麻豆传媒

The antiepileptic drug lamotrigine (Lamictal) may not cause orofacial birth defects, after all, but there's now more evidence it may be tied to clubfoot, a new study shows.

In a case-malformed control study funded by Lamictal manufacturer GlaxoSmithKline, use of lamotrigine during pregnancy wasn't significantly associated with orofacial clefts (adjusted OR 1.31, 95% CI 0.73–2.33) or cleft palate (aOR 1.60, 95% CI 0.70–3.65), , of the University of Ulster in Northern Ireland, and colleagues .

There was, however, a significant excess of clubfoot with lamotrigine monotherapy exposure (aOR 1.83, 95% CI 1.01–3.31), although this became nonsignificant in further analyses (aOR 1.43, 95% CI 0.66-3.08), they reported.

"The most important thing we found is that there was no evidence of a strong specific risk for orofacial clefts associated with lamotrigine," Dolk told 麻豆传媒. "We could find no statistically significant difference in the likelihood that a baby with orofacial clefts had been exposed to lamotrigine, compared to any other type of congenital anomaly. This is consistent with the combined published literature, other than the original study."

Lamotrigine, indicated for epilepsy and bipolar disorder, is thought to be safer than other antiepileptics, but the about orofacial birth defects following a signal from the North American AED Pregnancy Registry that suggested a six-fold increased risk of orofacial clefts, specifically cleft palate.

Studies done since then haven't shown a similar association, the researchers said.

In Dolk's previous study, she and her colleagues used EUROCAT congenital abnormality data from 19 registries from 1995 through 2005, and found an increased risk of clubfoot, but the finding could have been attributed to chance, prompting the current study.

This time, they used registries from the original 19 countries as well as Finland and Sweden for a population of 10.1 million births between 1995 and 2011. This more than doubled the number of births in their previous study, in part because of the increased use of lamotrigine in the later years.

AED exposure was recorded in six per 1,000 registrations, and AED monotherapy accounted for 80% of all AED exposure. Within this population, 157 children (12%) were exposed to lamotrigine monotherapy and 102 children (7%) were exposed to lamotrigine polytherapy. Maternal age was similar between those who had taken antiepileptic drugs and those who hadn't.

Although lamotrigine exposure wasn't significantly linked to orofacial clefts, exposure to antiepileptic drugs in general was significantly associated with both orofacial clefts (adjusted OR 1.34, 95% CI 1.11-1.62) and cleft palate (adjusted OR 1.97, 1.54-2.52).

These odds ratios were still elevated after the researchers excluded valproic acid, which is known to be linked to an increased risk of orofacial clefts, they said.

And although lamotrigine monotherapy exposure was tied to an excess of clubfoot, overall AED exposure wasn't associated with this condition (aOR 0.96, 95% CI 0.74-1.26), Dolk and colleagues reported.

Dolk said if there is a risk of orofacial clefts associated with lamotrigine, it is less than one in 550 exposed births, so clinicians don't need to avoid prescribing the drug during pregnancy. But because these clefts are associated with a range of antiepileptics, clinicians should "pay special attention" when diagnosing the clefts.

"We hope our study will give women and their clinicians more of the scientific evidence they need to weigh up the benefits and risks of different antiepileptic medications," she told 麻豆传媒.

Generally, Dolk said she hopes the study will help push policy makers to make sure studies that measure teratogenic risk for medications are done in a more timely manner.

"At present, there are huge gaps in the evidence we have regarding medication safety in pregnancy, which is intolerable," she said, "and leads on the one hand to women avoiding medication that they need for their own health and that of their baby, and on the other hand to women taking medication which does not have the best safety profile."

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