J Neurol DOI 10.1007/s00415-013-7239-x
ORIGINAL COMMUNICATION
Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy Gyri Veiby • Anne Kjersti Daltveit • Bernt A. Engelsen • Nils Erik Gilhus
Received: 1 November 2013 / Accepted: 30 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The primary aim of this study was to assess the risks of fetal growth restriction and birth defects in children exposed prenatally to newer and older antiepileptic drugs, using an unselected epilepsy cohort. Deliveries recorded in the compulsory Medical Birth Registry of Norway 1999–2011 formed the study population. All 2,600 children exposed to antiepileptic drugs during pregnancy were compared to all 771,412 unexposed children born to women without epilepsy. Children of untreated mothers with epilepsy served as an internal control group. The main outcomes were small for gestational age birth weight and head circumference, and major congenital malformations. Children exposed to antiepileptic drugs had a moderate risk of growth restriction. Infants exposed to topiramate had a considerable risk of microcephaly (11.4 vs. 2.4 %; OR 4.8; CI 2.5–9.3) and small for gestational age birth weight (24.4 vs. 8.9 %; OR 3.1; 95 % CI 1.9–5.3). Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, gabapentin, and Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-7239-x) contains supplementary material, which is available to authorized users. G. Veiby B. A. Engelsen N. E. Gilhus Department of Clinical Medicine, Section for Neurology, University of Bergen, Bergen, Norway G. Veiby (&) B. A. Engelsen N. E. Gilhus Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway e-mail: [email protected] A. K. Daltveit Department of Global Health and Primary Care, University of Bergen, Bergen, Norway A. K. Daltveit Medical Birth Registry of Norway, Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway
pregabalin had low malformation rates, whereas topiramate tended to have an elevated malformation rate. Valproate monotherapy was associated with a significant risk of birth defects (6.3 vs. 2.9 %; OR 2.5; CI 1.6–3.8), and specifically with septal heart defects and hypospadias. For mothers using valproate, the presence of major birth defect in one child was associated with a markedly increased risk for the siblings (42.9 vs. 6.7 %; OR 10.4; CI 2.3–46.7). Children of untreated mothers with epilepsy had malformation risk similar to the reference group. In conclusion, topiramate was associated with a substantial risk of fetal growth restriction, and possibly an increased malformation rate. Other newer-generation antiepileptic drugs had a low malformation rate. Valproate monotherapy had a significant malformation risk, especially in repeated pregnancies. Keywords Antiepileptic drugs Pregnancy Birth defects Microcephaly Birth weight
Introduction Teratogenic effects of antiepileptic drugs are a great concern in neurological practice. An increased malformation risk has mainly been associated with valproate [1–3]. Older-generation antiepileptic drugs have been linked to specific birth defects, such as spina bifida and orofacial clefts. Harmful effects of prenatal exposure to antiepileptic drugs do not only manifest as structural defects, but may include growth restriction and effects on cognitive development and behavior. Several recent studies have reported increased risk of developmental delay [4–12] and adverse perinatal outcome in such children [1, 2, 13]. Most women with active epilepsy are encouraged to continue antiepileptic drug treatment during pregnancy, as
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seizures can lead to serious fetal or maternal complications [13–17]. However, pregnancy complications rarely occur in relation to isolated generalized seizures [18]. Consequently, prescription of antiepileptic drugs to pregnant women is only justified if the drugs have a relatively low teratogenic potential. New drugs are continuously marketed without knowing their safety in pregnancy. Furthermore, the new antiepileptic drugs are increasingly used for a wide range of medical conditions other than epilepsy. Thus, their teratogenic potential has interest beyond the follow-up of women with epilepsy. The Medical Birth Registry of Norway (MBRN) contains a full, nationwide, unselected population of women with epilepsy, with and without antiepileptic drug treatment, and a large, valid reference group. The primary aim of this study was to determine the risks of fetal growth restriction and major congenital malformations with exposure to the various newer and older antiepileptic drugs during pregnancy.
Materials and methods The medical birth registry of Norway (MBRN) MBRN is a population-based registry, including all deliveries in Norway at 12 or more weeks of gestation. Data on maternal health prior to the pregnancy, complications during pregnancy, and perinatal outcome are in all cases collected by the attending physician and midwife at delivery. Based on information recorded from the first prenatal visit with the general practitioner until discharge from the hospital, a standardized notification form is sent to the MBRN, including compulsory information on maternal epilepsy, use of antiepileptic drugs, and folate supplementation. Maternal epilepsy is notified in a specific checkbox (yes/no), or coded according the International Classification of Diseases, 10th revision (ICD-10). Since 1999, antiepileptic drug use throughout the pregnancy (not distinguishing between trimesters) has been recorded according to the anatomical therapeutic chemical classification system (ATC). MBRN does not obtain information on seizure-activity or antiepileptic drug dose. All induced abortions after 12 weeks of gestation performed according to the Norwegian Abortion Act §2 are recorded in a separate national database; the Register of Pregnancy Terminations. The hospital that performs the abortion reports compulsory information on any prenatal or postnatal fetal diagnoses, as well as maternal diagnoses such as epilepsy. This study included the full cohort of 777,785 deliveries recorded in MBRN 1999–2011, and all 1,577 induced abortions due to fetal malformations/chromosomal defects
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recorded 2006–2011, supplied by our previously published data on induced abortions 1999–2005 [1]. In the primary analyses, adverse birth outcomes in children exposed prenatally to antiepileptic drugs were compared to the reference group of all unexposed children born to women without epilepsy. The exposed group included 2,600 deliveries with a recorded ATC-code for antiepileptic drug(s) during pregnancy, divided into subclasses of antiepileptic drugs used as monotherapy or polytherapy. Outcomes were analyzed for the entire drugexposed group, as well as categorized according to maternal epilepsy. All 3,773 deliveries from mothers with a history of epilepsy but no antiepileptic drug treatment served as an internal control group. The present study was approved by the Regional Committee for Medical Research Ethics in Western Norway, No. 2009/990 (115.09). Outcome variables and covariates Main outcome variables were major and specific congenital malformations, and small for gestational age (SGA) birth weight and head circumference based on the Norwegian population [19]. Congenital malformations were recorded during the neonatal period and during follow-up at pediatric wards within the first year. Major malformations included birth defects causing functional impairment, leading to surgical intervention, or both. Specific congenital malformations were categorized according to organ systems within ICD-10. Growth restriction was measured as SGA birth weight below the 10th percentile, and SGA head circumference below the 2.5th percentile—the most common definition of microcephaly [20]. Main outcome variables were selected a priori to reduce potential effects of multiple testing. Socio-demographic data included maternal age, nulliparity, single mother, parental education, smoking, and periconceptional folate supplementation (C4 times/week). Information on smoking habits was collected, provided the mother’s consent. Spontaneous abortions in previous pregnancies were categorized as early (\12 gestational weeks) or late (12–23 gestational weeks). Siblings of malformed children Based on index-cases, defined as children with major malformations in the mothers’ first delivery during the recording period, the malformation risk for siblings was examined, including siblings in the same pregnancy (twin) or first subsequent pregnancy. Siblings in later pregnancies were not included in these subanalyses, as 97 % of drug treated mothers with a malformed index-child had discontinued antiepileptic treatment in their second post-index pregnancy.
