{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:28:32Z","timestamp":1791181712003,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,3,20]],"date-time":"2012-03-20T00:00:00Z","timestamp":1332201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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<jats:sup>2<\/jats:sup> (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\u2010set 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\u2010related 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\u2010exposed children. Denominator\u2010based 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. Birth Defects Research (Part A), 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/bdra.23003","type":"journal-article","created":{"date-parts":[[2012,3,20]],"date-time":"2012-03-20T13:02:41Z","timestamp":1332248561000},"page":"187-207","source":"Crossref","is-referenced-by-count":179,"title":["Teratogen update: Methotrexate"],"prefix":"10.1002","volume":"94","author":[{"given":"Sara C.","family":"Hyoun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah G.","family":"Obi\u010dan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Scialli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,3,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006250-200806000-00044"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20503"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1701-2163(16)30422-4"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830360404"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp0810384"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9926(199802)57:2<51::AID-TERA2>3.0.CO;2-9"},{"key":"e_1_2_6_8_1","first-page":"469","article-title":"Transient inhibition of DNA synthesis by methotrexate in the rat embryo and foetus","volume":"26","author":"Berry CL","year":"1971","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_6_9_1","first-page":"54","volume-title":"Drugs in pregnancy and lactation","author":"Briggs GG","year":"2011"},{"key":"e_1_2_6_10_1","first-page":"359","article-title":"Metastatic choriocarcinoma in a viable intrauterine pregnancy treated with EMA\u2010CO in the third trimester. a case report","volume":"56","author":"Brudie LA","year":"2011","journal-title":"J Reprod Med"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400527"},{"key":"e_1_2_6_12_1","first-page":"241","article-title":"The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes","volume":"30","author":"Chakravarty EF","year":"2003","journal-title":"J Rheumatol"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0029-7844(03)00120-0"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33496"},{"key":"e_1_2_6_15_1","first-page":"94","article-title":"Metropolitan Atlanta Congenital Defects Program 40th Anniversary Edition Surveillance Report. 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