Research

JAMA Neurology | Original Investigation

Association Between Pregnancy and Perinatal

Outcomes Among Women With Epilepsy
Neda Razaz, PhD; Torbjörn Tomson, MD; Anna-Karin Wikström, MD, PhD; Sven Cnattingius, MD, PhD

Supplemental content
IMPORTANCE To date, few attempts have been made to examine associations between
exposure to maternal epilepsy with or without antiepileptic drug (AED) therapy and
pregnancy and perinatal outcomes.

OBJECTIVES To investigate associations between epilepsy in pregnancy and risks of

pregnancy and perinatal outcomes as well as whether use of AEDs influenced risks.

DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study was conducted on all
singleton births at 22 or more completed gestational weeks in Sweden from 1997 through
2011; of these, 1 424 279 were included in the sample. Information on AED exposure was
available in the subset of offspring from July 1, 2005, to December 31, 2011. Data analysis was
performed from October 1, 2016, to February 15, 2017.

MAIN OUTCOMES AND MEASURES Pregnancy, delivery, and perinatal outcomes. Multivariable
Poisson log-linear regression was used to estimate adjusted risk ratios (aRRs) and 95% CIs,
after adjusting for maternal age, country of origin, educational level, cohabitation with a
partner, height, early pregnancy body mass index, smoking, year of delivery, maternal
pregestational diabetes, hypertension, and psychiatric disorders.

RESULTS Of the 1 429 652 births included in the sample, 5373 births were in 3586 women
with epilepsy; mean (SD) age at first delivery of the epilepsy cohort was 30.54 (5.18) years.
Compared with pregnancies of women without epilepsy, women with epilepsy were at
increased risks of adverse pregnancy and delivery outcomes, including preeclampsia (aRR
1.24; 95% CI, 1.07-1.43), infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption (aRR,
1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI, 1.21-1.40), elective cesarean section
(aRR, 1.58; 95% CI, 1.45-1.71), and emergency cesarean section (aRR, 1.09; 95% CI, 1.00-1.20).
Infants of mothers with epilepsy were at increased risks of stillbirth (aRR, 1.55; 95% CI,
1.05-2.30), having both medically indicated (aRR, 1.24; 95% CI, 1.08-1.43) and spontaneous
(aRR, 1.34; 95% CI, 1.20-1.53) preterm birth, being small for gestational age at birth (aRR, 1.25;
95% CI, 1.13-1.30), and having neonatal infections (aRR, 1.42; 95% CI, 1.17-1.73), any congenital
malformation (aRR, 1.48; 95% CI, 1.35-1.62), major malformations (aRR, 1.61; 95% CI,
1.43-1.81), asphyxia-related complications (aRR, 1.75; 95% CI, 1.26-2.42), Apgar score of 4 to 6
at 5 minutes (aRR, 1.34; 95% CI, 1.03-1.76), Apgar score of 0 to 3 at 5 minutes (aRR, 2.42; 95%
CI, 1.62-3.61), neonatal hypoglycemia (aRR, 1.53; 95% CI, 1.34-1.75), and respiratory distress
syndrome (aRR, 1.48; 95% CI, 1.30-1.68) compared with infants of unaffected women. In
Author Affiliations: Clinical
women with epilepsy, using AEDs during pregnancy did not increase the risks of pregnancy Epidemiology Unit, Department of
and perinatal complications, except for a higher rate of induction of labor (aRR, 1.30; 95% CI, Medicine Solna, Karolinska University
1.10-1.55). Hospital, Karolinska Institutet,
Stockholm, Sweden (Razaz,
Cnattingius); Department of Clinical
CONCLUSIONS AND RELEVANCE Epilepsy during pregnancy is associated with increased risks Neuroscience, Karolinska Institutet,
of adverse pregnancy and perinatal outcomes. However, AED use during pregnancy is Stockholm, Sweden (Tomson);
generally not associated with adverse outcomes. Department of Women’s and
Children’s Health, Uppsala University,
Uppsala, Sweden (Wikström).
Corresponding Author: Neda Razaz,
PhD, Clinical Epidemiology Unit,
Department of Medicine Solna,
Karolinska University Hospital,
Karolinska Institutet, SE-171 76
JAMA Neurol. doi:10.1001/jamaneurol.2017.1310 Stockholm, Sweden
Published online July 3, 2017. (neda.razaz@gmail.com).

