Rodríguez-Pinilla Elvira, Mejías Consuelo, Prieto-Merino David, Fernández Paloma, Martínez-Frías María L
Spanish Collaborative Study of Congenital Malformations, Research Center on Congenital Anomalies, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain.
Drug Saf. 2008;31(6):537-43. doi: 10.2165/00002018-200831060-00008.
Hypospadias is one of the most frequently occurring genital anomalies described in infants prenatally exposed to valproic acid (VA). However, to our knowledge, only one publication has studied a potential causal relationship between VA and hypospadias, only estimating the unadjusted global risk. Here we present the results of a multivariate case-control study aimed at analysing and quantifying the specific risk of hypospadias in newborn infants exposed to VA during the first trimester of pregnancy.
The data analysed here were derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC), an ongoing, hospital-based, case-control study and surveillance system in which collaborating paediatricians identify case and control infants. The paediatricians collect the same data for both case and control infants, blinded to information on any prenatal exposure. The information includes 312 items related to many prenatal exposures, including drug exposure, reproductive and family history, and other characteristics. The sample analysed included 2,393 infants with hypospadias and 12,465 male controls.
The results showed that the unadjusted risk of hypospadias in infants prenatally exposed to VA was 5.23 (95% CI 2.31, 11.86; p < 0.00001). Once adjusted for 13 potential confounding factors using conditional logistic regression analyses, the value of the risk was of a similar magnitude (odds ratio = 5.71; 95% CI 1.78, 18.36; p = 0.003). In addition, the frequency of hypospadias in the study population was approximately 1.8/1000 births. This allowed us to calculate the specific risk for an infant with hypospadias to be born to an exposed mother, which was 1 child in 97 births to mothers using VA during the first trimester of pregnancy. We consider this information much more useful for risk assessment than the risk value itself.
An alteration of placental gonadotrophic stimulation caused by changes in gonadotropin-releasing hormone release produced by the effects of VA on GABA is a possible pathogenic mechanism. Our results support the relationship between prenatal exposure to VA and hypospadias.
尿道下裂是产前暴露于丙戊酸（VA）的婴儿中最常见的生殖器异常之一。然而，据我们所知，仅有一篇文献研究了VA与尿道下裂之间的潜在因果关系，仅估计了未调整的总体风险。在此，我们展示一项多变量病例对照研究的结果，旨在分析和量化妊娠头三个月暴露于VA的新生儿患尿道下裂的具体风险。
此处分析的数据源自西班牙先天性畸形协作研究（ECEMC），这是一项正在进行的、基于医院的病例对照研究及监测系统，参与协作的儿科医生负责识别病例和对照婴儿。儿科医生为病例和对照婴儿收集相同的数据，且对任何产前暴露信息不知情。这些信息包括312项与多种产前暴露相关的内容，包括药物暴露、生殖和家族史以及其他特征。分析的样本包括2393例尿道下裂婴儿和12465例男性对照。
结果显示，产前暴露于VA的婴儿患尿道下裂的未调整风险为5.23（95%置信区间2.31，11.86；p < 0.00001）。使用条件逻辑回归分析对13个潜在混杂因素进行调整后，风险值大小相似（比值比 = 5.71；95%置信区间1.78，18.36；p = 0.003）。此外，研究人群中尿道下裂的发生率约为1.8/1000活产。这使我们能够计算出暴露母亲所生患尿道下裂婴儿的具体风险，即妊娠头三个月使用VA的母亲每97次分娩中有1例。我们认为此信息对于风险评估比风险值本身更有用。
VA对γ-氨基丁酸的影响导致促性腺激素释放激素释放改变，进而引起胎盘促性腺激素刺激改变，这可能是一种致病机制。我们的结果支持产前暴露于VA与尿道下裂之间的关系。
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