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

• Kendrick et al. 2015: doi 10.1053/​j.ajkd.2014.11.019, ** Ananth et al. https://doi.org/10.1136/bmj.f6564 CKD, chronic kidney disease; NICU, neonatal intensive care unit. Table 14.5.7  Management of women with chronic kidney disease in pregnancy Management Details Preconception counselling Individualized risk assessment and counselling to allow: • Informed decision-​making • Optimization of BP/​medication/​disease activity prior to pregnancy Pregnancy care Access to multidisciplinary advice and care should be available including obstetrician, nephrologist/​expert physician and specialist midwife Monitoring renal function in pregnancy • eGFR is not validated in pregnancy (see Table 14.5.1) • Creatinine should be tracked in pregnancy with frequency dictated by severity of CKD, pregnancy progress, and clinical suspicion of pre-​eclampsia Avoid teratogenic medication See Table 14.5.8 Pre-​eclampsia prophylaxis • Prescribe low dose aspirin (75–​150 mg) by 12 weeks’ gestation • Consider calcium supplementation in women at risk of deficiency Treatment of hypertension Target blood pressure <140/​90 mm Hg Quantification of proteinuria Isolated proteinuria should not be attributed to infection and should always be quantified Venous thromboembolism (VTE) prophylaxis • Women with CKD should be risk assessed for VTE • Proteinuria increases risk • No consensus threshold for prophylaxis • Consider prophylactic LMWH at >2 g/​24 hours, PCR >200 mg/​mmol, ACR >140 mg/​mmol. Dose reduction may be indicated in CKD as renal clearance is significant. Gestational diabetes (GDM) Early screening should be considered in women: • With previous GDM • Taking steroids • Taking calcineurin inhibitors (tacrolimus/​ciclosporin) Surveillance for adverse outcomes • Manage as high risk for pre-​eclampsia • Fetal growth scans from 28 weeks’ gestation Delivery CKD and renal transplantation are not contraindications to vaginal delivery Post-​partum • Use medication with safety data in breastfeeding, e.g. enalapril (see Table 14.5.8) • Discharge when blood pressure stable <140/​90 mm Hg, creatinine stable, and any abnormal parameters from pregnancy improving • Antihypertensive requirements may fall with time • Ensure nephrology and obstetric follow up appropriate for CKD stage and pregnancy complications BP, blood pressure; CKD, chronic kidney disease; GDM, gestational diabetes; LMWH, low molecular weight heparin; VTE, venous thromboembolism.

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.