Birmingham and Birmingham Women’s Hospital, Birmingham, UK
Case History 1: A 26‐year‐old woman with Crohn’s disease presents for IVF treatment. She has never had abdominal surgery, and her gastrointestinal symptoms have been well controlled with azathioprine and adalimumab. However, her general practitioner has expressed concerns about continuing these two drugs in pregnancy.
Case History 2: Despite advice to avoid herbal medicines, a woman undergoing IVF treatment insisted on taking echinacea as she believed this herbal remedy boosted her immune system and reduced the risk of implantation failure, which she had suffered in two previous IVF cycles.
Background
Drugs may be harmful in pregnancy, with women and clinicians alike fearing their impact upon fetal development and growth. Congenital developmental disorders have been the subject of tales dating all the way back to prehistoric times and were initially attributed to supernatural causes [1]. In the 19th century, the concept of teratology as the study of developmental malformations in an embryo or fetus was first introduced by I. G. de Saint‐Hillaire [2]. Later on, in the 1930s, Hale described a set of experiments where pigs deprived of vitamin A exhibited a lack of eyeballs, pioneering experimental teratology as a modern science aimed at identifying possible causes of congenital defects [3]. The widely known thalidomide episode in the 1960s, where pregnant women exposed to this antiemetic gave birth to babies with limb deformities, remains a prime example of drug toxicity and its potential catastrophic effects in the offspring of healthy mothers [4].
Today, caution is advised to clinicians prescribing drugs for women who are pregnant or trying to conceive. This stems, to an extent, from a paucity of good‐quality data on safety of medications in pregnant women, who are often excluded from preapproval drug studies [5]. Yet pregnant women, and those trying to conceive, are frequently prescribed drugs with teratogenic potential. This may be due to preexisting medical conditions where the therapeutic benefits of a certain drug are thought to outweigh the teratogenic risk attributed to the medication [6–13]. For example, in the UK, 1 in every 164 women received a United States Food and Drug Administration (FDA) Pregnancy Risk category X prescription in early pregnancy between 1991 and 1999 [6]. Furthermore, over‐the‐counter medications are also used by a majority of women in early pregnancy [14,15].
Women planning to get pregnant, and particularly those undergoing assisted reproductive technology (ART) treatment, often present to their clinicians asking about drug safety in the preconception period and early pregnancy.
Management options
Drugs in the preconception stage and early pregnancy
Historically there has been a reluctance from researchers to enroll pregnant women in research trials, mostly due to fears of harm to the fetus [10]. Pregnant women are thus underrepresented in interventional studies, with efficacy and safety data often being extrapolated from analyses conducted in nonpregnant women. Cohort, registry and case‐control studies are the main sources of safety data of drugs in pregnancy, frequently relying on linkage methodology [7–10,15,16], while controlled interventional studies in pregnancy are often underpowered and focus mostly on labor and delivery rather than drug pharmacokinetics or teratogenicity [11,14,17]. In recent years, however, there has been an increasing number of scientists advocating a fair and representative inclusion of pregnant women in research [17,18].
In 1979, the FDA introduced a five‐letter risk classification to inform clinicians and women about a drug’s potential to cause congenital abnormalities if used in pregnancy (Table 7.1) [19]. This has recently been updated to a labeling system containing narrative summary information thought to be more patient‐friendly [20]. In the UK, the British National Formulary (BNF) simply categorizes drugs into those which may have harmful effects in pregnancy (indicating the potential abnormalities and trimester of risk) and those which are not known to be harmful in pregnancy [21].
The effects of drugs on pregnancy in general, and embryo development in particular, depend on a myriad of factors such as dose, duration of treatment, gestation of use, genetic susceptibility and placental clearance function [22]. In the first two weeks following fertilization, there is an “all‐or‐nothing” effect whereby drugs will either induce miscarriage or allow gestation to continue, although during this period certain exposures can still negatively affect surviving embryos [23]. The time of greatest teratogenic risk extends from the third to the eleventh week of pregnancy, when the basis of organogenesis is established [21]. Following the first trimester of gestation, adverse drug effects may result in growth restriction or disorders of the central nervous system and other organs, such as the kidneys and the heart [23].
The overall principles for prescribing drugs in women trying to conceive are as follows [21,24,25]:
1 Regularly reassess the need for medication in women trying to conceive or who become pregnant, and where possible consider nonpharmacological interventions.
2 Avoid drugs in the first trimester if possible.
3 Prescribe only if the expected benefit outweighs the risks.Table 7.1 FDA categories of risk for drugs in pregnancy [19].AAdequate and well‐controlled studies in animals and humans have failed to show fetal risk.BAnimal studies have failed to demonstrate a risk to the fetus, and there are no adequate and well‐controlled studies in pregnant women.CAnimal studies have shown an adverse effect on the fetus, and there are no adequate and well‐controlled studies in humans, although potential benefits may outweigh the risks.DEvidence of risk to the human fetus but benefits may still outweigh the risks.XEvidence of risk to the human fetus which clearly outweigh potential benefits—drug contraindicated in pregnancy.
4 Prescribe drugs that have long been used in pregnancy, with a good safety record, over new or untested drugs.
5 Use the smallest effective dose for the shortest period of necessity.
6 Consult a pharmacist or teratology information service when in doubt about a drug’s most up‐to‐date safety profile in pregnancy.
7 Always involve women in decisions made about pharmacological interventions in pregnancy.
A plethora of conditions are known to cause adverse pregnancy events. Chronic hypertension, for example, is linked to an increased risk of preeclampsia, fetal growth restriction and intrauterine fetal death [26]. Other diseases, such as diabetes mellitus and epilepsy, are known to increase the risk of congenital abnormalities if left untreated [27,28]. It may therefore be preferable to continue preconception medication or switch to drugs with a better safety profile in pregnant women with the aforementioned conditions and others, such as thyroid dysfunction, kidney disease or depression. In order to ensure patient safety, it is important that clinicians are adequately trained to identify teratogens and exercise the above principles when prescribing for women of reproductive age [25]. In addition, specialist input is frequently required in the management of women with chronic illnesses trying to conceive. For this reason, some hospitals offer multidisciplinary preconception clinics where maternal health clinicians and an extended multidisciplinary team of specialist physicians provide expert input in the management of complex medical conditions [29,30]. Women who conceive while on teratogens constitute an especially high‐risk group of patients and should have an early referral to a maternal‐fetal medicine specialist with multispecialty links, preferably in a tertiary referral center [31].
Table 7.2 provides examples of commonly prescribed drug classes and their safety profiles in pregnancy.
Table 7.2 Safety profile of different drug classes in pregnancy [6,21,24,25,32,33].
| Drug class | Considered safe in pregnancy—use if necessary |
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