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Verberne, Eline A.; de Haan, Emma; van Tintelen, J. Peter; Lindhout, Dick; van Haelst, Mieke M.
Reproductive toxicology, August 2019, 2019-08-00, Volume: 87Journal Article
•In utero methotrexate exposure can lead to a distinct malformation pattern.•This pattern includes microcephaly, craniosynostosis, heart defects and limb anomalies.•The teratogenic methotrexate dose is probably lower than previously suggested.•The critical period of methotrexate teratogenicity seems to be larger than previously suggested. Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the ‘fetal methotrexate syndrome’. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome.
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