Prescription drug use in pregnancy: more evidence of safety is needed

2012;14:87–92DOI: 10.1111/j.1744-4667.2012.00096.x

The Obstetrician & Gynaecologist

http://onlinetog.org

Review

Prescription drug use in pregnancy: more evidenceof safety is neededMelanie Chan MA MRCP,a Ian C K Wong BSc MSc PhD MRPharmS ITLM(HE),b Alastair Gordon Sutcliffe MD PhD FRCP

FRCPCHc,∗

aCore Medical Trainee, University College London Institute of Child Health, General and Adolescent Paediatrics Unit, 30 Guilford Street, LondonWC1N 1EH, UKbProfessor of Paediatric Medicines Research, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, TavistockSquare, London WC1H 9JP, UKcReader in General Paediatrics, University College London Institute of Child Health, General and Adolescent Paediatrics Unit, London, UK∗Correspondence: Alastair Gordon Sutcliffe. Email: [email protected]

Key content� Prescription drug use during pregnancy is prevalent, with 44–99%of women being prescribed medication during pregnancy.

� Pregnant women and their unborn children are considered avulnerable population; recent public health scares, such as H1N1,have highlighted the need for more detailed research intomedication use in pregnancy.

� The teratogenic risk of more than 80% of 468 drugs released in theUSA over the last 20 years remains to be clarified.

� Maternal physiological changes during pregnancy can alter drugpharmacokinetics, with poorly understood effects, while placentaltransfer of medications may have unknown fetal consequences.

� There is an urgent need for further research into the adverse effectsof drugs used in pregnancy.

Learning objectives� To know about the prevalence of prescription medication useduring pregnancy.

� To be aware of the lack of safety data available on fetal adverseeffects for commonly prescribed drugs.

Ethical issues� Drug companies are reluctant to carry out phase III clinical trials inpregnant women and they rely on animal models andpost-marketing surveillance for the identification of adverse effects.

� Is it unethical to prescribe drugs in pregnancy for which there islittle concrete safety data?

Keywords antidepressants / anti-epileptic drugs / congenitalmalformation / Medicines and Healthcare products RegulatoryAgency / US Food and Drug Administration

Please cite this paper as: Chan M, Wong ICK, Sutcliffe AG. Prescription drug use in pregnancy: more evidence of safety is needed. The Obstetrician & Gynaecologist2012;14:87–92.

Introduction

Prescription drug use during pregnancy is prevalent.Epidemiological studies estimate that 44–99% of women areprescribed medication during their pregnancy,1 and withup to half of all pregnancies in England being unplanned,2

many unborn children are exposed to drugs before womenrealise they are pregnant. The majority of prescriptionsare for pregnancy-related complaints and minor infections;however, a small proportion of women receive medication fortreatment of chronic diseases such as asthma, depression orhypertension. The recent H1N1 public health scare, whichaffected pregnant women more severely, has highlighted theneed for more detailed research on therapeutics in pregnancy.3

In obstetrics, where a risk assessment must be made toweigh up the benefit to the mother with the risk to theunborn child, prescribing decisions are critical. With evidence-based medicine a core concept of modern clinical care,obstetric prescribing practice is often founded on poorly

designed, inadequately powered observational and registry-based studies. Improvements in research methodology areneeded to provide reliable and reproducible evidence for thesafety and efficacy of medications commonly used duringpregnancy and their potential teratogenic and fetotoxic effects.

The prevalence of medication usein pregnancy

There have been numerous epidemiological studies that haveattempted to evaluate the prevalence of medication use inpregnancy and to estimate how many potentially teratogenicdrugs are being prescribed to this vulnerable population. Datacollected from the UK General Practice Research Database4

of 81 975 pregnant women estimated that 65% had beenprescribed at least one medication and that one in every 164women had received a US Food and Drug Administration(FDA) category X (Box 1) drug in early pregnancy.

