DOI: 10.1111/j.1744-4667.2012.00096.

x 2012;14:87–92
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Prescription drug use in pregnancy: more evidence

of safety is needed
Melanie Chan MA MRCP,a Ian C K Wong BSc MSc PhD MRPharmS ITLM(HE),b Alastair Gordon Sutcliffe MD PhD FRCP
c,∗
FRCPCH
a
Core Medical Trainee, University College London Institute of Child Health, General and Adolescent Paediatrics Unit, 30 Guilford Street, London
WC1N 1EH, UK
b
Professor of Paediatric Medicines Research, Centre for Paediatric Pharmacy Research, The School of Pharmacy, University of London, Tavistock
Square, London WC1H 9JP, UK
c
Reader in General Paediatrics, University College London Institute of Child Health, General and Adolescent Paediatrics Unit, London, UK
∗
Correspondence: Alastair Gordon Sutcliffe. Email: a.sutcliffe@ich.ucl.ac.uk

Key content Learning objectives

r Prescription drug use during pregnancy is prevalent, with 44–99%
of women being prescribed medication during pregnancy.
r Pregnant women and their unborn children are considered a
vulnerable population; recent public health scares, such as H1N1,
have highlighted the need for more detailed research into
medication use in pregnancy.
r The teratogenic risk of more than 80% of 468 drugs released in the
USA over the last 20 years remains to be clarified.
r Maternal physiological changes during pregnancy can alter drug
pharmacokinetics, with poorly understood effects, while placental
transfer of medications may have unknown fetal consequences.
r There is an urgent need for further research into the adverse effects
of drugs used in pregnancy.
r To know about the prevalence of prescription medication use
during pregnancy.
r To be aware of the lack of safety data available on fetal adverse
effects for commonly prescribed drugs.
Ethical issues
r Drug companies are reluctant to carry out phase III clinical trials in
pregnant women and they rely on animal models and
post-marketing surveillance for the identification of adverse effects.
r Is it unethical to prescribe drugs in pregnancy for which there is
little concrete safety data?
Keywords antidepressants / anti-epileptic drugs / congenital
malformation / Medicines and Healthcare products Regulatory
Agency / 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 & Gynaecologist
2012;14:87–92.