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 Research Original Investigation
B
etween 0.3% and 0.5% of all pregnancies occur among
women with epilepsy.1 To avoid the maternal and fe-
tal risks associated with seizures, maternal antiepilep-
tic drug (AED) therapy is often maintained during pregnancy,
despite increased risk of congenital malformations and
adverse cognitive development in the offspring of women
receiving AEDs.2,3
Follow-up studies of pregnant women with epilepsy have
focused mainly on associations between exposure to AEDs and
congenital malformations and cognition of the offspring.4,5
However, pregnancy and perinatal complications among
women with epilepsy may extend beyond the effect of treat-
ment with AEDs. Maternal mortality has been shown to be 10
times higher in women with epilepsy than in those without the
disorder.6,7 Epilepsy in women could increase the risks of mis-
carriage, preterm delivery, cesarean section, preeclampsia, and
gestational hypertension.8,9 A meta-analysis reported that,
among women with epilepsy, exposure to AEDs during preg-
nancy may increase the risks of fetal growth restriction, in-
duction of labor, postpartum hemorrhage, and admission to
the neonatal intensive care unit compared with those who are
not exposed to AEDs.9 Still, robust evidence from population-
based studies is sparse on the association between maternal
epilepsy and risks of adverse pregnancy outcomes and the con-
tribution of AEDs to these outcomes.
In a population-based study including more than 1.4 mil-
lion singleton-birth infants in Sweden, we investigated the as-
sociations between epilepsy in pregnancy and risks of preg-
nancy and perinatal outcomes. We also investigated whether
AED use influenced the risks.
Methods
This retrospective, nationwide cohort study included all single-
ton births at 22 or more completed gestational weeks in Swe-
den from 1997 through 2011. Using the person-unique na-
tional registration numbers of mothers and their offspring,10
individual information was obtained from the Medical Birth
Register,11 which contains information on antenatal, obstet-
ric, and neonatal care that is prospectively recorded on stan-
dardized forms on more than 98% of all births in Sweden; the
nationwide National Patient Register,12,13 which has pro-
vided diagnostic codes on hospital inpatient care since 1987
and hospital outpatient care from 2001; and the Prescribed
Drug Registry, which stores data on all drugs prescribed in am-
bulatory care and dispensed at a Swedish pharmacy since July
1, 2005.14 Maternal educational level and country of origin were
obtained from the Education Register15 and the Total Popula-
tion Register.10 Diagnoses in these databases were coded using
the Swedish version of the International Classification of Dis-
eases, Ninth Revision (ICD-9) from 1987 through 1996, and In-
ternational Statistical Classification of Diseases and Related
Health Problems, Tenth Revision (ICD-10) from 1997 onward.
Prescription medications were coded using the Drug Identifi-
cation Numbers and the Anatomical Therapeutic Chemical (ATC)
classification system. The study was approved by the Re-
search Ethics Committee at Karolinska Institutet, Stockholm,
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Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy
Key Points
Question What are the associations between maternal epilepsy,
antiepileptic drug use during pregnancy, and risks of pregnancy
and perinatal outcomes?
Findings In this population-based cohort study including more
than 1.4 million singleton births, we found that antiepileptic drug
use during pregnancy is generally not associated with adverse
maternal and fetal or neonatal outcomes. However, a diagnosis of
epilepsy still implies moderately increased risks of adverse
pregnancy, delivery, and perinatal outcomes.
Meaning Women with epilepsy should not be advised to
discontinue their treatment, if this is clinically indicated.
Preventive strategies aimed at mitigating the effect of maternal
epilepsy on pregnancy and perinatal outcomes are warranted.
Sweden. This study was based on encrypted data, for which
the ethics committees do not require informed consent.
Maternal Epilepsy
Maternal epilepsy was identified if it met any of the following
conditions16,17: (1) an occurrence of 2 or more diagnostic codes
for epilepsy (ICD-9 code 345 and ICD-10 code G40) on sepa-
rate dates or (2) an occurrence of 1 or more diagnosis codes for
convulsions (ICD-9 code 780.3 and ICD-10 code R56) and 1 or
more diagnosis codes for epilepsy among separate medical en-
counters; diagnosis of convulsion had to precede that of epi-
lepsy. The epilepsy cohort was restricted to individuals whose
epilepsy onset occurred before their child’s birth and those with
active epilepsy (ie, diagnosis code for epilepsy within 10 years
prior to conception).18 We classified epilepsy as either focal
(ICD-10 codes G40.0, G40.1, and G40.2), generalized (ICD-10
code G40.3), or nonspecific (if the women could not be as-
signed to either the generalized or focal groups).
AED Exposure
Using information from the Prescribed Drug Registry (start-
ing July 1, 2005),14 we were able to define AED exposure in a
subcohort of women as use of any redeemed medication be-
longing to ATC class N03A (antiepileptic) from July 1, 2005,
to December 31, 2011. The exposure window was defined as
30 days before the estimated day of conception to the day of
birth.
Pregnancy and Perinatal Outcomes
Pregnancy outcomes examined in this study were gestational
diabetes, preeclampsia, chorioamnionitis, maternal infection,
placental abruption, premature rupture of membranes, pro-
longed labor, induction of labor, mode of delivery, and postpar-
tum hemorrhage (eTable 1 in the Supplement reports specific
codes).
Perinatal outcomes included stillbirth, preterm birth, spon-
taneous and medically indicated preterm birth, small-for-
gestational-age (SGA) live birth, neonatal infection, presence
of congenital malformation detected during the first year of
life (divided into 2 categories: all malformations and major mal-
formations), asphyxia-related neonatal complications (includ-
ing meconium aspiration, hypoxic ischemic encephalopathy
jamaneurology.com
 Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy
and related conditions, and neonatal convulsions or sei-