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Statistics The analyses were performed using SPSS for Windows (IBM SPSS statistics). Two-sided p values B 0.05 were considered statistically significant. Baseline pregnancy characteristics in the exposed vs. reference group were compared using Pearson’s Chi square test. Mean birth weight, length, and head circumference were analyzed by Independent samples t test. The relative risk of adverse outcomes was estimated as odds ratio (OR) with the corresponding 95 % confidence interval (CI) and p value using unconditional logistic regression and adjustment for potential confounders. Included covariates were smoking during pregnancy (yes/no), periconceptional folate supplementation (yes/no), maternal age (\25, 25–29, 30–34, [34 years), child’s birth order (first, second, C third), and maternal chronic disease other than epilepsy (yes/no; heart disease, chronic hypertension, rheumatoid arthritis, prepregnancy diabetes, asthma, chronic urinary infection, thyroid disease). Additional adjustment for maternal and paternal educational level (B10 years, 11–13 years, C14 years) was performed based on an additional MBRNfile for the time period 1999–2009. Frequency of multiple births was similar in the drug-exposed and reference group, and was not adjusted for. Explorative analyses The choice of covariates in the regression model was based on a priori considerations. Post hoc, the effect of the included covariates was evaluated by comparing crude ORs to adjusted ORs. Stratified analysis with Breslow-Day homogeneity test was performed for each covariate to assess effect modification. Based on a supplementary MBRN file from 1999 to 2009, containing a more extensive variety of background variables, propensity-score matching was performed to evaluate any effects of baseline differences between the exposed and reference groups. Each child in the drug-exposed group was matched to a child in the reference group with an identical or very similar propensity score. Risk-estimates for the matched groups were then compared to the primary analysis. The predictors in the propensity score model included maternal and paternal age and educational level, child’s birth order, single mother, periconceptional folate supplementation, chronic maternal disease other than epilepsy, and maternal smoking habits. Handling of missing values Missing values for the outcome variables and covariates were generally low (\ 2 %), and were handled by listwise deletion in the analyses. The exception was smoking during
pregnancy, where information was missing for 16.5 %, due to lack of consent. Cases with missing data on smoking were coded as a separate category in the regression model.
Results Study population Exposure to antiepileptic drugs during pregnancy was recorded for 2,600 children (0.3 %), delivered by 1,989 women in 2,559 pregnancies. The majority (n = 2,086) had a mother with epilepsy. A total of 3,773 children (0.5 %) were born to women with a history of epilepsy but no antiepileptic drug treatment during pregnancy. All 771,412 unexposed children born to mothers without epilepsy formed the reference group. The most commonly used antiepileptic drugs during pregnancy were lamotrigine (n = 983), carbamazepine (n = 783), valproate (n = 410), and levetiracetam (n = 188). Other reported antiepileptic drugs were clonazepam (n = 166), oxcarbazepine (n = 97), topiramate (n = 90), phenobarbital (n = 40), gabapentin (n = 39), phenytoin (n = 37), pregabalin (n = 30), vigabatrin (n = 14), ethosuximide (n = 12), primidone (n = 6), clobazam (n = 6), and unspecified (n = 20). The majority were exposed to monotherapy (n = 2,309, 88.8 %), whereas 259 children (10.0 %) were exposed to two antiepileptic drugs and the remaining 32 (1.2 %) to three antiepileptic drugs. During the recording period, the use of antiepileptic drugs during pregnancy gradually shifted from mainly older to newer types (Supplement, eFig. 1A), especially evident for the polytherapy group (eFig. 1B). Pregnancy characteristics are presented in Table 1. Single parenting, low educational level, smoking, and earlier spontaneous abortion were moderately increased in the drug-exposed group. Periconceptional folate supplementation was two to three times as frequent in the exposed group (Table 1). Mothers with untreated epilepsy used folate supplementation similar to the reference group; 20.2 % prior to the pregnancy and 47.5 % during the first trimester. Use of antiepileptic drugs during pregnancy was identical between the four geographic health regions of Norway, whereas notification of untreated epilepsy ranged from 0.4 % to 0.7 %. Risk growth restriction Mean birth weight, length, and head circumference was lower in the drug-exposed group compared to the references (Table 2). This was most pronounced for topiramate, with a mean lesser weight of 393 grams (95 % CI 259–526 grams; p \ 0.001), mean lesser length of 2.2 cm (95 % CI
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J Neurol Table 1 Background characteristics of children exposed to antiepileptic drugs (AEDs) in utero compared to the reference group Characteristics
Reference n = 771,412
AED exposure in total n = 2,600
%
% (no.)a
Maternal age [37 years
AED exposure maternal epilepsy n = 2,086
p value
OR (95 % CI)
% (no.)a
p value
OR (95 % CI)
6.4
6.4 (167)
0.97
1.00 (0.86–1.17)
6.2 (130)
0.74
0.97 (0.81–1.16)
Nulliparous mother
41.4
45.4 (1,180)
\0.001
1.18 (1.09–1.27)
44.4 (927)
0.005
1.13 (1.04–1.23)
Single mother Lower education motherb
6.8 17.4
11.5 (300) 27.1 (556)
\0.001 \0.001
1.80 (1.60–2.03) 1.77 (1.60–1.95)
9.3 (193) 26.0 (441)
\0.001 \0.001
1.41 (1.21–1.63) 1.68 (1.50–1.87)
Lower education fatherb
18.3
23.1 (462)
\0.001
1.35 (1.21–1.50)
22.2 (367)
\0.001
1.28 (1.14–1.43) 1.25 (1.12–1.39)
Smoking in pregnancy
20
27.6 (634)
\0.001
1.52 (1.39–1.67)
23.8 (439)
\0.001
Folate preconceptionallyc
18.1
35.9 (934)
\0.001
2.54 (2.35–2.76)
39.1 (816)
\0.001
2.92 (2.67–3.19)
Folate during 1st trimester
45.6
73.3 (1,906)
\0.001
3.27 (3.00–3.57)
75.4 (1,573)
\0.001
3.65 (3.31–4.04)
Plural pregnancy
3.6
3.2 (82)
0.23
0.87 (0.70–1.09)
3.1 (65)
0.24
0.86 (0.67–1.10)
Previous early abortiond
20.7
23.7 (547)
\0.001
1.19 (1.08–1.31)
22.7 (417)
0.031
1.13 (1.01–1.26)
Previous late abortione
3.1
3.9 (88)
0.028
1.27 (1.03–1.57)
3.9 (70)
0.048
1.27 (1.00–1.62)
a
Numbers within different cells may not equal 100 % due to variation of missing values
b
Educational level corresponding to elementary school (10 years or less). Available 1999–2009
c
Use of folate supplementation within 1 month prior to conception Maternal previous spontaneous abortion \12th pregnancy week
d e
Maternal previous spontaneous abortion pregnancy weeks 12–23
Table 2 Risk of growth restriction in children exposed to antiepileptic drugs (AEDs) in utero compared to the reference group Neonatal outcome
Reference n = 771,412
AED exposure in total n = 2,600
AED exposure maternal epilepsy n = 2,086
Mean
Mean
Mean diff. (CI)a
p value
Mean
Mean diff. (CI)a
p value
Birth weight (g)
3,501
3,426
75.0 (48.1–101.8)
\0.001
3,441
60.6 (32.8–88.4)
\0.001
Birth length (cm)
50.0
49.6
0.35 (0.21–0.49)
\0.001
49.6
0.31 (0.16–0.47)
\0.001
Head circumference (cm)
35.1
34.9
0.23 (0.14–0.32)
\0.001
34.9
0.22 (0.12–0.32)
\0.001
b
p value
Growth parameters
%
% (no.)
Odds ratio (CI)
b
p value
% (no.)
Odds ratio (CI)
Growth restriction Birth weight \2,500 gc
5.4
7.6 (198)
1.15 (0.94–1.41)
0.17
7.5 (157)
1.25 (1.00–1.57)
0.054
SGA birth weight \10th perc.
8.9
10.7 (278)
1.17 (1.03–1.33)
0.013
10.7 (223)
1.19 (1.03–1.36)
0.018
SGA birth weight \2.5 perc.
2.2
3.0 (77)
1.30 (1.03–1.63)
0.025
3.0 (63)
1.37 (1.06–1.76)
0.015
SGA head circ. \10th perc.
