Valproate Linked to Neurodevelopmental Disorders, Other Antiseizure Meds Show No Association

Fresh research suggests that while valproate, a common antiseizure medication, carries a heightened risk of neurodevelopmental disorders in children exposed during pregnancy, other frequently used medications – levetiracetam, lamotrigine, phenytoin, and topiramate – do not appear to have the same association. The findings, published in BMJ on March 26, 2026, add to a growing body of evidence informing treatment decisions for women with epilepsy or migraine who are pregnant or planning to grow pregnant. Careful consideration of medication choices remains crucial, particularly given the need for continued seizure control during pregnancy.

Valproate and Neurodevelopmental Risk

The study, led by Loreen Straub, MD, MS, of Harvard Medical School, analyzed data from nearly 15,000 pregnant individuals diagnosed with epilepsy between 2000 and 2021, using data from two large U.S. Insurance databases. Researchers compared neurodevelopmental outcomes in children exposed to ten different antiseizure medications during the second half of pregnancy with those of unexposed children. The analysis revealed a significantly increased risk for any neurodevelopmental disorder in children whose mothers used valproate during pregnancy (HR = 1.29; 95% CI, 1.06-1.56). This aligns with previous research linking valproate to neurodevelopmental issues like autism.

Zonisamide as well showed an increased risk for neurodevelopmental disorders (HR = 1.41; 95% CI, 1.06-1.88), though researchers caution that the numbers exposed to this medication were relatively small, requiring further investigation.

Understanding Neurodevelopmental Disorders

Neurodevelopmental disorders encompass a range of conditions affecting brain development, impacting cognitive, learning, memory, and behavioral functions. These can include intellectual disability, attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and autism spectrum disorder. Diagnosing these conditions often relies on clinical evaluation and, in some cases, standardized testing.

Reassuring Signals for Other Medications

The study offered more reassuring findings for several other commonly prescribed antiseizure medications. Levetiracetam and phenytoin showed no association with adverse neurodevelopmental outcomes. Lamotrigine, levetiracetam, and phenytoin are frequently chosen for women with epilepsy due to existing safety data, and this study reinforces that practice.

However, the research also identified potential signals requiring further monitoring. Several medications – zonisamide, lamotrigine, oxcarbazepine, phenobarbital, and topiramate – were associated with an increased risk of intellectual disability, though the confidence intervals for some of these findings were wide, indicating less certainty. Oxcarbazepine and carbamazepine were also linked to a higher risk of ADHD, with hazard ratios ranging from 1.23 to 1.4. Topiramate showed a possible link with learning difficulty, but the wide confidence interval (HR = 1.23; 95% CI, 0.54-2.79) suggests this finding is less conclusive.

Balancing Seizure Control and Pregnancy Safety

“For practicing neurologists, I reckon the practical implication is to continue to prioritize maternal seizure control, but when there is a reasonable choice among effective options, treatment decisions should favor medications with the most reassuring pregnancy safety evidence for the developing child,” Dr. Straub told Healio. Maintaining adequate seizure control throughout pregnancy is paramount, as uncontrolled seizures pose significant risks to both mother and fetus.

The decision of which antiseizure medication to use during pregnancy is complex, requiring a careful assessment of individual patient factors. These include the type and severity of epilepsy, prior response to medications, dosage requirements, and any co-existing medical conditions.

The Importance of Individualized Treatment

It’s crucial to remember that these findings represent population-level associations and do not predict individual outcomes. Each patient’s situation is unique, and treatment decisions should be made in close consultation with a qualified neurologist and obstetrician.

Study Limitations and Future Research

The researchers acknowledge several limitations of their study. The observational nature of the analysis prevents establishing a causal relationship between antiseizure medication exposure and neurodevelopmental outcomes. The reliance on insurance claims data also introduces the potential for bias due to loss to follow-up and incomplete data.

Dr. Straub emphasized the need for replication of these findings in other healthcare systems and for studies with more detailed neurodevelopmental phenotyping. “Large-scale studies that can incorporate measures such as cognitive testing or IQ assessments could help clarify whether these signals reflect global intellectual impairment or more specific cognitive differences,” she stated.

What’s Next: Ongoing Surveillance and Guidance Updates

The findings from this study will likely inform ongoing discussions among neurologists, obstetricians, and regulatory agencies regarding the optimal management of epilepsy during pregnancy. Continued surveillance of neurodevelopmental outcomes in children exposed to different antiseizure medications is essential. The American Academy of Neurology and other professional organizations regularly review emerging evidence and update their guidelines accordingly. Patients and healthcare providers should stay informed about the latest recommendations.

Further research is also needed to understand the underlying mechanisms by which certain antiseizure medications may affect brain development. This knowledge could lead to the development of safer treatment options for women with epilepsy who are planning to become pregnant.

For more information: Loreen Straub, MD, MS can be reached at [email protected].