Antiseizure medications in pregnancy tied to child neurodevelopment risks

Study links antiseizure medications in pregnancy to higher risks of autism, ADHD, and intellectual disability in children, highlighting the need for careful treatment planning before conception.

In a recent study published in Nature Communications, researchers investigate how ASM use during pregnancy may increase the risk of neuropsychological conditions in children born from these mothers.

Are ASMs safe during pregnancy?

ASMs are crucial to managing epileptic seizures and mood disorders among psychiatric patients. However, valproate is contraindicated during the antenatal period due to its effects on intellectual development, which have been reported in several previous studies, including the Neurodevelopmental Effects of Antiepileptic Drugs study.

Moreover, the Nordic study provoked concerns about the use of other ASMs like topiramate during pregnancy. However, these studies produced conflicting evidence with small study sizes and limited follow-up periods, thus necessitating additional studies to elucidate the risks of these medications during the antenatal period.

Study findings

Neurological conditions in ASM-exposed children

The current longitudinal epidemiological study obtained data from the United Kingdom and national Swedish registries to create a diverse cohort of 3,182,773 children.

Of these children, 17,495 children were ASM-exposed. Among the exposed group, 78,442 children were autistic, whereas 26,787 and 155,329 children had intellectual disability and attention deficit hyperactivity disorder (ADHD), respectively.

ASM-exposed mothers had a higher number of healthcare visits, were more likely to also be prescribed antidepressants and anti-psychotics, were at a greater risk of neurodevelopmental disorders, and were more likely to have given birth in recent years.

At 12 years of age, the children of unexposed mothers had a 3% risk of autism, 0.9% risk of intellectual disability, and 2.5% risk of ADHD, respectively.

Exposure-outcome associations

Considering different types of ASM for each outcome, the greatest risk of all three outcomes was with valproate monotherapy. More specifically, the risk of autism was 4.85%, followed by 4.3% for ASM polytherapy that included valproate. Gabapentin monotherapy was associated with a 3.67% risk of autism.

Thus, the risk of autism was 78% higher with valproate monotherapy, 50% higher with polytherapy, and 25% higher with carbamazepine as compared to unexposed children.

For ADHD, valproate and phenytoin monotherapy were associated with a 6.3% risk as compared to 5.9% with polytherapy. The risk of ADHD was increased by 20% with valproate monotherapy, whereas pregabalin reduced the risk by 33%.

These findings confirm that valproate use during pregnancy was associated with a higher risk of autism, intellectual disability, and ADHD in children as compared to non-exposed children.

Topiramate exposure was associated with a 2.5-fold increased risk of intellectual disability, whereas the risk of autism and intellectual disability was increased by 25% and 30% in children exposed antenatally to carbamazepine, respectively.

The absolute risk for each of these conditions increases with the use of topiramate, carbamazepine, and valproate from 0.3% to 2.1 more cases for every 100 children exposed antenatally by age 12.

Other ASMs vs. lamotrigine

Lamotrigine use during pregnancy was not likely to increase the risk of neurodevelopmental disability. As compared to lamotrigine, ASMs like carbamazepine, valproate, other ASMs, and polytherapy increased the risk of autism.

Intellectual disability risk was higher with topiramate, valproate, and polytherapy as compared to lamotrigine, whereas ADHD was more likely among children on valproate and polytherapy.

Sibling analyses

Siblings were analyzed for the same outcomes to compensate for unknown or unmeasured confounding resulting from common genetic or environmental factors.

Phenytoin was associated with an 11.5- and 9.48-fold risk for autism and ADHD, respectively. However, these findings were based on observations in a small sample of exposed children.

Analysis by ASM indication

Children of mothers with epilepsy, mental illness, or somatic conditions were at an increased risk of autism, intellectual disability, and ADHD as compared to the risk in the whole sample, independent of ASM use. However, these results should be carefully interpreted, as they may be biased due to unmeasured confounding factors.

Conclusions

The study findings indicate a higher risk of neurodevelopmental outcomes in children born to mothers using valproate, topiramate, carbamazepine, and ASM polytherapy during pregnancy.

The teratogenic risk associated with ASM polytherapy is likely attributed to the effects of valproate and carbamazepine in most of these combinations, as well as the probably increased severity of the medical condition in these mothers. The total effect estimate might vary if all exposed pregnancies were included rather than only those ending in live births.

Journal reference:

• Madley-Dowd, P., Ahlqvist, V. H., Forbes, H., et al. (2024). Antiseizure medication use during pregnancy and children’s neurodevelopmental outcomes. Nature Communications. doi:10.1038/s41467-024-53813-1.