Anatomical and Behavioral Effects of in Utero Exposure to Antiepileptic Drugs
Authors: Meador Kimford 
Published: November 2005

Increased Rate of Major Malformations in Offspring Exposed to Valproate during Pregnancy

Wyszynski DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB, Antiepileptic Drug Pregnancy Registry

Neurology 2005;64:961–965

Purpose

To determine the rate of occurrence of major malformations in infants whose mothers had taken the drug valproic acid (VPA) as monotherapy during the first trimester of pregnancy and had enrolled in the North American Antiepileptic Drug Pregnancy Registry.

Methods

Data were collected from pregnant women throughout the United States and Canada through telephone-based interviews. Each woman was interviewed at enrollment, at 7 months’ gestation, and postpartum. With her written permission, the medical records of each mother and her infant were obtained. The major malformations tabulated were those identified at or before age 5 days. The prevalence of congenital malformations among offspring of monotherapy VPA-exposed women was compared with that among infants of women exposed to all other antiepileptic drugs (internal comparison group) and with that among newborns in the Active Malformations Surveillance Program at Brigham and Women's Hospital (external comparison group).

Results

Sixteen affected cases were identified among 149 VPA-exposed women (proportion: 10.7%; 95% CI: 6.3 to 16.9%). The prevalence in the internal comparison group was 2.9% (95% CI: 2.0 to 4.1%; odds ratio: 4.0; 95% CI: 2.1 to 7.4; P < 0.001). Assuming a 1.62% prevalence in the external comparison group, the relative risk of having an affected offspring for VPA-exposed women was 7.3 (95% CI: 4.4 to 12.2; P < 0.001).

Conclusions

Maternal exposure to VPA during the first trimester of pregnancy significantly increased the risk of major malformations. Lamotrigine and the Risk of Malformations in Pregnancy Cunnington M, Tennis P; International Lamotrigine Pregnancy Registry Scientific Advisory Committee Neurology 2005;64(6):955–960

Purpose

To report the frequency of major malformations in lamotrigine (LTG)-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry.

Methods

Health care professionals throughout the world can voluntarily enroll LTG-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects.

Results

Among 414 first-trimester exposures to LTG monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6 to 5.1%). Among the 88 first-trimester exposures to LTG polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7 to 21.7%). Among 182 first-trimester exposures to LTG polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0 to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to LTG monotherapy or polytherapy.

Conclusions

The risk of all major birth defects after first-trimester exposure to LTG monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3 to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects. Critical Relationship between Sodium Valproate Dose and Human Teratogenicity: Results of the Australian Register of Anti-Epileptic Drugs in Pregnancy Vajda FJ, O'Brien TJ, Hitchcock A, Graham J, Cook M, Lander C, Eadie MJ J Clin Neurosci 2004;11:854–858

Purpose

To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different antiepileptic drugs (AEDs) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study.

Methods

A voluntary, Australia-wide, telephone-interview–based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; and taking AEDs for a nonepilepsy indication. Four hundred fifty eligible women were enrolled over a 40-month period. Three hundred ninety-six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes.

Results

The 354 (87.8%) pregnancy outcomes resulted in a healthy live birth; 26 (6.5%) had an FM; 4 (1%), a death in utero; 1 (0.2%), a premature labour with stillbirth; 14 (3.5%), a spontaneous abortion; and 4, lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (16.0%) compared with those exposed to all other AEDs (16.0 vs. 2.4%; P < 0.01) or no AEDs (16.0% vs.3.1%; P < 0.01). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (1975 vs. 1128 mg, P < 0.01). The incidence of FM with VPA doses ≥1100 mg was 30.2% versus 3.2% with doses <1100 mg ( P < 0.01).

Conclusions

A dose–effect relation occurs for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy. Neuropsychological Effects of Exposure to Anticonvulsant Medication In Utero Vinten J, Adab N, Kini U, Gorry J, Gregg J, Baker GA; Liverpool and Manchester Neurodevelopment Study Group Neurology 2005;64:949–954

Purpose

To investigate the long-term differential drug effects on cognitive functioning in school-aged children exposed to antiepileptic drugs (AEDs) in utero.

Methods

Mothers with epilepsy were recruited from specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region. The mothers and their children were recruited without prior knowledge of their AED treatment during pregnancy or the health of the offspring. A battery of neuropsychological tests was applied to each mother–child pair to obtain a neuropsychological profile for each child.

Results

Neuropsychological investigation was performed on 249 children between the ages of 6 and 16 years. Children exposed to sodium valproate had a significantly lower verbal IQ when compared with children exposed to other AEDs or not exposed at all. The same children were more likely to have an IQ below 69 and more likely to have memory impairment when compared with the other groups. The mothers’ IQs, exposure to sodium valproate, and the number of tonic–clonic seizures during pregnancy were significant predictors of verbal IQ in this population.

Conclusions

This retrospective study highlights the potential harmful effects of sodium valproate exposure in utero on neuropsychological development.