8.7
10.8 (277)
1.24 (1.09–1.40)
0.001
10.9 (225)
1.27 (1.10–1.46)
0.001
SGA head circ. \2.5 perc.
2.4
3.4 (87)
1.39 (1.12–1.72)
0.003
3.4 (70)
1.42 (1.12–1.80)
0.004
SGA small for gestational age according to percentile (perc.) a
Mean difference with 95 % confidence interval (CI), independent samples T test
b
Odds ratio with 95 % confidence interval (CI), adjusted for maternal age, parity, smoking, and chronic maternal disease other than epilepsy
c
Additional adjustment for premature delivery
1.6–2.9 cm; p \ 0.001), and a mean lesser head circumference of 1.5 cm (95 % CI 1.1–1.9 cm; p \ 0.001). The overall risk of SGA children was modestly increased in the drug-exposed group (Table 2), and substantially increased for topiramate-exposure (Fig. 1). Topiramate as monotherapy (n = 48) had a high risk of SGA head circumference (14.9 vs. 2.4 %; adjusted OR 7.21;
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95 % CI 3.23–16.1) and SGA birth weight (25.0 vs. 8.9 %; adjusted OR 3.29; 95 % CI 1.70–6.39). Children of mothers with untreated epilepsy had a slightly increased risk of SGA birth weight (10.3 vs. 8.9 %; adjusted OR 1.15; 95 % CI 1.03–1.27), but the risk of SGA head circumference was identical to the reference group.
J Neurol Fig. 1 Fetal growth restriction in children exposed to antiepileptic drugs compared to the reference group. Risk of SGA head circumference \ 2.5th percentile red filled box, and SGA birth weight \ 10th percentile black filled box. Odds ratio with 95 % confidence interval, adjusted for maternal age, parity, smoking, and chronic disease other than epilepsy
Table 3 Risk of major congenital malformation in children exposed to antiepileptic drugs in utero compared to the reference group Exposed groupsb,c,d
Antiepileptic drug monotherapy n = 2,309 % (no./total)
References (n = 771,412) All antiepileptic drugs
Antiepileptic drug polytherapy n = 291
OR (95 % CI)a
p value
1.27 (1.02–1.59)
0.036
2.9 3.4 (79/2,309)
% (no./total)
OR (95 % CI)a
p value
1.29 (0.68–2.42)
0.43
2.9 3.4 (10/291)
Valproate sodium
6.3 (21/333)
2.47 (1.58–3.84)
\0.001
5.2 (4/77)
2.03 (0.74–5.56)
0.17
Carbamazepine
2.9 (20/685)
1.06 (0.68–1.66)
0.79
2.0 (2/98)
0.75 (0.19–3.06)
0.69
Phenobarbital Clonazepam
7.4 (2/27) 1.8 (2/113)
2.75 (0.65–11.6) 0.65 (0.16–2.62)
0.17 0.54
7.7 (1/13) 7.5 (4/53)
2.93 (0.38–22.5) 3.11 (1.12–8.63)
0.30 0.03
Lamotrigine
3.4 (28/833)
1.26 (0.87–1.84)
0.22
2.7 (4/150)
1.02 (0.38–2.77)
0.96
Levetiracetam
1.7 (2/118)
0.63 (0.16–2.55)
0.52
2.9 (2/70)
1.08 (0.27–4.43)
0.91
Oxcarbazepine
1.8 (1/57)
0.64 (0.10–4.61)
0.66
2.5 (1/40)
0.82 (0.11–5.99)
0.85
Topiramate
4.2 (2/48)
1.66 (0.40–6,85)
0.48
7.1 (3/42)
2.62 (0.81–8.53)
0.11
a
Odds ratio with 95 % confidence interval (CI), adjusted for maternal age, parity, smoking, folate supplementation, and maternal chronic disease other than epilepsy
b c
The malformation rate was 3.3 % (1/30) for exposure to pregabalin monotherapy Monotherapy with phenytoin, vigabatrin, ethosuximide, primidone, clobazam, or gabapentin had no recoded major malformations
d
Analyses excluding the 514 drug exposed children where the mother did not have a diagnosis of epilepsy are presented in eTable 1 in the Supplement (online only)
Risk of major birth defects A total of 89 children exposed to antiepileptic drugs in utero were born with a major malformation. The malformation risk was slightly increased for antiepileptic drugs in general, and similar for monotherapy and polytherapy (Table 3). Valproate was the only monotherapy with significantly more malformations. Exposure to topiramate or phenobarbital was associated with a higher, but not significantly increased, malformation rate. Monotherapy with carbamazepine, oxcarbazepine,
clonazepam, lamotrigine, levetiracetam, and pregabalin was not associated with an increased risk. The remaining monotherapies had no recorded malformations. Older antiepileptic drugs as part of polytherapy tended to have higher malformation rates compared to polytherapy with the newer drugs (Table 3). The polytherapy group was too small to examine specific antiepileptic drug combinations. Analyses including only drug-exposed children of mothers with epilepsy showed similar risk estimates as the overall exposed group (Supplement, eTable 1).
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Risk of specific birth defects
For the 514 drug-exposed children without maternal epilepsy (97.7 % monotherapy), the malformation risk was identical to the reference group (2.9 vs. 2.9 %; adjusted OR 1.05; 95 % CI 0.63–1.76). The risk was not significantly increased for the 56 valproate-exposed children in this group (3.6 vs. 2.9 %; adjusted OR 1.28; 95 % CI 0.31–5.24). The malformation risk among women with untreated epilepsy was the same as for the reference group (2.8 vs. 2.9 %; adjusted OR 0.98; 95 % CI 0.81–1.19).
Birth defects were examined for main organ-systems, as well as for selected midline birth defects (Fig. 2a–d). Hypospadias and septal heart defects were increased in the drug-exposed group (Fig. 2a). The risk was especially high for valproate monotherapy (Fig. 2c), including septal heart defects (1.8 vs. 0.7 %; adjusted OR 2.69; 95 % CI 1.20–6.03) and hypospadias (1.2 vs. 0.2 %; adjusted OR 5.71; 95 % CI 2.13–15.3).
Fig. 2 Risk of specific birth defects in children exposed to antiepileptic drugs in utero compared to the reference group. (1) Odds ratio (OR) with 95 % confidence interval, adjusted for maternal age, parity,
smoking, periconceptional folate use, and chronic disease other than epilepsy. (2) Percentage (%) and number (no.) of specific malformation within the drug-exposed group
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Four children in the drug-exposed group had orofacial clefts; one was exposed to lamotrigine, one to carbamazepine, one to levetiracetam, and one to polytherapy. The single child with spina bifida was exposed to valproate monotherapy. There was no increased risk for any of the examined specific birth defects in children of mothers with untreated epilepsy. Three children in this group had spina bifida.
matching generally had an insignificant effect on the riskestimates in the drug-exposed group (Supplement, eTables 4–6).
Malformations in siblings
In this unselected national cohort, the risks of growth restriction and major malformations in children exposed prenatally to antiepileptic drugs were modestly increased. Topiramate was strongly associated with microcephaly and low birth weight. Exposure to carbamazepine or polytherapy also had a significant risk of fetal growth restriction. Monotherapy or polytherapy with the newer antiepileptic drugs was generally associated with a low malformation risk. The exception was topiramate, which tended to have an elevated malformation rate. Infants exposed to monotherapy with valproate had a twofold to threefold higher risk of major malformations, and a considerably higher risk of hypospadias and septal heart defects. A significant malformation risk was not observed for the small group of valproate-exposed children of mothers without epilepsy. For mothers using valproate in repeated pregnancies, birth defects in one child were associated with a high risk of birth defects in the next. Among the other older antiepileptic drugs, carbamazepine was associated with a low malformation rate, whereas phenobarbital had a higher but not significant risk.
