Previous studies have indicated that infants exposed to valproic acid in pregnancy are at increased risk for a range of malformations, including neural tube defects.  While these studies have shown an association between valproic acid and various malformations, they have been limited in their ability to quantify the risk of certain, less common malformations.  To do this, large population-based case–control studies are more appropriate.

A large study published in the New England Journal of Medicine attempted to clarify the risks associated with first trimester exposure to valproic acid.  In the first part of the study, the researchers utilized data from cohort studies to identify malformations which were found more commonly than expected among offspring exposed to valproic acid monotherapy during the first trimester of pregnancy. In eight studies including a total of 1565 pregnancy outcomes, there were 118 major malformations as defined by EUROCAT. The overall rate of major congenital malformations was 7.5%.

The following 14 malformations were found more commonly among valproate-exposed offspring: spina bifida, microcephaly, ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary-valve atresia, hypoplastic right heart, cleft palate (without associated cleft lip), diaphragmatic hernia, gastroschisis, hypospadias, club foot, polydactyly, and craniosynostosis.

The authors then conducted a population-based, case–control study to assess the risk of these malformations using the antiepileptic study database established by the European Surveillance of Congenital Anomalies (EUROCAT).  The study sample consisted of 3,881,592 live births and stillbirths, of which 98,075 involved a major congenital malformation.

The analysis included 37,154 cases, defined as all live births, fetal deaths after at least 20 weeks of gestation, and terminations of pregnancy after prenatal diagnosis with at least one of the above listed malformations.  Also included were 39,472 controls with major malformations other than those under study (control group 1) and 11,763 controls with malformations associated with chromosomal abnormalities (control group 2).

Use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration.  Adjusted odds ratios were as follows:

  • Spina bifida                                         12.7
  • Atrial septal defect                          2.5
  • Cleft palate                                         5.2
  • Hypospadias                                      4.8
  • Polydactyly                                         2.2
  • Craniosynostosis                              6.8

Consistent with previous studies, first trimester use of valproic acid is associated with an increased risk of several different types of malformations.  These data highlight the importance of discussing the reproductive safety of this medication and encouraging effective contraception in women of reproductive age who are on valproic acid.  This is crucial since neural tube defects occur so early in the course of fetal development, often before the woman may be aware she may be pregnant.  If possible, valproic acid should be avoided during pregnancy.

Ruta Nonacs, MD PhD

Jentink J, Loane MA, Dolk H, et al. Valproic Acid Monotherapy in Pregnancy and Major congenital Malformations. N Engl J Med. 2010; 362: 2185-2193.

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