C© 2012 Royal College of Obstetricians and Gynaecologists 87

Prescription drug use in pregnancy: more evidence of safety is needed

Box 1. US Food and Drug Administration (FDA)classification system for drugs used in pregnancy35

Category ofdrug inpregnancy ExplanationA Adequate and well-controlled studies have failed

to demonstrate a risk to the fetus in the firsttrimester of pregnancy (and there is no evidenceof risk in later trimesters).

B Animal reproduction studies have failed todemonstrate a risk to the fetus and there are noadequate and well-controlled studies inpregnant women.

C Animal reproduction studies have shown anadverse effect on the fetus and there are noadequate and well-controlled studies in humans,but potential benefits may warrant use of thedrug in pregnant women despite potential risks.

D There is positive evidence of human fetal risk basedon adverse reaction data from investigational ormarketing experience or studies in humans, butpotential benefits may warrant use of the drugin pregnant women despite potential risks.

X Studies in animals or humans have demonstratedfetal abnormalities and/or there is positiveevidence of human fetal risk based on adversereaction data from investigational or marketingexperience, and the risks involved in use of thedrug in pregnant women clearly outweighpotential benefits.

The proportion of pregnant women in Canada and theUSA taking category D and X medications has been estimatedat 4.8–5.2% and 3.9–4.6% respectively (including oralcontraceptives), with the most frequently prescribed drugs inthe 270 days before delivery reported as being anti-asthmatics,antibiotics, analgesics, anxiolytics and antidepressants.5, 6

Asthma and obstructive pulmonary disease were the mostcommon chronic conditions, in 2.6% of the pregnantpopulation, followed by thyroid insufficiency (0.8%), epilepsy(0.7%), rheumatoid arthritis (0.5%), diabetes mellitus (0.5%),hypertension (0.4%), inflammatory bowel disease (0.4%) andsevere mental disorders (0.2%).7

A large Canadian registry study8 looked at the prevalenceof fetotoxic medication use in pregnancy and attempted tocorrelate it with adverse fetal outcomes. From a populationof 109 344 women, 56% filled a prescription for at leastone medication during their pregnancy, with 6.3% of thoseprescriptions having recognised fetotoxic or teratogenic effects.As might be expected, there was a statistically significantdifference between the rates of major congenital malformationsin live born babies exposed to known fetotoxic drugs whencompared with those with no exposure (8.2%, 95% confidenceinterval [CI] 8.0–10.0 versus 7.1%, 95% CI 6.9–7.3).

In a recently published Irish prospective cohort study9

looking at 23 989 pregnancies, it was reported that 39.2% of

Box 2. Factors increasing the prevalence of fetotoxicmedication use during pregnancy9

• Unplanned pregnancy• Multiple pregnancy• Nulliparity• Unemployment• Age >25 years• Single status• Smoking

women were exposed to at least one medication (excludingfolic acid) in their first trimester. Factors that were found toincrease the prevalence of potentially fetotoxic medication useduring pregnancy are listed in Box 2.

In summary, a number of cohort and registry-basedepidemiological studies have shown that prescription drug usein pregnancy is commonplace, with a small but significantproportion of women taking medications that are known tobe fetotoxic or teratogenic. In 2010 there were over 720 000maternities in England and Wales,10 which equates to over 4300mothers a year taking category X medications. The prescribingof potentially hazardous drugs during pregnancy necessitatesan accurate risk–benefit assessment to be made: something thatis often carried out in the absence of reliable and reproducibleevidence.

Medication use and congenitalmalformations

The baseline prevalence of congenital malformations isestimated at 2–3% of all births, of which approximately1% are considered attributable to prescription drug useduring pregnancy.11 With over 723 000 live births recordedin 2010,10 approximately 200 babies would be expected tohave drug-related birth defects annually in England and Wales.Consequently the overall contribution of teratogenic drugs tofetal malformations is much less than that perceived by thegeneral public and the medical profession, but it remains oneof the few causes over which we can exert some influence. Fewerthan 20 drugs or groups of drugs are known to be teratogenicand for the majority (with the exception of thalidomide andisotretinoin), >90% of pregnancies exposed during the firsttrimester will result in a healthy baby.12 A complex interplaybetween gestational age at exposure, drug dosage, durationof treatment, pharmacokinetics, placental transfer, randommutations and genetic predisposition can all affect the finalpregnancy outcome.