A total of 61 malformed index-cases were identified in the exposed group. The malformation rate among their 18 siblings was increased compared to siblings of index-cases in the reference group (22.2 %, n = 4, vs. 6.7 %; unadjusted OR 3.97; 95 % CI 1.30–12.1). The increase was mainly confined to siblings of valproate-exposed indexcases, where three out of seven siblings (all valproateexposed) were born with a major malformation (42.9 % vs 6.7 %; unadjusted OR 10.4; 95 % CI 2.3–46.7). In the exposed group, 16 of the 18 siblings were exposed to the identical antiepileptic drug(s) as the index-case. Pregnancy terminations due to birth defects From 2006 to 2011, induced abortions due to malformations were performed for nine pregnancies in women with epilepsy and 1,577 pregnancies in women without epilepsy, corresponding to 0.33 and 0.43 % of all deliveries, respectively. In the epilepsy group, recorded birth defects were Down’s syndrome (n = 3), spina bifida (n = 1), Klinefelter’s syndrome (n = 1), cystic kidney (n = 1), reduction deformity (n = 1), nuchal translucency (n = 1), and multiple malformations (n = 1). None were significantly increased compared to the reference group. In contrast, data from 1999 to 2005 showed a higher frequency of late abortions due to spina bifida among women with epilepsy (five out of 14 pregnancy terminations) [1]. Explorative analyses Risk-estimates in the drug-exposed groups were only negligibly affected by adjustment (Supplement, eTables 2 and 3). In the stratified analyses, risk of major malformations in the drug exposed vs. reference group was slightly higher for pregnancies using periconceptional folate (3.7 vs. 2.6 %; unadjusted OR 1.44; 95 % CI 1.14–1.83). In the polytherapy group, the risk of microcephaly was mainly increased for children of mothers with chronic disease in addition to epilepsy (17.1 vs. 2.3 %; unadjusted OR 8.61; 95 % CI 3.57–20.8). None of the other covariates acted as significant effect-modifiers. Additional adjustment for a variety of background variables and propensity-score
Discussion Key findings
Interpretation Pregnancy-related risks of antiepileptic drugs have primarily focused on birth defects. Our results show that mothers using antiepileptic drugs also have a higher risk of SGA infants, consistent with previous data [2]. Our findings include a risk of microcephaly, with very limited previous documentation [1, 21]. Both small birth weight and microcephaly are associated with short-term and longterm morbidity [22–24]. Hence, fetal growth restriction may contribute to the neurodevelopmental effects observed with antiepileptic drugs [25]. The risk of microcephaly and low birth weight was highest for children exposed to topiramate. Anorexia and weight loss are side effects of topiramate in adults, and the drug is increasingly used to reduce obesity [26]. A previous study also reports reduced birth weight with topiramate [27]. Whether this is caused by effects on fetal metabolism, the intrauterine growth environment, or is secondary to low maternal caloric intake, is uncertain. Interestingly, valproate and levetiracetam, which have both been associated with weight gain
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in adults [28], did not lead to fetal growth restriction. Carbamazepine- or polytherapy-exposed infants also had a significant risk of adverse fetal growth, in line with previous reports [1, 21]. In the polytherapy group, this was mainly confined to women with additional non-epileptic chronic disease, indicating a multifactorial etiology. Infants of untreated mothers with epilepsy had a somewhat higher risk of low birth weight, but no signs of affected head size, suggesting that epilepsy per se may be associated with some degree of intrauterine growth restriction. In this unselected cohort, newer antiepileptic drugs such as levetiracetam, lamotrigine, oxcarbazepine, gabapentin, or pregabalin had a low risk of major birth defects, as also reported from the Danish birth registry [29]. However, topiramate tended to have an elevated malformation risk, in line with other recent reports [29, 30]. Among the older antiepileptic drugs, carbamazepine had a low overall malformation rate, but an increased risk of respiratory defects. Valproate was the only monotherapy with a significantly increased malformation rate. Specifically, the risk of hypospadias and septal heart defects was increased with valproate, as was also found in the EUROCAT study [31]. Some women are susceptible to this teratogenic effect, as we found a substantially higher malformation rate in repeated pregnancies of women using valproate, consistent with a recent study [32]. Both studies are limited by a small number of index-cases; but held together, the data clearly suggest that maternal or fetal factors contribute to valproate-induced malformations. Underlying factors may involve genetic polymorphisms, variations in drug or folic acid metabolism, placenta drug-transport, and interactions between genotype and environmental factors [33, 34]. Uncovering such vulnerability should promote patient-tailored therapy as part of pre-pregnancy planning [35]. The risk of birth defects associated with use of multiple antiepileptic drugs was lower than previously reported in MBRN [1]. Long-term monitoring indicates that this is due to an increased use of newer antiepileptic drugs parallel to a decreased use of older antiepileptic drugs as part of polytherapy. Drug combinations including the newer antiepileptic drugs may be less teratogenic, and could represent a favorable alternative to high-dose monotherapy with older antiepileptic drugs such as valproate. Indeed, we found that monotherapy with valproate was associated with a higher malformation rate than polytherapy with valproate, in line with data from the North American Antiepileptic Drug Pregnancy Registry [36]. Women using antiepileptic drugs are usually examined with early ultrasound scanning. Thus, the risk of serious malformations could potentially be underestimated due to a higher frequency of medically induced abortions. In this study, the rate of induced abortions due to birth defects was similar for women with epilepsy and controls, and
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abortions due to spina bifida were considerably lower during the later vs. earlier study period, further supporting a low teratogenic risk with many of the newer antiepileptic drugs. Study strengths and limitations This study had the major strength of a large population. All deliveries in Norway during the recording period were included, excluding selection bias. MBRN is a national registry with satisfactory diagnostic validity, including for maternal epilepsy [37–39]. Notification of maternal epilepsy and antiepileptic drug use during pregnancy is compulsory, registered at the first prenatal visit and throughout the pregnancy. The proportion of antiepileptic drugexposed pregnancies (0.3 %) was as expected, did not vary between different geographic regions, and corresponds to the prescription rate of antiepileptic drugs during pregnancy in Norway [40]. As the majority of women with a reported history of epilepsy were untreated, underreporting of antiepileptic drug treatment may be a concern. Any such misclassification should have overestimated the risks in the untreated group. However, the malformation rate for pregnancies in women with untreated epilepsy was identical to the reference group. Our previous validation study showed that untreated epilepsy during pregnancy mainly consists of women with non-active epilepsy [11]. This could reflect that pregnancy is postponed to periods with less active epilepsy, or that such women are more likely to become pregnant than women with active epilepsy. The results were generally not affected by adjustment, stratification, or propensity-score matching, suggesting that the adverse outcomes in the exposed group were not due to baseline differences. Still, unmeasured parameters might have influenced some of the observed drug-exposure associations. Unfortunately, we were not able to include information on seizures, epilepsy type, drug dose, or maternal body weight. Any protective effects of folate could not be evaluated due to probable confounding by indication. Important limitations were the small size of some of the exposed groups, and that the study may have been underpowered to detect risk of specific birth defects for each drug.
Conclusion The increased risk of microcephaly, low birth weight, and possibly birth defects in children exposed to topiramate is a major concern. If possible, topiramate should be avoided during pregnancy. Use of lamotrigine, carbamazepine, oxcarbazepine, and levetiracetam appeared to be relatively safe, but further studies are required regarding the risk of
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specific birth defects. Valproate was the only monotherapy associated with a significant risk, especially in mothers with an earlier malformed child. The malformation rate with polytherapy was lower than previously reported, probably due to a shift towards newer antiepileptic drugs and less use of valproate. Conflicts of interest Dr Veiby has received travel support from UCB Pharma and lecture fees from GlaxoSmithKline. Dr Engelsen has received travel support from GlaxoSmithKline and lecture fees from Lundbeck. Authors Gilhus and Daltveit have no conflicts of interest.
