BRIEF COMMUNICATION

Malformation in index pregnancy in women with epilepsy is

not followed by recurrence in subsequent pregnancy
Shehanaaz Begum, Sankara P. Sarma, and Sanjeev V. Thomas

Epilepsia, 54(12):e163–e167, 2013

doi: 10.1111/epi.12411

SUMMARY
Use of antiepileptic drugs (AEDs) in pregnant women with epilepsy (WWE) is associ-
ated with an increased risk of major congenital malformations (MCM). Previous stud-
ies have suggested that WWE who had a malformation in their index pregnancy were
at an increased risk of recurrence in future pregnancies. We aimed to assess the risk of
recurrence of MCM in 1,616 WWE from Kerala Registry of Epilepsy and Pregnancy.
The pregnancy outcome of women (n = 246) with two prospective pregnancies in the
registry were analyzed. They had partial seizures with or without generalization
(57.3%) or generalized seizures (42.7%). Polytherapy was used in 26.4% (index preg-
nancy) and 23.6% (follow-up pregnancy). The mean dosage of AED for valproate was
498 mg/day and carbamazepine was 555 mg/day. The malformation rate in the index
S. Begum is a Senior pregnancy was 8.5% (21/246) and in the follow-up pregnancy was 8.9% (22/246) with
Research Fellow in only one recurrence. There was no increased risk of MCM in follow-up pregnancy for
Kerala Registry of those who had MCM in the index pregnancy (p = 0.70; OR 0.49; 95% CI 0.06–3.80). The
Epilepsy and use of any specific drug, continuation of the same drug or a change in drug therapy
Pregnancy, between two pregnancies did not alter the recurrence risk.
Department of KEY WORDS: Women with epilepsy, Antiepileptic drugs, Teratogenesis, Recurrence,
Neurology. Major congenital malformations.

The use of antiepileptic drugs (AEDs) is associated with
risk of major congenital malformation (MCM) of about 5–
9% in comparison to a background risk of 1–3% (Meador
et al., 2008; Tomson et al., 2011). There is inadequate data
on risk of recurrence of malformations to provide evidence
based counseling to women with epilepsy (WWE) who are
considering a second pregnancy. Data from the United
Kingdom Epilepsy and Pregnancy Register (UKEPR) and
the Australian Pregnancy Register (APR) indicate that the
risk of malformation recurrence in subsequent pregnancy is
increased if the index pregnancy had a malformation
(Campbell et al., 2013; Vajda et al., 2013). There is little
Accepted September 10, 2013; Early View publication October 18,
2013.
Kerala Registry of Epilepsy and Pregnancy, Sree Chitra Tirunal Institute
for Medical Sciences and Technology, Trivandrum, Kerala State, India
Address correspondence to Sanjeev V. Thomas, Professor of Neurology,
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sci-
ences and Technology, Trivandrum 695011, India. E-mail: sanjeev.v.
thomas@gmail.com
Wiley Periodicals, Inc.
© 2013 International League Against Epilepsy
prospective data on the recurrence risk from other parts of
the world. We aimed to estimate the risk of recurrence of
MCM in follow-up pregnancy for the index pregnancies that
had MCM from the data from the registry in Kerala, India.
Materials and Methods
Kerala Registry of Epilepsy and Pregnancy (KREP) is
prospectively following up WWE from preconception per-
iod, through pregnancy and delivery until their children are
12 years of age. The main objective is to estimate the MCM
risk in this cohort. We ascertain malformation status ante
natally (detailed anomaly scan and serum alpha feto protein
estimation) and postnatally (clinical examination at birth,
echocardiography and abdomen ultrasonography at
3 months of age followed by further verifications up to
1 year of age) (Beghi & Annegers, 2001; Thomas et al.,
2001; Tomson et al., 2011) We had 2,140 registrations
between April 1998 and March 2013.
In this study, we considered all WWE who had two or
more pregnancies registered in KREP. For each woman we
defined index pregnancy as the first pregnancy in the