A large birth defect registry study13 published in 2010 lookedat 18 131 cases with at least one major malformation exposedto medication in the first trimester of pregnancy. They foundthe following statistically significant associations:

88 C© 2012 Royal College of Obstetricians and Gynaecologists

Chan et al.

Box 3. Teratogenic mechanisms associated withmedication use15

• Folate antagonism, e.g. anti-epileptic drugs, methotrexate,trimethoprim, sulfasalazine and metformin

• Endocrine disruption, e.g. diethylstilbestrol, fertility hormones,oral contraceptives

• Neural crest cell disruption, e.g. retinoids and bosentan• Oxidative stress, e.g. thalidomide, anti-epileptic drugs, class III

anti-arrhythmics, iron supplements• Vascular disruption, e.g. misoprostol, aspirin, ergotamine,

pseudoephedrine• Specific receptor or enzyme-mediated teratogenesis, e.g. ACE

(angiotensin-converting-enzyme) inhibitors, angiotensin IIreceptor blockers, statins, non-steroidal inflammatory drugs

� thyroxine with unilateral kidney agenesis� valproic acid with spina bifida and hypospadias� carbamazepine with isolated spina bifida and cleft palate� barbiturates with isolated cleft palate� insulin with isolated ventricular septal, secundum atrial

septal and cardiac outflow tract defects� benzodiazepines with isolated cleft lip/palate.

Such an array of associations highlights the usefulness ofsuch registries for epidemiological purposes and for suggestingpotential targets for further research.

The teratogenic mechanisms of different medications arediverse. Although drugs are subjected to animal testing priorto release on the market, this does not always predict adverseeffects on the human fetus accurately. Thalidomide remainsthe most infamous example of the limitations of animal modelsas predictors of teratogenesis. Having been tested in pregnantanimals, it proved to have devastating effects on the fetus, whichcould not be reliably reproduced in animals retrospectively.While some teratogenic outcomes are now well recognised,such as the association between thalidomide and phocomelia;tetracyclines and teeth staining; and sodium valproate andspina bifida, for the vast majority of drugs our knowledge ofpregnancy safety data remains minimal. In fact, the teratogenicrisk of more than 80% of 468 drugs released in the USA overthe last 20 years remains to be clarified.14 A recently publishedreview of this topic identified six teratogenic mechanismsassociated with medication use (Box 3).15

Pharmacokinetic principles in pregnancy

The maternal physiological changes that occur duringpregnancy can alter drug pharmacokinetics significantly.Almost every substance used for therapeutic purposes can anddoes pass from mother to fetus; of importance is whether therate and extent of transfer are sufficient to result in significantconcentrations within the fetus.16 The principal changes inmaternal physiology and their impact on drug metabolism are

summarised below: as a general rule, the volume of distributionand clearance of drugs is increased, resulting in lower plasmaconcentrations of medications.17

� Increased progesterone reduces gastric emptying andintestinal motility, with a maximum effect in the thirdtrimester, thereby reducing the absorption of drugs.

� There is reduced plasma protein and reduced proteinbinding.

� Increased total bodyweight and fat distribution mean a largervolume of distribution for both hydrophilic and lipophilicdrugs.

� Altered drug metabolism via phase I oxidative and phase IIconjugation mechanisms and induction of the cytochromeP450 system, with increased hepatic blood flow, increasesthe amount of drug available to the liver to metabolise.

� An increase of 40–65% in glomerular filtration rate increasesrenal elimination of certain drugs.

� Drug transfer occurs mainly by diffusion across the placenta,favouring lipophilic drugs, and is limited by placental bloodflow.

Most compounds, both exogenous and endogenous, crossthe placenta in detectable amounts, given sufficient time andsensitivity of detection.18 If a group of drugs is not known tohave teratogenic effects and no other data are available, thena comparison of lipid solubility, molecular weight, ionisationand degree of protein binding may assist the clinical selectionof an appropriate drug for more efficient transfer (fetal drugtherapy) or less efficient transfer (limited fetal exposure). Drugsthat are more readily passed via the placenta are usually:18

� highly lipid soluble, e.g. diazepam� small molecules (<600 daltons), e.g. propylthiouracil� non-ionised, e.g. phenobarbital� low protein binding in maternal plasma, e.g. ampicillin.

