Birth outcomes after prenatal exposure to antiepileptic drugs—A population‐based study

Kilic, Demet; Pedersen, Henrik; Kjaersgaard, Maiken Ina Siegismund; Parner, Erik Thorlund; Vestergaard, Mogens; Sørensen, Merete Juul; Olsen, Jørn; Bech, Bodil Hammer; Christensen, Jakob; Pedersen, Lars

doi:10.1111/epi.12758

Cited by 61 publications

(77 citation statements)

References 23 publications

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“…When studied as a single group, infants with intrauterine growth restriction, irrespective of cause, have increased mortality and morbidity [10]. The differences in ponderal index, birth weight and SGA in this study were mostly small, but significant and in line with other studies [2,6,7]. However, to evaluate whether growth restrictions in infants of mothers with epilepsy are associated with later morbidity or neurocognitive deficiencies, more studies with extensive follow up are required.…”

Section: Discussionsupporting

confidence: 79%

“…the indication for treatment, and this is unfortunately where registers with un-validated epilepsy diagnoses may fall short. Another factor in intra uterine growth is the maternal weight before and during pregnancy, a factor that has not been controlled for in recent studies [2,7]. An estimation of gestational age depends upon provision of a reliable date of last menstruation.…”

mentioning

confidence: 99%

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Intrauterine growth retardation in foetuses of women with epilepsy

Farmen

Grundt

Tomson

et al. 2015

Seizure

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Impaired intrauterine growth of foetuses in women with epilepsy was identified. The frequency of SGA and low ponderal index was highest in Lamotrigine exposed infants. The epilepsy group had a higher risk profile for having smaller babies, in being younger at age, lower in body weight and more frequent smokers. However despite these differences, the effects of epilepsy and AED exposure were significant. The ponderal index may be a useful supplement to more established measures assessing intrauterine growth in epilepsy.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Intrauterine growth retardation in foetuses of women with epilepsy

Farmen

Grundt

Tomson

et al. 2015

Seizure

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“…Antiepileptic drugs are previously reported as risk factors for intrauterine growth retardation . It could be argued that low birth weight might be a confounding factor for acute CS in this study as it is a factor that is also associated with breech presentation and breech presentation is associated with acute CS.…”

Section: Discussionmentioning

confidence: 71%

Increased rate of acute caesarean sections in women with epilepsy: results from the Oppland Perinatal Database in Norway

Farmen

Grundt

Nakling

et al. 2018

Euro J of Neurology

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Background and purpose Studies in women with epilepsy ( WWE ) regarding pregnancy and labour complications have disclosed contradictory results. Our purpose was to investigate whether WWE have a higher risk of acute caesarean section ( CS ) or pregnancy complications than women without epilepsy or women with other chronic diseases and, if we found a higher risk, to explore potential explanations. Methods The study used prospectively registered obstetric data from the Oppland Perinatal Database in the period 2001–2011, containing information on 18 244 births, including 110 singleton pregnancies in mothers with validated epilepsy. Data regarding epilepsy were collected retrospectively from medical records. Results Epilepsy was a significant risk factor for acute CS , breech presentation and low birth weight in offspring [odds ratio ( OR), 1.93, 95% confidence interval (CI), 1.2–3.1; OR, 2.29, 95% CI, 1.2–4.6 and OR, 2.10, 95% CI, 1.0–4.2, respectively]. In multivariate logistic regression analysis, antiepileptic drug exposure was an independent risk factor for acute CS ( OR, 2.00; 95% CI, 1.06–3.77) and polytherapy was a significant risk factor for breech presentation ( OR, 5.37; 95% CI, 1.13–25.57). Seizure frequency during pregnancy had no influence on the complication rate. Conclusions We found that WWE using antiepileptic drugs during pregnancy had increased rates of acute CS , breech presentation and low birth weight, and that seizure frequency during pregnancy did not influence the complication rate.

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“…One study identified in our literature search reported that the relative risk for the association between levetiracetam versus lamotrigine monotherapy and SGA was 1.3 (1.0 to 1.7 ) [16], which compares with the OR in our study for monotherapy or polytherapy combined: 1.3 (0.5 to 3.0). Comparisons with women unexposed to AEDs were less clear: one study reported that levetiracetam exposure was associated with shorter pregnancies and lighter infants [14], one reported lighter infants but practically null effects on duration of pregnancy and head circumference [20], and one reported protective effects for SGA and microcephaly [24]. The pooled risk for congenital malformations in subjects exposed to levetiracetam has been reported as similar to that for the unexposed, although some individual studies reported increased risk [4].…”

Section: Levetiracetammentioning

confidence: 99%

Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth

Margulis

Hernández–Dı́az

McElrath

et al. 2019

Preprint

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38 Background: The associations of individual antiepileptic drugs (AEDs) with pregnancy duration 39 and size at birth, and potential dose relations, are not well characterized.40 Methods: This cohort study used nationwide Swedish register data (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013). Adjusting for 41 smoking, epilepsy and other AED indications, we used linear and quantile regression to explore 42 associations with pregnancy duration, and birth weight, length, and head circumference (the last 43 three operationalized as z-scores). We used logistic regression for preterm delivery, small for 44 gestational age, and microcephaly. Lamotrigine was the reference drug.45 Results: 6,720 infants were exposed to AEDs in utero; AED exposure increased over the study 46 period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on 47 average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard 48 deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs 49 smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-50 1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference. 51 Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 52 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and were 0.1 SDs smaller (-0.1 [-0.3 to 0.1]) in head 53 circumference. Valproic acid-exposed infants had, on average, the same duration of gestation 54 and birth weight z-score, but were 0.2 SDs smaller (-0.2 [-0.2 to -0.1]) in head circumference. 55 More negative associations at the left tail of pregnancy duration and birth weight z-score, effect-56 measure modification, and dose-response relations were noted for some of the associations.57 Observed associations were generally of smaller magnitude than that of smoking, assessed as a 58 potential confounder in the same models. 4 59 Conclusions: In comparison with lamotrigine, valproic acid and carbamazepine had a more 60 negative association with head circumference than other study AEDs. 5 INTRODUCTION63 Epilepsy and antiepileptic drugs (AEDs) have been associated with adverse pregnancy, fetal, and 64 neonatal outcomes [1]. AEDs differ in their risk for congenital malformations [2][3][4], and some 65 associations have been found to be dose dependent [4][5][6]. Newer AEDs are generally considered 66 safer than the older drugs, with the possible exception of topiramate [7]. Antiepileptic drugs also 67 differ in the magnitude of their associations with adverse neurodevelopmental outcomes in the 68 offspring, which also appear to be dose dependent [8][9][10]. The exploration of indication and dose 69 is important because confounding by indication has been a concern and AED doses are often 70 higher in epilepsy than in other conditions [11]. 71 A meta-analysis has shown elevated point estimates for the association of AEDs...

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Birth outcomes after prenatal exposure to antiepileptic drugs—A population‐based study

Cited by 61 publications

References 23 publications

Intrauterine growth retardation in foetuses of women with epilepsy

Intrauterine growth retardation in foetuses of women with epilepsy

Increased rate of acute caesarean sections in women with epilepsy: results from the Oppland Perinatal Database in Norway

Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth

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