury. Liver biopsy is typically not warranted. Hepatic haematoma, infarction, and rupture In some patients with severe hypertension-​related disease, hep- atic haematomas, liver infarction, and liver rupture may occur. Computed tomography (CT) or MRI of the liver may identify hep- atic infarction/​rupture, haemorrhage, or subcapsular haematoma. A 50% maternal mortality has been reported for this complication with the prevalence of hepatic rupture being higher with severe thrombocytopenia. Hepatic adenoma, hepatocellular carcinoma, and haemangiomas may also rupture during pregnancy. Contained haematomas should be managed conservatively with blood transfusion and supportive measures. Infection can occur within areas of infarction or haematoma. Haemodynamic in- stability suggests persistent active bleeding and mandates hepatic angiography, arterial embolization of the hepatic artery or surgical exploration. Surgical options include packing, hepatic artery liga- tion, or resection of the affected liver. No long term maternal com- plications have been reported. Management of HELLP/​Severe
hypertension-​related disease Women with HELLP syndrome may require a high-​dependency or intensive care unit (ITU), given the potential complications of encephalopathy, renal dysfunction, hepatic rupture, and bleeding. Prompt delivery is paramount particularly after 32–​34 weeks’ ges- tation, if fetal distress is present or there is evidence of maternal end-​organ disease. Management of hypertension involves the use of labetolol, hydralazine, and nifedepine. Intravenous magnesium sulphate with platelet and/​or coagulation support is recommended, particularly in the presence of bleeding. If gestation is less than 34 weeks, corticosteroids should be administered to promote fetal lung maturity. Hepatic or renal failure mandates admission to intensive care for monitoring. Indications for liver transplantation can include per- sistent bleeding from haematoma, hepatic rupture, or liver failure. The risk of recurrence of HELLP syndrome and pre-​eclampsia in subsequent pregnancies is increased. HELLP syndrome typically re- solves post-​delivery, although temporary postnatal deterioration is not uncommon. Acute fatty liver of pregnancy Acute fatty liver of pregnancy (AFLP) is a medical and obstetric emergency. Defined as microvesicular fatty infiltration of hep- atocytes occurring in usually the third trimester. Maternal and fetal mortality rates are significantly increased and range between 1 to 20%. It is a rare disorder affecting 1 in 7000 to 1 in 16 000 deliv- eries but is one of the commoner causes of liver failure in pregnancy. A UK-​based prospective study involving 229 centres identified 57 confirmed cases in a total of 1 132 964 maternities giving an inci- dence of 5/​100 000 maternities, with 74% cases identified at a me- dian gestation age of 36 weeks. Caesarean section rate was 74%. Aetiology Acute fatty liver of pregnancy is part of the spectrum of mitochon- drial cytopathies which includes Reye’s syndrome and other drug re- lated liver disease. Common characteristics of these disorders include vomiting, hypoglyacaemia, lactic acidosis, hyperammonaemia, and microvesicular fat deposition in organs. Abnormality in mitochon- drial β-oxidation is recognized as the causative aetiology of some cases of acute fatty liver of pregnancy. The enzyme, long chain 3-​ hydoxyacyl coenzyme A  dehydrogenase (LCHAD) is part of the mitochondrial trifunctional protein, which is an important enzyme complex associated with the inner mitochondrial membrane. A landmark study demonstrated that sick infants born to mothers with acute fatty liver of pregnancy with features of HELLP syn- drome had defects in fatty acid β-oxidation and were deficient in LCHAD predominately due to a mutation on one or both alleles of the α subunit of the trifunctional protein. The risk of development of maternal liver disease during pregnancy is 20 times higher in fe- tuses with fatty acid oxidation defects when compared to the general population. The accumulation of fetal fatty acids with their return to the maternal circulation results in deposition in the liver thus causing liver toxicity. Table 14.9.4  Classification systems used in HELLP syndrome Tennessee system* AST >70 IU/​litre LDH >600 IU/​litre Platelets <100 × 109/litre Mississippi system Class I: Platelets <50 × 109/​litre Class II: Platelets 50–​100 × 109/​litre and AST>40 IU/litre and LDH >600 IU/litre Class III: Platelets 100–​150 × 109/​litre