zures), 5-minute Apgar score, neonatal hypoglycemia,
neonatal jaundice, and respiratory distress (eTable 1 and
eTable 2 in the Supplement report specific ICD codes). The
Birth Register includes live births from 22 completed gesta-
tional weeks onward. Information on stillbirths was avail-
able from 28 weeks onward from 1997 to July 1, 2008, and
thereafter from 22 gestational weeks. In the present study,
stillbirth was defined as a fetal death at 28 completed weeks
or later.
Gestational age in completed weeks was estimated
using the date of the early second trimester ultrasonogra-
phy (which is offered to all women; 95% accept) in 87.7% of
the women,19 the date of the last menstrual period in 7.4%
of the women, or postnatal assessment in 4.9% of the
women. Preterm birth was categorized as birth earlier than
37 completed weeks’ gestation. Medically indicated preterm
birth was defined as being born preterm and having an
induced onset of labor or a cesarean section before onset of
labor. The SGA was defined using the current Swedish stan-
dard for normal fetal growth and categorized into less than
the 10th percentile (SGA) and 10th percentile or higher
(non-SGA).20 Induced abortion due to detected malforma-
tion at the 18 gestational weeks’ ultrasonography are legal
until 21 gestational weeks in Sweden. These pregnancies are
therefore not included in the Medical Birth Register.
Other Covariates
Maternal characteristics included age at delivery, country of
origin, educational level, cohabitation with a partner, parity,
height, early pregnancy body mass index (calculated as weight
in kilograms divided by height in meters squared), smoking
during early pregnancy, year of delivery, and maternal pre-
existing chronic conditions, such as pregestational diabetes,
hypertension, and any psychiatric disorders. Maternal age at
delivery was calculated as date of delivery minus mother’s
birth date. Parity was defined as the number of births of
each mother. Body mass index, categorized according to the
World Health Organization recommendation,21 was calcu-
lated using weight measured at registration to antenatal
care, wearing light indoor clothing, and self-reported
height. Information on cohabitation with a partner was
obtained at the first antenatal visit. Mothers who reported
daily smoking at the first antenatal visit and/or at 30 to 32
gestational weeks were classified as smokers, whereas
mothers who only stated that they were nonsmokers were
classified as nonsmokers. Any psychiatric morbidity and
substance abuse before the child’s birth were defined using
inpatient and outpatient primary or secondary diagnoses of
any psychiatric condition and substance abuse (eTable 1 in
the Supplement reports specific codes).
Statistical Analysis
Maternal characteristics of women with and without epi-
lepsy and those receiving and not receiving AEDs during
pregnancy were compared using logistic regression. Multi-
variable Poisson log-linear regression models were used
to estimate adjusted risk ratios (aRRs). For the computation
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Original Investigation Research
of 95% CIs, generalized estimating equations, with an
assumed unstructured correlation structure, were used to
account for the correlations of sequential births to the same
mother in the study. Models were adjusted for maternal age,
country of origin, educational level, cohabitation with a
partner, parity, height, body mass index, smoking, year of
delivery, pregestational diabetes, hypertension, and psychi-
atric disorders. Pregnancy and neonatal events were rare in
the relatively small AED-treated cohort. For all analyses that
included the AED-treated cohort (all births from July 1,
2005, to December 31, 2011 only), we therefore used a pro-
pensity score approach to optimize adjustment for the
above covariates.22 We calculated propensity scores using
multivariable logistic regression, with exposure to AEDs as a
dependent variable and all adjustment covariates as predic-
tors. To obtain adjusted estimates, the resulting propensity
score was entered into the Poisson log-linear regression
models as a continuous variable. Data were analyzed with
the use of SAS software, version 9.4 (SAS Institute). Two-
sided P values less than <.05 were considered to indicate
statistical significance. No adjustment was made for mul-
tiple comparisons. Data analysis was performed from Octo-
ber 1, 2016, to February 15, 2017.
Results
The final sample included 1 424 279 pregnancies of 869 947
mothers without epilepsy and 5373 pregnancies of 3586 moth-
ers with epilepsy. Mean (SD) age at first delivery of the epi-
lepsy cohort was 30.54 (5.18) years. During the period for which
we had information on AED exposure (July 1, 2005, to Decem-
ber 31, 2011), there were 3231 offspring of mothers with epi-
lepsy, of whom 42.2% (n = 1363) were exposed to AEDs 1 month
before and/or during pregnancy. Lamotrigine (628 [46.1%]) and
carbamazepine (418 [30.7%]) were the most commonly used
AEDs, and 181 infants (13.3%) were exposed to polytherapy
(eTable 3 in the Supplement).
Compared with women without epilepsy, women with
epilepsy were younger at the time of delivery, primiparous,
born in the Nordic countries, had a lower educational level,
smoked, lived without a partner, were obese (body mass
index, ≥30), and had a higher frequency of chronic condi-
tions, such as pregestational diabetes, hypertension, psychi-
atric diagnosis, and substance abuse (Table). Among women
with epilepsy, those receiving AEDs during pregnancy were
older, more often primiparous, and born in non-Nordic
countries.
Pregnancies in women with epilepsy were associated with
elevated risks of preeclampsia (aRR, 1.24; 95% CI, 1.07-1.43),
infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption
(aRR, 1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI,
1.21-1.40), elective cesarean section (aRR, 1.58; 95% CI, 1.45-
1.71), and emergency cesarean section (aRR, 1.09; 95% CI,
1.00-1.20) compared with pregnancies in women without
epilepsy (Figure 1A). There was a higher frequency of post-
partum hemorrhage in pregnancies of women with epilepsy
compared with those without epilepsy; however, this asso-
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 Research Original Investigation Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy

