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