The

n e w e ng l a n d j o u r na l

of

m e dic i n e

original article

Valproic Acid Monotherapy in Pregnancy

and Major Congenital Malformations
Janneke Jentink, M.Sc., Maria A. Loane, M.Sc., Helen Dolk, Dr.P.H.,
Ingeborg Barisic, Dr.P.H., Ester Garne, M.D., Joan K. Morris, Ph.D.,
and Lolkje T.W. de Jong-van den Berg, Ph.D.,
for the EUROCAT Antiepileptic Study Working Group*

A bs t r ac t
Background

The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations
are limited.
Methods

We first combined data from eight published cohort studies (1565 pregnancies in
which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more
common among the offspring of women who had received valproic acid during the
first trimester. We then assessed the associations between use of valproic acid during
the first trimester and these 14 malformations by performing a casecontrol study
with the use of the European Surveillance of Congenital Anomalies (EUROCAT)
antiepileptic-study database, which is derived from population-based congenitalanomaly registries. Registrations (i.e., pregnancy outcomes with malformations
included in EUROCAT) with any of these 14 malformations were compared with
two control groups, one consisting of infants with malformations not previously
linked to valproic acid use (control group 1), and one consisting of infants with
chromosomal abnormalities (control group 2). The data set included 98,075 live
births, stillbirths, or terminations with malformations among 3.8 million births in
14 European countries from 1995 through 2005.
Results

Exposure to valproic acid monotherapy was recorded for a total of 180 registrations,
with 122 registrations in the case group, 45 in control group 1, and 13 in control
group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI],
7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8
to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5);
and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid
were similar to results for exposure to other antiepileptic drugs.

From the Department of Pharmacoepidemiology and Pharmacoeconomics, Division of Pharmacy, University of Groningen, Groningen, the Netherlands (J.J.,
L.T.W.J.-B.); the EUROCAT Central Registry, Institute of Nursing Research and
School of Nursing, University of Ulster,
Northern Ireland, United Kingdom (M.A.L.,
H.D.); Childrens University Hospital Zagreb, Zagreb, Croatia (I.B.); Lillebaelt Hospital, Kolding, Denmark (E.G.); and the
Wolfson Institute of Preventive Medicine,
Barts and the London School of Medicine
and Dentistry, Queen Mary University of
London, London (J.K.M.). Address reprint requests to Dr. de Jong-van den
Berg at the Department of Pharmacoepidemiology and Pharmacoeconomics,
University of Groningen, A. Deusinglaan
1, 9713 AV Groningen, the Netherlands,
or at [email protected].
*Members of the European Surveillance
of Congenital Anomalies (EUROCAT)
Antiepileptic Study Working Group are
listed in the Appendix.
N Engl J Med 2010;362:2185-93.
Copyright 2010 Massachusetts Medical Society.

Conclusions

The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no
use of antiepileptic drugs or with use of other antiepileptic drugs.
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alproic acid, which has been used

for the treatment of seizure for more than
30 years, has long been recognized as a
teratogen. Maternal exposure to valproic acid
monotherapy during the first trimester was first
linked to an increased risk of congenital spina
bifida in the 1980s1-6; subsequent studies confirmed this increased risk and also suggested
increased risks of other major congenital malformations.7,8 Recently, the American Academy of
Neurology recommended avoidance of valproic acid
during pregnancy if possible.9 However, if treatment with valproic acid has been providing good
seizure control, it can be difficult to change the
drug before or during pregnancy.10,11
Although a number of cohort studies of women exposed to valproic acid in pregnancy have
shown an association with a range of malformations,12-17 these studies have had limited power
individually to detect excess risks of specific malformations. For rare outcomes, such as these specific malformations, large population-based case
control studies are more appropriate.18
We combined the data from cohort studies to
identify indications that malformations were occurring at greater frequency than expected among
offspring exposed to valproic acid during the first
trimester of pregnancy. We then conducted a
population-based, casecontrol study to test our
hypotheses, using the antiepileptic-study database
established by European Surveillance of Congenital Anomalies (EUROCAT).