Table. Maternal Characteristics of First Recorded Pregnancy According to Maternal Epilepsy and Maternal AED Use During Pregnancya

No. (%)
Not Receiving
No Epilepsy Epilepsy AED Receiving AED
Maternal Characteristic (n = 869 947) (n = 3586) P Value (n = 1015) (n = 926)a P Value
Age, y
≤19 23 231 (2.7) 117 (3.3) 25 (2.5) 46 (5.0)
20-24 145 625 (16.7) 655 (18.3) 178 (17.5) 189 (20.4)
25-29 291 605 (33.5) 1144 (31.9) .03 304 (30.0) 294 (31.8) .003
30-34 268 613 (30.9) 1090 (30.4) 327 (32.2) 252 (27.2)
≥35 140 873 (16.2) 580 (16.2) 181 (17.8) 145 (15.7)
Country of birth
Nordic 708 737 (81.5) 3122 (87.1) 855 (84.2) 802 (86.6)
<.001 .33
Non-Nordic 160 342 (18.4) 462 (12.9) 159 (15.7) 123 (13.3)
Data missing 868 (0.1) 2 (0.06) 1 (0.1) 1 (0.1)
Educational level, y
≤9 82 308 (9.5) 542 (15.1) 139 (13.7) 159 (17.2)
10-11 142 011 (16.3) 654 (18.2) 126 (12.4) 108 (11.7)
12 220 672 (25.4) 976 (27.2) <.001 295 (29.1) 289 (31.2)
.15
13-14 124 051 (14.3) 458 (12.8) 131 (12.9) 114 (12.3)
≥15 286 750 (33.9) 892 (24.9) 304 (30.0) 243 (26.2)
Data missing 14 155 (1.6) 64 (1.8) 20 (2.0) 13 (1.4)
Cohabiting with partner
Yes 765 720 (88.0) 3051 (85.1) 875 (86.2) 781 (84.3)
<.001 .05
No 57 110 (6.6) 357 (10.0) 109 (10.7) 96 (10.4)
Data missing 47 117 (5.4) 178 (5.0) 31 (3.0) 49 (5.3)
Parity
1 248 355 (28.6) 1305 (36.4) 800 (78.8) 743 (80.2)
2 402 479 (46.3) 1521 (42.4) 151 (14.9) 103 (11.1)
<.001 <.001
3 157 088 (18.1 540 (15.1) 43 (4.2) 58 (6.3)
≥4 62 025 (7.1) 220 (6.1) 21 (2.1) 22 (2.4)
Median (Q1-Q3) 2 (1-3) 2 (1-2) 2 (1-2) 1 (1-2)
Height, cm
≤159 113 348 (13.0) 529 (14.8) 148 (14.6) 132 (14.3)
160-164 216 959 (24.9) 910 (25.4) 234 (23.1) 248 (26.8)
.02 .37
165-169 248 109 (28.5) 970 (27.1) 287 (28.3) 245 (26.5)
≥170 269 345 (31.0) 1083 (30.2) 315 (31.0) 279 (30.1)
Data missing 22 186 (2.6) 94 (2.6) 31 (3.1) 22 (2.4)
Smoking
No 736 252 (84.6) 2911 (81.2) 879 (86.6) 757 (81.7)
<.001 <.001
Yes 90 159 (10.4) 504 (14.1) 109 (10.7) 107 (11.6)
Data missing 43 536 (5.0) 171 (4.8) 27 (2.7) 62 (6.7)
Year of delivery
1997-1999 229 581 (26.4) 561 (15.6) NA NA
2000-2004 276 078 (31.7) 1084 (30.2) NA NA
<.001
2005-2008 204 935 (23.6) 999 (27.9) 458 (45.1) 541 (58.4)
2009-2011 159 353 (18.3) 942 (26.3) 557 (54.9) 385 (41.6)
BMI
<18.5 20 758 (2.4) 81 (2.3) 26 (2.6) 22 (2.4)
18.5-24.9 493 378 (56.7) 1792 (50.0) 491 (48.4) 474 (51.2)
25.0-29.9 182 556 (21.0) 856 (23.9) 281 (27.7) 202 (21.8)
<.001 .08
30.0-34.9 54 540 (6.3) 345 (9.6) 96 (9.5) 97 (10.5)
35.0-39.9 15 822 (1.8) 101 (2.8) 32 (3.2) 28 (3.0)
≥40.0 5344 (0.6) 38 (1.1) 10 (.99) 15 (1.6)
Data missing 97 549 (11.2) 373 (10.4) 79 (7.9) 88 (9.5)