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ORIGINAL COMMUNICATION
Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy Gyri Veiby • Anne Kjersti Daltveit • Bernt A. Engelsen • Nils Erik Gilhus
Received: 1 November 2013 / Accepted: 30 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The primary aim of this study was to assess the risks of fetal growth restriction and birth defects in children exposed prenatally to newer and older antiepileptic drugs, using an unselected epilepsy cohort. Deliveries recorded in the compulsory Medical Birth Registry of Norway 1999–2011 formed the study population. All 2,600 children exposed to antiepileptic drugs during pregnancy were compared to all 771,412 unexposed children born to women without epilepsy. Children of untreated mothers with epilepsy served as an internal control group. The main outcomes were small for gestational age birth weight and head circumference, and major congenital malformations. Children exposed to antiepileptic drugs had a moderate risk of growth restriction. Infants exposed to topiramate had a considerable risk of microcephaly (11.4 vs. 2.4 %; OR 4.8; CI 2.5–9.3) and small for gestational age birth weight (24.4 vs. 8.9 %; OR 3.1; 95 % CI 1.9–5.3). Carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, gabapentin, and Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-7239-x) contains supplementary material, which is available to authorized users. G. Veiby B. A. Engelsen N. E. Gilhus Department of Clinical Medicine, Section for Neurology, University of Bergen, Bergen, Norway G. Veiby (&) B. A. Engelsen N. E. Gilhus Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway e-mail: [email protected] A. K. Daltveit Department of Global Health and Primary Care, University of Bergen, Bergen, Norway A. K. Daltveit Medical Birth Registry of Norway, Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway
pregabalin had low malformation rates, whereas topiramate tended to have an elevated malformation rate. Valproate monotherapy was associated with a significant risk of birth defects (6.3 vs. 2.9 %; OR 2.5; CI 1.6–3.8), and specifically with septal heart defects and hypospadias. For mothers using valproate, the presence of major birth defect in one child was associated with a markedly increased risk for the siblings (42.9 vs. 6.7 %; OR 10.4; CI 2.3–46.7). Children of untreated mothers with epilepsy had malformation risk similar to the reference group. In conclusion, topiramate was associated with a substantial risk of fetal growth restriction, and possibly an increased malformation rate. Other newer-generation antiepileptic drugs had a low malformation rate. Valproate monotherapy had a significant malformation risk, especially in repeated pregnancies. Keywords Antiepileptic drugs Pregnancy Birth defects Microcephaly Birth weight
Introduction Teratogenic effects of antiepileptic drugs are a great concern in neurological practice. An increased malformation risk has mainly been associated with valproate [1–3]. Older-generation antiepileptic drugs have been linked to specific birth defects, such as spina bifida and orofacial clefts. Harmful effects of prenatal exposure to antiepileptic drugs do not only manifest as structural defects, but may include growth restriction and effects on cognitive development and behavior. Several recent studies have reported increased risk of developmental delay [4–12] and adverse perinatal outcome in such children [1, 2, 13]. Most women with active epilepsy are encouraged to continue antiepileptic drug treatment during pregnancy, as
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seizures can lead to serious fetal or maternal complications [13–17]. However, pregnancy complications rarely occur in relation to isolated generalized seizures [18]. Consequently, prescription of antiepileptic drugs to pregnant women is only justified if the drugs have a relatively low teratogenic potential. New drugs are continuously marketed without knowing their safety in pregnancy. Furthermore, the new antiepileptic drugs are increasingly used for a wide range of medical conditions other than epilepsy. Thus, their teratogenic potential has interest beyond the follow-up of women with epilepsy. The Medical Birth Registry of Norway (MBRN) contains a full, nationwide, unselected population of women with epilepsy, with and without antiepileptic drug treatment, and a large, valid reference group. The primary aim of this study was to determine the risks of fetal growth restriction and major congenital malformations with exposure to the various newer and older antiepileptic drugs during pregnancy.
Materials and methods The medical birth registry of Norway (MBRN) MBRN is a population-based registry, including all deliveries in Norway at 12 or more weeks of gestation. Data on maternal health prior to the pregnancy, complications during pregnancy, and perinatal outcome are in all cases collected by the attending physician and midwife at delivery. Based on information recorded from the first prenatal visit with the general practitioner until discharge from the hospital, a standardized notification form is sent to the MBRN, including compulsory information on maternal epilepsy, use of antiepileptic drugs, and folate supplementation. Maternal epilepsy is notified in a specific checkbox (yes/no), or coded according the International Classification of Diseases, 10th revision (ICD-10). Since 1999, antiepileptic drug use throughout the pregnancy (not distinguishing between trimesters) has been recorded according to the anatomical therapeutic chemical classification system (ATC). MBRN does not obtain information on seizure-activity or antiepileptic drug dose. All induced abortions after 12 weeks of gestation performed according to the Norwegian Abortion Act §2 are recorded in a separate national database; the Register of Pregnancy Terminations. The hospital that performs the abortion reports compulsory information on any prenatal or postnatal fetal diagnoses, as well as maternal diagnoses such as epilepsy. This study included the full cohort of 777,785 deliveries recorded in MBRN 1999–2011, and all 1,577 induced abortions due to fetal malformations/chromosomal defects
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recorded 2006–2011, supplied by our previously published data on induced abortions 1999–2005 [1]. In the primary analyses, adverse birth outcomes in children exposed prenatally to antiepileptic drugs were compared to the reference group of all unexposed children born to women without epilepsy. The exposed group included 2,600 deliveries with a recorded ATC-code for antiepileptic drug(s) during pregnancy, divided into subclasses of antiepileptic drugs used as monotherapy or polytherapy. Outcomes were analyzed for the entire drugexposed group, as well as categorized according to maternal epilepsy. All 3,773 deliveries from mothers with a history of epilepsy but no antiepileptic drug treatment served as an internal control group. The present study was approved by the Regional Committee for Medical Research Ethics in Western Norway, No. 2009/990 (115.09). Outcome variables and covariates Main outcome variables were major and specific congenital malformations, and small for gestational age (SGA) birth weight and head circumference based on the Norwegian population [19]. Congenital malformations were recorded during the neonatal period and during follow-up at pediatric wards within the first year. Major malformations included birth defects causing functional impairment, leading to surgical intervention, or both. Specific congenital malformations were categorized according to organ systems within ICD-10. Growth restriction was measured as SGA birth weight below the 10th percentile, and SGA head circumference below the 2.5th percentile—the most common definition of microcephaly [20]. Main outcome variables were selected a priori to reduce potential effects of multiple testing. Socio-demographic data included maternal age, nulliparity, single mother, parental education, smoking, and periconceptional folate supplementation (C4 times/week). Information on smoking habits was collected, provided the mother’s consent. Spontaneous abortions in previous pregnancies were categorized as early (\12 gestational weeks) or late (12–23 gestational weeks). Siblings of malformed children Based on index-cases, defined as children with major malformations in the mothers’ first delivery during the recording period, the malformation risk for siblings was examined, including siblings in the same pregnancy (twin) or first subsequent pregnancy. Siblings in later pregnancies were not included in these subanalyses, as 97 % of drug treated mothers with a malformed index-child had discontinued antiepileptic treatment in their second post-index pregnancy.