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S. Begum et al.
registry and follow-up pregnancy as the next pregnancy for
which she was registered again. Pre index pregnancies, if
any were not included. All live births and terminations after
anomaly scans (irrespective of malformation status) were
included. Pregnancy loss (abortions, intrauterine deaths
or stillbirths) without anomaly scans were excluded. All
cases where major malformations were detected on antena-
tal ultrasonography (in the case of abortions or medical
terminations), neonatal physical examination, and echocar-
diography or abdomen ultrasonography at 3 months of age
were included as positive cases. Malformation rate is the
number of positive cases expressed as a percentage of the
total number of pregnancies where malformation status was
ascertained.
The prescribed daily dose was recorded from the clinical
records and compliance was ascertained through the daily
medication- seizure – pregnancy calendar maintained by the
patient. No drug levels were monitored. The highest daily
dose any time in a month is taken as the representative daily
dose for that month. The mean of the daily dose for the
months of pregnancy is recorded as the mean daily dose for
that pregnancy.
A MCM is defined as an abnormality that can interfere
with the quality of life and warrants definite management.
Asymptomatic cardiac malformations detected by echocar-
diography were rigorously defined as: atrial septal defect: a
defect >5 mm size in the interatrial septum confirmed by
Doppler echo at 3 months of age, patent ductus arteriosus:
Persistent flow across the ductus at 3 months of age. Any
defects in the ventricular septum or other complex malfor-
mations such as tetralogy of Fallot were included as MCMs.
We excluded from MCM all patent foramen ovale (defect in
interatrial septum <5 mm) and trivial valvular regurgitation
or stenosis (detected only on Doppler echo and not demand-
ing medical attention). Minor asymptomatic and unex-
plained dilatations of the pelvi-ureteric system of the
kidneys detected only on ultrasonography were also
excluded. Congenital malformation rates were further ana-
lyzed with respect to individual AED exposure and mono
and polytherapy. Statistical significance of differences were
ascertained by Fisher’s exact t-test, McNemar test or
chi-square test and odds ratios (ORs) with 95% confidence
intervals (CIs).
Results
Of the 1,616 WWE who had pregnancies under KREP,
there were 634 repeat pregnancies. We excluded 142 preg-
nancies without malformation screening: spontaneous abor-
tions prior to malformation screening (61), incomplete
screening for malformation (13), medical termination of
pregnancy prior to malformation screening (27), intrauter-
ine deaths (9), stillbirths (4), lost to follow-up (4) or third
pregnancy (24). Remaining 492 pregnancies in 246 women
were included in this analysis. Their mean age (SD) at time
Epilepsia, 54(12):e163–e167, 2013
doi: 10.1111/epi.12411
of index pregnancy was 24.1 (3.7) years. The mean interval
between two pregnancies was 1,233  693 days. The sei-
zures were classified as generalized seizures in 105 (42.7%)
and partial with or without generalization in 141 (57.3%).
Four WWE had inter district change of residence between
two consecutive pregnancies. The AED usage and seizure
control in index and follow-up pregnancies of WWE are
given in Table 1.
The overall control of convulsive seizures during preg-
nancy was good (22% in index pregnancy and 15.4% in fol-
low-up pregnancy); the proportion of women who were
totally seizure free was 45.9% in index pregnancy and
63.8% in follow-up pregnancy (See Table 1). AED treat-
ment was unchanged between pregnancies for 166 WWE
(67.5%) while it was changed for 73 (29.7%) (See Table 2).
The malformation rate in the index pregnancy was 21/246
(8.5%; 95% CI 5.7–12.7) and in the follow-up pregnancy
was 22/246 (8.9%; 95% CI 6.0–13.2). These rates were
comparable to that for the group who had only one preg-
nancy in the registry (7.2%; 95% CI 5.9–8.8). MCM had
occurred for 42 of the 246 women in index or follow-up
pregnancy of which only one had MCM in both pregnan-
cies. There was no increased risk of MCM in follow-up
pregnancy for those who had MCM in the index pregnancy
(See Table 2).
There were 166 women (67.5%) who had same treatment
in the index and follow-up pregnancy. AED treatment was
changed for 73 patients (29.7%). Seven women were off
AEDs in both pregnancies. The risk of recurrence of MCM
was not different for those who had a change versus those
who did not have a change in the AED therapy between
index and follow-up pregnancy. There was no difference in
the recurrence risk, for any given AED exposure.
There was no difference in the risk of malformation
recurrence between those exposed to valproate (VPA) and
those exposed to AEDs other than VPA in the index preg-
nancy (See Table 2). Out of the 64 WWE on VPA in index
pregnancy, 16 stopped it before follow-up pregnancy.
Among the 48 who were on VPA in index and follow-up
pregnancy, MCM occurred in four index and six follow-up
pregnancies but none of them were recurrence for the same
person (See Table 2).
Discussion
The background of a pregnancy registry had given us an
opportunity to prospectively estimate the risk of recurrence
of malformations in consecutive pregnancies for WWE. We
did not observe any excess risk of MCM in follow-up preg-
nancy if the index pregnancy had a MCM. In this study of
492 pregnancies in 246 women, 43 pregnancies had MCM
(42 women). Only one woman had recurrence of MCM in
the follow-up pregnancy. The MCM rates (8.5% in index
pregnancy and 8.9% in follow-up pregnancy) were compa-
rable to the rate of MCM in other pregnancy registries
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Epilepsy Pregnancy, Birth Defect Recurrence

