Teratogen update: Methotrexate

Abstract

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m 2 (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.

Maternal environmental risk factors for congenital hydrocephalus: a systematic review

“…26 The 13 studies included in this systematic review have highlighted important factors associated with an increased risk of CH development. Nevertheless an additional point that needs to be made is that, aside from 1 meta-analysis, 23 5 large cohort studies, 5,13,18,20,26 and 3 case-control studies, 4,14,15 the remaining evidence was drawn from 3 case series and 1 case report. Moreover, even in the large-scale cohort and case-control studies, assessment of individual risk factors for CH was based on a limited number of cases.…”

“…Thus, the aforementioned findings should be interpreted cautiously and regarded as possible future avenues of research under epidemiological, clinical, and preclinical settings. 1,10,13,20,30 …”

Fertility, pregnancy planning, and pharmacotherapy during the pregnancy, postpartum and breastfeeding period in patients with rheumatoid arthritis and other inflammatory arthropathies

“…According to the authors the incidence of miscarriages and developmental anomalies in the studied group of patients was similar to that in the healthy population [16]. Of interest was, however, the higher risk of embryopathy in the form of pulmonary valve atresia, craniosynostosis and developmental anomalies of the limbs [17].…”

“…Według autorów częstość poronień i zaburzeń rozwojowych w badanej grupie chorych była porównywalna z częstością dotyczącą zdrowej populacji [16]. Zwraca się jednak uwagę na większe ryzyko wystą-pienia embriopatii w postaci atrezji płucnej (zarośnięcie zastawki tętnicy płucnej), przedwczesnego zarośnięcia szwów czaszkowych (craniosynostosis) oraz zaburzeń rozwojowych kończyn [17].…”

“…[17]. Metotreksat w nieznacznych ilościach przechodzi do mleka matki, dlatego Amerykań-skie Towarzystwo Pediatryczne (American Academy of Pediatrics -AAP) nie zaleca stosowania tego leku w czasie laktacji z uwagi na ryzyko supresji immunologicznej, neutropenii oraz nieznany wpływ na rozwój dziecka lub na karcynogenezę [19].…”