Section 14  Medical disorders in pregnancy 2622 Clinical features and diagnosis The clinical presentation of acute fatty liver of pregnancy varies from nausea and abdominal pain to hepatic encephalopathy, dia- betes insipidus, and jaundice. Risk factors include twin pregnancies and nulliparity. An inverse relationship may exist between body mass index and acute fatty liver of pregnancy, in contrast to the rate of elevated body mass index (BMI) in patients with pre-​eclampsia. Common laboratory abnormalities include raised AST/​ALT, INR, serum urate levels, and bilirubin. Hypoglycaemia is a poor prog- nostic sign. Serum ammonia concentrations rise, and lactic acid- osis is present in severe disease. Evidence of renal dysfunction is common. Differential diagnosis includes HELLP syndrome and viral hepatitis. Interestingly, ultrasound and even computed tom- ography may be inconsistent at detecting fatty infiltration. Although the gold standard for diagnosis is liver biopsy this is rarely performed or necessary. The characteristic microscopic change is microvescicular steatosis. The Swansea diagnostic criteria represent an alternative to liver biopsy (Box 14.9.1) and were shown to be a reliable diagnostic tool in a UK prospective cohort study of liver disorders in pregnancy. Management Prompt delivery is essential in women with acute fatty liver of preg- nancy once any coagulopathy and hypoglycaemia have been treated. Steroids are required for lung maturation in preterm fetuses. In the post-​partum phase, women can develop a prolonged cholestatic phase taking up to four weeks for resolution. Liver transplantation warrants consideration in cases of severe hepatic encephalopathy, liver rupture, and where there is failure of recovery of liver func- tion. The baby should be assessed for signs of hypoglycaemia, hep- atic failure, myopathy, and other features associated with defects in fatty acid oxidation. An increased recurrence rate has only been reported in women who carry the LCHAD mutations although recurrent acute fatty liver of pregnancy may also reoccur in women without detectable LCHAD mutations. Infants born to mothers with acute fatty liver of pregnancy should be screened for defects of fatty acid oxidation. Intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy, also called obstetric cholestasis, is the commonest liver-​specific disorder of pregnancy. It affects 0.67% of pregnancies in the United Kingdom, but there is geographical variability in prevalence with increased rates in women from Chile and South Asia. Its cause is not known. Clinical presentation The typical presenting symptom is pruritus. This usually occurs in the third trimester although it has been reported as early as seven weeks of gestation, and it may affect any part of the body but most com- monly occurs on the palms and soles. There are no specific dermato- logical changes, although women may have excoriations secondary to scratching (Fig. 14.9.1). Affected women have raised serum bile acids and usually have elevated liver transaminases. Bilirubin is not raised in most cases (Table 14.9.3). Many women report dark urine and there may be steatorrhoea, a possible explanation for reports of increased risk of post-​partum haemorrhage due to reduced absorp- tion of vitamin K. Gestational diabetes mellitus occurs more com- monly in women with intrahepatic cholestasis of pregnancy. Women with intrahepatic cholestasis of pregnancy have increased rates of adverse pregnancy outcome, including spontaneous preterm labour, fetal asphyxial events, meconium-​stained amniotic fluid, Box 14.9.1  Criteria for diagnosis of acute fatty liver of pregnancy (Six or more of the following features in the absence of another explanation) • Vomiting • Abdominal pain • Polydipsia/​polyuria • Encephalopathy • Elevated bilirubin (>14 µmol/​l) • Hypoglycaemia (<4 mmol/​l) • Elevated urate (>340 µmol/​l) • Leucocytosis (>11 × 106/​l) • Ascites or bright liver on ultrasound scan • Elevated AST/​ALT (>42 IU/​l) • Elevated ammonia (>47 µmol/​l) • Renal impairment (Creatinine >150 µmol/​l) • Coagulopathy (PT >14 s or APTT >34 s) • Microvesicular steatosis on liver biopsy Reproduced from CL Ch’ng, et al. (2002). Prospective study of liver dysfunc- tion in pregnancy in Southwest Wales. Gut, 51, 876–​880, with permission from BMJ Publishing Group Ltd. Fig. 14.9.1  Typical appearance of the skin in a woman with intrahepatic cholestasis of pregnancy. Dermatological changes include scratch marks with skin discolouration and more generalized skin lesions.