Me thods
EUROCAT Database

of

m e dic i n e

are managed in a standard software program that

is used by all registries and includes error checks.20
Infants or fetuses having only malformations categorized as minor according to EUROCAT definitions were excluded.20 One syndrome and up to
eight malformations are coded with International
Classification of Diseases, Ninth Revision (ICD-9) or
International Classification of Diseases, Tenth Revision
(ICD-10) codes, with British Pediatric Association
(BPA) one-digit extensions. These codes are regrouped into the standard EUROCAT malformation subgroups.20 Maternal illness before and
during pregnancy (ICD-9 or ICD-10 code plus descriptive information) and drug exposure in the
first trimester of pregnancy (descriptive information or Anatomical Therapeutic Chemical [ATC]
code22) are recorded. The first trimester is defined
as the period from the first day of the last menstrual period through the 12th week of gestation.
Ascertainment of Exposure

Information on maternal antiepileptic-drug exposure is mainly obtained from medical hospital

records generated during pregnancy (for all 19 registries). Five registries also use other prospectively recorded sources of information (records from
general practitioners, pharmacy records, and medical records held by the patient), and three registries use a structured interview or questionnaire
after birth to acquire additional information on
drug exposure. The persons who recorded information in registries were not aware of the specific
hypothesis of the study. Antiepileptic drugs are
available by prescription only and are typically
supplied for long-term use; thus, medical records
were considered to be a good source of data for
ascertainment of exposure.
To be included in the EUROCAT antiepilepticstudy database, a registry must have recorded a
diagnosis of maternal epilepsy or antiepilepticdrug exposure for at least 3 registrations per 1000
(to exclude registries with low rates of exposure
ascertainment) and must have recorded a complete drug name or ATC code for at least 80% of
all pregnancies exposed to antiepileptic drugs
throughout the study period (to exclude registries
with incomplete data on exposure to antiepileptic drugs).

We used the EUROCAT antiepileptic-study databases, which included data on affected live births,
stillbirths, fetal deaths after 20 or more weeks of
gestation, and terminations of pregnancy after
prenatal diagnosis for the years 1995 through
2005 from 19 population-based EUROCAT registries in 14 countries (for more information, see
Section 1 of the Supplementary Appendix, available with the full text of this article at NEJM
.org).19 The study sample consisted of 3,881,592
live births and stillbirths, of which 98,075 involved a major congenital malformation.
The standard data recorded for each registration are described in EUROCAT Guide 1.3.20 Mul- Study Design
tiple sources are used to ascertain pregnancy out- We searched PubMed, Web of Science, and Emcomes with malformations (registrations).21 Data base for studies addressing exposure to valproic
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Valproic Acid and Congenital Malformations

acid in pregnancy. Eight cohort studies met the

inclusion criteria and were included in the review
(see Section 2 in the Supplementary Appendix for
a description of the inclusion criteria).12-17,23,24
These eight studies included 1565 pregnancy outcomes in which there was exposure to valproic
acid monotherapy during the first trimester; in
118 of these outcomes there was a major congenital malformation as defined by EUROCAT. The
overall rate of major congenital malformations
was 7.5% (95% confidence interval [CI], 6.3 to 9.0)
(Table 1).
All 14 malformations with prevalences that were
significantly higher in the studies of maternal
exposure to valproic acid than in the EUROCAT
reference group (of 3.8 million) (P<0.05) were
included in the casecontrol study. The number
of cases with each of these 14 malformations is
detailed in Section 2 in the Supplementary Appendix.
To minimize the chances that we missed a
group that warranted inclusion by looking only
at cohort studies in the literature review, we also
searched casecontrol studies. The one additional
group we found limb-reduction malformations25,26 was excluded to avoid a possible un-

derestimation in the casecontrol analyses; we

examined the group with limb-reduction malformations separately.
We used the EUROCAT antiepileptic-study data
base to compare the odds of exposure to valproic
acid monotherapy among cases (for each of the
14 malformations identified from the literature
review) with the odds of exposure in two groups
of controls a group with major malformations
other than those under study and a group with
malformations associated with chromosomal abnormalities. Exposure to valproic acid monotherapy during the first trimester was compared with
the absence of exposure to antiepileptic drugs
and with exposure to an antiepileptic-drug monotherapy other than valproic acid.
Cases were defined as all live births, fetal
deaths after at least 20 weeks of gestation, and
terminations of pregnancy after prenatal diagnosis with at least one of the following malformations: spina bifida, microcephaly, ventricular
septal defect, atrial septal defect, tetralogy of
Fallot, pulmonary-valve atresia, hypoplastic right
heart, cleft palate (without associated cleft lip),
diaphragmatic hernia, gastroschisis, hypospadias,
clubfoot, polydactyly, and craniosynostosis. All

Table 1. Overview of Studies Included in the Analysis.