Introduction designed, inadequately powered observational and registry-

Prescription drug use during pregnancy is prevalent.
Epidemiological studies estimate that 44–99% of women are
prescribed medication during their pregnancy,1 and with
up to half of all pregnancies in England being unplanned,2
many unborn children are exposed to drugs before women
realise they are pregnant. The majority of prescriptions
are for pregnancy-related complaints and minor infections;
however, a small proportion of women receive medication for
treatment of chronic diseases such as asthma, depression or
hypertension. The recent H1N1 public health scare, which
affected pregnant women more severely, has highlighted the
need for more detailed research on therapeutics in pregnancy.3
In obstetrics, where a risk assessment must be made to
weigh up the benefit to the mother with the risk to the
unborn child, prescribing decisions are critical. With evidence-
based medicine a core concept of modern clinical care,
obstetric prescribing practice is often founded on poorly
based studies. Improvements in research methodology are
needed to provide reliable and reproducible evidence for the
safety and efficacy of medications commonly used during
pregnancy and their potential teratogenic and fetotoxic effects.
The prevalence of medication use
in pregnancy
There have been numerous epidemiological studies that have
attempted to evaluate the prevalence of medication use in
pregnancy and to estimate how many potentially teratogenic
drugs are being prescribed to this vulnerable population. Data
collected from the UK General Practice Research Database4
of 81 975 pregnant women estimated that 65% had been
prescribed at least one medication and that one in every 164
women 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 of
drug in
pregnancy Explanation
A Adequate and well-controlled studies have failed
to demonstrate a risk to the fetus in the first
trimester of pregnancy (and there is no evidence
of risk in later trimesters).
B Animal reproduction studies have failed to
demonstrate a risk to the fetus and there are no
adequate and well-controlled studies in
pregnant women.
C Animal reproduction studies have shown an
adverse effect on the fetus and there are no
adequate and well-controlled studies in humans,
but potential benefits may warrant use of the
drug in pregnant women despite potential risks.
D There is positive evidence of human fetal risk based
on adverse reaction data from investigational or
marketing experience or studies in humans, but
potential benefits may warrant use of the drug
in pregnant women despite potential risks.
X Studies in animals or humans have demonstrated
fetal abnormalities and/or there is positive
evidence of human fetal risk based on adverse
reaction data from investigational or marketing
experience, and the risks involved in use of the
drug in pregnant women clearly outweigh
potential benefits.
The proportion of pregnant women in Canada and the
USA taking category D and X medications has been estimated
at 4.8–5.2% and 3.9–4.6% respectively (including oral
contraceptives), with the most frequently prescribed drugs in
the 270 days before delivery reported as being anti-asthmatics,
antibiotics, analgesics, anxiolytics and antidepressants.5, 6
Asthma and obstructive pulmonary disease were the most
common chronic conditions, in 2.6% of the pregnant
population, 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%) and
severe mental disorders (0.2%).7
A large Canadian registry study8 looked at the prevalence
of fetotoxic medication use in pregnancy and attempted to
correlate it with adverse fetal outcomes. From a population
of 109 344 women, 56% filled a prescription for at least
one medication during their pregnancy, with 6.3% of those
prescriptions having recognised fetotoxic or teratogenic effects.
As might be expected, there was a statistically significant
difference between the rates of major congenital malformations
in live born babies exposed to known fetotoxic drugs when
compared with those with no exposure (8.2%, 95% confidence
interval [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
88
Box 2. Factors increasing the prevalence of fetotoxic
medication use during pregnancy9
• Unplanned pregnancy
• Multiple pregnancy
• Nulliparity
• Unemployment
• Age >25 years
• Single status
• Smoking
women were exposed to at least one medication (excluding
folic acid) in their first trimester. Factors that were found to
increase the prevalence of potentially fetotoxic medication use
during pregnancy are listed in Box 2.
In summary, a number of cohort and registry-based
epidemiological studies have shown that prescription drug use
in pregnancy is commonplace, with a small but significant
proportion of women taking medications that are known to
be fetotoxic or teratogenic. In 2010 there were over 720 000
maternities in England and Wales,10 which equates to over 4300
mothers a year taking category X medications. The prescribing
of potentially hazardous drugs during pregnancy necessitates
an accurate risk–benefit assessment to be made: something that
is often carried out in the absence of reliable and reproducible
evidence.
Medication use and congenital
malformations
The baseline prevalence of congenital malformations is
estimated at 2–3% of all births, of which approximately
1% are considered attributable to prescription drug use
during pregnancy.11 With over 723 000 live births recorded
in 2010,10 approximately 200 babies would be expected to
have drug-related birth defects annually in England and Wales.
Consequently the overall contribution of teratogenic drugs to
fetal malformations is much less than that perceived by the
general public and the medical profession, but it remains one
of the few causes over which we can exert some influence. Fewer
than 20 drugs or groups of drugs are known to be teratogenic
and for the majority (with the exception of thalidomide and
isotretinoin), >90% of pregnancies exposed during the first
trimester will result in a healthy baby.12 A complex interplay
between gestational age at exposure, drug dosage, duration
of treatment, pharmacokinetics, placental transfer, random
mutations and genetic predisposition can all affect the final
pregnancy outcome.
A large birth defect registry study13 published in 2010 looked
at 18 131 cases with at least one major malformation exposed
to medication in the first trimester of pregnancy. They found
the following statistically significant associations:

C 2012 Royal College of Obstetricians and Gynaecologists

Box 3. Teratogenic mechanisms associated with
medication 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 II
receptor blockers, statins, non-steroidal inflammatory drugs
r thyroxine with unilateral kidney agenesis
r the amount of drug available to the liver to metabolise.
r
valproic acid with spina bifida and hypospadias
carbamazepine with isolated spina bifida and cleft palate
r renal elimination of certain drugs.
r
barbiturates with isolated cleft palate
insulin with isolated ventricular septal, secundum atrial
septal and cardiac outflow tract defects
r benzodiazepines with isolated cleft lip/palate.
Such an array of associations highlights the usefulness of
such registries for epidemiological purposes and for suggesting
potential targets for further research.
The teratogenic mechanisms of different medications are
diverse. Although drugs are subjected to animal testing prior
to release on the market, this does not always predict adverse
effects on the human fetus accurately. Thalidomide remains
the most infamous example of the limitations of animal models
as predictors of teratogenesis. Having been tested in pregnant
animals, it proved to have devastating effects on the fetus, which
could 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 and
spina bifida, for the vast majority of drugs our knowledge of
pregnancy safety data remains minimal. In fact, the teratogenic
risk of more than 80% of 468 drugs released in the USA over
the last 20 years remains to be clarified.14 A recently published
review of this topic identified six teratogenic mechanisms
associated with medication use (Box 3).15
Pharmacokinetic principles in pregnancy
The maternal physiological changes that occur during
pregnancy can alter drug pharmacokinetics significantly.
Almost every substance used for therapeutic purposes can and
does pass from mother to fetus; of importance is whether the
rate and extent of transfer are sufficient to result in significant
concentrations within the fetus.16 The principal changes in
maternal physiology and their impact on drug metabolism are