Due to the ethical and practical difficulties of collectingdata in the form of blood, amniotic fluid, cord blood andfetal samples, limited information is available on the specificpharmacokinetics and pharmacodynamics of drugs used inpregnancy. This significant gap in our knowledge presents anopportunity for designing novel adequately controlled researchprotocols that are both ethically and practically acceptable topregnant women.

Current evidence for the safety ofcommon medications used in pregnancy

Here we review the evidence for the fetal safety of two relativelycommon groups of drugs: anti-epileptics and antidepressants.



Anti-epileptic drugs (AEDs)Sodium valproate was first introduced in 1967; however,it was not until 15 years later that its teratogenic riskbecame apparent and was described in the literature,19, 20

highlighting the difficulties involved in detecting potentialteratogens. Nonetheless, AEDs are the most studied group ofdrugs in pregnancy, with an estimated 1 in 250 pregnanciesexposed. National Institute for Health and Clinical Excellence(NICE) guidelines state that it is not possible to commenton the teratogenic risks of AEDs in view of the limited dataavailable. Preliminary data collated from the UK Epilepsyand Pregnancy Register showed that the risk of congenitalmalformations with the use of one AED was 3.7% (n = 2598),compared with 6.0% (n = 770) in those women taking twoor more AEDs.21 Specific malformation rates for valproate,carbamazepine and lamotrigine are estimated at 7.2%, 2.3%and 3%, respectively. A systematic review and meta-analysis22

of registry and cohort studies found that the risk of congenitalmalformations was significantly increased with valproatemonotherapy (10.73%) and AED polytherapy (16.78%), withthe combination of valproate and two other AEDs increasingthe risk to 25%. The most common birth defects identified werecardiovascular malformations, in particular ventricular septaldefects, followed by musculoskeletal defects, with the incidenceof ear/neck/face defects, cleft lip and spina bifida significantlyincreased in both the monotherapy and polytherapy groups.Neurodevelopmental outcome does not appear to be adverselyaffected by in utero exposure to AED monotherapy;23 however,studies have found that in utero exposure to valproate isassociated with lower mean IQ scores when compared withcontrols and other AEDs.24, 25 Evidence for the fetal adverseeffects of newer AEDs such as levetiracetam, oxcarbazepineand topiramate is even more scarce.

AntidepressantsUp to 4% of women use antidepressants during pregnancy, with2.3% taking selective serotonin reuptake inhibitors (SSRIs).26

In 2005 a manufacturer’s warning was issued regarding thepossible association of paroxetine with fetal cardiovascularanomalies; however, studies have been contradictory.A meta-analysis27 of pregnancy outcomes after exposureto SSRIs (including paroxetine) did not find a statisticallysignificant effect on the rate of congenital malformations whencompared to controls. Similarly, a large birth defect registrystudy28 found no association between maternal SSRI use andcardiac malformations; however, a link was found betweenexposure and anencephaly, craniosynostosis and omphalocele.Subsequent studies looking specifically at paroxetine havefound that first-trimester exposure significantly increases therisk of cardiovascular malformations.29, 30

In 2007 NICE recommended fluoxetine as the SSRI ofchoice in pregnancy; however, the Medicines and Healthcare

products Regulatory Agency (MHRA) recently issued a drugsafety update warning that fluoxetine may also increasethe risk of congenital cardiac malformations, to a similardegree as paroxetine. A large, prospective, multicentrecontrolled observational study31 confirmed the associationof both paroxetine and fluoxetine use in the first trimesterwith fetal cardiovascular anomalies. Interestingly, the studyshowed a stronger link between fluoxetine use and cardiacmalformations than with paroxetine (odds ratio 4.47 versus2.66, respectively). The lack of consistent data means there isno clear SSRI of choice in pregnancy.

