Valproic Acid in Pregnancy Linked to Several Congenital Malformations

Megan Brooks

June 09, 2010

June 9, 2010 — A new study confirms that first-trimester exposure to valproic acid is associated with an increased risk for spina bifida compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

The study also links first-trimester valproic acid exposure to increased risk for 5 other congenital malformations: atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis.

"It is well known that first trimester exposure to valproic acid is associated with increased risk of spina bifida, confirmed in this study. But data on the risks of other specific birth defects are limited," study investigator Lolkje T.W. de Jong-van den Berg, PhD, from the Department of Pharmacoepidemiology and Pharmacoeconomics, University of Groningen, the Netherlands, noted in an email to Medscape Neurology.

"The reason is that most studies are too small to evaluate the risk of other specific birth defects of which the prevalence is rare."

However, it should be recognized, the authors conclude, that although the relative risks for several malformations were increased in association with valproic acid use in early pregnancy, the absolute rates are low. The majority of children born to mothers who took valproic acid while pregnant do not have malformations, they write.

Their study was published in the June 10 issue of The New England Journal of Medicine.

For this report, Dr. de Jong-van den Berg and colleagues combined data from 8 published cohort studies, including a total of 1565 pregnancies during which women were exposed to valproic acid, among which 118 major malformations were found.

They found 14 malformations that were significantly (P < .05) more common among the offspring of women who had taken valproic acid during the first trimester. The investigators tested these associations by performing a case-control study within the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database.

Included in the analysis were 37,154 cases, defined as having at least 1 of the following 14 malformations: spina bifida, microcephaly, ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary valve atresia, hypoplastic right heart, cleft palate, diaphragmatic hernia, gastroschisis, hypospadias, clubfoot, polydactyly, and craniosynostosis. Also included were 39,472 control patients without chromosomal abnormalities (control group 1) and 11,763 control patients with chromosomal abnormalities (control group 2).

Exposure to valproic acid monotherapy was documented in 122 patients with malformations, 45 control group 1 participants, and 12 control group 2 patients. The frequency of exposure to valproic acid was 3 times as high among patients with malformations, at 3.3 per 1000 registrations — that is, pregnancy outcomes with malformations included in EUROCAT — as among control patients in both groups, where the frequency was 1.1 per 1000.

Key Findings

"We found an increased risk with valproic acid exposure for 6 of the 14 malformations," Dr. de Jong-van den Berg said. Risk for spina bifida was 12 to 16 times as high for exposed fetuses, depending on the control group used, and risks for the 5 other conditions were 2 to 7 times as high.

Risk for Malformations Associated With First-Trimester Valproic Acid Monotherapy vs No First Trimester Antiepileptic Drug (Control Group 1)

Condition Adjusted Odds Ratios 95% Confidence Interval
Spina bifida 12.7 7.7 - 20.7
Atrial septal defect 2.5 1.4 - 4.4
Cleft palate 5.2 2.8 - 9.9
Hypospadias 4.8 2.9 - 8.1
Polydactyly 2.2 1.0 - 4.5
Craniosynostosis 6.8 1.8 - 18.8

The results were generally similar in analyses comparing case patients with the control participants in group 2. The researchers also found an association between limb defects and exposure to valproic acid monotherapy as compared with no antiepileptic drug exposure — a finding that has been seen in previous case-control studies, they note.

The risks for most of these malformations (5/6) remained significantly increased in analyses comparing exposure to valproic acid monotherapy with exposure to other antiepileptic drug monotherapy. This supports a "relationship of these malformations to valproic acid specifically rather than to antiepileptic drugs generally or to underlying epilepsy," the authors say.

Steer Clear When Possible; Planning Ahead Critical

Current guidelines from the American Academy of Neurology recommend avoiding valproic acid in pregnant women, if possible, because of the risk for major congenital malformations as well as poor cognitive outcomes.

"In my group, we steer away from [valproic acid] unless it is the only drug that works," Sandra L. Helmers, MD, MPH, who was not involved in the study, noted in a telephone interview with Medscape Neurology.

Because switching drugs during or just before pregnancy is difficult, a forward-thinking approach is important, she added.

"This new study again emphasizes how important this issue is in not only women who are pregnant but women of childbearing age. That means you have to plan ahead, from day 1 — that means teenage women with epilepsy — and discuss this with them," added Dr. Helmers, who is an associate professor of neurology and pediatrics at Emory University School of Medicine in Atlanta and a member of the American Academy of Neurology.

Dr. de Jong-van den Berg and coauthors and Dr. Helmers have disclosed no relevant financial relationships.

N Engl J Med. 2010;362:2185-2193.

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