EFFECTS OF METHOTREXATE ON TROPHOBLAST PROLIFERATION AND LOCAL IMMUNE-RESPONSES

Methotrexate is a folic acid analogue that has been used successfully for the treatment of ectopic pregnancy and, in conjunction with misopr ostol, for medical abortions of early intrauterine pregnancies. To adm inister the most efficacious treatment requires knowledge of the mecha nism underlying the induction of methotrexate-induced abortion. This s tudy was designed to ascertain trophoblast integrity, proliferation an d differentiation following administration of methotrexate, In additio n, to determine if methotrexate affects the local uterine immune respo nse, we ascertained the numbers and identities of decidual leukocytes following treatment. Ten women with undesired intrauterine pregnancies of 42-49 days gestation were recruited to receive methotrexte 50 mg/m (2) i.m. A suction aspiration was performed 7 days later. Tissues from gestational age-matched elective surgical abortions were used as cont rols. Additionally specimens from women who received methotrexate and misoprostol for abortion in a clinical trial of oral methotrexate in c ombination with misoprostol, who had a suction abortion because of con tinued embryonic cardiac activity 14 days after the methotrexate, were evaluated, Immunoreactivity to proliferating cell nuclear antigen and cyclin D3 antibodies was used to demonstrate a marked reduction in th e proliferation index of cytotrophoblasts from methotrexate-treated ab ortions. Methotrexate treatment failures and non-treated pregnancies h ad a much higher proliferation index. There was no direct destruction of the syncytiotrophoblast, as indicated by the continued presence of human placental lactogen and beta-human chorionic gonadotrophin protei ns. A decrease in the total number of leukocyte cells was observed in the decidua of methotrexate-treated samples, with the large granular l ymphocyte (LGL) cells showing the greatest decline in numbers. Our con clusions from this study are that methotrexate acts primarily to derai l the normal developmental programme of the trophoblast stem cell popu lation, as well as to decrease LGL cell numbers in the decidua.