(continued)

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 Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy Original Investigation Research

Table. Maternal Characteristics of First Recorded Pregnancy According to Maternal Epilepsy and Maternal AED Use During Pregnancya (continued)

No. (%)
Not Receiving
No Epilepsy Epilepsy AED Receiving AED
Maternal Characteristic (n = 869 947) (n = 3586) P Value (n = 1015) (n = 926)a P Value
Pregestational diabetes
No 866 170 (99.6) 3552 (99.1) 1003 (98.8) 914 (98.7)
<.001 .82
Yes 3777 (0.4) 34 (0.9) 12 (1.2) 12 (1.3)
Pregestational hypertension
No 864 759 (99.4) 3550 (99.0) 1002 (98.7) 915 (98.8)
.002 .85
Yes 5188 (0.6) 36 (1.0) 13 (1.3) 11 (1.2)
Any psychiatric diagnoses
No 842 149 (96.8) 3148 (87.8) 905 (89.2) 812 (87.7) .31
<.001
Yes 27 798 (3.2) 438 (12.2) 110 (10.8) 114 (12.3)
Substance misuse
No 867 095 (99.7) 3505 (97.7) 991 (97.6) 904 (97.6)
<.001 .98
Yes 2852 (0.3) 81 (2.3) 24 (2.4) 22 (2.4)
Abbreviations: AED, antiepileptic drug; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); NA, not applicable.
a
Information on AED exposure was available only during the period from July 1, 2005, to December 31, 2011. Results determined with logistic regression.

ciation was of borderline significance (aRR, 1.11, 95% CI,
0.97-1.26). No increased risks of premature rupture of mem-
branes and prolonged labor were observed in the epilepsy
group.
The frequency of stillbirth was higher in offspring
of women with epilepsy compared with those without epi-
lepsy (0.6% vs 0.3%) (Figure 1B). After adjustment for
potential confounders, neonates of women with epilepsy
had significantly higher risks of stillbirth, being born
SGA, both medically indicated and spontaneous preterm
births, any and major congenital malformations, neonatal
infections, asphyxia-related complications, low 5-minute
Apgar scores, and neonatal hypoglycemia and respiratory
distress compared with neonates of unaffected women
(Figure 1B).
Among pregnancies in women with epilepsy who gave
birth between July 2005 and December 2011, the rate of pre-
eclampsia was higher in those receiving AEDs compared with
pregnancies in women who did not receive AEDs (Figure 2A).
However, in the propensity score–adjusted analyses, only
induction of labor remained statistically significant (aRR, 1.30;
95% CI, 1.10-1.55) (Figure 2A).
Offspring of women exposed to AEDs had a higher fre-
quency of major malformation (6.7% vs 4.7%), respiratory
distress (6.0% vs 4.5%), and being SGA (9.5% vs 6.9%) at
birth, compared with the nonexposed offspring (Figure 2B).
The propensity score–adjusted analyses showed no statisti-
cally significant increased risk of adverse neonatal out-
comes between the 2 groups for any of the neonatal out-
comes.
Stratifying the analyses by type of AED monotherapy (1
AED type during pregnancy) and polytherapy (>1 AED
type during pregnancy) and by gestational age (term ≥37
weeks vs preterm 22-36 weeks) revealed similar results,
although statistical power was reduced. Among women
receiving relatively common monotherapy, the highest rate
of major malformations (10.6%) was obtained in pregnan-
cies with fetal exposure to valproic acid (eTable 3 in the
Supplement).
Discussion
In this nationwide cohort study, women with active epilepsy
had higher risks of preeclampsia, maternal infection, placen-
tal abruption, induction of labor, and both emergency and elec-
tive cesarean section. Offspring of women with epilepsy were
at higher risks of stillbirth, both medically indicated and spon-
taneous preterm births, SGA live birth, neonatal infection, any
and major malformations, asphyxia-related neonatal compli-
cations, low 5-minute Apgar scores, and less severe but more
prevalent neonatal complications, including neonatal hypo-
glycemia and respiratory distress. In women with epilepsy,
using AEDs during pregnancy did not increase the risks of preg-
nancy and perinatal complications significantly, except for a
higher rate of induction of labor.
Higher risks of pregnancy complications among women
with epilepsy have previously been reported in some6,9 but not
all studies.23,24 In our study, we further observed increased risks
of placental abruption and maternal infection among women
with epilepsy compared with the unaffected women. In addi-
tion, we confirmed the earlier described associations between
maternal epilepsy and higher risks of preterm birth, SGA live
birth, low Apgar score, and major malformation.6,9,25 The in-
creased risk of stillbirth (55%) was also consistent with previ-
ous studies that had supported a significant, albeit smaller, risk
increase.6,26 Moreover, our study showed that women with epi-
lepsy were more likely than women without epilepsy to have
an infant who experienced asphyxia-related neonatal compli-
cations, neonatal hypoglycemia, and neonatal respiratory dis-
tress. To date, few previous studies have explored the poten-
tial role of maternal epilepsy and the more prevalent neonatal

