Congenital cardiac defects: a possible association of aminopterin syndrome and in utero methotrexate exposure?

Pediatr Cardiol. 2011 Apr;32(4):518-20. doi: 10.1007/s00246-011-9913-z. Epub 2011 Feb 17.


Folate antagonist are chemotherapeutic agents used in many neoplastic, autoimmune, and inflammatory disorders. The first suggestions that folic acid antagonists were teratogenic in humans were based on reports of failed terminations in mothers given aminopterin in the first trimester. Newborns who survived after aminopterin exposure were noted for years to have defects of the neural tube, skull, or limbs. There is now a well-defined syndrome of congenital anomalies associated with the use of aminopterin. The aminopterin syndrome consists of cranial dysostosis, hypertelorism, anomalies of the external ears, micrognathia, limb anomalies, and cleft palate. The use of aminopterin has now fallen out of favor. Methotrexate is a folate antagonist that is now used more frequently. A similar pattern of malformations has been found in fetuses exposed to methotrexate. If used during pregnancy, it can cause congenital malformations or fetal death. A consistent association between methotrexate exposure and cardiac, renal, or gastrointestinal malformations has not been reported. We report two patients who presented with classic features of aminopterin syndrome combined with significant congenital cardiac malformations after first-trimester in utero methotrexate exposure. Both of these patients survived to undergo corrective cardiac surgery.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Drug-Induced*
  • Abnormalities, Multiple / chemically induced*
  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / surgery
  • Adult
  • Angiography
  • Cardiac Surgical Procedures / methods*
  • Craniofacial Abnormalities / chemically induced
  • Craniofacial Abnormalities / diagnosis
  • Craniofacial Abnormalities / surgery
  • Diagnosis, Differential
  • Echocardiography
  • Female
  • Follow-Up Studies
  • Heart Defects, Congenital / chemically induced*
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / surgery
  • Humans
  • Infant
  • Intellectual Disability / chemically induced
  • Intellectual Disability / diagnosis
  • Intellectual Disability / surgery
  • Lupus Erythematosus, Systemic / drug therapy
  • Male
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use
  • Pregnancy
  • Pregnancy Complications / drug therapy
  • Prenatal Exposure Delayed Effects*


  • Methotrexate

Supplementary concepts

  • Pseudoaminopterin syndrome