Lagarce Laurence, Bernard Nathalie, Carlier Patrick, Phelipot-Lates Silviana, Perault-Pochat Marie-Christine, Drablier Guillaume, Bourneau-Martin Delphine, Lainé-Cessac Pascale
Service de pharmacologie et toxicologie, centre régional de pharmacovigilance, CHU d'Angers, 4, rue Larrey, 49933 Angers cedex 9, France.
Centre régional de pharmacovigilance, hospices civils de Lyon, 69424 Lyon, France.
Therapie. 2016 Sep;71(4):389-94. doi: 10.1016/j.therap.2015.12.005. Epub 2016 Feb 15.
Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3 to 6 months following MTX therapy. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP.
MATERIAL/METHODS: Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed.
Data were obtained on 52 pregnant women. The median age of patients was 28 (18-38), and the median gestational age at inclusion was 7 weeks after last menstrual period (3-22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 to 210mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3 spontaneous abortions (6.7%) occurring 63 to 94 days after MTX administration, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6-20.4).
DISCUSSION/CONCLUSION: Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However, the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings.
甲氨蝶呤（MTX）是一种已知的致畸药物，常用于异位妊娠（EP）的非标签治疗。由于MTX多聚谷氨酸化衍生物会在细胞内留存数周，因此建议在MTX治疗后的3至6个月内避免受孕。我们报告了孕前接触MTX治疗EP后的妊娠随访情况。
材料/方法：分析了Terappel数据库中记录的在注射MTX治疗EP后3个月内发生妊娠的前瞻性病例。
获取了52名孕妇的数据。患者的中位年龄为28岁（18 - 38岁），纳入时的中位孕周为末次月经后7周（3 - 22周）。最后一次注射MTX与受孕之间的时间间隔为12天至13周，MTX总剂量为40至210毫克。在45例已知结局的妊娠中，有39例活产（87%），3例自然流产（6.7%）发生在MTX给药后63至94天，2例选择性终止妊娠，1例因胎膜早破、羊水过少和关节挛缩（受孕前9周和8周分别注射48毫克MTX）后进行药物引产。在40例可检查的婴儿或胎儿中还观察到另外2例严重畸形：法洛四联症（受孕前6周注射MTX），以及核型正常的脑室扩大（受孕前9至13周注射50毫克MTX）。严重畸形的发生率为7.5%（可信区间95%：1.6 - 20.4）。
讨论/结论：尽管这项前瞻性研究显示严重畸形率高于一般人群预期，但观察到的畸形与甲氨蝶呤胚胎病的典型模式不一致。然而，法洛四联症的病例让人联想到先前发表的早期妊娠期间接触MTX的病例。由于样本量小，需要更有力的研究来证实或反驳这些发现。