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Statistics The analyses were performed using SPSS for Windows (IBM SPSS statistics). Two-sided p values B 0.05 were considered statistically significant. Baseline pregnancy characteristics in the exposed vs. reference group were compared using Pearson’s Chi square test. Mean birth weight, length, and head circumference were analyzed by Independent samples t test. The relative risk of adverse outcomes was estimated as odds ratio (OR) with the corresponding 95 % confidence interval (CI) and p value using unconditional logistic regression and adjustment for potential confounders. Included covariates were smoking during pregnancy (yes/no), periconceptional folate supplementation (yes/no), maternal age (\25, 25–29, 30–34, [34 years), child’s birth order (first, second, C third), and maternal chronic disease other than epilepsy (yes/no; heart disease, chronic hypertension, rheumatoid arthritis, prepregnancy diabetes, asthma, chronic urinary infection, thyroid disease). Additional adjustment for maternal and paternal educational level (B10 years, 11–13 years, C14 years) was performed based on an additional MBRNfile for the time period 1999–2009. Frequency of multiple births was similar in the drug-exposed and reference group, and was not adjusted for. Explorative analyses The choice of covariates in the regression model was based on a priori considerations. Post hoc, the effect of the included covariates was evaluated by comparing crude ORs to adjusted ORs. Stratified analysis with Breslow-Day homogeneity test was performed for each covariate to assess effect modification. Based on a supplementary MBRN file from 1999 to 2009, containing a more extensive variety of background variables, propensity-score matching was performed to evaluate any effects of baseline differences between the exposed and reference groups. Each child in the drug-exposed group was matched to a child in the reference group with an identical or very similar propensity score. Risk-estimates for the matched groups were then compared to the primary analysis. The predictors in the propensity score model included maternal and paternal age and educational level, child’s birth order, single mother, periconceptional folate supplementation, chronic maternal disease other than epilepsy, and maternal smoking habits. Handling of missing values Missing values for the outcome variables and covariates were generally low (\ 2 %), and were handled by listwise deletion in the analyses. The exception was smoking during
pregnancy, where information was missing for 16.5 %, due to lack of consent. Cases with missing data on smoking were coded as a separate category in the regression model.
Results Study population Exposure to antiepileptic drugs during pregnancy was recorded for 2,600 children (0.3 %), delivered by 1,989 women in 2,559 pregnancies. The majority (n = 2,086) had a mother with epilepsy. A total of 3,773 children (0.5 %) were born to women with a history of epilepsy but no antiepileptic drug treatment during pregnancy. All 771,412 unexposed children born to mothers without epilepsy formed the reference group. The most commonly used antiepileptic drugs during pregnancy were lamotrigine (n = 983), carbamazepine (n = 783), valproate (n = 410), and levetiracetam (n = 188). Other reported antiepileptic drugs were clonazepam (n = 166), oxcarbazepine (n = 97), topiramate (n = 90), phenobarbital (n = 40), gabapentin (n = 39), phenytoin (n = 37), pregabalin (n = 30), vigabatrin (n = 14), ethosuximide (n = 12), primidone (n = 6), clobazam (n = 6), and unspecified (n = 20). The majority were exposed to monotherapy (n = 2,309, 88.8 %), whereas 259 children (10.0 %) were exposed to two antiepileptic drugs and the remaining 32 (1.2 %) to three antiepileptic drugs. During the recording period, the use of antiepileptic drugs during pregnancy gradually shifted from mainly older to newer types (Supplement, eFig. 1A), especially evident for the polytherapy group (eFig. 1B). Pregnancy characteristics are presented in Table 1. Single parenting, low educational level, smoking, and earlier spontaneous abortion were moderately increased in the drug-exposed group. Periconceptional folate supplementation was two to three times as frequent in the exposed group (Table 1). Mothers with untreated epilepsy used folate supplementation similar to the reference group; 20.2 % prior to the pregnancy and 47.5 % during the first trimester. Use of antiepileptic drugs during pregnancy was identical between the four geographic health regions of Norway, whereas notification of untreated epilepsy ranged from 0.4 % to 0.7 %. Risk growth restriction Mean birth weight, length, and head circumference was lower in the drug-exposed group compared to the references (Table 2). This was most pronounced for topiramate, with a mean lesser weight of 393 grams (95 % CI 259–526 grams; p \ 0.001), mean lesser length of 2.2 cm (95 % CI
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J Neurol Table 1 Background characteristics of children exposed to antiepileptic drugs (AEDs) in utero compared to the reference group Characteristics
Reference n = 771,412
AED exposure in total n = 2,600
%
% (no.)a
Maternal age [37 years
AED exposure maternal epilepsy n = 2,086
p value
OR (95 % CI)
% (no.)a
p value
OR (95 % CI)
6.4
6.4 (167)
0.97
1.00 (0.86–1.17)
6.2 (130)
0.74
0.97 (0.81–1.16)
Nulliparous mother
41.4
45.4 (1,180)
\0.001
1.18 (1.09–1.27)
44.4 (927)
0.005
1.13 (1.04–1.23)
Single mother Lower education motherb
6.8 17.4
11.5 (300) 27.1 (556)
\0.001 \0.001
1.80 (1.60–2.03) 1.77 (1.60–1.95)
9.3 (193) 26.0 (441)
\0.001 \0.001
1.41 (1.21–1.63) 1.68 (1.50–1.87)
Lower education fatherb
18.3
23.1 (462)
\0.001
1.35 (1.21–1.50)
22.2 (367)
\0.001
1.28 (1.14–1.43) 1.25 (1.12–1.39)
Smoking in pregnancy
20
27.6 (634)
\0.001
1.52 (1.39–1.67)
23.8 (439)
\0.001
Folate preconceptionallyc
18.1
35.9 (934)
\0.001
2.54 (2.35–2.76)
39.1 (816)
\0.001
2.92 (2.67–3.19)
Folate during 1st trimester
45.6
73.3 (1,906)
\0.001
3.27 (3.00–3.57)
75.4 (1,573)
\0.001
3.65 (3.31–4.04)
Plural pregnancy
3.6
3.2 (82)
0.23
0.87 (0.70–1.09)
3.1 (65)
0.24
0.86 (0.67–1.10)
Previous early abortiond
20.7
23.7 (547)
\0.001
1.19 (1.08–1.31)
22.7 (417)
0.031
1.13 (1.01–1.26)
Previous late abortione
3.1
3.9 (88)
0.028
1.27 (1.03–1.57)
3.9 (70)
0.048
1.27 (1.00–1.62)
a
Numbers within different cells may not equal 100 % due to variation of missing values
b
Educational level corresponding to elementary school (10 years or less). Available 1999–2009
c
Use of folate supplementation within 1 month prior to conception Maternal previous spontaneous abortion \12th pregnancy week
d e
Maternal previous spontaneous abortion pregnancy weeks 12–23
Table 2 Risk of growth restriction in children exposed to antiepileptic drugs (AEDs) in utero compared to the reference group Neonatal outcome
Reference n = 771,412
AED exposure in total n = 2,600
AED exposure maternal epilepsy n = 2,086
Mean
Mean
Mean diff. (CI)a
p value
Mean
Mean diff. (CI)a
p value
Birth weight (g)
3,501
3,426
75.0 (48.1–101.8)
\0.001
3,441
60.6 (32.8–88.4)
\0.001
Birth length (cm)
50.0
49.6
0.35 (0.21–0.49)
\0.001
49.6
0.31 (0.16–0.47)
\0.001
Head circumference (cm)
35.1
34.9
0.23 (0.14–0.32)
\0.001
34.9
0.22 (0.12–0.32)
\0.001
b
p value
Growth parameters
%
% (no.)
Odds ratio (CI)
b
p value
% (no.)
Odds ratio (CI)
Growth restriction Birth weight \2,500 gc
5.4
7.6 (198)
1.15 (0.94–1.41)
0.17
7.5 (157)
1.25 (1.00–1.57)
0.054
SGA birth weight \10th perc.
8.9
10.7 (278)
1.17 (1.03–1.33)
0.013
10.7 (223)
1.19 (1.03–1.36)
0.018
SGA birth weight \2.5 perc.
2.2
3.0 (77)
1.30 (1.03–1.63)
0.025
3.0 (63)
1.37 (1.06–1.76)
0.015
SGA head circ. \10th perc.
