In the largest study of its kind to date, researchers at Indiana University attempt to elucidate previously inconclusive literature on antiseizure drugs, autism, and ADHD.
Findings from a recent study published in Neurology reveal that the use of lamotrigine in patients with epilepsy who are pregnant does not increase the incidence of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in children; however, valproic acid was associated with a higher risk of ASD and ADHD.1
In the largest known sample to date, data were collected from 14,614 children born to women with epilepsy. Lamotrigine use (n = 996; 6.82%) was not found to be associated with an increased risk of ASD (hazard ratio [HR], 0.86; 95% CI, 0.88–1.79) or ADHD (HR, 1.01; 95% CI, 0.91–1.52), while carbamazepine use (n = 1417; 9.7%) showed a weak association with ASD risk (HR, 1.26; 95% CI, 0.88–1.79) and no statistically significant association with ADHD risk (HR, 1.18; 95% CI, 0.91–1.52).1
Principal investigator Kelsey Wiggs, BA, BS, a PhD candidate in clinical psychology at Indiana University, told NeurologyLive, “Our findings add to a growing body of evidence that has documented the relative safety of lamotrigine...it seems to be a great alternative to valproic acid, as it is also effective in treating generalized seizures.”
Children whose mothers used any ASM (n = 3316) were found to have an elevated risk of ASD (HR, 1.79; 95% CI, 1.39–2.30) and ADHD (HR, 1.27; 95% CI, 1.06–1.52). These data were largely unaffected by confounding factors. After adjusting for monotherapy, valproic acid (n = 699; 4.78%) use showed the strongest associations, with a 2.3-fold elevated risk of ASD (95% CI, 1.82–3.89) and a 1.7-fold elevated risk of ADHD (95% CI, 1.28–2.38) compared with children whose mothers reported no use of ASMs.
“Valproic acid is the first-line treatment for managing generalized seizures. Thus, these women are in a particular bind when it comes to trying to ensure safety for themselves and their unborn children, as having seizures also put both the pregnant woman and unborn child at risk,” Wiggs said. Despite its risks, taking another medication “may not be an option for all women.”
Altogether, children born to women in this study who did or did not use ASMs had a higher overall incidence of ASD (n = 7846; 0.89%) and ADHD (n = 16,478; 2.14%) than the general population, reflecting an association between epilepsy and ASD/ADHD that is beginning to be explored, but with a yet-unknown mechanism.
Wiggs and colleagues were unable to investigate the impact of ASM dose or medication switch on associations. While they analyzed the effects of monotherapy, the effects of ASM polytherapy itself were not studied. Sensitivity analyses supported the data of the primary analysis, despite confounding factors. Notably, the investigators stopped following the children after tallying the incidence of ASD and ADHD at age 10, so long-term effects were not observed.
Associations between ASMs, birth defects, ASD, and ADHD have been studied before, but with marked smaller sample sizes.2 Wiggs and colleagues adjusted for many covariates that other studies had not taken into account, such as maternal and paternal psychiatric disorders and epilepsy.
Wiggs told NeurologyLive that she would like to see more extensive research on the effects of ASMs during pregnancy, such as the long-term effects on children, associations with ASMs, ASD, ADHD, and birth defects, and on the risks and benefits of newer ASMs like levetiracetam.
Managing epilepsy during pregnancy can be a daunting task for many. Sanjeev V. Thomas, MD, DM, chief of neurology at Sree Chitra Tirunal Institute for Medical Sciences and Technology, discussed his strategies with NeurologyLive at the 2019 International Epilepsy Congress.3 He noted that despite serious concerns, research suggests that almost 90% of women with epilepsy who are pregnant will have no complications and will deliver healthy babies. “Proper preparation and planning of pregnancy ahead and making the treatment safer for the mother and the child will be the most important thing,” he said.