Study

Country

Birth Years Included

First-Trimester Exposure to Valproic

Acid Monotherapy
Exposed
Pregnancies

Births with
Malformation

number
Samrn et al.14

Germany, Finland,
and the Netherlands

Kaaja et al.24

Finland

Sabers et al.23

Denmark

Vajda et al.

15

Wide et al.16
17

19721990

Malformation
Rate
% (95% CI)

184

16

8.7 (5.413.7)

Jan. 1980Sept. 1998

61

6.6 (2.615.7)

Sept. 1996May 2000

30

6.7 (1.921.3)

Australia

July 1999Oct. 2002

89

15

16.9 (10.526.0)

Sweden

July 1995Dec. 2001

268

26

9.7 (6.713.8)

United States

Feb. 1997Nov. 2003

149

16

10.7 (6.316.8)

Meador et al.12

United Kingdom
and United States

Oct. 1999Feb. 2004

69

12

17.4 (10.228.0)

Morrow et al.13

United Kingdom

Wyszynski et al.

Dec. 1996March 2005

715

44

6.2 (4.68.2)

All studies

19722005

1565

135

8.6 (7.310.1)

All studies, excluding

minor malformations*

19722005

1565

118

7.5 (6.39.0)

* According to the classification of major congenital malformations in the European Surveillance of Congenital Anomalies (EUROCAT) registry, based on the International Classification of Diseases, 10th Edition, 17 malformations were minor and were therefore excluded from the
analysis.

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cases with a diagnosed chromosomal or monogenic syndrome were excluded.

Control group 1 included live births, fetal
deaths after 20 weeks or more of gestation, and
pregnancy terminations after prenatal diagnosis
that involved major malformations other than the
14 malformations under study. We excluded chromosomal disorders (the disorders in control
group 2), as well as identified syndromes (1806
registrations); cleft lip, cleft lip and palate, or the
Pierre Robin sequence without a reported cleft
palate (3382); limb-reduction defects (1704); and
anencephaly or encephalocele (1759). We also
excluded five controls for which type of birth
was unknown. Control group 2 comprised live
births, fetal deaths after 20 weeks or more of
gestation, and pregnancy terminations after prenatal diagnosis that involved malformations associated with chromosomal abnormalities. We excluded two of the entries in this group because
type of birth was unknown.
All registrations with recorded maternal antiepileptic-drug use or maternal epilepsy were selected, verified by the registry, and coded according to the name of the antiepileptic drug. After
verification, 99.9% of the antiepileptic drugs to
which mothers were exposed in the first trimester of pregnancy had been identified. To minimize the risk of misclassification, we excluded
all registrations for which there had been a previous diagnosis of maternal epilepsy but for which
there was no history of maternal antiepileptic-drug
use in the first trimester (a total of 96 cases, 122
controls in group 1, and 19 controls in group 2).
Statistical Analysis

Logistic-regression analysis was used to calculate

odds ratios with Stata software, version 10. Crude
odds ratios were calculated for all registries, including those without records of valproic acid exposure. Odds ratios were adjusted for maternal
age (categorized as less than 25 years, 25 to 29
years, 30 to 34 years, or more than 34 years) and
the childs year of birth (categorized as being between 1995 and 1998, between 1999 and 2001, or
between 2002 and 2005). Odds ratios were also
adjusted for the individual registry (registries with
no entries for valproic acid exposure were excluded) in the comparison of exposure to valproic acid
monotherapy with no exposure to antiepileptic
drugs; there were too few controls to make this

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adjustment in other comparisons. For anomalies

for which there were fewer than six cases with
exposure to valproic acid, no adjustments were
made and the exact confidence intervals are presented.