Table 1. Antiepileptic drug usage and malformations in index and follow-up pregnancy
Index pregnancy Follow-up pregnancy
Proportion (%) with Proportion (%) with
seizures Mean dosage seizures
AED N (%) Mean dosage (SD) mg/day Any seizure type GTCS N (%) (SD) mg/day Any seizure type GTCS
All cases 246 54.1 22 246 36.2 15.4
1 171 47.9 20.5 163 34.4 15.9
2 or more 65 78.4 29.2 58 56.9 20.7
No AED 10 0 0 25a 0 0
Phenobarbitone 54 83 (44) 59.3 27.7 47 81 (37) 51.1 19.1
Lamotrigine 6 185 (105) 66.7 50 9 170 (113) 44.4 22.2
Primidone 3 425 (153) 100 33.3 3 333 (288) 33.3 0
Clonazepam 7 1.2 (0.7) 71.4 28.5 5 1.3 (0.7) 60 40
Phenytoin 46 193 (98) 69.5 23.9 33 251 (84) 57.6 24.2
Clobazam 20 7.1 (6) 95 35 18 12 (6.7) 66.6 11.1
Carbamazepine 108 555 (280) 61 16.6 94 552 (308) 41.5 13.8
Valproate 64 498 (311) 42.1 31.3 66 472 (277) 25.8 15.2
Topiramate 0 2 75 (35) 100 0
Leviteracetam 1 1,500 100 100 4 1,208 25 0
Oxcarbazepine 5 897 (258) 80 40 5 1,023 (377) 80 80
Cardiacb 7 (33.3) 8 (36.4)
Nervous systemc 2 (9.5) 4 (18)d
Skeletale 5 (23.8) 0
Genito urinary 4 (19) 5 (22.7)
Gastro intestinal 1 (4.8) 4 (18)
Multiple system 2 (9.5) 1 (4.5)
a
Includes 7 who were off AEDs in the index pregnancy also.
b
Cardiac: ASD, PDA, TOF.
c
Nervous system: neural tube defect, hydrocephalus.
e
Skeletal: Polydactyly, Congenital Talipes Equino Varus.
d
One case with NTD also had CTEV in follow-up pregnancy.

Table 2. Malformation (MCM) rate for the follow-up pregnancy according to the malformation status in the index
pregnancy and AED usage
Follow-up pregnancy
Index pregnancy malformation status MCM-Yes (%) MCM-No OR CI p
All index pregnancies (246)
MCM-Yes (21) 1 20 0.49 0.06–3.80 0.703
MCM-No (225) 21 204
VPA used (64)
MCM – Yes (7) 0 7 0.90 0.819–0.978 1.000
MCM – No (57) 6 51
Other AEDs (182)
MCM – Yes (14) 1 13 0.79 0.10–6.42 1.000
MCM – No (168) 15 153
AED changed (73)
MCM – Yes (9) 0 9 0.89 0.82–0.97 0.300
MCM– No (64) 7 (10.9) 54
AED unchanged (166)
MCM-Yes (12) 1 11 0.91 0.11–7.57 0.930
MCM-No (154) 14 (9.1) 140
Valproate used in both pregnancies (48)
MCM-Yes (4) 0 4 0.86 0.77–0.97 1.000
MCM-No (44) 6 (13.6) 38

