The use of valproic acid during the first trimester was associated with a significantly increased risk of spina bifida, atrial septal defects, and several other congenital malformations, compared with no exposure to an antiepileptic drug or the use of other types of antiepileptic drugs during the first trimester, according to results of a case-control study involving a European database of congenital malformations.

These results “provide further support for the recommendation of the American Academy of Neurology to avoid the use of valproic acid, if possible, in pregnant women,” concluded lead author Janneke Jentink of the University of Groningen, the Netherlands, and associates for the European Surveillance of Congenital Anomalies (EUROCAT) Antiepileptic Study Working Group.

“Since switching drugs during or just before pregnancy is difficult, the risks associated with valproic acid use should be routinely considered in choosing therapy for women with childbearing potential,” they added (N. Engl. J. Med. 2010;362:2185-93).

The investigators first identified 14 congenital malformations that were significantly more common in eight published studies of 1,565 pregnancies exposed to valproic acid. They then conducted a case-control study that evaluated the association of those 14 malformations with valproic acid monotherapy during the first trimester, using data from the EUROCAT database of almost 100,000 cases of malformations among live births, stillbirths, fetal deaths after at least 20 weeks’ gestation, and pregnancy terminations from 1995 to 2005 in 14 European countries. These cases were compared with two control groups: malformation cases that were not among the 14 linked to valproic acid in the literature review, and another group of malformations cases associated with chromosomal abnormalities.

Exposure to valproic acid monotherapy during the first trimester was associated with a significantly increased risk of 6 of the 14 malformations, when compared with no first trimester exposure to antiepileptic drugs (AEDs): spina bifida was associated with a 13-fold greater risk; atrial septal defects with a 2.5 times greater risk; cleft palate and hypospadias, both with a 5-fold greater risk; polydactyly with twice the risk: and craniosynostosis with a 7-fold greater risk.

The risk of the remaining eight malformations – microcephaly, tetralogy of Fallot, pulmonary-valve atresia, diaphragmatic hernia, ventricular septal defect, hypoplastic right heart, gastroschisis, and club foot – were not increased when compared with no AED exposure during the first trimester.

The associations were “generally similar” when the risk associated with monotherapy with valproic acid during the first trimester were compared with exposure to other AEDs, with two exceptions; first trimester exposure to valproic acid was not associated with a significant increase in the risk of craniosynostosis but was associated with a significantly increased risk of ventricular septal defects, compared with exposure to another AED.

When compared with the controls with malformations associated with chromosomal abnormalities, the results also were “generally similar,�� the authors said.

Limitations of the study included the lack of information on possible confounders and the use of controls with malformations instead of controls without malformations, the authors noted.

Despite their findings regarding the increased relative risks of several malformations associated with first trimester exposure to valproic acid, they pointed out that “the absolute rates of the specific malformations are low, and the majority of children born to mothers who take valproic acid do not have malformations.”

Using spina bifida as an example, the baseline prevalence of spina bifida is about 0.5 cases/1,000, the absolute risk of having a child with spina bifida is about 0.6% for cases of first trimester exposure to valproic acid monotherapy, based on the 12.7 odds ratio in their study. Based on the odds ratios found, the estimates of the absolute risks of the other malformations are 0.5% for atrial septal defect, 0.3% for cleft palate, 0.7% for hypospadias, 0.2% for polydactyl, and 0.1% for craniosynostosis.

Previous studies have associated prenatal valproic use to a range of malformations but have had “limited power individually to detect excess risks of specific malformations,” the researchers noted.

The EUROCAT database is supported by a variety of public funds; GlaxoSmithKline provided funding for a lamotrigine study when the AED database was developed, but was not involved in this study. At press time, no disclosure information was available at nejm.org.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一项对欧洲先天性畸形数据库进行病例对照研究的结果显示，与孕早期未服用抗癫痫药或应用其他类型抗癫痫药相比，孕早期服用丙戊酸与脊柱裂、房间隔缺损和其他多种先天性畸形风险显著增加有关。

 

这些结果“进一步支持了美国神经病学学会(AAN)让孕妇尽可能不服用丙戊酸的建议，”本文的第一作者、荷兰格罗宁根大学的Janneke Jentink以及欧洲先天性异常监测(EUROCAT)抗癫痫研究工作组的同行总结道。

 

“既然妊娠期期间或之前换药有难度，那么对于育龄期妇女在选择治疗时就应常规考虑与服用丙戊酸相关的风险，”他们补充说(N. Engl. J. Med. 2010;362:2185-93)。

 

在8项已发表的共1,565例妊娠期服用丙戊酸的研究中，研究者们首次查出了14种发病率显著增加的先天性畸形。随后，他们开展了一项病例对照研究，对这14种畸形与孕早期服用丙戊酸单药治疗的相关性进行评估，所用数据来自EUROCAT数据库，该数据库包括1995年~2005年14个欧洲国家中近100,000例畸形病例，分别处于不同的阶段或情况，其中包括活婴、死婴、20周孕龄以上的胎儿死亡以及妊娠终止。研究者将这些病例与以下2个对照组相比较：文献综述中与丙戊酸相关的其他畸形病例(除外这14种畸形)；与染色体异常有关的畸形病例。

 

与孕早期未服用抗癫痫药(AED)相比，孕早期接受丙戊酸单药治疗与14种畸形中的6种发病风险显著增加有关：脊柱裂风险增加13倍；房间隔缺损风险增加2.5倍；腭裂和尿道下裂风险均增加5倍；多指(趾)风险增加2倍；颅缝早闭风险增加7倍。

 

与孕早期未服用AED相比，其余8种畸形的发生风险未增加，它们是小脑畸形、法洛四联症、肺动脉瓣闭锁、膈疝、室间隔缺损、右心发育不全、腹裂和足内翻。

 

将孕早期接受丙戊酸单药治疗相关的风险与服用其他AED比较时，相关性“大体相近”，两种畸形例外；与孕早期服用其他AED相比，服用丙戊酸与颅缝早闭风险显著增加无关，但与室间隔缺损风险显著增加有关。

 

作者说，与染色体异常相关的畸形对照比较时，结果也“大体相近”。

 

本研究的局限性包括缺乏有关可疑干扰因素的资料及使用畸形对照而无非畸形对照，作者们指出。

 

尽管结果显示，孕早期服用丙戊酸可导致多种畸形的相对风险增加，但他们指出：“特定畸形的绝对发生率很低，服用丙戊酸母亲所生儿童大多数并未发生畸形。”

 

以脊柱裂为例，脊柱裂基线患病率约为0.5例/1,000，基于本研究的风险比值比12.7，孕早期服用丙戊酸单药治疗娩出脊柱裂婴儿的绝对风险约为0.6%。基于此比值比结果，其他畸形的绝对风险估计分别为：房间隔缺损0.5%，腭裂0.3%，尿道下裂0.7%，多指(趾)0.2%，颅缝早闭0.1%。

 

先前的研究将产前丙戊酸治疗与一系列畸形相关联，但“在单独检测特定畸形的风险增加值方面效能有限，”研究者指出。

 

EUROCAT数据库得到多种公共基金的资助；葛兰素史克在AED数据库建立之时为拉莫三嗪研究提供了资助，但未参与本研究。发稿时，nejm.org网站无相关利害披露。

 

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