Antidepressant use in late pregnancy is also associatedwith neonatal complications: both SSRIs and tricyclicantidepressants increase the risk of prematurity, feedingproblems, respiratory distress syndrome, and endocrine andmetabolic and temperature regulation disorders.32 In addition,SSRIs were associated with hypoglycaemia and neonatalconvulsions (although it remains unclear whether this issecondary to serotonin toxicity or a withdrawal effect) andpersistent pulmonary hypertension of the newborn.33

Practical and ethical considerations

Few drugs are licensed for use in pregnancy and our evidencebase for the safety of drugs we do use remains limited.Drug companies do not recruit pregnant women to theirpre-marketing clinical trials unless the drug in questionis specifically aimed at pregnancy-related disease. Insteadthey rely on phase IV post-marketing surveillance trials andvoluntary adverse effect reporting systems such as the MHRAYellow Card Scheme in the UK and FDA’s MedWatch in theUSA. The low incidence of birth defects contributes to thedifficulty in detecting potentially harmful drugs in pregnancy,and pharmacovigilance trials often continue for many years.For example, SSRIs are one of the most commonly prescribedgroups of medications for depression; however, only now,20 years after release, are we beginning to associate their usewith fetal cardiac malformations.29, 30

Exclusion of pregnant women from clinical trials meansthat when new drugs are released onto the market there isalmost no information on their safety and efficacy in pregnancyother than that obtained from animal studies, which is notcompletely predictive of human risk. Parallels can be drawnwith paediatrics, where a lack of research and the ethicalminefield means most drugs are prescribed ‘off-label’ andtheir dosages and safety profiles extrapolated from adult data.However, with recent legislation encouraging research in thisvulnerable population,34 a substantial number of labellingchanges have been made to medications used in children. Manyargue that it is, in fact, unethical not to include paediatricand obstetric populations in drug trials. Paediatric research


Chan et al.

methodology could be applied to obstetrics and the value ofusing pre-existing data to answer new questions should not beunderestimated.

Pregnancy registries are the most commonly used dataresource for researching drug teratogenicity, with establisheddatabases for monitoring the effects of AEDs. These databasescan, however, vary between countries with differences infunding and ethnicity and are open to considerable selectionbias, confounding and limited sample size. Registries, inaddition to uncontrolled cohort, observational and casestudies, form the basis for most of our knowledge of adversemedication effects in pregnancy. Randomised controlled drugtrials in pregnancy would be subject to rigorous ethicalconstraints; however, it should be considered ethical to includepregnant women if there are no other effective treatments forserious or life-threatening conditions, or to study drugs alreadyin use that have an acceptable safety profile. As the incidenceof drug-related birth defects is so small, powering such studiesadequately would also prove a challenge.

For prescribing health professionals there are a number ofsources available for information on specific medications andtheir safety in pregnancy. The British National Formulary, drugcompanies, MHRA and the Royal College of Obstetricians andGynaecologists all provide generalised information on drugsuitability in pregnancy. For more specific advice, the UKTeratology Information Service (see Websites section) providesa risk assessment telephone service for health professionals,with up-to-date evidence-based appraisals of drug safetyin pregnancy. They also collect data prospectively on drugexposure and pregnancy outcomes.

Conclusion

In summary, prescription drug use in pregnancy is prevalent;however, the teratogenic and fetotoxic effects of the majorityof drugs used in pregnancy remain unknown. While there arenumerous ethical and practical issues surrounding research inthis area, it is imperative that further large-scale, well-designedstudies are conducted to elucidate the potential risks to thedeveloping fetus and allow mothers and medical professionalsto make informed clinical decisions regarding their care.Reassurance as to the safety of certain medications can alsoaid compliance and improve maternal disease control, whichmay result in better pregnancy outcomes. With the trends inadvancing age of the maternal population, the treatment ofchronic disease in pregnancy is expected to increase; however,our knowledge of the adverse fetal effects of treatments remainsworryingly incomplete.

Websites

UK Teratology Information Service [uktis.org]

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Prescription drug use in pregnancy: more evidence of safety is needed