14.9  Liver and gastrointestinal diseases of pregnancy 2623 and stillbirth. Several studies have shown that these adverse out- comes occur more commonly in pregnancies where the maternal serum bile acid concentration is ≥40 µmol/litre, and a recent meta- analysis reported that stillbirth occurs more commonly if the ma- ternal serum bile acid concentration is ≥100 µol/litre. Treatment Women with intrahepatic cholestasis of pregnancy should have regular liver function tests and serum bile acids performed, and investigations should be performed to exclude hepatitis C, auto- immune hepatitis, or primary biliary cholangitis. Women with se- vere cholestasis or steatorrhoea should have a coagulation screen performed. An abdominal ultrasound will evaluate whether there are gallstones or another hepatobiliary cause of cholestasis. The drug most commonly used to treat intrahepatic cholestasis of pregnancy is ursodeoxycholic acid (UDCA), typically at a starting dose of 500 mg BD, rising to a maximum of 2 g daily. This reduces maternal pruritus and biochemical abnormalities in approximately 75% of cases, but it is not known whether it also protects against adverse fetal outcome. Otherwise, aqueous cream with 1–​2% menthol may improve the sensation of pruritus and vitamin K 10 mg OD is advis- able for women with steatorrhoea. Other drugs that have been used with varying success are S-​adenosyl methionine, cholestyramine, and activated charcoal. Rifampicin has been used in conjunction with UDCA for women with a limited response to the latter drug, as the drugs have synergistic actions to induce hepatic biliary transport proteins that enhance excretion of bile acids. Delivery and post-​partum Many clinicians choose to induce labour in women with intrahepatic cholestasis of pregnancy between 37–​38 weeks’ gestation as still- birth in this condition typically occurs at later gestational weeks. This practice is not associated with an increase in operative delivery. Symptoms and hepatic dysfunction typically resolve rapidly after delivery of the fetus, and therefore UDCA and other drugs can usu- ally be stopped within a small number of days. It is important to ensure that liver function tests return to normal by three months post-​partum, and if not then further investigation should be per- formed to exclude other hepatic pathology. Women should be ad- vised to avoid oestrogen-​containing contraception, and that the condition has a high rate of recurrence in subsequent pregnancies. Hyperemesis gravidarum Nausea and vomiting is common in pregnancy. In contrast, hyperemesis gravidarum, characterized by intractable vomiting, re- sulting in dehydration, ketosis, and ≥5% weight loss, is seen in 0.3–​ 2% of all pregnancies. Its exact cause is unclear, but a combination of hormonal factors, abnormal gastric motility, and changes in the autonomic nervous system are thought to play a role. Risk factors include pre-​existing diabetes and multiple pregnancies, increased body mass index, previous psychiatric illness, and molar pregnancy. Clinical features and diagnosis Hyperemesis gravidarum may begin as early as the fourth week of gestation and typically resolves by the eighteenth week. Serum AST and ALT may be markedly raised (Table 14.9.3). Other findings include elevated serum urea and creatinine levels, hypophosphataemia, hypomagnesaemia, hypokalaemia, and biochemical hyperthyroidism. These typically resolve on reso- lution of vomiting. Ongoing elevation in liver enzymes should trigger consideration of alternative diagnoses. There is no role for liver biopsy, as this is non​specific. Management Treatment of hyperemesis gravidarum is supportive and includes intravenous re-​hydration, electrolyte replacement, antiemetics, and gradual re-​introduction of oral intake. Vitamin supplementation especially thiamine is mandatory to prevent Wernicke’s encephal- opathy. Most patients will require day case treatment or hospital admission, but relapse is common. Recurrence in subsequent preg- nancies is common. Liver diseases incidental to pregnancy Viral hepatitis in pregnancy Viral hepatitis is probably the most commonly recognized cause of jaundice occurring during pregnancy worldwide. There is no spe- cific change in the presentation, clinical features, or general outcome for hepatitis A virus, hepatitis B, hepatitis C, cytomegalovirus, or Epstein–​Barr virus infection in pregnancy. Hepatitis B virus can present in an acute or chronic form. For pa- tients with acute hepatitis B, transmission