C 2012 Royal College of Obstetricians and Gynaecologists
Chan et al.
summarised below: as a general rule, the volume of distribution
and clearance of drugs is increased, resulting in lower plasma
concentrations of medications.17
r Increased progesterone reduces gastric emptying and
intestinal motility, with a maximum effect in the third
trimester, thereby reducing the absorption of drugs.
r There is reduced plasma protein and reduced protein
binding.
r Increased total bodyweight and fat distribution mean a larger
volume of distribution for both hydrophilic and lipophilic
drugs.
r Altered drug metabolism via phase I oxidative and phase II
conjugation mechanisms and induction of the cytochrome
P450 system, with increased hepatic blood flow, increases
r An increase of 40–65% in glomerular filtration rate increases
r Drug transfer occurs mainly by diffusion across the placenta,
favouring lipophilic drugs, and is limited by placental blood
flow.
Most compounds, both exogenous and endogenous, cross
the placenta in detectable amounts, given sufficient time and
sensitivity of detection.18 If a group of drugs is not known to
have teratogenic effects and no other data are available, then
a comparison of lipid solubility, molecular weight, ionisation
and degree of protein binding may assist the clinical selection
of an appropriate drug for more efficient transfer (fetal drug
therapy) or less efficient transfer (limited fetal exposure). Drugs
that are more readily passed via the placenta are usually:18
r highly lipid soluble, e.g. diazepam
r small molecules (<600 daltons), e.g. propylthiouracil
r non-ionised, e.g. phenobarbital
r low protein binding in maternal plasma, e.g. ampicillin.
Due to the ethical and practical difficulties of collecting
data in the form of blood, amniotic fluid, cord blood and
fetal samples, limited information is available on the specific
pharmacokinetics and pharmacodynamics of drugs used in
pregnancy. This significant gap in our knowledge presents an
opportunity for designing novel adequately controlled research
protocols that are both ethically and practically acceptable to
pregnant women.
Current evidence for the safety of
common medications used in pregnancy
Here we review the evidence for the fetal safety of two relatively
common groups of drugs: anti-epileptics and antidepressants.
89
Prescription drug use in pregnancy: more evidence of safety is needed
Anti-epileptic drugs (AEDs)
Sodium valproate was first introduced in 1967; however,
it was not until 15 years later that its teratogenic risk
became apparent and was described in the literature,19, 20
highlighting the difficulties involved in detecting potential
teratogens. Nonetheless, AEDs are the most studied group of
drugs in pregnancy, with an estimated 1 in 250 pregnancies
exposed. National Institute for Health and Clinical Excellence
(NICE) guidelines state that it is not possible to comment
on the teratogenic risks of AEDs in view of the limited data
available. Preliminary data collated from the UK Epilepsy
and Pregnancy Register showed that the risk of congenital
malformations with the use of one AED was 3.7% (n = 2598),
compared with 6.0% (n = 770) in those women taking two
or 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 congenital
malformations was significantly increased with valproate
monotherapy (10.73%) and AED polytherapy (16.78%), with
the combination of valproate and two other AEDs increasing
the risk to 25%. The most common birth defects identified were
cardiovascular malformations, in particular ventricular septal
defects, followed by musculoskeletal defects, with the incidence
of ear/neck/face defects, cleft lip and spina bifida significantly
increased in both the monotherapy and polytherapy groups.
Neurodevelopmental outcome does not appear to be adversely
affected by in utero exposure to AED monotherapy;23 however,
studies have found that in utero exposure to valproate is
associated with lower mean IQ scores when compared with
controls and other AEDs.24, 25 Evidence for the fetal adverse
effects of newer AEDs such as levetiracetam, oxcarbazepine
and topiramate is even more scarce.
Antidepressants
Up to 4% of women use antidepressants during pregnancy, with
2.3% taking selective serotonin reuptake inhibitors (SSRIs).26
In 2005 a manufacturer’s warning was issued regarding the
possible association of paroxetine with fetal cardiovascular
anomalies; however, studies have been contradictory.
A meta-analysis27 of pregnancy outcomes after exposure
to SSRIs (including paroxetine) did not find a statistically
significant effect on the rate of congenital malformations when
compared to controls. Similarly, a large birth defect registry
study28 found no association between maternal SSRI use and
cardiac malformations; however, a link was found between
exposure and anencephaly, craniosynostosis and omphalocele.
Subsequent studies looking specifically at paroxetine have
found that first-trimester exposure significantly increases the
risk of cardiovascular malformations.29, 30
In 2007 NICE recommended fluoxetine as the SSRI of
choice in pregnancy; however, the Medicines and Healthcare
90
products Regulatory Agency (MHRA) recently issued a drug
safety update warning that fluoxetine may also increase
the risk of congenital cardiac malformations, to a similar
degree as paroxetine. A large, prospective, multicentre
controlled observational study31 confirmed the association
of both paroxetine and fluoxetine use in the first trimester
with fetal cardiovascular anomalies. Interestingly, the study
showed a stronger link between fluoxetine use and cardiac
malformations than with paroxetine (odds ratio 4.47 versus
2.66, respectively). The lack of consistent data means there is
no clear SSRI of choice in pregnancy.
Antidepressant use in late pregnancy is also associated
with neonatal complications: both SSRIs and tricyclic
antidepressants increase the risk of prematurity, feeding
problems, respiratory distress syndrome, and endocrine and
metabolic and temperature regulation disorders.32 In addition,
SSRIs were associated with hypoglycaemia and neonatal
convulsions (although it remains unclear whether this is
secondary to serotonin toxicity or a withdrawal effect) and
persistent pulmonary hypertension of the newborn.33
Practical and ethical considerations
Few drugs are licensed for use in pregnancy and our evidence
base for the safety of drugs we do use remains limited.
Drug companies do not recruit pregnant women to their
pre-marketing clinical trials unless the drug in question
is specifically aimed at pregnancy-related disease. Instead
they rely on phase IV post-marketing surveillance trials and
voluntary adverse effect reporting systems such as the MHRA
Yellow Card Scheme in the UK and FDA’s MedWatch in the
USA. The low incidence of birth defects contributes to the
difficulty in detecting potentially harmful drugs in pregnancy,
and pharmacovigilance trials often continue for many years.
For example, SSRIs are one of the most commonly prescribed
groups of medications for depression; however, only now,
20 years after release, are we beginning to associate their use
with fetal cardiac malformations.29, 30
Exclusion of pregnant women from clinical trials means
that when new drugs are released onto the market there is
almost no information on their safety and efficacy in pregnancy
other than that obtained from animal studies, which is not
completely predictive of human risk. Parallels can be drawn
with paediatrics, where a lack of research and the ethical
minefield means most drugs are prescribed ‘off-label’ and
their dosages and safety profiles extrapolated from adult data.
However, with recent legislation encouraging research in this
vulnerable population,34 a substantial number of labelling
changes have been made to medications used in children. Many
argue that it is, in fact, unethical not to include paediatric
and obstetric populations in drug trials. Paediatric research

