Exposure to Valproate in Utero May Increase Risk of Autism, ADHD

iStock/Mohammed Haneefa Nizamudeen

Using the treasure trove that is national Swedish health data, researchers have found more evidence that the anticonvulsant valproate poses risks if taken during pregnancy.

Valproate, which is used to treat epilepsy, migraines, and bipolar disorder, has previously been linked to neural tube birth defects. This new analysis found that children exposed to valproate in the womb had an elevated risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) compared with those who were not exposed to the medication in the womb.

The research, conducted by a team at Indiana University along with colleagues at Sweden’s Karolinska Institutet, used Swedish birth and medical registers to identify 14,614 children born between 1996 and 2011 to mothers with epilepsy. About 23% of the mothers used an anticonvulsant during the first trimester of pregnancy, with carbamazepine (9.7%), lamotrigine (6.8%), and valproate (4.8%) being the three most commonly prescribed medications.

After factoring in numerous variables that also contribute to ASD or ADHD risk—including demographic characteristics, other medications used by the mothers, parental psychiatric history, and seizure severity—the investigators found that children who were exposed to valproate in the womb were 2.3 times as likely to be diagnosed with ASD and 1.74 times as likely to be diagnosed with ADHD as children who were not exposed to anticonvulsants. They also identified a small risk of ASD for carbamazepine exposure, but only in mothers who took this medication in combination with another anticonvulsant. There were no observable ASD or ADHD risks to children exposed to lamotrigine in the womb.

Lead author Kelsey Wiggs, a Ph.D. student at Indiana University’s Developmental Psychopathology Lab, told Psychiatric News that these findings provide some of the strongest evidence to date that valproate may cause neurodevelopmental problems, given the large sample size and robust efforts to adjust for external variables. “[W]e cannot be definite about causality, because we could not adjust for every possible influence,” such as genetic factors, she said.

“While it’s important to identify evidence of risk, we should not overlook when we find evidence of relative safety,” Wiggs continued. “And our data add to a growing body of evidence that lamotrigine is a good option for women with epilepsy who may become pregnant.”

Veerle Bergink, M.D., the director of Mount Sinai Hospital’s Women’s Mental Health Program, noted that these latest findings in women with epilepsy align with other research on the effects of exposure to the anticonvulsants in the womb. “In terms of teratogenicity [potential damage to embryos], we know that valproate and to a lesser extent carbamazepine are risky agents, while lamotrigine is a safer alternative,” she said. Bergink was not involved with the current study.

Though safer than other anticonvulsants, lamotrigine may not always be the answer for women of reproductive age who have bipolar disorder, Bergink cautioned. “The clinical problem with lamotrigine is that it is effective for depressive symptoms, but not so much for mania,” she said.

“Bipolar is complicated, and we don’t have that single, frontline choice for women who are or may become pregnant,” Bergink continued. Lithium is a highly effective mood stabilizer for bipolar disorder, but this medication also comes with risks of neurological problems in offspring, if taken during the first trimester.

“The best guidance [for psychiatrists] we can give is to try and aim for monotherapy in pregnant women ... and keep them on the lowest dose possible during pregnancy,” Bergink said. “Importantly, ramp the dose back up after delivery, since the first few weeks after childbirth pose the greatest risk of symptom relapse in women with bipolar disorder.”

The study by Wiggs and colleagues was published in Neurology. It was supported by multiple grants from the National Institutes of Health, along with the Swedish Initiative for Research on Microdata in the Social and Medical Sciences and the Swedish Research Council. ■