Methotrexate in pregnancy: still many unanswered questions

Abstract

Methotrexate (MTX) is a folate antagonist with known teratogenicity including abortifacient effects that interfere with DNA synthesis. We want to discuss on which findings teratogenicity is based and which open questions still exist. In this context, we introduce a recent Italian study by Zanetti et al 1 on pregnancy outcomes after therapeutic use of MTX in women with rheumatoid arthritis (RA). MTX is on the WHO list of essential medicines. In addition to the approved indications for the drug treatment of malignancies and inflammatory disorders, it is used for the non-surgical treatment of ectopic pregnancy and elective termination of pregnancy (TOP). The dose differs according to indication and also plays a role in teratology. Paracelsius already pointed to the fact that the ‘dose makes the poison’. As often, teratogenicity in humans was discovered by case reports describing a similar phenotype of malformations (MTX embryopathy), at first after failed TOP. Already in the 50th, the teratogenic effects of aminopterin,2 a structurally similar but more potent folate antagonist was described. In 1968, the first case of an infant with MTX-induced congenital malformations after failed attempted TOP was published.3 Since then, multiple similar case reports have been reported,4 also after misdiagnosed ectopic pregnancies.5 The guideline dosage for the indication of ectopic pregnancy is a single intramuscular administration of 50 mg/m². Even though the teratogenicity of MTX is indisputable, not every malformation in an infant after intrauterine exposure is attributable to the drug. The following considerations should be taken into account:

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