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 Research Original Investigation Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy

Figure 1. Delivery, Pregnancy, and Perinatal Outcomes Among Women With and Women Without Epilepsy,
Sweden, 1997-2011

A Pregnancy and delivery outcomes

Favors Favors
No. (%) Women Women
Without Epilepsy With Epilepsy Adjusted RR With Without
Outcome (n = 1 424 279) (n = 5373) (95% CI) Epilepsy Epilepsy
Gestational diabetes 14 015 (1.0) 69 (1.2) 1.14 (0.86-1.50)
Preeclampsia 39 964 (2.8) 214 (4.0) 1.24 (1.07-1.43)
Chorioamnionitis 2817 (0.2) 17 (0.3) 1.44 (0.87-2.39)
Maternal infection 9173 (0.6) 66 (1.2) 1.85 (1.43-2.29)
Placental abruption 5564 (0.4) 40 (0.7) 1.68 (1.18-2.38)
Premature rupture of membranes 22 160 (1.6) 97 (1.8) 1.20 (0.98-1.48)
Prolonged labor 11 072 (0.8) 40 (0.7) 0.86 (0.62-1.18)
Induced labor 155 430 (10.9) 844 (15.7) 1.31 (1.21-1.40)
Elective cesarean section 107 655 (7.6) 711 (13.2) 1.58 (1.45-1.71)
Emergency cesarean section 109 038 (7.7) 493 (9.2) 1.09 (1.00-1.20)
Postpartum hemorrhage 66 908 (4.7) 285 (5.3) 1.11 (0.97-1.26)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Adjusted RR (95% CI)

B Perinatal outcomes
Favors Favors
No. (%) Women Women
Without Epilepsy With Epilepsy Adjusted RR With Without
Outcome (n = 1 424 279) (n =.5373) (95% CI) Epilepsy Epilepsy
Stillbirth 4802 (0.3) 32 (0.6) 1.55 (1.05-2.30)
Preterm birth (<37 wk) 668 841 (4.7) 416 (7.7) 1.49 (1.34-1.66) Pregnancy and delivery (A) and
Medically indicated preterm birth 18 601 (1.3) 158 (2.9) 1.24 (1.08-1.43) perinatal (B) outcomes determined
Spontaneous preterm birth 48 517 (3.4) 248 (4.6) 1.34 (1.20-1.53) using multivariable Poisson log-linear
Small for gestational age 89 463 (6.3) 451 (8.4) 1.25 (1.13-1.30) regression models adjusted for
maternal age, country of origin,
Neonatal infections 21 332 (1.5) 116 (2.2) 1.42 (1.17-1.73)
educational level, cohabitation with a
Any congenital malformations 83 845 (5.9) 480 (8.9) 1.48 (1.35-1.62)
partner, parity, height, early
Major malformations 46 632 (3.3) 301 (5.6) 1.61 (1.43-1.81) pregnancy body mass index, smoking
Asphyxia-related complications 6053 (0.4) 44 (0.8) 1.75 (1.26-2.42) during pregnancy, prepregnancy
Apgar score 4–6 10 927 (0.8) 65 (1.2) 1.34 (1.03-1.76) hypertension, prepregnancy
Apgar score 0–3 2905 (0.2) 27 (0.5) 2.42 (1.62-3.61) diabetes, any psychiatric disorders,
Neonatal hypoglycemia 37 923 (2.7) 250 (4.7) 1.53 (1.34-1.75) and year of delivery. Denominator for
Neonatal jaundice 59 212 (4.2) 227 (4.2) 0.95 (0.83-1.09) stillbirth was all births at 28
completed weeks or later and the
Neonatal respiratory distress 44 729 (3.1) 282 (5.2) 1.48 (1.30-1.68)
denominator for the remaining
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 variables in the figure was live births
Adjusted RR (95% CI) at 22 completed weeks or later. RR
indicates risk ratio.

