Edison Robin J, Muenke Maximilian
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-3717, USA.
Am J Med Genet A. 2004 Dec 15;131(3):287-98. doi: 10.1002/ajmg.a.30386.
The cholesterol-lowering "statin" drugs are contraindicated in pregnancy, but few data exist on their safety in human gestation. We reviewed case reports for patterns suggesting drug-related effects on prenatal development and considered a variety of mechanisms by which such effects, if confirmed, might occur. This uncontrolled case series included all FDA reports of statin exposures during gestation, as well as others from the literature and from manufacturers. Exposures and outcomes were reviewed and were tabulated by individual drug. Age-specific rates of exposure to each drug among women of child-bearing age were estimated. Of 214 ascertained pregnancy exposures, 70 evaluable reports remained after excluding uninformative cases. Among 31 adverse outcomes were 22 cases with structural defects, 4 cases of intrauterine growth restriction, and 5 cases of fetal demise. There were two principal categories of recurrent structural defects: cerivastatin and lovastatin were associated with four reports of severe midline CNS defects; simvastatin, lovastatin, and atorvastatin were all associated with reports of limb deficiencies, including two similar complex lower limb defects reported following simvastatin exposure. There were also two cases of VACTERL association among the limb deficiency cases. All adverse outcomes were reported following exposure to cerivastatin, simvastatin, lovastatin, or atorvastatin, which are lipophilic and equilibrate between maternal and embryonic compartments. None were reported following exposure to pravastatin, which is minimally present in the embryo. Statins reaching the embryo may down-regulate biosynthesis of cholesterol as well as many important metabolic intermediates, and may have secondary effects on sterol-dependent morphogens such as Sonic Hedgehog. The reported cases display patterns consistent with dysfunction of cholesterol biosynthesis and Sonic Hedgehog activity. Controlled studies are needed to investigate the teratogenicity of individual drugs in this class.
降低胆固醇的“他汀类”药物在孕期禁用，但关于其在人类妊娠期安全性的数据较少。我们回顾了病例报告，以寻找提示药物对产前发育有相关影响的模式，并考虑了此类影响（若得到证实）可能发生的多种机制。这个非对照病例系列纳入了美国食品药品监督管理局（FDA）所有关于妊娠期他汀类药物暴露的报告，以及来自文献和制药商的其他报告。对暴露情况和结局进行了回顾，并按每种药物列表。估计了育龄女性中每种药物的年龄特异性暴露率。在214例已确定的妊娠暴露病例中，排除无信息价值的病例后，剩下70份可评估报告。在31例不良结局中，有22例结构缺陷、4例宫内生长受限和5例胎儿死亡。复发性结构缺陷主要有两类：西立伐他汀和洛伐他汀与4例严重中线中枢神经系统缺陷报告相关；辛伐他汀、洛伐他汀和阿托伐他汀均与肢体缺陷报告相关，包括辛伐他汀暴露后报告的两例类似复杂下肢缺陷。在肢体缺陷病例中还有两例VACTERL综合征。所有不良结局均在暴露于西立伐他汀、辛伐他汀、洛伐他汀或阿托伐他汀后报告，这些药物具有亲脂性，可在母体和胚胎区室之间达到平衡。普伐他汀暴露后未报告任何不良结局，该药物在胚胎中含量极低。到达胚胎的他汀类药物可能会下调胆固醇以及许多重要代谢中间体的生物合成，并可能对依赖固醇的形态发生素如音猬因子产生继发影响。报告的病例显示出与胆固醇生物合成和音猬因子活性功能障碍一致的模式。需要进行对照研究以调查此类个别药物的致畸性。
