Pregnancy

Use of these epilepsy drugs during pregnancy linked to child’s autism

A photo of a box of Epilim 200 (sodium valproate) tablets with a warning label for women and girls regarding pregnancy risks.

According to a population-based cohort study, children exposed prenatally to anticonvulsants had an increased risk of autism spectrum disorders (ASD) and intellectual disability (ID).

Around age 8, children were two to four times more likely to be diagnosed with these neurodevelopmental disorders if their mothers had taken topiramate or valproate monotherapy during pregnancy. Exposure to levetiracetam-carbamazepine or lamotrigine-topiramate duo therapy was also associated with a similar risk, reported Marte-Helene Bjørk, MD, PhD, of Haukeland University Hospital in Norway, and colleagues from JAMA Neurology.

Bjørk’s group suggested that topiramate does not appear to be a safe alternative to valproate. “Women of childbearing potential who are prescribed topiramate should be informed of the potential risks, and these should be weighed against the benefits and available treatment options.”

Exposure to other anticonvulsants such as oxcarbazepine, carbamazepine and clonazepam has not been associated with any increase in neurodevelopmental disorders in children of epileptic mothers.

These results largely correspond to what has been seen in previous records.

Valproate has been associated with one of the highest risks of birth defects and neurodevelopmental problems among antiepileptic drugs, while levetiracetam and lamotrigine have had some of the best safety data to date, noted Page Pennell, MD, chair of the department of neurology at the University of Pittsburgh School of Medicine, in an interview with MedPage today.

Overall, however, doctors are still “completely blind” to the safety of most epilepsy drugs in pregnancy, lamented Kimford Meador, MD, of Stanford University School of Medicine and his Neuroscience Health Center in Palo Alto, California.

Beyond the few that are known to be dangerous and the few that seem fairly safe, “for the other 30 or so drugs, we don’t know,” he said.

“When you’re in the clinic and a woman comes in and she’s burned off those first meds – either they didn’t work or she got a rash on lamotrigine, she got depressed on levetiracetam, that happens – and she has primary generalized epilepsy, you don’t know where to go next,” Meador said. “There’s no data, except maybe avoid valproate if you can.”

Women with epilepsy usually need anticonvulsant drugs during pregnancy. Currently, about 0.5% of pregnant women use anticonvulsants, according to a study from 2020.

Still, the actual number is unknown because there is no national reporting system in place in the United States, Meador noted. Manufacturers are not required to test children’s outcomes, and there is not enough funding to examine the underlying mechanisms linking these drugs and children’s neurological development.

Some regulatory agencies like the European Medicines Agency advised clinicians stop prescribing valproate — a drug on the World Health Organization Essential Medicines List — to women of childbearing age in 2014. The FDA requires valproate labeling to include a warning against use during pregnancy.

Last month, the producer of valproate was obligatory pay nearly €500,000 in damages to a French family with a child with ASD associated with valproate.

“With regulatory warnings cautioning against the use of valproate in women of childbearing potential, safety data is urgently needed for alternative treatment options,” Bjørk and colleagues stress.

Since no adverse neurological developments were observed with the use of levetiracetam-lamotrigine in their study, they suggested that future research should focus on this duotherapy to learn more about its safety and effectiveness during pregnancy.

Investigators used data from the study based on the Nordic Register of Antiepileptic Drugs in Pregnancy (SCAN-AED), which includes data from Denmark, Finland, Iceland, Norway and Sweden collected from 1996 to 2017. Children were diagnosed with ASD and ID using ICD-10 codes.

Nearly 4.5 million children participated in the study and 48.7% were girls. The median age was 8 years old.

Children whose mothers filled prescriptions for anticonvulsant drugs from 90 days before the last menstrual period until birth represented 0.6% of the cohort and were compared with unexposed controls.

Neurodevelopmental risk increased with a higher dose of anticonvulsant drugs, the researchers reported.

The study results generally remained the same when the authors expanded the exposed cohort to include the children of women who filled their prescriptions within 2 years of pregnancy, but not within 90 days of their last menstrual period.

Bjørk and his co-authors said their inability to collect data on paternal and family history was a limitation of the study.

“Epidemiological, clinical and preclinical studies support our findings,” they asserted. “Previous national registry studies have shown similar strength associations between valproate use during pregnancy and ASD and ID.”

Disclosures

The study was funded by a grant from NordForsk and the Research Council of Norway. Bjørk disclosed relationships (fees, grants or otherwise) with Valproate, Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, Teva and Lilly.

Pennell did not disclose any relevant industry relationships.

Meador has received research support from the NIH and Eisai. The Epilepsy Study Consortium pays Meador University for its research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma and Vivus Pharmaceuticals.

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