Anticonvulsants during pregnancy: risk of autism in children

NEW research has reinforced the need to educate GPs and other prescribers about the potential risks associated with specific antiseizure drugs when weighing the benefits of prescribing women of childbearing age.

Among pregnant women, five out of 1,000 take anticonvulsants, and women with epilepsy who do not take the drug during pregnancy are at risk for seizures. Previous studies (here and here) have shown that pregnant women with epilepsy have higher mortality than women without epilepsy, and some of this risk can be attributed to seizures. Therefore, it is essential that prescribers know the risk to the child and which anticonvulsants can be used to ensure the health of both mother and child.

The SCAN-AED study, a Nordic registry-based study of antiepileptic drugs in pregnancy, reported a significantly increased risk of adverse neurodevelopment in children whose mothers were treated with antiepileptic drugs during pregnancy.

The study (of which we are co-authors) is based on real data from more than 4 million mother-child pairs in five countries followed for 20 years, with 25,000 children exposed before birth to anticonvulsants, 16,000 born to mothers with epilepsy.

The results show that prenatal exposure to topiramate and valproate was associated with a two- to four-fold increased risk of autism spectrum disorder and intellectual disability. They also suggest high risks of neurodevelopmental disorders in children with common anticonvulsant duotherapies.

Among 21,634 unexposed children of epileptic mothers, 1.5% had a diagnosis of autism and 0.8% of intellectual disability by the age of 8 years. In age-matched children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, were autistic, and 3.1% and 2.4% had intellectual disability. After adjusting for a wide range of potential confounders, the analysis yielded hazard ratios of 2.8 (95% confidence interval [CI], 1.4 to 5.7) for autism and 3.5 (95% CI, 1.4 to 8.6) for intellectual disability after exposure to topiramate and 2.4 (95% CI, 1 .7 to 3.3) and 2.5 (95% CI, 1.7 to 3.7), respectively, after exposure to valproate. These combinations were dose-dependent, showing elevated risks with higher daily doses of valproate (³ 750 mg) and with topiramate (³ 100 mg).

While previous research has found an association of similar magnitude between valproate exposure during pregnancy and childhood neurodevelopmental disorders, the current findings on topiramate are novel. Topiramate is no longer recommended for first-line use in most guidelines because it carries an increased risk of birth defects in babies exposed before birth, but safety evidence on long-term outcomes is sparse .

Reassuringly, our latest findings confirm previous findings that lamotrigine and levetiracetam monotherapy is not associated with increased risks of autism and intellectual disability in children of women with epilepsy. These anticonvulsant drugs are widely recommended as first-line treatment in women of childbearing age and considered effective for focal and generalized epilepsies, without the risk of aggravating the frequency of seizures.

Worryingly, however, our data suggest that some common duos are associated with an increased risk of neurodevelopmental disorders in children in the same range as exposure to topiramate and valproate, even without these being part of the duos. -medications. Children whose mothers had used a combination of levetiracetam and carbamazepine as well as a combination of lamotrigine and topiramate had 2.5- to 3.5-fold increased risks. However, this did not apply to children born to mothers who had used a combination of levetiracetam and lamotrigine.

The SCAN-AED study is an ongoing study funded by the Nordic governments and led by researchers in Norway, Denmark, Finland, Iceland, Sweden and Australia, with the aim of optimizing drug choice and folic acid treatment in pregnant women with epilepsy. This is one of the first studies large enough to investigate the long-term risks of monotherapy and combination therapies with more than one antiepileptic drug, which some women with epilepsy may need to make sure they don’t have a seizure during pregnancy.

The evidence provided in this multi-register longitudinal study is important for both physicians and women with epilepsy. Notably, our results suggest that topiramate may not be a safe alternative to valproate, showing a clear association with adverse neurodevelopment in children exposed to topiramate, particularly at doses of 100 mg daily.

The results are highly relevant to prescribers in Australia. They highlight the importance of clear alignment of regulatory warnings, prescribing restrictions, and clinical guidelines to facilitate informed treatment decisions and optimal prescribing practices. Currently, valproate is available under the Australian Government’s Pharmaceutical Benefits Scheme (PBS) for unrestricted reimbursement, despite widespread regulatory warnings against its use in women of childbearing age (here and here).

The PBS restrictions were recently updated to allow the use of levetiracetam and lamotrigine as first-line treatment in women of childbearing potential. Topiramate is listed on the PBS for seizures ― if other antiepileptic drugs have failed to control satisfactorily ― and as a prophylaxis to treat migraines if contraindicated or intolerant to other drugs indicated in the guidelines (e.g. b-blockers, pizotifen).

General practitioners and other prescribers should be aware of the potential risks associated with specific anticonvulsants when weighing the benefits of prescribing them to women of childbearing potential.

Associate Professor Helga Zoega is a pharmacoepidemiologist in the School of Population Health, School of Medicine and Health, University of New South Wales. She is also a professor of public health at the University of Iceland in Reykjavík.

Associate Professor Marte-Helene Bjørk works in the Department of Clinical Medicine at the University of Bergen and the Department of Neurology at Haukeland University Hospital in Bergen, Norway.

Statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of WADA, the MJA Where Preview+ unless otherwise stated.

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