Antiepileptic drugs (AEDs), most commonly lamotrigine (Lamictal) and valproic acid (Depakote), have become widely used medications for the treatment of patients with bipolar disorder. There is considerable data to support the reproductive safety of lamotrigine; however, other antiepileptic drugs — specifically valproic acid — carry significant risks during pregnancy and thus should be avoided. Several years ago, researchers raised concerns about the use of topiramate (Topamax) and increased risk for oral clefts. A new study indicates that prenatal exposure to topiramate may also increase risk for neurodevelopmental disorders.    

To examine risk for neurodevelopmental disorders in children exposed prenatally to AEDs, researchers analyzed data from a Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED). This is a population-based cohort study collecting health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017). The cohort includes about 4.5 million pregnancies with livebirths.  

Neurodevelopmental outcomes were compared across different groups determined by exposure to a particular AED or combination of AEDs. The control group consisted of children born to mothers with epilepsy who did not take AEDs during pregnancy (n=21,634). The medical records were used to identify children with autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). The median (IQR) age at the end of follow-up was 8 (4.0-12.1) years. 

Among the 21,634 unexposed children born to mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% of a diagnosis of intellectual disability (ID) by 8 years of age. In same-aged children exposed to topiramate monotherapy, the prevalence of ASD was 4.3% and the prevalence of ID was 3.1%. Similar rates of ASD and ID were observed in children exposed to valproate monotherapy: 2.7% and 2.4%, respectively.

Accounting for potential confounders, the researchers calculated adjusted hazards ratios.  Children exposed to topiramate monotherapy had a 2.8-fold increase in risk for ASD (aHR 2.5, 95% CI, 1.4-5.7) and a 3.5-fold increase in risk for ID (aHR 3.5, 95% CI, 1.4-8.6). Children exposed to valproate monotherapy were also at increased risk for ASD (aHR 2.4; 95% CI, 1.7-3.3) and ID (aHR 2.5; 95% CI, 1.7-3.7). Lamotrigine exposure was not associated with increased risk of ASD or other neurodevelopmental disorders. The aHRs were elevated with higher AED doses compared to children in the general population. 

Topiramate and Neurodevelopmental Outcomes (Bjork et al,2022) by Ruta Nonacs, MD PhD

While previous studies have shown higher rates of ASD and neurodevelopmental disorders in children with prenatal exposure to valproate, this is to our knowledge the first study to raise concerns about exposure to topiramate. Especially alarming is the finding that topiramate is similar to valproate in terms of risk of neurodevelopmental disorders. Fortunately, it is a medication that we do not use that often to treat psychiatric patients, but many women of reproductive age use topiramate for migraine prophylaxis and weight reduction (Qsymia is a combination of phentermine and topiramate used to treat obesity). 

Ruta Nonacs, MD PhD

Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. JAMA Neurol. 2022 Jul 1;79(7):672-681.

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