Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations

Department of Pharmacoepidemiology and Pharmacoeconomics, Division of Pharmacy, University of Groningen, Groningen, the Netherlands.
New England Journal of Medicine (Impact Factor: 55.87). 06/2010; 362(23):2185-93. DOI: 10.1056/NEJMoa0907328
Source: PubMed


The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited.
We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005.
Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs.
The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

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    • "We found that up to 1 % of women under 30 years of age, 1 % to 4 % between 31 and 40 years, and up to7 % of those aged 44 years were using agents acting on the renin-angiotensin system from risk category D. For pregnant women, antihypertensives with lower risk category might be considered. Antiepileptic medicines such as valproate121314and carbamazepine[12,141516are associated with an increased risk for major congenital malformations, including neural tube defects and should be prescribed with caution in pregnancy[17]. Topiramate is associated with an increased risk for oral clefts[18,19]and the Food and Drug Administration (FDA) in US issued a change in label to warn of the potential risk[20]. "
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    ABSTRACT: Background This study aimed to examine current utilisation of prescribed medicines amongst Australian women of child-bearing age, with a particular focus on the extent of use of medicines in Category D and X risk groups, which are moderate and high risk teratogens, respectively. The use of those medicines may pose risk of birth defects in pregnant women. Methods A retrospective cross-sectional study was undertaken involving all women of child-bearing age (15 to 44 years) who were dispensed medicines in 2013 using the 10 % random sample of dispensing data from the Australian Government Department of Human Services. Dispensing patterns were reported by medicine, therapeutic class, pregnancy risk category and women’s age. Results Over one-third of women aged 15 to 44 years received at least one prescribed medicine in 2013. Psychoanaleptics, antibiotics and analgesics were the top three classes. Around 9 % of all dispensings were for medicines from risk category D, with statins, agents acting on renin-angiotensin system, and some anti-epileptic agents being the most commonly used. Both statins and agents acting on renin-angiotensin system showed increasing use with age, estimated to be 35,600 women nationally for each group. Collectively between 2 % and 4 % of women used anti-epileptics from risk category D in each year of age, with overall use estimated to be 51,000 women nationally. Below 1 % of all dispensings were for category X medicines, mainly isotretinoin. Conclusions It is important for medical practitioners to offer counselling around pregnancy planning and the risk of birth defects when prescribing moderate or high risk teratogens to women in child-bearing age. For the antihypertensives and some anti-epileptics, alternative medicines with lower risk categorization are available.
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    • "However, various side effects in the use of VPA have been also reported. VPA can cause many congenital malformations (Jentink et al., 2010; Witczak et al., 2010). It was also reported to significantly increase fibrosarcomas and adenocarcinomas of the uterus and cervix (Watkins et al., 1992). "
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    • "It has become apparent from these studies that the rate of congenital malformations significantly increases in newborns exposed to AEDs during the first trimester of pregnancy and it is higher if more than one AED is taken [3], it is dose dependent and affected by other variables such as parental history of MCMs [12]. The highest risk has been observed with high dose of valproic acid exposure as compared to other AEDs such as carbamazepine, phenytoin and lamotrigine [13]. Few studies have investigated the role of epilepsy in the pathogenesis of MCMs, evaluating the outcome of pregnancies of healthy women and epileptic women not exposed to AEDs or other teratogens. "

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