C 2012 Royal College of Obstetricians and Gynaecologists

methodology could be applied to obstetrics and the value of
using pre-existing data to answer new questions should not be
underestimated.
Pregnancy registries are the most commonly used data
resource for researching drug teratogenicity, with established
databases for monitoring the effects of AEDs. These databases
can, however, vary between countries with differences in
funding and ethnicity and are open to considerable selection
bias, confounding and limited sample size. Registries, in
addition to uncontrolled cohort, observational and case
studies, form the basis for most of our knowledge of adverse
medication effects in pregnancy. Randomised controlled drug
trials in pregnancy would be subject to rigorous ethical
constraints; however, it should be considered ethical to include
pregnant women if there are no other effective treatments for
serious or life-threatening conditions, or to study drugs already
in use that have an acceptable safety profile. As the incidence
of drug-related birth defects is so small, powering such studies
adequately would also prove a challenge.
For prescribing health professionals there are a number of
sources available for information on specific medications and
their safety in pregnancy. The British National Formulary, drug
companies, MHRA and the Royal College of Obstetricians and
Gynaecologists all provide generalised information on drug
suitability in pregnancy. For more specific advice, the UK
Teratology Information Service (see Websites section) provides
a risk assessment telephone service for health professionals,
with up-to-date evidence-based appraisals of drug safety
in pregnancy. They also collect data prospectively on drug
exposure and pregnancy outcomes.
Conclusion
In summary, prescription drug use in pregnancy is prevalent;
however, the teratogenic and fetotoxic effects of the majority
of drugs used in pregnancy remain unknown. While there are
numerous ethical and practical issues surrounding research in
this area, it is imperative that further large-scale, well-designed
studies are conducted to elucidate the potential risks to the
developing fetus and allow mothers and medical professionals
to make informed clinical decisions regarding their care.
Reassurance as to the safety of certain medications can also
aid compliance and improve maternal disease control, which
may result in better pregnancy outcomes. With the trends in
advancing age of the maternal population, the treatment of
chronic disease in pregnancy is expected to increase; however,
our knowledge of the adverse fetal effects of treatments remains
worryingly incomplete.
Websites
UK Teratology Information Service [uktis.org]