R e sult s
A total of 37,154 cases, 39,472 controls without
chromosomal abnormalities (control group 1),
and 11,763 controls with chromosomal abnormalities (control group 2) were included in the
study. The frequency of maternal use of antiepileptic drugs overall in the first trimester of pregnancy was 5.7 per 1000 registrations, and the
frequency of maternal use of valproic acid specifically was 2.0 per 1000. The frequency of exposure to valproic acid was three times as high
among cases (3.3 per 1000 registrations) as among
controls in both groups (1.1 per 1000) (Table 2).
In analyses of cases and the controls in
group 1, exposure to valproic acid monotherapy
during the first trimester as compared with no
exposure to antiepileptic drugs during that period
was associated with significant increases in the
risks of spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis but not in the risks of microcephaly, tetralogy
of Fallot, pulmonary-valve atresia, diaphragmatic
hernia, ventricular septal defect, hypoplastic right
heart (no exposed cases), gastroschisis, or clubfoot (Table 3). Adjustment for reporting registry,
birth year of the registration, and maternal age
did not substantively affect the results (see Section 3 in the Supplementary Appendix for details).
Using the same control group, we found generally similar associations between valproic acid
exposure and malformations when valproic acid
monotherapy was compared with monotherapy
with another antiepileptic drug with two exceptions. When compared with use of another
antiepileptic drug, valproic acid use was not associated with a significantly increased risk of craniosynostosis but was associated with a significantly
increased risk of ventricular septal defect.
In corresponding analyses comparing cases
with the controls in group 2 (those with chromosomal abnormalities), the results were generally
similar. Separate analyses of the suggested association between valproic acid exposure and limb
reduction showed a significantly increased risk

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Valproic Acid and Congenital Malformations

Table 2. Exposure to Antiepileptic Drugs in the First Trimester of Pregnancy among Cases and Controls with Congenital
Malformations.*
Cases
(N=37,154)

Exposure

no.
No exposure to antiepileptic drugs

Control Group 1
(N=39,472)

no./1000
registrations

no.

Control Group 2
(N=11,763)

no./1000
registrations

no.

no./1000
registrations

36,869

39,290

11,725

Any antiepileptic-drug monotherapy or

polytherapy

285

7.7

182

4.6

38

3.2

Any antiepileptic-drug monotherapy

223

6.0

155

3.9

32

2.7

Valproic acid monotherapy

122

3.3

45

1.1

13

1.1

Other monotherapy

101

2.7

110

2.8

19

1.6

* Malformations included spina bifida, microcephaly, ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary-valve atresia, hypoplastic right heart, cleft palate, diaphragmatic hernia, gastroschisis, hypospadias, clubfoot,
polydactyly, and craniosynostosis.
Among these patients, 58 received carbamazepine, 21 received lamotrigine, 8 received phenobarbital, 4 received oxcarbazepine, 3 received clonazepam, 2 received phenytoin, 1 received methylphenobarbital, 1 received topiramate, and 3
received unspecified medications.
Among these patients, 65 received carbamazepine, 18 received lamotrigine, 9 received phenobarbital, 7 received oxcarbazepine, 3 received phenytoin, 3 received primidone, 2 received clonazepam, 1 received ethosuximide, 1 received
methylphenobarbital, and 1 received topiramate.
Among these patients, 10 received carbamazepine, 4 received phenobarbital, 2 received lamotrigine, 1 received clonazepam, 1 received oxcarbazepine, and 1 received phenytoin.

of limb reduction (crude odds ratio, 3.4; 95% CI,

1.6 to 7.2) as compared with the absence of exposure to antiepileptic drugs.
In control group 1, we also compared the distribution of malformations among controls exposed to valproic acid with the distribution among
controls without exposure to antiepileptic drugs
and found no significant differences (data not
shown). We found no malformations other than
those reported in the literature that had a significant association with valproic acid exposure in
this group.