Epilepsia, 54(12):e163–e167, 2013

doi: 10.1111/epi.12411
e166
S. Begum et al.
(Campbell et al., 2013; Vajda et al., 2013). The use of any
specific drug, continuation of the same drug or a change in
drug therapy between two pregnancies did not alter the
recurrence risk.
Our results differ from that from the registries in United
Kingdom and Australia, where researchers had demon-
strated an increased risk of recurrence of MCM in follow-up
pregnancy, if the index pregnancy had MCM (Campbell
et al., 2013; Vajda et al., 2013). All three studies had simi-
lar proportion of repeat registrations (20–23%) within the
registry and the spectrum of malformations is comparable.
The maternal age, seizure types and AED usage are compa-
rable between these registries. There are differences
between these studies in terms of population (Caucasian vs.
Asian), methodology (United Kingdom registry had
excluded women with family history of malformations and
pregnancy loss without malformations), selection criteria
(Australian study had included retrospective cases also) and
AED exposure (higher dosage and more of newer AEDs in
United Kingdom and Australia).
The malformation risk for valproate was higher than
that of other AEDs in this study, as observed elsewhere.
Nevertheless, we did not observe any excess risk of
recurrence of MCM associated with any AED exposure
particularly valproate. It is possible that the low recurrence
risk in our study is related to the low dosage of AED
exposure in contrast to the dosage in the other registries.
The mean dosage of VPA monotherapy in the United
Kingdom registry was 948.1 mg/day for the normal group
and 1,065 mg/day for the MCM group. The comparable
values for carbamazepine were 632 and 682 mg/day in the
United Kingdom registry. In the Australian registry, the
mean daily dose of VPA was 882 mg/day (first pregnancy)
and 803 mg/day (second pregnancy) for the normal group
and 1,148 or 1,057 mg/day for the MCM group. The mean
dose in KREP for valproate was 474 mg/day (index
pregnancy), 452 mg/day (follow-up pregnancy) for normal
outcome and 693 mg/day (index pregnancy) 665 mg/day
(follow-up pregnancy) for the MCM group. These expo-
sures are in the range of 50% (for normal outcome) to 65%
(for the MCM group) that of United Kingdom registry. The
risk of recurrence appears to be low in the setting of low
dose of AEDs. The teratogenic impact of AEDs had been
shown to be dose dependent (Tomson et al., 2011).
Although the dosage of AEDs were on lower side in this
study, there was good control of convulsive seizures (15–
22%). The control of seizures with valproate was superior to
other AEDs although the dosage is rather low (Table 1)
(Thomas et al., 2012). The overall seizure control during
pregnancy in this study is comparable to that reported
from EURAP Study Group (2006) and Australia (Vajda
et al., 2008). One should not directly extrapolate seizure
control during pregnancy to seizure control in non-preg-
nant state as the treatment objectives and strategies in
these situations are not identical. It appears that the
Epilepsia, 54(12):e163–e167, 2013
doi: 10.1111/epi.12411
recurrence risk for malformation is low when the AED
exposure is at low dosage. Another reason could be the
ethnic difference between populations as this study is
exclusively on Asian Indians while the other two studies
are mostly on Caucasian population.
Birth defects in a population have a polygenic etiology.
About 10% of MCM is attributed to environmental factors
and only <1% are related to chemicals, prescription drugs
and high ionizing radiations (Brent, 2004). Population based
studies from different geographical areas have pointed
towards a genetic basis for malformation recurrence (Stol-
tenberg et al., 1999). Studies from Norway and Denmark
have shown that malformation recurrence risk remained
low, when women had moved to new geographical location
(Lie et al., 1994) or when partners had changed (Christen-
sen et al., 1995). Caution should be exercised while extrap-
olating from large epidemiological studies to higher risk
groups such as WWE who constitute only 0.1–0.2% of the
population. There was little geographical movement
between pregnancies in this study. The absence of increased
risk in this study is unlikely to be due to geographic
movement or changes in partners. Drugs probably add to the
polygenic mechanism and induce malformations if the fetus
is exposed to a suprathreshold dosage at a critical point in
organogenesis (Brent, 2004).
In this study, normal outcome in index pregnancy was
not associated with reduced risk of MCM in follow-up
pregnancy, even when the AEDs are same in both
pregnancies. In our series, 14 of the 154 (9.1%) who had
normal index pregnancy outcome had MCM in follow-up
pregnancy, even while the AEDs were unchanged. Simi-
lar trends were observed with and without valproate (see
Table 2).
Our data suggests that the malformation recurrence risk
may be dose dependent and at low dose there may not be
increased risk of recurrence. We believe that there is an
opportunity to try low dose of AEDs in well controlled
women planning pregnancy. An occasional myoclonus or
mild partial seizure may be more acceptable to some women
who are considering pregnancy than the potential risk of
major malformation associated with standard doses of an-
tiepileptic drugs. A limitation of this study is the rather
small number of cases (n = 246) available to analyse the
impact of various antiepileptic drugs on malformation
recurrence. The comparable numbers for the United King-
dom registry and Australian registries were 646 and 228
respectively. The outcome of 1,006 follow-up pregnancies
(503 with malformation in index pregnancy and 503 without
malformation in index pregnancy) need to be ascertained in
order to achieve a power (1 – beta) of 80%. Hence great cau-
tion should be applied while interpreting these data particu-
larly with AED specific risk of recurrence of MCM. The
population genetic contribution and socioeconomic and
environmental factors also need to be addressed in future
studies.

Disclosure
None of the authors have any conflicts of interest to disclose. We
confirm that we have read the Journal’s position on issues involved in
ethical publication and affirm that this report is consistent with those
guidelines.
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Epilepsia, 54(12):e163–e167, 2013
doi: 10.1111/epi.12411