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Prenatal exposure to valproic acid during pregnancy and limb deficiencies: a case-control study
E Rodríguez-Pinilla1, I Arroyo, J Fondevilla
1Estudio Colaborativo Español de Malformaciones Congénitas, Facultad de Medicina, Universidad Complutense, Madrid, Spain. luisama@eucmos.sim.ucm.es
Insights
Prenatal exposure to valproic acid (VPA) significantly increases the risk of limb deficiencies in newborns. This study found a 6.17-fold increased odds of limb defects in infants exposed to VPA during early pregnancy.
Area of Science:
- Teratology and Developmental Toxicology
- Obstetrics and Gynecology
- Pediatric Neurology
Background:
- Valproic acid (VPA) is a widely used antiepileptic drug during pregnancy.
- Congenital malformations, including limb deficiencies, are a known concern with prenatal drug exposure.
- The specific risk of limb deficiencies associated with VPA requires further elucidation.
Purpose of the Study:
- To investigate the association between prenatal valproic acid (VPA) exposure and the occurrence of limb deficiencies in infants.
- To quantify the risk of limb deficiencies in newborns exposed to VPA during the first trimester of pregnancy.
Main Methods:
- A case-control study was conducted using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC).
- Data included 22,294 malformed infants and 21,937 control infants, with specific attention to antiepileptic drug use during gestation.
- Statistical analysis, including odds ratios and confidence intervals, was performed to assess the risk, controlling for confounders.
Main Results:
- Among infants exposed to VPA in the first trimester, 36.8% (21/57) exhibited congenital limb defects.
- A statistically significant increased risk for limb deficiencies was observed, with an odds ratio of 6.17 (95% CI 1.28-29.66, P = 0.023).
- The estimated risk for women treated with VPA of having a baby with limb deficiencies is approximately 0.42%.
Conclusions:
- Prenatal exposure to valproic acid (VPA) is associated with a significantly elevated risk of congenital limb deficiencies.
- These findings underscore the importance of careful risk-benefit assessment when prescribing VPA to pregnant women.
- Further research into the teratogenic mechanisms of VPA and the development of safer alternatives is warranted.
Abstract:
We conducted a case-control study using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC) on the relationship between prenatal exposure to valproic acid (VPA) and the presence of limb deficiencies in newborn infants. Among a total of 22,294 consecutive malformed infants (once we excluded genetic syndromes) and 21,937 control infants with specified data on antiepileptic drugs during gestation, 57 malformed infants and 10 control infants were exposed to VPA during the first trimester of pregnancy. Of the total of malformed infants exposed to VPA, 36.8% (21/57) presented with congenital limb defects of different types (including overlapping digits, talipes, clubfoot, clinodactyly, arachnodactyly, hip dislocation, pre- and postaxial polydactyly, etc.), three of them having limb deficiencies. The result of the case-control analysis shows a risk for limb deficiencies of odds ratio = 6.17 [confidence interval (CI) 1.28-29.66, P = 0.023], after controlling for potential confounder factors. If we consider that in our population the prevalence at birth of this type of defect is 6.88 per 10,000 livebirths (95% CI 6.43-7.36) we can estimate that the risk for women treated with VPA of having a baby with limb deficiencies would be around 0.42%. The limb deficiencies in the three patients exposed to VPA were the following: the first case was a newborn infant with hypoplasia of the left hand, the second patient was a newborn infant with unilateral forearm defect and hypoplastic first metacarpal bone in the left hand, and the third patient presented with short hands with hypoplastic first metacarpal bone, absent and hypoplastic phalanges, retrognathia, facial asymmetry, hypospadias, teleangiectatic angioma in skull, and hypotonia.