C 2012 Royal College of Obstetricians and Gynaecologists
Chan et al.
References
1 Bakker MK, Jentink J, Vroom F, Van Den Berg PB, de Walle HE, et al.
Drug prescription patterns before, during and after pregnancy for
chronic, occasional and pregnancy-related drugs in the Netherlands.
BJOG 2006;113:559–68 [http://dx.doi.org/10.1111/
j.1471–0528.2006.00927.x].
2 Rowlands S. Contraception and abortion. J R Soc Med
2007;100:465–8 [http://dx.doi.org/10.1258/jrsm.100.10.465].
3 Goldkind SF, Sahin L, Gallauresi B. Enrolling pregnant women in
research — lessons from the H1N1 influenza pandemic. N Engl J
Med 2010;362:2241–3 [http://dx.doi.org/10.1056/NEJMp1003462].
4 Hardy JR, Leaderer BP, Holford TR, Hall GC, Bracken MB. Safety of
medications prescribed before and during early pregnancy in a cohort
of 81 975 mothers from the UK General Practice Research Database.
Pharmacoepidemiol Drug Saf 2006;15:555–64 [http://dx.doi.org/
10.1002/pds.1269].
5 Andrade SE, Gurwitz JH, Davis RL, Chan KA, Finkelstein JA, Fortman
K, et al. Prescription drug use in pregnancy. Am J Obstet Gynecol
2004;191:398–407 [http://dx.doi.org/10.1016/j.ajog.2004.04.025].
6 Wen SW, Yang T, Krewski D, Yang Q, Nimrod C, Garner P, et al.
Patterns of pregnancy exposure to prescription FDA C, D and X drugs
in a Canadian population. J Perinatol 2008;28:324–9
[http://dx.doi.org/10.1038/jp.2008.6].
7 Malm H, Martikainen J, Klaukka T, Neuvonen PJ. Prescription drugs
during pregnancy and lactation — a Finnish register-based study. Eur
J Clin Pharmacol 2003;59:127–33.
8 Kulaga S, Zargarzadeh AH, Berard A. Prescriptions filled during
pregnancy for drugs with the potential of fetal harm. BJOG
2009;116:1788–95 [http://dx.doi.org/10.1111/j.1471-0528.
2009.02377.x].
9 Cleary BJ, Butt H, Strawbridge JD, Gallagher PJ, Fahey T, Murphy DJ.
Medication use in early pregnancy-prevalence and determinants of
use in a prospective cohort of women. Pharmacoepidemiol Drug Saf
2010;19:408–17.
10 Office for National Statistics. Statistical Bulletin. Births and Deaths in
England and Wales, 2010. Newport, UK: ONS; 2010 [www.ons.
gov.uk/ons/rel/vsob1/death-reg-sum-tables/2010/births-and-deaths-
summary-tables-stats-bulletin-2010.pdf].
11 De Santis M, Straface G, Carducci B, Cavaliere AF, De Santis L,
Lucchese A, et al. Risk of drug-induced congenital defects. Eur J
Obstet Gynecol Reprod Biol 2004;117:10–9 [http://dx.doi.
org/10.1016/j.ejogrb.2004.04.022].
12 Webster WS, Freeman JA. Prescription drugs and pregnancy. Expert
Opin Pharmacother 2003;4:949–61 [http://dx.doi.org/
10.1517/14656566.4.6.949].
13 Lisi A, Botto LD, Robert-Gnansia E, Castilla EE, Bakker MK, Bianca S,
et al. Surveillance of adverse fetal effects of medications (SAFE-Med):
findings from the International Clearinghouse of Birth Defects
surveillance and research. Reprod Toxicol 2010;29:433–42
[http://dx.doi.org/10.1016/j.reprotox.2010.03.005].
14 Lo WY, Friedman JM. Teratogenicity of recently introduced
medications in human pregnancy. Obstet Gynecol 2002;100:465–73
[http://dx.doi.org/10.1016/S0029-7844(02)02122-1].
15 van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den
Berg LT, Roeleveld N. Teratogenic mechanisms of medical drugs.
Hum Reprod Update 2010;16:378–94 [http://dx.doi.org/
10.1093/humupd/dmp052].
16 Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation:
A Reference Guide To Fetal And Neonatal Risk. 8th edition. USA:
Lippincott Williams & Wilkins; 2008.
17 Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in
pregnancy. Best Pract Res Clin Obstet Gynaecol 2001;15:819–26
[http://dx.doi.org/10.1053/beog.2001.0231].
18 Blackburn ST. Maternal, Fetal and Neonatal Physiology: A Clinical
Perspective. Third edition. Saunders: 2007.
91
 Prescription drug use in pregnancy: more evidence of safety is needed