Discussion
In a review of published cohort studies, we identified 14 major congenital malformations for which
the risk appeared to be significantly increased in
association with exposure to valproic acid monotherapy during the first trimester of pregnancy as
compared with no exposure to antiepileptic drugs
during the first trimester. We then tested these
indications in a large population-based case
control study and found significant associations
between exposure to valproic acid monotherapy
in the first trimester (as compared with no exposure to antiepileptic drugs) and six of these

conditions: spina bifida, atrial septal defect, cleft

palate, hypospadias, polydactyly, and craniosynostosis. Risks for five of these conditions were 2 to
7 times as high for exposed fetuses, and the risk
for the sixth condition, spina bifida, was 12 or
16 times as high, depending on the control group
used. We also found an association between limb
defects and exposure to valproic acid monotherapy as compared with no exposure to antiepileptic drugs, as suggested in previous casecontrol
studies.
Significant associations with valproic acid exposure were noted for five of the six specific
malformations in analyses comparing exposure
to valproic acid monotherapy with other antiepileptic-drug monotherapy; an association with
craniosynostosis was not found. A significant
association with ventricular septal defect was
detected, but only for the comparison of cases
with controls in the group that had malformations not associated with a chromosomal abnormality not for the comparison of cases with
the other control group. Although the observational nature of this study precludes a conclusion
about cause and effect, these findings support a
relationship of these malformations to valproic
acid specifically rather than to antiepileptic drugs

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generally or to underlying epilepsy. Valproic acid is

used for various indications in European countries, which means that its use is unlikely to be
very strongly related to a particular type or severity of epilepsy. However, we do not have infor-

of

m e dic i n e

mation on the type or severity of epilepsy and

therefore cannot rule out the possibility of confounding by indication.
Studies evaluating the risk of general malformations after in utero exposure to an antiepilep-

Table 3. Odds Ratios for Malformations with Exposure to Valproic Acid Monotherapy as Compared with No Antiepileptic-Drug (AED)
Exposure and with Exposure to Monotherapy with Other Antiepileptic Drugs in Control Groups 1 and 2.*
Adjusted Odds Ratio for
Valproic Acid Monotherapy
vs. No AED (95% CI)

Adjusted Odds Ratio for

Valproic Acid Monotherapy
vs. Other AED Monotherapy
(95% CI)

Control group 1

12.7 (7.720.7)

5.7 (2.612.3)

Control group 2

16.3 (8.033.4)

3.5 (1.210.0)

Control group 1

2.5 (0.39.7)

1.6 (0.114.7)

Control group 2

2.6 (0.311.6)

1.0 (0.19.8)

Control group 1

1.6 (0.92.7)

2.2 (1.14.4)

Control group 2

1.8 (0.83.9)

1.5 (0.64.2)

2.5 (1.44.4)

3.2 (1.57.0)

3.3 (1.47.4)

2.4 (0.87.0)

Type of Malformation

No. with
Malformation

No. with Malformation

Exposed to Valproic
Acid Monotherapy

2,046

27

Nervous system
Spina bifida

Microcephaly

696

Heart
Ventricular septal defect

Atrial septal defect

11,711

8,267

19

19

Control group 1
Control group 2
Tetralogy of Fallot

960

Control group 1

2.8 (0.68.6)

1.5 (0.27.9)

Control group 2

2.8 (0.510.4)

0.9 (0.15.5)

Control group 1

2.8 (0.116.7)

2.4 (0.0193.6)

Control group 2

2.9 (0.119.5)

1.5 (0.0120.7)

Pulmonary-valve atresia

Hypoplastic right heart

311

85

Control group 1

Control group 1

5.2 (2.89.9)

3.0 (1.27.4)

Control group 2

5.2 (2.212.3)

1.9 (0.65.9)

Control group 2
Cleft palate

2,244

Diaphragmatic hernia

754

13

Control group 1

2.3 (0.39.0)

1.2 (0.18.9)

Control group 2

2.4 (0.310.7)

0.7 (0.16.1)

1.1 (0.06.5)

1.2 (0.024.0)

1.1 (0.07.6)

0.7 (0.015.6)

Control group 1

4.8 (2.98.1)

6.7 (2.915.2)

Control group 2

6.3 (2.615.2)

4.1 (1.115.0)

Gastroschisis

798

Control group 1
Control group 2
Hypospadias (male outcome
only)

