Different regimens of delivering high-dose MTX (60–100 mg or more) to a patient with ectopic pregnancy have been described [1]. Typically, misdiagnosed intrauterine pregnancy which is treated as ectopic pregnancy exposes the fetus to high-dose MTX during critical stages of embryogenesis. This is the only situation in medicine where a highly teratogenic dose of a drug is given to a pregnant woman.

MTX, a folic acid antagonist and DNA synthesis inhibitor in rapidly dividing cells, has been implicated in as a human teratogen , particularly when used in a high dose during the first trimester of pregnancy. MTX embryopathy (the aminopterin syndrome) is characterized by intrauterine growth restriction, miscarriage, stillbirth, cardiac defects, dysmorphic facial features, neural tube and skeletal anomalies, and mental retardation [1, 2] (Table 10.1).

Until recently it was believed that the low oral weekly dose of MTX, given in rheumatological conditions, did not result in the aminopterin syndrome; however, such a case was described in Argentina in 2013 [3].

The absolute risk of MTX embryopathy can only be estimated due to underreporting of cases because of medicolegal fears of erroneous of ectopic pregnancy. The largest observational study by our group included eight pregnant women who were misdiagnosed as an ectopic pregnancy and treated with 50–184 mg MTX. None of these pregnancies resulted in the birth of healthy newborn (two newborns had major malformations compatible with MTX embryopathy (one of them had a stillbirth at 30 gestational weeks), three of eight pregnancies resulted in spontaneous miscarriage less than 2 weeks after MTX treatment , and three of eight women terminated the pregnancy based on their physician advice) [1].

Overall, the risk of this patient having a baby with birth defects is substantially increased when compared to the population baseline of 1–3 % [4].

Theoretically, MTX embryopathy may be attenuated by folinic acid coadministration by countering the antifolate effect MTX. Leucovorin injection (a structural analogue of folinic acid) in animals ameliorated MTX teratogenic effect [5]. In a rabbit model, leucovorin was administered up to 24 h after MTX injection.