8.7
10.8 (277)
1.24 (1.09–1.40)
0.001
10.9 (225)
1.27 (1.10–1.46)
0.001
SGA head circ. \2.5 perc.
2.4
3.4 (87)
1.39 (1.12–1.72)
0.003
3.4 (70)
1.42 (1.12–1.80)
0.004
SGA small for gestational age according to percentile (perc.) a
Mean difference with 95 % confidence interval (CI), independent samples T test
b
Odds ratio with 95 % confidence interval (CI), adjusted for maternal age, parity, smoking, and chronic maternal disease other than epilepsy
c
Additional adjustment for premature delivery
1.6–2.9 cm; p \ 0.001), and a mean lesser head circumference of 1.5 cm (95 % CI 1.1–1.9 cm; p \ 0.001). The overall risk of SGA children was modestly increased in the drug-exposed group (Table 2), and substantially increased for topiramate-exposure (Fig. 1). Topiramate as monotherapy (n = 48) had a high risk of SGA head circumference (14.9 vs. 2.4 %; adjusted OR 7.21;
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95 % CI 3.23–16.1) and SGA birth weight (25.0 vs. 8.9 %; adjusted OR 3.29; 95 % CI 1.70–6.39). Children of mothers with untreated epilepsy had a slightly increased risk of SGA birth weight (10.3 vs. 8.9 %; adjusted OR 1.15; 95 % CI 1.03–1.27), but the risk of SGA head circumference was identical to the reference group.
J Neurol Fig. 1 Fetal growth restriction in children exposed to antiepileptic drugs compared to the reference group. Risk of SGA head circumference \ 2.5th percentile red filled box, and SGA birth weight \ 10th percentile black filled box. Odds ratio with 95 % confidence interval, adjusted for maternal age, parity, smoking, and chronic disease other than epilepsy
Table 3 Risk of major congenital malformation in children exposed to antiepileptic drugs in utero compared to the reference group Exposed groupsb,c,d
Antiepileptic drug monotherapy n = 2,309 % (no./total)
References (n = 771,412) All antiepileptic drugs
Antiepileptic drug polytherapy n = 291
OR (95 % CI)a
p value
1.27 (1.02–1.59)
0.036
2.9 3.4 (79/2,309)
% (no./total)
OR (95 % CI)a
p value
1.29 (0.68–2.42)
0.43
2.9 3.4 (10/291)
Valproate sodium
6.3 (21/333)
2.47 (1.58–3.84)
\0.001
5.2 (4/77)
2.03 (0.74–5.56)
0.17
Carbamazepine
2.9 (20/685)
1.06 (0.68–1.66)
0.79
2.0 (2/98)
0.75 (0.19–3.06)
0.69
Phenobarbital Clonazepam
7.4 (2/27) 1.8 (2/113)
2.75 (0.65–11.6) 0.65 (0.16–2.62)
0.17 0.54
7.7 (1/13) 7.5 (4/53)
2.93 (0.38–22.5) 3.11 (1.12–8.63)
0.30 0.03
Lamotrigine
3.4 (28/833)
1.26 (0.87–1.84)
0.22
2.7 (4/150)
1.02 (0.38–2.77)
0.96
Levetiracetam
1.7 (2/118)
0.63 (0.16–2.55)
0.52
2.9 (2/70)
1.08 (0.27–4.43)
0.91
Oxcarbazepine
1.8 (1/57)
0.64 (0.10–4.61)
0.66
2.5 (1/40)
0.82 (0.11–5.99)
0.85
Topiramate
4.2 (2/48)
1.66 (0.40–6,85)
0.48
7.1 (3/42)
2.62 (0.81–8.53)
0.11
a
Odds ratio with 95 % confidence interval (CI), adjusted for maternal age, parity, smoking, folate supplementation, and maternal chronic disease other than epilepsy
b c
The malformation rate was 3.3 % (1/30) for exposure to pregabalin monotherapy Monotherapy with phenytoin, vigabatrin, ethosuximide, primidone, clobazam, or gabapentin had no recoded major malformations
d
Analyses excluding the 514 drug exposed children where the mother did not have a diagnosis of epilepsy are presented in eTable 1 in the Supplement (online only)
Risk of major birth defects A total of 89 children exposed to antiepileptic drugs in utero were born with a major malformation. The malformation risk was slightly increased for antiepileptic drugs in general, and similar for monotherapy and polytherapy (Table 3). Valproate was the only monotherapy with significantly more malformations. Exposure to topiramate or phenobarbital was associated with a higher, but not significantly increased, malformation rate. Monotherapy with carbamazepine, oxcarbazepine,
clonazepam, lamotrigine, levetiracetam, and pregabalin was not associated with an increased risk. The remaining monotherapies had no recorded malformations. Older antiepileptic drugs as part of polytherapy tended to have higher malformation rates compared to polytherapy with the newer drugs (Table 3). The polytherapy group was too small to examine specific antiepileptic drug combinations. Analyses including only drug-exposed children of mothers with epilepsy showed similar risk estimates as the overall exposed group (Supplement, eTable 1).
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Risk of specific birth defects
For the 514 drug-exposed children without maternal epilepsy (97.7 % monotherapy), the malformation risk was identical to the reference group (2.9 vs. 2.9 %; adjusted OR 1.05; 95 % CI 0.63–1.76). The risk was not significantly increased for the 56 valproate-exposed children in this group (3.6 vs. 2.9 %; adjusted OR 1.28; 95 % CI 0.31–5.24). The malformation risk among women with untreated epilepsy was the same as for the reference group (2.8 vs. 2.9 %; adjusted OR 0.98; 95 % CI 0.81–1.19).
Birth defects were examined for main organ-systems, as well as for selected midline birth defects (Fig. 2a–d). Hypospadias and septal heart defects were increased in the drug-exposed group (Fig. 2a). The risk was especially high for valproate monotherapy (Fig. 2c), including septal heart defects (1.8 vs. 0.7 %; adjusted OR 2.69; 95 % CI 1.20–6.03) and hypospadias (1.2 vs. 0.2 %; adjusted OR 5.71; 95 % CI 2.13–15.3).
Fig. 2 Risk of specific birth defects in children exposed to antiepileptic drugs in utero compared to the reference group. (1) Odds ratio (OR) with 95 % confidence interval, adjusted for maternal age, parity,
smoking, periconceptional folate use, and chronic disease other than epilepsy. (2) Percentage (%) and number (no.) of specific malformation within the drug-exposed group
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Four children in the drug-exposed group had orofacial clefts; one was exposed to lamotrigine, one to carbamazepine, one to levetiracetam, and one to polytherapy. The single child with spina bifida was exposed to valproate monotherapy. There was no increased risk for any of the examined specific birth defects in children of mothers with untreated epilepsy. Three children in this group had spina bifida.
matching generally had an insignificant effect on the riskestimates in the drug-exposed group (Supplement, eTables 4–6).
Malformations in siblings
In this unselected national cohort, the risks of growth restriction and major malformations in children exposed prenatally to antiepileptic drugs were modestly increased. Topiramate was strongly associated with microcephaly and low birth weight. Exposure to carbamazepine or polytherapy also had a significant risk of fetal growth restriction. Monotherapy or polytherapy with the newer antiepileptic drugs was generally associated with a low malformation risk. The exception was topiramate, which tended to have an elevated malformation rate. Infants exposed to monotherapy with valproate had a twofold to threefold higher risk of major malformations, and a considerably higher risk of hypospadias and septal heart defects. A significant malformation risk was not observed for the small group of valproate-exposed children of mothers without epilepsy. For mothers using valproate in repeated pregnancies, birth defects in one child were associated with a high risk of birth defects in the next. Among the other older antiepileptic drugs, carbamazepine was associated with a low malformation rate, whereas phenobarbital had a higher but not significant risk.