2190

5,395

32

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Valproic Acid and Congenital Malformations

Table 3. (Continued.)
Adjusted Odds Ratio for
Valproic Acid Monotherapy
vs. No AED (95% CI)

Adjusted Odds Ratio for

Valproic Acid Monotherapy
vs. Other AED Monotherapy
(95% CI)

Control group 1

1.6 (0.73.7)

1.3 (0.53.9)

Control group 2

2.2 (0.86.7)

1.2 (0.34.7)

2.2 (1.04.5)

7.1 (1.828.4)

2.4 (0.96.4)

4.4 (0.822.6)

Control group 1

6.8 (1.818.8)

4.9 (0.755.2)

Control group 2

7.0 (1.722.9)

2.9 (0.435.8)

Type of Malformation

No. with
Malformation

No. with Malformation

Exposed to Valproic
Acid Monotherapy

3,676

Limb
Clubfoot

Polydactyly

3,500

Control group 1
Control group 2
Craniosynostosis

520

* Control group 1 included registrations without chromosomal abnormalities, and control group 2 registrations with chromosomal abnormalities. For the number of cases with no exposure to valproic acid, see Section 3 in the Supplementary Appendix, available with the full text of
this article at NEJM.org.
A case or control may have been counted in more than one subgroup.
Odds ratios were adjusted for reporting registry, birth year, and maternal age unless otherwise indicated.
Odds ratios were adjusted for birth year and maternal age only.
Microcephaly and clubfoot occurred without spina bifida.
Odds ratios were not adjusted because of the small number of exposed cases.

tic drug as compared with no such exposure have

shown that the risk is significantly higher with
exposure to valproic acid than with exposure to
other antiepileptic drugs. Furthermore, these studies have suggested increased risks of malformations in general in association with higher doses
of valproic acid as compared with lower doses.13,15-17 Since our data set does not include dose
information, we were not able to address this
question.
Previous studies of valproic acid monotherapy
during the first trimester and the risk of specific
malformations, other than spina bifida,27,28 have
generally been limited by relatively small samples
or potential selection bias, since they have not
been population-based.11,13,15,17 Our results are
in line with those of another large, populationbased, casecontrol registry study of congenital
malformations in which the control group had
malformations; specific associations were reported
between valproic acid exposure and spina bifida,
hypospadias, malformations of the brain and
heart, and limb-reduction malformations.26
A recent study showed that children exposed
to valproic acid in utero were more likely to have
impaired cognitive function at 3 years of age than
children exposed in utero to other antiepileptic
drugs.29 The American Academy of Neurology has

recommended avoiding valproic acid in pregnancy, if possible, on the basis of evidence that exposure to valproic acid is associated with an increased risk of major congenital malformations
and poor cognitive outcomes and confers a higher
risk than that associated with exposure to other
antiepileptic drugs.9
For malformations seen less frequently, our
study was able to rule out very large risks but not
smaller risks. The confidence limits were wide,
showing that even a study of nearly 4 million pregnancies is not enough to address a potentially
moderate association between rare malformations
and relatively rare drug exposures.
A limitation of our study, as discussed above,
is the lack of information on potential confound
ers. Furthermore, we used controls with malformations instead of those without malformations, since EUROCAT does not include detailed
population-based data on pregnancy outcomes
without malformations. An advantage of using
controls with malformations is that it minimizes
the potential for recall bias and other possible
sources of differential exposure ascertainment,
although such biases would be unlikely to influence the results, since most drug information
was recorded before the outcome of pregnancy
was known. Use of controls with malformations

