Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy

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 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.

Pregabalin use early in pregnancy and the risk of major congenital malformations

“…Another study had previously reported 1 malformation in 30 infants prenatally exposed to pregabalin monotherapy, a risk no different from their reference. 8 Our study included 477 pregabalinexposed women, of whom 353 were on monotherapy, and was replicated in 174 pregabalin-exposed women in MarketScan (118 on monotherapy). The CIs around the main effect estimates from the 4 studies largely overlap (figure e-2), and the accumulated evidence results in a null RR, which suggests that the posited increase in risk is likely explained by chance in the setting of a small sample size.…”

Oxcarbazepine-loaded polymeric nanoparticles: development and permeability studies across in vitro models of the blood–brain barrier and human placental trophoblast

“…[3][4][5][6][7] In a review of the Medical Birth Registry of Norway from 1999 to 2011, the odds ratio for major congenital malformations in children exposed to any AED in utero was 1.27 (95% confidence interval: 1.02-1.59). 8 Epileptic therapy during pregnancy, therefore, requires balance between the benefits to pregnant women and the associated risks of AEDs upon the developing fetus.…”

Journal Club: Pregnancy outcome following maternal exposure to pregabalin may call for concern

“…2,3 Although human data are scarce, pregabalin is a Category C drug: risks cannot be ruled out, but potential benefits may justify the risks of pregabalin during pregnancy. Suggested teratogenic mechanisms include reproductive toxicity, skeletal malformation, neural deficits, spontaneous abortions, growth retardation, and behavioral abnormalities.…”