19 Robert E, Guibaud P. Maternal valproic acid and congenital neural
tube defects. Lancet 1982;2:937 [http://dx.doi.org/10.1016/
S0140-6736(82)90908-4].
20 Bjerkedal T, Czeizel A, Goujard J, Kallen B, Mastroiacova P, Nevin N,
et al. Valproic acid and spina bifida. Lancet 1982;2:1906.
21 Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et
al. Malformation risks of antiepileptic drugs in pregnancy: a
prospective study from the UK Epilepsy and Pregnancy Register. J
Neurol Neurosurg Psychiatry 2006;77:193–8 [http://dx.doi.org/
10.1136/jnnp.2005.074203].
22 Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy
outcomes in women with epilepsy: a systematic review and
meta-analysis of published pregnancy registries and cohorts. Epilepsy
Res 2008;81:1–13 [http://dx.doi.org/10.1016/j.eplepsyres.2008.04.
022].
23 Adab N, Tudur SC, Vinten J, Williamson P, Winterbottom J. Common
antiepileptic drugs in pregnancy in women with epilepsy. Cochrane
Database Syst Rev 2004;(3):CD004848.
24 Banach R, Boskovic R, Einarson T, Koren G. Long-term developmental
outcome of children of women with epilepsy, unexposed or exposed
prenatally to antiepileptic drugs: a meta-analysis of cohort studies.
Drug Saf 2010;33:73–9 [http://dx.doi.org/10.2165/
11317640-000000000-00000].
25 Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell
DT, Cohen M, et al; NEAD Study Group. Cognitive function at 3 years
of age after fetal exposure to antiepileptic drugs. N Engl J Med
2009;360:1597–605 [http://dx.doi.org/10.1056/NEJMoa08
03531].
26 Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D.
Placental passage of antidepressant medications. Am J Psychiatry
2003;160:993–6 [http://dx.doi.org/10.1176/appi.ajp.160.5.993].
27 Rahimi R, Nikfar S, Abdollahi M. Pregnancy outcomes following
exposure to serotonin reuptake inhibitors: a meta-analysis of clinical
92
trials. Reprod Toxicol 2006;22:571–5 [http://dx.doi.org/10.1016/
j.reprotox.2006.03.019].
28 Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of
selective serotonin-reuptake inhibitors in pregnancy and the risk of
birth defects. N Engl J Med 2007;356:2684–92 [http://dx.doi.
org/10.1056/NEJMoa066584].
29 Bar-Oz B, Einarson T, Einarson A, Boskovic R, O’Brien L, Malm H, et
al. Paroxetine and congenital malformations: meta-analysis and
consideration of potential confounding factors. Clin Ther
2007;29:918–26 [http://dx.doi.org/10.1016/j.clinthera.
2007.05.003].
30 Bakker MK, Kerstjens-Frederikse WS, Buys CH, de Walle HE, de
Jong-van den Berg LT. First-trimester use of paroxetine and
congenital heart defects: a population-based case-control study.
Birth Defects Res A Clin Mol Teratol 2010;88:94–100.
31 Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, Di
Gianantonio E, et al. Paroxetine and fluoxetine in pregnancy: a
prospective, multicentre, controlled, observational study. Br J Clin
Pharmacol 2008;66:695–705.
32 Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE,
Smith D, et al. Risks of congenital malformations and perinatal
events among infants exposed to antidepressant medications during
pregnancy. Pharmacoepidemiol Drug Saf 2007;16:1086–94
[http://dx.doi.org/10.1002/pds.1462].
33 Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik
C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of
persistent pulmonary hypertension of the newborn. N Engl J Med
2006;354:579–87 [http://dx.doi.org/10.1056/NEJMoa052744].
34 European Union Paediatric Regulation No. 1901/2006 [http://ec.
europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_
1901_en.pdf].
35 US Federal Drug Administration pregnancy categories [http://depts.
washington.edu/druginfo/Formulary/Pregnancy.pdf].

C 2012 Royal College of Obstetricians and Gynaecologists