Women with epilepsy who take the anti-seizure medication valproic acid while pregnant are at more than double the risk of having children with autism spectrum disorder and nearly twice the risk of their children having attention deficit hyperactivity disorder (ADHD), according to a new study by Indiana University researchers. Other anti-seizure drugs, carbamazepine and lamotrigine, by contrast, showed no increased risk for autism or ADHD.
“The findings add to a growing body of evidence that suggests the relative safety of some seizure drugs over others,” said lead author Kelsey Wiggs, a graduate student in the IU Department of Psychological and Brain Sciences. “A first-line treatment for generalized epilepsy, valproic acid has been strongly discouraged for women of childbearing age because of associations with birth defects in children, an outcome that has, for the most part, not been linked with the use of lamotrigine.”
The study is published in Neurology, the medical journal of the American Academy of Neurology.
As Wiggs explained it, pregnant women with epilepsy are caught in an excruciating double bind. “Medication is the only way to manage the seizures that put both the woman and her unborn child at risk. And yet, the most effective seizure medication is also linked to a growing number of harmful outcomes for the child,” she said. “Unlike pregnant women with some mental health conditions, who may be able to manage their symptoms with behavioral therapy, those with epilepsy have no clear alternative.”
Studying the use of the three medications, the researchers looked at 14,614 children born to women with epilepsy between 1996 and 2011. About 23 percent of those women reported using a seizure medication in their first trimester. As the three most used drugs during pregnancy, carbamazepine was taken by 10 percent of the women, lamotrigine by 7 percent of the women, and valproic acid by 5 percent of the women.
Using medical records, they identified which children were later diagnosed with autism or ADHD.
Of the children exposed to valproic acid, 36 out of 699 developed autism by the age of 10, compared to 154 out 11,298 who were not exposed to any anti-seizure medication. A total of 54 out of 699 taking valproic acid developed ADHD by the age of 10, compared to 251 out of 11,298 who were not exposed.
Women who reported using valproic acid during the first trimester had a 2.3 times greater risk of having children diagnosed with autism and a 1.7 times greater risk of children diagnosed with ADHD than women who reported using no anti-seizure medications.
Though a causal link between valproic acid and a heightened risk for autism and ADHD is possible, researchers could not rule out other possible explanations for the link. For instance, the severity of the mother’s epilepsy may yet have an effect on the child’s development, as could the presence of bipolar disorder which the drug also treats. The study controlled for these two possibilities, yet some chance of their impact persists. A possible genetic overlap between epilepsy, autism and ADHD, could also explain the increase in the two neurodevelopmental disorders.
Yet despite the adverse outcomes with the use of one drug, the findings held out hope in another medication lamotrigine which researchers say not only has the same uses as valproic acid, it’s also (unlike carbamazepine) a first line of treatment, so it's a really good alternative option.
“Our study expands upon prior work on birth outcomes by demonstrating a link between valproic acid and longer-term problems,” said Brian D’Onofrio, principal investigator of the study and a professor in the Department of Psychological and Brain Sciences. “Our findings suggest that women who use anti-seizure medications, particularly valproic acid, should weigh potential fetal insult, as well as ongoing seizure management, into their decision-making with their doctors if they are considering becoming pregnant.”
In addition to Wiggs and D’Onofrio, the study’s other researchers include research scientist Martin Rickert and graduate student Ayesha Sujan in the IU Department of Psychological and Brain Sciences; IU School of Public Health professor Patrick Quinn; Henrik Larsson, Paul Lichtenstein and Sara Oberg, who are faculty at the Karolinska Institute.
This study was supported by the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the National Institute on Drug Abuse of the National Institutes of Health, the Swedish Initiative for Research on Microdata in the Social and Medical Sciences and the Swedish Research Council for Health, Working Life and Welfare.