Schaefer Christof, Hannemann Doreen, Meister Reinhard, Eléfant Elisabeth, Paulus Wolfgang, Vial Thierry, Reuvers Minke, Robert-Gnansia Elisabeth, Arnon Judy, De Santis Marco, Clementi Maurizio, Rodriguez-Pinilla Elvira, Dolivo Alla, Merlob Paul
Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie, Berliner Betrieb für Zentrale Gesundheitliche Aufgaben, Spandauer Damm 130, Haus 10, 14050 Berlin, Germany.
Thromb Haemost. 2006 Jun;95(6):949-57. doi: 10.1160/TH06-02-0108.
Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.
已知维生素K拮抗剂（VKA）具有致畸作用；然而，关于出生缺陷的相对风险以及最敏感时期仍存在不确定性。在一项多中心（n = 12）的观察性前瞻性研究中，我们将666名暴露于苯丙香豆素（n = 280）、醋硝香豆素（n = 226）、氟茚二酮（n = 99）、华法林（n = 63）和苯茚二酮（n = 2）的孕妇与未暴露的对照组（n = 1094）进行了比较。数据由欧洲致畸学信息服务网络（ENTIS）的合作机构在1988年至2004年期间的个体风险咨询过程中收集。主要结局指标为香豆素胚胎病和其他出生缺陷、流产率、出生体重和早产情况。孕早期暴露后严重出生缺陷的发生率显著增加（比值比3.86，95%置信区间1.86 - 8.00）。然而，仅出现两例香豆素胚胎病（0.6%；均为苯丙香豆素所致）。早产更为常见（16.0%对7.6%，比值比2.61，95%置信区间1.76 - 3.86），与对照组相比，分娩时的平均孕周（37.9对39.4，p<0.001）以及足月儿的平均出生体重（3166克对3411克；p < 0.001）更低。采用生存分析方法，流产率达到42%对14%（风险比3.36；95%置信区间2.28 - 4.93）。总之，孕期使用VKA会增加结构缺陷和其他不良妊娠结局的风险。然而，香豆素胚胎病的风险非常小，尤其是在孕早期（末次月经首日之后）第8周之前未进行治疗的情况下。因此，如果在孕早期发生（意外）暴露，不建议选择性终止想要的妊娠。在孕期任何VKA暴露的情况下，均应建议由产科医生进行密切随访，包括二级超声检查。