of the virus to the child occurs in 50% of cases with 70% of children infected if acute viral hepatitis B occurs in the third trimester. For patients with chronic hepatitis B, transmission of virus is dependent on the degree of viral replication and the quantity of HBV DNA detectable in the serum of the mother. Transmission rates above 90% have been reported from mothers who are HBV DNA positive and these are typically hepatitis B E antigen positive. Vaccination programmes throughout Southeast Asia and in the developed world have reduced transmis- sion rates dramatically. Following transmission, up to 80% of chil- dren become chronic hepatitis B carriers. Therefore, strategies exist to limit this transmission rate. Firstly, the use of antiviral therapy such as tenofovir disoproxil fumarate 245 mg daily to reduce the HBV DNA level in the third trimester for appropriate patients re- duces viral load, and transmission rate. Secondly the use of hepa- titis B immunoglobulin with hepatitis B vaccination in the neonate within seven days of birth and at 1, 2, and 12 months of age also reduces the transmission rate significantly. Mother-​to-​child transmission (MTCT) of hepatitis C virus has become the leading cause of paediatric infection, at an approximate rate of 5%. Maternal HIV co-​infection is a significant risk factor for MTCT and anti-​HIV therapy during pregnancy can reduce the transmission rate of both viruses. A high maternal viral load is an im- portant, but unpreventable risk factor since no antihepatitis C virus treatment can be given in pregnancy. Obstetric procedures, such as amniocentesis or invasive fetal monitoring, should be used with cau- tion as they could expose the fetus to maternal blood, although evi- dence is lacking on the real risk of these obstetric practices. Mode of delivery and type of feeding do not represent significant risk factors for MTCT. Therefore, there is no reason to offer elective caesarean section or discourage breastfeeding to hepatitis C virus-​infected pa- tients. Antibody conversion of infants following transmission may take 6–​12 months, although measurement of hepatitis C virus RNA levels will allow for early diagnosis.

Section 14  Medical disorders in pregnancy 2624 Hepatitis E virus is problematic in pregnancy typically occurring in epidemic form in Southeast Asia, the Indian subcontinent, and the Middle East. The development of acute liver failure in the third trimester can be associated with a mortality of up to 20%. Pregnancy in patients with cirrhosis Many patients with chronic liver disease and cirrhosis are infertile. However, patients with autoimmune liver diseases such as auto- immune hepatitis, primary sclerosing cholangitis, and primary bil- iary cholangitis may become pregnant. Patients with autoimmune hepatitis should be maintained on baseline immunosuppression throughout pregnancy (azathioprine plus/​minus prednisolone). For patients treated with mycophenolate mofetil pre-​pregnancy, they should be converted to an alternative immunosuppressant such as azathioprine, tacrolimus, or cyclosporine prior to planned preg- nancy. A 20–​25% risk of flare in autoimmune hepatitis occurs fol- lowing delivery in the first three months post-​partum, and this is reduced if immunosuppressive treatment is maintained. Patients with established cirrhosis should be screened for varices in the second trimester. This is to facilitate and guide appropriate peri-​ partum care. The presence of small varices in otherwise well compen- sated cirrhotic patients should not preclude against a vaginal delivery. Variceal bleeding in pregnancy Even in normal patients without liver disease, varices develop during pregnancy. This is related to changes in cardiac output, azygos blood flow, increased circulating blood volume and changes in splanchnic haemodynamics. For patients with non​cirrhotic portal hyperten- sion, a bleeding rate in pregnancy of 13% has been reported. In cir- rhotic patients contemplating pregnancy, pre-​pregnancy screening and appropriate treatment of large varices should be undertaken. Propranolol is not contraindicated in pregnancy and episodes of variceal bleeding should be treated with normal endoscopic ap- proaches including endoscopic band ligation, histoacryl glue, whereas transjugular intrahepatic shunts should be reserved for rescue therapy and field endoscopic treatment. There are limited safety data for vasoconstrictors such as terlipressin, but they may be used in women with life-​threatening