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Aminopterin/methotrexate embryofetopathy

Synonym(s) Aminopterin embryopathy syndrome
Fetal aminopterin syndrome
Prevalence <1 / 1 000 000
Inheritance Not applicable
Age of onset Antenatal
  • Q86.8
  • C0432367
MeSH -
  • 10071183


Disease definition

Aminopterin/Methotrexate embryofetopathy is a syndrome of developmental anomalies characterized by growth deficiency, facial dysmorphism and skull, limb and neural defects secondary to maternal exposure to aminopterin or methotrexate (MTX) during pregnancy.


At least 51 cases have been reported in the last decades; prevalence and incidence values are not available.

Clinical description

Fetuses and neonates present with short stature, skull anomalies (delayed calvarial ossification, craniosynostosis and cloverleaf skull), facial dysmorphism (hypertelorism, broad nasal bridge, prominent eyes, micrognathia, abnormal external ears), cleft palate, hydrocephalus, limb anomalies (shortness, ossification defects, talipes equinovarus, hypodactyly, syndactyly, hypoplastic toes, hypoplastic nails) and neural tube defects. In some cases, cardiac malformations such as tetralogy of Fallot, pulmonary atresia or ventricular septal defects have been reported. Occasional encephalic anomalies are absent corpus callosum, hypoplastic cerebellum and, more rarely, holoprosencephaly. Psychomotor development is usually normal, but cases with mild to severe intellectual deficit are reported.


The syndrome is caused by exposure during the first trimester of pregnancy to aminopterin or MTX, two folate antagonists. Aminopterin is no longer used, but MTX is used as an abortifacient (especially in case of suspected ectopic pregnancy), in inflammatory diseases (Crohn's disease, psoriasis, rheumatoid arthritis) and in malignancies (at higher doses). The teratogenic effect was described very early, given the anti-mitotic activity. The malformation rate after in utero exposure to aminopterin or MTX is not known, but it is dose- and time-related. It has been suggested that the critical period for MTX-induced teratogenicity is from 6 to 8 weeks after conception. Paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring, but therapy discontinuation 3-6 months before conception is usually advised.

Diagnostic methods

Diagnosis is based on clinical examination and a history of maternal/paternal exposure.

Differential diagnosis

Differential diagnosis includes various genetic diseases presenting with one of the following signs: anomalies of the developing calvaria, micrognathia with cleft palate (including Pierre Robin syndrome - see this term), limb reduction defects and hand/feet anomalies. An "aminopterin syndrome sine aminopterin (ASSA) syndrome" (see this term) has been described..

Antenatal diagnosis

Antenatal diagnosis can be oriented by 2nd-3rd trimester ultrasound if intrauterine growth retardation (IUGR), oligo-polyhydramnios and/or malformations are seen in an at-risk pregnancy.

Management and treatment

MTX and aminopterin should not be administered in pregnant women. A pregnancy could be considered, 3-6 months after MTX treatment has been stopped by women or men. Women with chronic diseases should be counseled to plan their pregnancies. In case of exposure during the 6 months preceding conception, folic acid supplementation (5 mg/day) is recommended in the preconception period (1-3 months) and for the whole first trimester of pregnancy. Folic acid supplementation (5 mg/day) is recommended throughout pregnancy for women exposed to aminopterin or MTX during pregnancy. Pregnancies exposed to aminopterin or MTX should be carefully monitored with second level ultrasounds and fetal heart ultrasound to control potential anomalies. Cardiac malformations can be corrected by surgery.


Prognosis depends on the extent and severity of malformations.

Expert reviewer(s)

  • Dr Matteo CASSINA
  • Pr Maurizio CLEMENTI

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