complications. Our results are in line with those of one previ-
ous study observing a 2-fold increased risk of respiratory dis-
tress in offspring of women with epilepsy.25
We found that women with epilepsy who used AEDs during
pregnancy were not at greater risk of adverse pregnancy out-
comes, with the exception of an increased risk of induction of
labor and a non-significantly increased risk of preeclampsia.
This finding is in contrast to previous findings of higher risks
of antepartum and postpartum hemorrhage and cesarean
section in women with epilepsy using AEDs.9,27 Further-
more, unlike previous studies,25,28,29 we found no signifi-
cantly increased risk of adverse perinatal outcomes in off-
spring of women with epilepsy exposed to AEDs compared
with nonexposed infants (although the rates for SGA live
birth and major malformation were borderline significant).
Our study differs from previous studies examining the effects
of AED exposure on pregnancy outcomes in a number of
ways. First, in this Swedish cohort, lamotrigine and carba-
mazepine accounted for approximately 77% of the treated
pregnancies, whereas valproic acid and topiramate, known to
be associated with increased risks of malformations, were
used in only 19.2% and 4.0% of the pregnancies, respec-
tively. Nevertheless, in line with other studies, among
women receiving relatively common monotherapy, our data
also suggest that valproic acid poses a greater risk for major
malformation. Second, we utilized a previously validated
case definition for epilepsy,16,17 rather than relying on a single
ICD code to identify epilepsy. Third, unlike a previous Swed-
ish study,30 that used self-reported data from the Medical
Birth Registry, in our study, AED use in the most recent years,
was captured from the Prescribed Drug Registry. Fourth, we
included women with “active” epilepsy to ensure clinical rel-
evance, given that epilepsy is considered to be “resolved” for
individuals who have remained seizure-free for the past 10
years.18 Fifth, in our study, we made comparisons between
outcomes of women with epilepsy who were receiving AEDs

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 Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy Original Investigation Research

Figure 2. Delivery, Pregnancy, and Perinatal Outcomes Among Women With Epilepsy by Antiepileptic Drug
(AED) Use During Pregnancy, Sweden, 2005-2011

A Pregnancy and delivery outcomes in epilepsy

Favors Favors
Women With Women With
No. (%) Epilepsy Epilepsy
Not Receiving Receiving AED Adjusted RR Receiving Not Receiving
Outcome AED (n = 1868) (n = 1363) (95% CI) AED Therapy AED Therapy
Gestational diabetes 27 (1.4) 23 (1.7) 0.94 (0.55-1.59)
Preeclampsia 56 (3.0) 67 (4.9) 1.39 (0.96-2.00)
Chorioamnionitis 8 (0.4) 3 (0.2) 0.41 (0.07-2.30)
Maternal infection 15 (0.8) 18 (1.3) 1.33 (0.66-2.65)
Placental abruption 12 (0.6) 7 (0.5) 0.83 (0.30-2.31)
Premature rupture of membranes 33 (1.8) 24 (1.8) 0.98 (0.56-1.74)
Prolonged labor 16 (0.9) 10 (0.7) 0.72 (0.28-1.86)
Induced labor 269 (14.4) 261 (19.1) 1.30 (1.10-1.55)
Elective cesarean section 237 (12.7) 191 (14.0) 1.02 (0.85-1.22)
Emergency cesarean section 162 (8.7) 138 (10.1) 1.03 (0.81-1.30)
Postpartum hemorrhage 95 (5.1) 90 (6.6) 1.08 (0.79-1.48)

0 0.5 1.0 1.5 2.0 2.5 3.0

Adjusted RR (95% CI)

B Perinatal outcomes in epilepsy

Favors Favors
Women With Women With
No. (%) Epilepsy Epilepsy
Not Receiving Receiving AED Adjusted RR Receiving Not Receiving
Outcome AED (n = 1868) (n = 1363) (95% CI) AED Therapy AED Therapy
Stillbirth 9 (0.5) 6 (0.4) 0.66 (0.17-2.60)
Preterm birth (<37 wk) 128 (6.9) 99 (7.3) 0.97 (0.74-1.27)
Medically indicated preterm birth 46 (2.5) 42 (3.1) 1.11 (0.77-1.61) Pregnancy and delivery (A) and
Spontaneous preterm birth 82 (4.4) 55 (4.0) 0.91 (0.73-1.15) perinatal (B) outcomes determined
using propensity score approach to
Small for gestational age 128 (6.9) 130 (9.5) 1.25 (0.97-1.61)
adjust for confounders, including
Neonatal infections 26 (1.4) 27 (2.0) 1.28 (0.78-2.45)
maternal age, country of origin,
Any congenital malformations 135 (7.2) 123 (9.0) 1.17 (0.90-1.25) educational level, cohabitation with a
Major malformations 87 (4.7) 91 (6.7) 1.30 (0.95-1.77) partner, parity, height, early
Asphyxia-related complications 10 (0.5) 5 (0.4) 0.55 (0.17-1.75) pregnancy body mass index, smoking
Apgar score 4–6 16 (0.9) 16 (1.2) 1.10 (0.48-2.51) during pregnancy, prepregnancy
Apgar score 0–3 10 (0.5) 5 (0.4) 0.60 (0.21-1.65) hypertension, prepregnancy
Neonatal hypoglycemia 72 (3.9) 65 (4.8) 1.14 (0.81-1.59) diabetes, and any psychiatric
Neonatal jaundice 87 (4.7) 54 (4.0) 0.75 (0.53-1.08) disorders. Denominator for stillbirth
was all births at 28 completed weeks
Neonatal respiratory distress 84 (4.5) 81 (6.0) 1.30 (0.92-1.81)
or later and the denominator for the
0 0.5 1.0 1.5 2.0 2.5 3.0 remaining variables in the figure was
Adjusted RR (95% CI) live births at 22 completed weeks or
later. RR indicates risk ratio.