haemorrhage. Pregnancy following Liver Transplantation Successful pregnancy following liver transplantation has been widely reported and fertility will return typically within six months of transplant. Best outcomes are reported for pregnancies under- taken greater than one year following the transplant operation since this reduces the risk of acute cellular rejection and other infective complications. Tacrolimus, cyclosporine, azathioprine, and cortico- steroid therapy are widely and safely used in pregnancy. Specific complications in pregnancy related to a higher prevalence of hyper- tension/​pre-​eclampsia and preterm delivery have been reported. Patients on mycophenolate should be converted to an alternative immunosuppressant prior to pursuing pregnancy. Gastrointestinal diseases of pregnancy Inflammatory bowel disease The respective incidence of Crohn’s disease and ulcerative colitis is 10.7 and 12.2 per 100 000. Both disorders typically affect women at reproductive age. While fertility is reduced in women with active disease, or if there is scarring or inflammation affecting reproductive tissues, for most women there is no major impact on the ability to conceive. Clinical presentation Women with inflammatory bowel disease should have pre-​ pregnancy counselling as this will enable evidence-​based deci- sions to be made about drug treatment. Ideally women should have been in remission for several months, as disease activity at conception does influence the risk of flare in pregnancy (Box 14.9.2). The pre-​pregnancy period is a good time to ensure there are no deficiencies of vitamins D, B12, or iron, and women should be encouraged to take folic acid supplementation. Most drugs used to treat inflammatory bowel disease can be taken in preg- nancy (Table 14.9.5) and women should be informed that the greatest risk of flare occurs in those that discontinue treatment. There is an increased risk of spontaneous miscarriage, preterm la- bour and small for gestational age infants, and the risk of low birth weight increases further in women with disease flares. If women continue their medication, the risk of disease flare is the same as in non​pregnant women. Treatment Most drugs used to treat inflammatory bowel disease, including bio- logical therapies, are safe in pregnancy and lactation (Table 14.9.5). The only drug that is contraindicated is methotrexate as this causes congenital abnormalities and spontaneous miscarriage. Some studies have found increased rates of small for gestational age and preterm infants in women treated with thiopurines or cyclosporine, but it is difficult to establish whether this is related to severity of the underlying disease or due to use of the drug. Overall, the benefits of treatment with these drugs, and with glucocorticoids, outweighs the possible association with preterm or small infants, and women should be encouraged to continue to take drugs that maintain dis- ease remission, particularly given the clearly documented increase in these complications in women with disease flares. Biologic therapy is well tolerated in pregnancy and there are accumulating data to support the use of these drugs in pregnancy and during breast- feeding. Ideally, IgG1 antibody therapies (infliximab, adalimumab, and golimumab) should be avoided in the third trimester as they are transported across the placenta, and levels of these drugs are higher in fetal than maternal blood in late pregnancy. However, some women have severe flares, necessitating treatment. The infants of Box 14.9.2  Relationship between disease activity at the time of conception and the risk of flare of inflammatory bowel disease in pregnancy If active disease at the time of conception: Ulcerative colitis •​ 45% will have flare •​ 30% will have stable disease •​ 25% will improve Crohn’s disease •​ 33% will have a flare •​ 34% will have stable disease •​ 33% will improve

