Exposure to antiepileptic drugs in utero and child development: A prospective population‐based study

Abstract

Summary Purpose Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an impact on early child development. Methods From mid-year 1999 through December 2008, children of mothers recruited at 13–17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 –children), and mothers reported on their child’s motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months of age (44,147 children). The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate-supplementation, and child congenital malformation or low birth weight. Key findings A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1 % vs. 2.9 %; OR, 2.0; 95 % Confidence Interval [CI], 1.1–3.7) and autistic traits (3.5 % vs. 0.9 %; OR, 2.7; CI, 1.1–6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5 % vs. 3.3 %; OR, 2.2; CI, 1.1–4.2), sentence skills (11.2 % vs. 4.8 %; OR, 2.1; CI, 1.2–3.6), and autistic traits (6.0 % vs. 1.5 %; OR, 3.4; CI, 1.6–7.0). The drug-exposed children also had increased risk of congenital malformations (6.1 % vs. 2.9 %; OR, 2.1; CI, 1.4–3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range. Significance Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy

“…They found significantly elevated rates in children exposed to monotherapy (5.6%) but not polytherapy, and this reflected a particular increase in children exposed to lamotrigine (9%) but not valproate or carbamazepine. 13 The lack of dose information in the latter study prevents further interrogation of the pattern of results for valproate, which differs from previous studies.…”

“…The different rates of elevated CARS scores across the AED exposure groups in our study suggest that maternal epilepsy per se does not account for autism traits in their offspring, and recent data from women with epilepsy who did not take AEDs during pregnancy found no evidence for elevated autism risk. 13 Genetic factors may mediate the association between valproate exposure and poor neurodevelopmental outcome, and this may be dose-dependent; additional studies are required to clarify this.…”

IQ at 6 years after in utero exposure to antiepileptic drugs

“…1 Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, [2][3][4] retrospective studies, 5,6 and prospective studies. [7][8][9][10][11][12][13][14][15] Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.…”

Medication safety in pregnancy – Results from the MoBa study

“…At three years of age, the exposed children had increased risk of gross motor delay (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), poor sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). Confounding by the underlying epileptic illness could not explain the findings as children born to women with epilepsy who did not use antiepileptic drugs had no increased risks and children of fathers with epilepsy generally scored within the normal range (34). In the second study, the impact of breast feeding, while using antiepileptics, on infant neurodevelopment was specifically assessed, but no harmful effects of breastfeeding was detected (35).…”

“…MoBa data have been used in three other studies to assessed long-term neurodevelopmental outcomes after exposure to antidepressants (33) and antiepileptics, respectively (34,35). In the first study, one of the most important findings was the association between longterm in utero exposure to SSRI-antidepressants (n=161) and language delay at three years of age (adjusted relative risk ratios 2.30, 95% CI 1.21-4.37).…”