vs those with epilepsy who were not receiving AEDs, while
most previous studies compared AED use in women with
epilepsy with a large reference cohort of women without epi-
lepsy, which introduces confounding by indication bias.31
Finally, we were able to account for data clustering arising
from consecutive births of the same mother and adjust for
several confounding variables not considered in previous
studies, such as maternal preexisting chronic conditions.
The physiologic changes occurring in pregnancy signifi-
cantly alter the volume of distribution and elimination of AEDs
and consequently decrease the plasma concentration.32 This
action could theoretically influence the potential adverse ef-
fects of AEDs on maternal and perinatal outcomes, unless dose
adjustments are made. The clinical recommendation in Swe-
den is to monitor AED serum concentrations with dose adjust-
ment throughout the pregnancy. In addition, women with epi-
lepsy who are receiving AEDs during pregnancy may receive
extra surveillance and monitoring from their clinicians that may
have contributed to the comparable outcomes observed in our
study. The teratogenicity of AEDs to the developing fetus has
been of concern for women in whom discontinuation of AED
therapy during pregnancy cannot be considered owing to the
possibility of seizures. 28 Our findings reveal that the in-
creased risks of complications during pregnancy, labor, and the
neonatal period might be due to pathologic factors related to
epilepsy as a chronic disease more than being the effect of AEDs
per se. Such epilepsy-related factors may be associated with
the many comorbidities of epilepsy (eg, autoimmune
disorders).29,33 Therefore, women with epilepsy should not be
advised to discontinue clinically indicated treatment. Ad-
verse effects of AED use have also been shown to be counter-
balanced by the seizure control effect of AEDs.34,35

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 Research Original Investigation Association Between Pregnancy and Perinatal Outcomes in Women With Epilepsy

Limitations disease severity, seizure frequency during pregnancy, dosage

The main limitation of our study was that the Patient Drug Reg-
ister only provides information on drugs that have been dis-
pensed from pharmacies, and the adherence to treatment is
unknown. However, previous research has shown high agree-
ment between maternal reports of AED use during pregnancy
and filled prescriptions for AEDs.36 We also lacked informa-
tion about malformations subjected to induced abortions,
which may have influenced the estimated association be-
tween exposure to AEDs and risk of major malformation in the
offspring toward the null. In our AED-exposed cohort, we
cannot rule out the possibility of false-negative results due to
a lack of power to detect a meaningful difference. Finally, given
our nonexperimental study design, the observed associa-
tions between exposure to maternal epilepsy and AEDs and
pregnancy outcomes are not evidence of a causal relation-
ship. The impact of other possible confounders, such as
of AED exposure, AED serum levels, or exposure to other po-
tential teratogens, needs to be assessed in future studies.
Conclusions
Our findings provide reassurance to women with epilepsy that
AED use during pregnancy is generally not associated with ad-
verse maternal and fetal or neonatal outcomes, although it is
important to be aware that AEDs differ in their teratogenic po-
tential. However, a diagnosis of epilepsy still implies a mod-
erately increased risk of adverse pregnancy, delivery, and peri-
natal outcomes. This information should improve counseling
for women with epilepsy who contemplate discontinuing their
treatment during pregnancy and provide useful information
to their health care clinicians.

ARTICLE INFORMATION
Accepted for Publication: May 9, 2017.
Published Online: July 3, 2017.
doi:10.1001/jamaneurol.2017.1310
Author Contributions: Dr Razaz had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Concept and design: Razaz, Wikström, Cnattingius.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Razaz.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Razaz.
Obtained funding: Cnattingius.
Administrative, technical, or material support:
Razaz, Cnattingius.
Supervision: Razaz, Cnattingius.
Conflict of Interest Disclosures: Dr Tomson is
associate editor of Epileptic Disorders, he has
received speaker’s honoraria to his institution from
Livanova, Eisai, UCB, and BMJ India, honoraria to his
institution for advisory boards from UCB and Eisai,
and research support from Stockholm County
Council, CURE, GSK, Bial, UCB, Novartis, and Eisai.
No other disclosures were reported.
Funding/Support: The study was supported by
grant 2014-0073 from the Swedish Research
Council for Health, Working Life and Welfare, an
unrestricted grant from Karolinska Institutet
(Distinguished Professor Award to Professor
Cnattingius), and grant 2014-3561 from the Swedish
Research Council (Dr Wikström).
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Probst C. Pregnancy outcomes in women with
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antiepileptic drugs. Lancet Neurol. 2012;11(9):803-
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4. Koo J, Zavras A. Antiepileptic drugs (AEDs)
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Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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