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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    • "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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    • "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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    ABSTRACT: IAMSAARD, S.; ARUN, S.; BURAWAT, J.; SUKHORUM, W.; BOONRUANGSRI, P.; NAMKING, M.; UABUNDIT, N.; NUALKAEW, S. & SRIPANIDKULCHAI, S. Phyllanthus emblica L. branch extract ameliorates testicular damage in valproic acid-induced rats. Int. J. Morphol., 33(3):1016-1022, 2015. SUMMARY: Valproic acid (VPA), widely used in treating epileptic patients, can damage reproductive parameters causing male infertility. This study aimed to investigate protective effect of Phyllanthus emblica L. branch (PE) extract on rat testicular damage induced with VPA. Male rats were divided into 6 groups (control, VPA, 250 mg/kgBW PE only, and 50, 100, 250 mg/kgBW PE+VPA, respectively). Animals were pretreated with PE for 23 days and co-administered with VPA for 10 days before all reproductive parameters were determined. The results showed all doses of PE significantly protected the decrease testicular weight and testosterone level in VPA rats. PE significantly improved the decrease sperm concentration in VPA treated rats. Moreover, testicular histology of PE+VPA groups showed declining of testicular histopathologies as compared to VPA group. Therefore, it seems that PE branch extract can prevent testicular damages including male reproductive parameters in rats induced with VPA.
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    • "Witczak et al. [4] reported that newborns of mothers exposed to valporate are at increased risk for major congenital malformations, cognitive impairment and fetal death. Jentink et al. [5] found that there is significant association between exposure of the unborn child to VPA monotherapy in the first trimester and Spina bifida, arterial septa defects, cleft palate, hypospadias, polydactyl and craniosynostosis. Isojarvi et al. [6] reported that valproate was associated with sperm abnormalities in men with epilepsy. "
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    ABSTRACT: The present study investigated the cytogenetic and testicular damage induced by the antiepileptic drug, sodium valporate (SVP) in albino rats and the effect of saffron aqueous extracts. Treating rats with SVP caused a significant increase in the chromosomal aberrations either structural or numerical and decreased the mitotic index. Besides, animals administered SVP showed DNA damage appeared in the single strand breaks (comet assay). Testis of SVP-treated rats showed many histopathological changes. A significant decrease in seminiferous tubules and their epithelial heights diameters and inhibition of spermatogenesis was recorded. In addition, the number of sperm head abnormalities was increased. Biochemical results revealed an increase in malondialdhyde (MDA) which is lipid peroxidation marker and a significant decrease in the level of serum antioxidant enzyme, catalase (CAT) and reducing antioxidant power (RAP). Animals given SVP and saffron showed an improvement in chromosomal aberrations, mitotic index, DNA damage and testicular alterations caused by SVP. Moreover, MDA decreased and CAT and RAP increased. It is concluded from the present results that the ameliorative effects of saffron extract against SVP-induced cytogenetic and testicular damage in albino rats may be due to the presence of one or more antioxidant components of saffron.
    Anatomy & cell biology 09/2014; 47(3):171-179. DOI:10.5115/acb.2014.47.3.171
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