14.9  Liver and gastrointestinal diseases of pregnancy 2625 women treated with biologic agents should not receive live vaccines for the first six months of life. If a woman has a flare in pregnancy, the treatment is the same as for non​pregnant women. Clostridium difficile infection is more common in pregnant women with inflammatory bowel disease and stool samples should be tested in women with new diarrhoea. If imaging is required, magnetic resonance imaging is preferred as this avoids radiation exposure. Flexible sigmoidoscopy and colonoscopy can be performed if indicated, with appropriate sedation. The indi- cations for surgery are the same as for non​pregnant individuals. Delivery and post-​partum Women with inflammatory bowel disease have higher rates of cae- sarean section than the background population. However, for most women with inactive disease there is no contraindication to va- ginal delivery, and caesarean section should be performed only for obstetric reasons. There are two groups of women where decisions about mode of delivery should be made on a case-​by-​case basis. For women with active perianal disease there is a risk of perineal trauma, and caesarean section should be considered. For women with an ileal pouch-​anal anastomosis, it is important to avoid anal sphincter damage to preserve continence. It is advisable to have a multidisciplinary discussion, including the colorectal surgeon, to decide about mode of delivery in this group of women. There is some evidence that vaginal delivery does not significantly affect pouch function, but the opinion of the surgical and gastrointes- tinal team will be invaluable to individualized decision-​making in this context. Gallstones and acute cholecystitis Gallstones and gallbladder sludge occur more commonly in preg- nant women. Several prospective studies have reported rates of 8–​10% in the third trimester and puerperium. Affected women more commonly have a raised body mass index, and gallstones are also more commonly diagnosed in women with intrahepatic cholestasis of pregnancy. Most pregnant women with gallstones are asymptomatic, and this group should be managed conservatively. If a woman develops symptoms of acute cholescystitis, she should be given intravenous fluids, antibiotics, and feeding should be stopped. Surgical manage- ment is usually preferred, as 40% of women treated medically have relapse. If surgery is required, a laparoscopic approach is usually preferred as this is associated with lower rates of complication and shorter operative recovery than open surgery. Appendicitis The commonest presenting symptoms of appendicitis in pregnancy are right lower quadrant pain, although retrocaecal appendicitis may result in flank or back pain. Other characteristic symptoms are anorexia, vomiting, abdominal guarding or rebound, but they may be absent. The white blood cell count and C-​reactive protein are usu- ally raised. Graded abdominal ultrasound imaging usually achieves a diagnosis in the first two trimesters, but may be difficult in late pregnancy. Magnetic resonance imaging is safe in pregnancy and increasing data support its use due to high sensitivity and specifi- city in pregnant women. As with acute cholecystitis, laparoscopic re- moval is associated with lower complication rates than open surgery. Pancreatitis Acute pancreatitis is rare, affecting approximately 1 in 10 000 preg- nant women. The commonest cause is gallstones, but it may also be caused by hypertriglyceridaemia, alcohol abuse, hyperparathyr- oidism, or drugs (e.g. thiazide diuretics), and approximately 10% of cases are idiopathic. The most valuable tests for diagnosis are Table 14.9.5  Drugs used to treat inflammatory bowel disease in pregnancy Drug name High or low risk in pregnancy High or low risk in breastfeeding Methotrexate High •​ teratogenicity and fetal loss High •​ transferred in breast milk Corticosteroids (budesonide and prednisolone) Low •​ possible slight increase in the risk of cleft lip/​palate, but benefits for women with flares outweigh risks Low Aminosalicylates (sulfasalazine and mesalazine) Low •​ sulphasalazine interferes with folate metabolism so essential to give high-​dose folic acid (5 mg OD) Low Thiopurines (azathioprine and 6-​mercaptopurine) Low •​ no increase in congenital abnormalities, but care with starting during pregnancy due to associated low risk of pancreatitis, hepatic impairment, or bone marrow suppression Low Cyclosporine Low Medium •​ transferred to breast milk Anti TNFα agents (IgG1 antibodies—​infliximab, adalimumab, golimumab) Low •​ but ideally avoid in 3rd trimester due to risk of immune suppression
in neonatea Low Anti TNFα agents (pegylated Fab fragment—​certolizumab) Low •​ not actively transported across the placenta, therefore less concern about treatment in the 3rd trimester Likely low, but limited data IgG1—​immunoglobulin G1; TNFα—​tumour necrosis factor alpha a If a woman has severe disease the clinical need for these agents may necessitate treatment. All neonates of women treated with Anti-​TNFα agents in pregnancy should not receive live vaccines for the first six months of life.