A total of 61 malformed index-cases were identified in the exposed group. The malformation rate among their 18 siblings was increased compared to siblings of index-cases in the reference group (22.2 %, n = 4, vs. 6.7 %; unadjusted OR 3.97; 95 % CI 1.30–12.1). The increase was mainly confined to siblings of valproate-exposed indexcases, where three out of seven siblings (all valproateexposed) were born with a major malformation (42.9 % vs 6.7 %; unadjusted OR 10.4; 95 % CI 2.3–46.7). In the exposed group, 16 of the 18 siblings were exposed to the identical antiepileptic drug(s) as the index-case. Pregnancy terminations due to birth defects From 2006 to 2011, induced abortions due to malformations were performed for nine pregnancies in women with epilepsy and 1,577 pregnancies in women without epilepsy, corresponding to 0.33 and 0.43 % of all deliveries, respectively. In the epilepsy group, recorded birth defects were Down’s syndrome (n = 3), spina bifida (n = 1), Klinefelter’s syndrome (n = 1), cystic kidney (n = 1), reduction deformity (n = 1), nuchal translucency (n = 1), and multiple malformations (n = 1). None were significantly increased compared to the reference group. In contrast, data from 1999 to 2005 showed a higher frequency of late abortions due to spina bifida among women with epilepsy (five out of 14 pregnancy terminations) [1]. Explorative analyses Risk-estimates in the drug-exposed groups were only negligibly affected by adjustment (Supplement, eTables 2 and 3). In the stratified analyses, risk of major malformations in the drug exposed vs. reference group was slightly higher for pregnancies using periconceptional folate (3.7 vs. 2.6 %; unadjusted OR 1.44; 95 % CI 1.14–1.83). In the polytherapy group, the risk of microcephaly was mainly increased for children of mothers with chronic disease in addition to epilepsy (17.1 vs. 2.3 %; unadjusted OR 8.61; 95 % CI 3.57–20.8). None of the other covariates acted as significant effect-modifiers. Additional adjustment for a variety of background variables and propensity-score
Discussion Key findings
Interpretation Pregnancy-related risks of antiepileptic drugs have primarily focused on birth defects. Our results show that mothers using antiepileptic drugs also have a higher risk of SGA infants, consistent with previous data [2]. Our findings include a risk of microcephaly, with very limited previous documentation [1, 21]. Both small birth weight and microcephaly are associated with short-term and longterm morbidity [22–24]. Hence, fetal growth restriction may contribute to the neurodevelopmental effects observed with antiepileptic drugs [25]. The risk of microcephaly and low birth weight was highest for children exposed to topiramate. Anorexia and weight loss are side effects of topiramate in adults, and the drug is increasingly used to reduce obesity [26]. A previous study also reports reduced birth weight with topiramate [27]. Whether this is caused by effects on fetal metabolism, the intrauterine growth environment, or is secondary to low maternal caloric intake, is uncertain. Interestingly, valproate and levetiracetam, which have both been associated with weight gain
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in adults [28], did not lead to fetal growth restriction. Carbamazepine- or polytherapy-exposed infants also had a significant risk of adverse fetal growth, in line with previous reports [1, 21]. In the polytherapy group, this was mainly confined to women with additional non-epileptic chronic disease, indicating a multifactorial etiology. Infants of untreated mothers with epilepsy had a somewhat higher risk of low birth weight, but no signs of affected head size, suggesting that epilepsy per se may be associated with some degree of intrauterine growth restriction. In this unselected cohort, newer antiepileptic drugs such as levetiracetam, lamotrigine, oxcarbazepine, gabapentin, or pregabalin had a low risk of major birth defects, as also reported from the Danish birth registry [29]. However, topiramate tended to have an elevated malformation risk, in line with other recent reports [29, 30]. Among the older antiepileptic drugs, carbamazepine had a low overall malformation rate, but an increased risk of respiratory defects. Valproate was the only monotherapy with a significantly increased malformation rate. Specifically, the risk of hypospadias and septal heart defects was increased with valproate, as was also found in the EUROCAT study [31]. Some women are susceptible to this teratogenic effect, as we found a substantially higher malformation rate in repeated pregnancies of women using valproate, consistent with a recent study [32]. Both studies are limited by a small number of index-cases; but held together, the data clearly suggest that maternal or fetal factors contribute to valproate-induced malformations. Underlying factors may involve genetic polymorphisms, variations in drug or folic acid metabolism, placenta drug-transport, and interactions between genotype and environmental factors [33, 34]. Uncovering such vulnerability should promote patient-tailored therapy as part of pre-pregnancy planning [35]. The risk of birth defects associated with use of multiple antiepileptic drugs was lower than previously reported in MBRN [1]. Long-term monitoring indicates that this is due to an increased use of newer antiepileptic drugs parallel to a decreased use of older antiepileptic drugs as part of polytherapy. Drug combinations including the newer antiepileptic drugs may be less teratogenic, and could represent a favorable alternative to high-dose monotherapy with older antiepileptic drugs such as valproate. Indeed, we found that monotherapy with valproate was associated with a higher malformation rate than polytherapy with valproate, in line with data from the North American Antiepileptic Drug Pregnancy Registry [36]. Women using antiepileptic drugs are usually examined with early ultrasound scanning. Thus, the risk of serious malformations could potentially be underestimated due to a higher frequency of medically induced abortions. In this study, the rate of induced abortions due to birth defects was similar for women with epilepsy and controls, and
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abortions due to spina bifida were considerably lower during the later vs. earlier study period, further supporting a low teratogenic risk with many of the newer antiepileptic drugs. Study strengths and limitations This study had the major strength of a large population. All deliveries in Norway during the recording period were included, excluding selection bias. MBRN is a national registry with satisfactory diagnostic validity, including for maternal epilepsy [37–39]. Notification of maternal epilepsy and antiepileptic drug use during pregnancy is compulsory, registered at the first prenatal visit and throughout the pregnancy. The proportion of antiepileptic drugexposed pregnancies (0.3 %) was as expected, did not vary between different geographic regions, and corresponds to the prescription rate of antiepileptic drugs during pregnancy in Norway [40]. As the majority of women with a reported history of epilepsy were untreated, underreporting of antiepileptic drug treatment may be a concern. Any such misclassification should have overestimated the risks in the untreated group. However, the malformation rate for pregnancies in women with untreated epilepsy was identical to the reference group. Our previous validation study showed that untreated epilepsy during pregnancy mainly consists of women with non-active epilepsy [11]. This could reflect that pregnancy is postponed to periods with less active epilepsy, or that such women are more likely to become pregnant than women with active epilepsy. The results were generally not affected by adjustment, stratification, or propensity-score matching, suggesting that the adverse outcomes in the exposed group were not due to baseline differences. Still, unmeasured parameters might have influenced some of the observed drug-exposure associations. Unfortunately, we were not able to include information on seizures, epilepsy type, drug dose, or maternal body weight. Any protective effects of folate could not be evaluated due to probable confounding by indication. Important limitations were the small size of some of the exposed groups, and that the study may have been underpowered to detect risk of specific birth defects for each drug.
Conclusion The increased risk of microcephaly, low birth weight, and possibly birth defects in children exposed to topiramate is a major concern. If possible, topiramate should be avoided during pregnancy. Use of lamotrigine, carbamazepine, oxcarbazepine, and levetiracetam appeared to be relatively safe, but further studies are required regarding the risk of
J Neurol
specific birth defects. Valproate was the only monotherapy associated with a significant risk, especially in mothers with an earlier malformed child. The malformation rate with polytherapy was lower than previously reported, probably due to a shift towards newer antiepileptic drugs and less use of valproate. Conflicts of interest Dr Veiby has received travel support from UCB Pharma and lecture fees from GlaxoSmithKline. Dr Engelsen has received travel support from GlaxoSmithKline and lecture fees from Lundbeck. Authors Gilhus and Daltveit have no conflicts of interest.
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