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for comparison could lead to a conservative estimation of the risk associated with valproic acid
exposure if some of the malformations present
in the control group were also associated with
this exposure; however, by design we excluded
from the control groups malformations previously associated with valproic acid exposure. The
rate of valproic acid exposure was similar in the
two control groups (1.1 per 1000), and the point
estimates for the control group with chromosomal abnormalities were similar but slightly
higher than those for the control group without
chromosomal abnormalities in comparisons of
exposure to an antiepileptic drug with no such
exposure. We therefore concluded that there was
likely to be little or no contamination of our
control groups with malformation types associated with valproic acid exposure and that underestimation of odds ratios because of this bias was
unlikely.
Although the relative risks of several malformations were increased in association with exposure to valproic acid during the first trimester, it
should be recognized that the absolute rates of
specific malformations are low, and the majority
of children born to mothers who take valproic
acid do not have malformations. For example, the
baseline prevalence of spina bifida is about 0.5
cases per 1000 (see Section 2 in the Supplementary Appendix). We calculated an adjusted odds
ratio of 12.7 for the risk of spina bifida when
comparing exposure to valproic acid with no
exposure to an antiepileptic drug (Table 3); the
absolute risk of having a child with spina bifida
is approximately 0.6% in cases of exposure to valproic acid monotherapy during the first trimester. The estimated absolute risks for the other
five malformations after exposure are as follows:

of

m e dic i n e

atrial septal defect, 0.5%; cleft palate, 0.3%; hypospadias, 0.7%; polydactyly, 0.2%; and craniosynostosis, 0.1%. In determining whether to prescribe antiepileptic drugs, as well as which drug
to prescribe, several factors must be taken into
account, among them the goal of optimizing
seizure control in the individual patient. The
decision should be made by the patient and her
clinician after consideration of the benefits and
risks of various agents.
In summary, we found that exposure to val
proic acid during the first trimester was associated
with increased risks of six specific malformations,
as compared with no exposure to antiepileptic
drugs, and the risks of five of these six malformations remained significantly increased when we
compared valproic acid exposure with exposure to
other antiepileptic drugs. Our findings provide
further support for the recommendation of the
American Academy of Neurology to avoid the use
of valproic acid, if possible, in pregnant women.9
Since switching drugs during or just before pregnancy is difficult, the risks associated with valproic acid use should be routinely considered in
choosing therapy for women with childbearing
potential.
The EUROCAT Central Database is supported in part by the
European Union Public Health Programme, with a variety of
sources of public funding for individual registries. Additional
funding was obtained from GlaxoSmithKline for a study of lamo
trigine, during which the antiepileptic-study database was constructed. GlaxoSmithKline was not involved in the present study.
Drs. Garne and Barisic report that their registry received funding from GlaxoSmithKline for the data submitted to the lamo
trigine study.
Dr. Jentink reports receiving travel reimbursements from
GlaxoSmithKline through the University of Ulster. No other potential conflict of interest relevant to this article was reported.
We thank J. Morrow and K. Wide for providing us with more
detailed information about the cases than was available in their
reports and D. Wellesley for case review.

Appendix
Members of the EUROCAT Antiepileptic Study Working Group include the following: C. Verellen-Dumoulin (Centre de Gntique
Humaine Institut de Pathologie et de Gntique), V. Nelen (Provinciaal Instituut voor Hygiene), Belgium; I. Barisic (Childrens University Hospital Zagreb), Croatia; E. Garne (Lillebaelt Hospital, Kolding), Denmark; B. Khoshnood (Institut National de la Sant et de la
Recherche Medicale), B. Doray (Registre des Malformations Congenitales dAlsace), France; S. Poetzsch (Otto-von-Guericke Universitt
Megdeburg), A. Wiesel (Johannes Gutenberg Universitt, Geburtenregister Mainzer Modell), Germany; M. OMahony (Health Service
Executive), Ireland; A. Pierini (Istituto di Fisiologia Clinica del Consiglio Nazionale delle Ricerche), F. Rivieri (Azienda Ospedaliero
Universitaria di Ferrara), Italy; M. Gatt (Department of Health Information and Research), Malta; M. Bakker (University Medical Center
Groningen, University of Groningen), the Netherlands; K. Melve (Norwegian Institute of Public Health, Medical Birth Registry of Norway), Norway; A. Latos-Bielenska, J.P. Mejnartowicz (Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu), Poland; I. Portillo (Direccion Salud Publica, Departamento Sanidad, Gobierno Vasco), Spain; M.-C. Addor (Registre Vaudois des Malformations),
Switzerland; D. Tucker (Swansea National Health Service Trust, Congenital Anomaly Register and Information Service for Wales), D.
Wellesley (Southampton University Hospitals Trust), United Kingdom.

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Valproic Acid and Congenital Malformations

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