Section 14  Medical disorders in pregnancy 2626 serum amylase or lipase. Treatment is the same as for non​pregnant women, in addition to surgical or medical management of the underlying cause. Gastro-​oesophageal reflux and peptic ulcer Gastro-​oesophageal reflux disease affects approximately 40% of pregnant women. Most women have a benign course and symp- toms resolve after delivery. Simple treatments are often effective, including lifestyle modification and use of antacids, alginates, or sucralfate. If required both H2-​antagonists and proton pump inhibi- tors have good safety data for use in pregnancy. Peptic ulcer disease is considerably less common and typic- ally presents with epigastric pain, postprandial nausea, vomiting and anorexia. If suspected, endoscopic investigation can be per- formed in pregnant women. It is advisable to also screen for Helicobacter Pylori. Peptic ulcer can be treated with the same drugs that are used for gastro-​oesophageal reflux disease and the commonest treatment regimens used for Helicobacter Pylori can be used in pregnancy (proton pump inhibitor, amoxicillin, clarithromycin). Coeliac disease Coeliac disease is an autoimmune disorder of the small intestine. It should be considered in pregnant women presenting with diarrhoea or unexplained abdominal pain. Serology for anti-​endomysial, antigliadin, and antitissue transglutamase antibodies is reliable in pregnancy, and endoscopy can be performed for a definitive diag- nosis if indicated. Affected women should be referred for dietary advice, and compliance can be assessed using serial serological meas- urements. This is important as inadequately controlled women are at risk of deficiency of fat soluble vitamins, calcium malabsorption, and oxalate kidney stone formation. There is evidence for an in- creased risk of intrauterine growth restriction and preterm birth in undiagnosed disease. Gastrointestinal cancer Malignancies affecting the gastrointestinal tract are rare women of reproductive age. However, they should be considered in women with unexplained, severe symptoms of weight loss, abdominal pain, anorexia, nausea, vomiting, constipation, or rectal bleeding. Many of these symptoms are common in pregnancy, but gastric or colon cancer may be present if they are ongoing or severe. If suspected, endoscopic investigation should be pursued. Pregnancy does not affect the serum concentration of carcinoembryonic antigen, so this can be used as a prognostic or monitoring test for women with known colorectal cancer. FURTHER READING Ch’ng CL, et al. (2002). Prospective study of liver dysfunction in preg- nancy in Southwest Wales. Gut, 51, 876–​80. Geenes V, et al. (2013). Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes:  a prospective population-​based case-​control study. Hepatology, 59, 1482–​91. Ibdah JA, et al. (1999). A fetal fatty-​acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med, 340, 1723–​31. Knight M, et al. (2008). A prospective national study of acute fatty liver of pregnancy in the UK. Gut, 57, 951–​6. Mahadevan U, Matro R (2015). Care of the pregnant patient with in- flammatory bowel disease. Obstet Gynecol, 126, 401–​12. Walker I, Chappell LC, Williamson C (2013). Abnormal liver function tests in pregnancy. BMJ, 347, f6055. Westbrook RH, et al. (2012). Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun, 38, J239–​44. Westbrook RH, et al. (2015). Outcomes of pregnancy following liver transplantation:  the King’s College Hospital experience. Liver Transpl, 21, 1153–​9. Williamson C, Geenes V (2014). Intrahepatic cholestasis of pregnancy. Obstet Gynecol, 124, 120–​33.