Similar to our findings in children aged 3 years and 4·5 years,3,16
children with fetal exposure to valproate had reduced IQ (7–10 points) at 6 years compared with other commonly used antiepileptic drugs (ie, carbamazepine, lamotrigine, and phenytoin). Valproate exposure was also associated with worse verbal and memory abilities compared with the other antiepileptic drugs, and worsened non-verbal and executive functions compared with lamotrigine. Teratogens act in a dose-dependent manner and according to genetic susceptibility. An increased valproate dose was associated with reduced IQ, verbal, non-verbal, memory, and executive function, but other antiepileptic drugs had no dose effects. Thus, fetal exposure to valproate is associated with a range of cognitive deficits.
Outcomes in children exposed to low-dose valproate (<1000 mg per day) did not differ from those in children exposed to the other low or high dose antiepileptic drugs; however, sample sizes might have restricted delineation of differences. For example, low-dose valproate (<700 mg per day) had an increased risk for major malformation compared with low-dose lamotrigine (<300 mg per day).17
Studies in animals suggest that apoptotic effects of valproate on the immature brain begin below typical therapeutic doses.18
Thus, a safe dose of valproate is unknown.
One limitation of this study was the number of participants lost to follow-up. However, cognitive testing was available for at least one age in 279 (90%) of 311 children. Because age-6 IQ is correlated strongly to earlier cognitive outcomes, these data help compensate for children lost to follow-up. The relation of earlier outcomes to age-6 IQ might allow for early detection and intervention.
IQ scores improved with age. Practice effects might have contributed to this improvement, and improvements might also be related to intervention programmes. Families were provided results at each test age and assisted in referral to intervention programmes if indicated. Another limitation was that data for intervention programme enrolment were not collected systematically. The effects of practice and intervention programmes might have reduced the apparent effects of fetal exposure to antiepileptic drugs. The absence of a healthy control group was a further limitation. However, the 7–10 IQ point reduction for valproate compared with other antiepileptic drugs is clinically significant even if the mean valproate IQ was in the normal range.
Verbal and non-verbal indexes were reported as standard scores, so they should be equivalent in the absence of selective effects. However, verbal scores were lower than non-verbal scores for lamotrigine and valproate. Practice effects might differentially affect verbal versus non-verbal scores, but this explanation seems unlikely in view of the small practice effects for DAS verbal and non-verbal cluster scores.6
Furthermore, the difference was present on the first exposure to DAS at 3 years of age, and the difference decreased from 3–6 years of age with repeated testing. This finding is also consistent with other studies that have reported verbal impairments associated with fetal valproate exposure19–21
and impaired language in children with fetal antiepileptic drug exposure.22
Typical functional brain asymmetries include left cerebral dominance for language and handedness. The development of these asymmetries can be changed by environmental factors during early neural development.23
Atypical lateralisation is increased in various developmental disorders including fetal alcohol syndrome.23
The relatively lower verbal versus non-verbal performances and the reduced frequency of right-handedness in the lamotrigine and valproate groups suggest that fetal exposure to some antiepileptic drugs might affect normal cerebral lateralisation. However, our study was limited because we did not assess family handedness or directly measure brain lateralisation.
Other factors related to child IQ in our study include higher maternal IQ and older gestational age. However, maternal IQ was not related to child IQ for the valproate group, although it was for each of the other antiepileptic drug groups, suggesting valproate exposure disrupts this otherwise strong association.
Maternal periconceptional folate was associated with higher age-6 IQ. This finding should be interpreted with caution because periconceptional folate was one of several confounding variables, and was established by retrospective maternal interview. The US Public Health Service and Center for Disease Control and Prevention recommend that all women of childbearing age consume 0·4 mg folate daily to prevent birth defects (ie, spina bifida).24
Folate is important for normal fetal development, and severe deficiency or inborn errors of folate metabolism can result in mental retardation.25
Folate deficiency can lead to fetal neuronal apoptosis and reduced neuronal progenitor cells.26
A study of maternal folate status later in pregnancy and one older periconceptional folate study found no relation with cognitive outcome, but seven recent studies have reported positive associations of periconceptional folate with neurodevelopmental outcomes (appendix
Thus, our finding adds to the evidence that periconceptional folate might have beneficial effects on cognitive development.
Strengths of this study are our prospective design, use of masked cognitive assessments with standardised measures, and detailed monitoring of multiple potential confounding factors. Limitations are its relatively small non-population-based sample, loss to follow-up, non-randomisation, inadequate pharmacokinetics, and no unexposed controls. Detection of dose effects for non-valproate antiepileptic drugs might require larger sample sizes as noted for malformations associated with carbamazepine, lamotrigine, and phenobarbital.17
Antiepileptic drug clearance is variable during pregnancy;29
future studies should measure antiepileptic drug levels to better assess intrauterine exposure. Randomised pregnancy trials of antiepileptic drugs are not possible, and observational studies might be confounded by differences in baseline characteristics (eg, maternal IQ, dose, ethnic group, or epilepsy type). Our analyses suggest that these baseline group differences do not explain our findings, but some residual confounding effects are possible. Thus, observational studies require replication.
Most women with epilepsy cannot avoid use of antiepileptic drugs during pregnancy because of the risks from seizures to both mother and child. Based on anatomical and cognitive risks,2,3
we propose that valproate is a poor first-choice antiepileptic drug for most women of childbearing potential. However, a few women with generalised epilepsy can only be controlled by valproate.
Many gaps exist in our knowledge about epilepsy care during preconception and pregnancy.2
The mechanisms underlying observed deficits are uncertain, but antiepileptic drugs might affect fetal neurodevelopment via neuronal apoptosis induced by antiepileptic drugs, reduced neurotrophin expression, decreased neuronal survival-promoting proteins, reduced neurogenesis, or impaired physiology in remaining neurons.18
Many antiepileptic drugs are untested in animal models and have not been assessed in clinical cohorts. Additional research is needed to confirm our findings and to improve our knowledge for care in this population. In conclusion, we noted that fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Women requiring an antiepileptic drug and their clinicians should be aware of these findings in choosing their treatment (panel).