SAINT-DENIS, France — France's national agency for health and product safety, L'Agence nationale de sécurité du médicament et des produits de santé (ANSM), and the national insurance fund for employed workers, Caisse Nationale de l'Assurance Maladie des Travailleurs Salariés, have published results of the second phase of their drug safety program looking at exposure to valproic acid and other drugs for the treatment of epilepsy and bipolar disorder during pregnancy.
The report concludes that between 2150 and 4100 children exposed in utero to the antiepileptic drug valproic acid (Depakine, Sanofi Aventis) have had at least one major congenital malformation since the drug was put on the market in 1967.
Figures confirm the "highly teratogenic nature of valproate," said the agency in a press release dated April 20.
These findings are from the second part of the ANSM's study of the risks associated with fetal exposure to this antiepileptic agent, which is indicated for the treatment of epilepsy and bipolar disorder.
Results of the first part of the study, which were published in August 2016, showed a high prevalence of exposure to valproic acid and its derivatives in pregnant women, with 14,322 exposed pregnancies between 2007 and 2014.
The results of an ongoing investigation of neurodevelopmental disorders are expected in the second half of this year.
Fourfold Increase in Risk
The study of the risk for major birth defects associated with in utero exposure to valproic acid was based on SNIIRAM (French National Health Insurance Information System) data for the period from 2011 to 2015.
In all, for this period, data on close to 2 million pregnant women were analyzed. Of these, 2323 had been exposed to valproic acid: 1345 for epilepsy and 978 for bipolar disorder.
The risk for major birth defects is, relative to the general population, four times higher in children born to women treated with valproic acid for epilepsy (46.5/1000 vs 10.2/1000) compared with twice as high for women treated for bipolar disorder (22.2/1000 vs. 10.2/1000).
According to the agency's estimates, the total number of children exposed to valproic acid in utero with at least one major birth defect since the drug was put on the market in 1967 is between 2150 (lower range) and 4100 (upper range), or 1900 to 3800 such children among women treated for the indication of epilepsy vs 250 to 300 for the indication of bipolar disorder.
Compared with children born of unexposed pregnancies, those born of pregnancies exposed to valproic acid for the indication of epilepsy are at significantly higher risk for the following:
Spina bifida (6.5% vs 0.3%);
Ventricular septal defect (11.2% vs 2.7%);
Atrial septal defect (19.1% vs 1.9%);
Pulmonary artery atresia (2.2% vs 0.1%);
Left ventricular hypoplasia (2.2% vs 0.1%);
Cleft palate (3.4% vs 0.7%);
Anorectal atresia (3.4% vs 0.3%);
Hypospadias (22.7% vs 4.8%); and
Preaxial polydactyly (2.2% vs 0.2%).
Conversely, children born of pregnancies exposed to valproic acid for the indication of bipolar disorder are at significantly higher risk for the following:
Hypospadias (17.5% vs 4.8%) and
Craniostenosis (4.2% vs 0.4%).
Dose-Response Effect in Epilepsy
Overall, the results show that the risk for major birth defects increases with the dose of valproic acid administered during pregnancy to treat epilepsy.
Risk for Major Congenital Malformation With Valproic Acid for Epilepsy During Pregnancy
| Endpoint |
Dose <700 mg/day |
Dose of 700 to 1500 mg/day |
Dose ≥1500 mg/day |
Polytherapy |
| Odds ratio of a major birth effect |
0.9 |
5.0 |
8.7 |
6.3 |
However, no dose-response effect was observed for the indication of bipolar disorder.
To explain this difference in risk by indication, the agency points out that level of exposure may be lower in women treated for bipolar disorder: "Indeed, as observed in the first part of the study, early treatment interruptions are common in cases of bipolar disorder," the ANSM statement notes. "On the other hand, compliance in this indication is probably not as good as in epilepsy."
For other drugs used to treat epilepsy and bipolar disorder, the risk for major congenital malformation appears less marked but varies by agent, the statement notes. All the antiepileptic agents are subject to a thorough evaluation of the teratogenic risk conducted by the ANSM, which is being finalized.
An exploratory study on neurodevelopmental disorders is expected in the second half of 2017. These disorders, the ANSM notes, are even more difficult to identify in the medicoeconomic databases of health insurance.
This program of pharmacoepidemiologic studies was undertaken as part of a global action plan conducted since 2014 in France by the health authorities on the risks associated with valproate-based medicines and antiepileptic drugs during exposure during pregnancy.
Valproate and its derivatives are indicated for the treatment of partial or generalized epilepsy in adults and children, as well as for the treatment of manic episodes of bipolar disorder. "Because of the risk of birth defects and neurodevelopmental disorders in the unborn child exposed in utero," the ANSM notes that these medicines should not be prescribed in girls, adolescents, women of childbearing age, and pregnant women, except in cases of treatment failure, the statement notes.
A guideline document issued by the American Academy of Neurology and American Epilepsy Society in 2009 also recommends against use of valproate in women of childbearing age because of the risk for congenital malformations.
The report's release comes on the heels of publication of the book titled Dépakine: le scandale, by Marine Martin, a whistleblower about the risks of valproic acid and the mother of two children exposed in utero to her antiepileptic medication.
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Cite this: ANSM Report Examines Risk for Valproic Acid Birth Defect - Medscape - May 01, 2017.
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