USE OF METHOTREXATE IN PREGNANCY

Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate is used (at various doses) for the treatment of cancer, rheumatic disorders, Crohn’s disease and psoriasis. High-dose methotrexate is also used in the termination of pregnancy and the treatment of ectopic pregnancy.

High-dose methotrexate for medical termination and treatment of ectopic pregnancy
High-dose methotrexate is an abortifacient and a teratogen. There are multiple case reports describing malformed infants who were exposed to ~50mg/m2 methotrexate in utero following failed medical termination of pregnancy and during the treatment of misdiagnosed ectopic pregnancies.

High-dose methotrexate exposure appears to cause a distinct embryopathy that includes craniofacial defects, malformations of the digits, and defects of the spine and ribs. There are also reports of ear, kidney and lung defects, and hypospadias. The majority of these cases involve exposures that were reported to have taken place between four and eight gestational weeks. There are a number of case reports of infants who also have cardiac defects (notably Tetralogy of Fallot) who were exposed to high-dose methotrexate between five and six gestational weeks.

Methotrexate embryopathy also appears to incorporate intrauterine growth restriction, and there is evidence that affected individuals might experience reduced growth into childhood and beyond. Due to a lack of data, it is unclear whether gestational methotrexate exposure might be associated with preterm delivery or increased risk of intrauterine death in exposed fetuses surviving beyond 24 weeks’ gestation. Normal and abnormal neurodevelopment has been reported following gestational exposure to high-dose methotrexate; however, in the majority, no adverse neurodevelopmental outcomes were identified in individuals both with and without methotrexate embryopathy. Overall, the available data are limited, and because there are no large-scale controlled studies of high-dose methotrexate exposure in pregnancy, the risk of any adverse pregnancy outcome following exposure remains unquantified.

Methotrexate for auto-immune disease
Methotrexate is generally used in low doses (≤25mg/week) to treat autoimmune disease. Data are too limited to facilitate an evidence-based risk assessment of adverse pregnancy outcomes following low-dose methotrexate exposure.

A single small study found that miscarriage rates were increased approximately two-fold in women exposed to low-dose methotrexate in early pregnancy compared to non-exposed women from both disease-matched and healthy control groups. Case reports detail 69 infants gestationally exposed to methotrexate in the treatment of maternal autoimmune illness. Although the majority describe uneventful outcomes, five reports describe infants with birth defects that have been reported in (but are not exclusive to) methotrexate embryopathy. Some of these exposures involved doses reportedly as low as 7.5mg/week. Conclusions regarding the aetiology of the birth defects described in these case reports are limited by concurrent medication exposures and lack of comprehensive genetic testing to rule out other diagnoses. Two small cohort studies and a single case-control study provided no convincing evidence of an association between gestational low-dose methotrexate exposure and congenital malformation in the infant. However, these studies were underpowered and larger studies are therefore required.

A single study has assessed the impact of gestational methotrexate exposure on fetal weight and gestational age at delivery, finding that these outcomes did not differ significantly between exposed and non-exposed infants. No studies have assessed neurodevelopmental outcomes following gestational methotrexate exposure specifically for the treatment of maternal autoimmune disease.

Methotrexate for cancer treatment
Methotrexate is used at various doses for the treatment of cancer, often alongside other embryotoxic/teratogenic antineoplastic agents. As such, interpretation of the available data is limited by variation in maternal doses and may also be heavily influenced by both concomitant exposures and severe maternal illness.

There are no large-scale controlled studies of pregnancy outcomes following methotrexate exposure in cancer chemotherapy and data are too limited to permit an evidence-based risk assessment. Case reports describing pregnancy outcomes following first trimester exposure to methotrexate in chemotherapy treatment detail 10 uneventful pregnancy outcomes, one miscarriage, one stillbirth of a non-malformed infant, two infants with minor malformations, and one infant with severe craniofacial abnormalities following multiple exposures to 80mg/week from gestational week nine. It is noteworthy that some chemotherapeutic regimens might utilise methotrexate doses that overlap with those used for the other indications described in this document. The data on fetal risk relating to use in these indications might therefore apply to methotrexate use in cancer treatment.

Pre-conceptual exposure to methotrexate
Owing to the theoretical risk of accumulation of intracellular methotrexate administered preconceptually, the manufacturers of methotrexate recommend avoiding pregnancy until six months post-exposure. The British Society for Rheumatology and British Health Professionals recommendations (published 2016) state that methotrexate at any dose should be avoided in pregnancy and stopped three months in advance of conception.
Data from inadvertent conception within six months of treatment do not provide strong evidence that methotrexate exposure is associated with increased rates of miscarriage or congenital malformation in the infant but are limited both in quantity and methodologically. Additionally, many of the reported cases relate to methotrexate treatment for autoimmune illness, where doses were likely to have been significantly lower than those used for elective termination and to treat ectopic pregnancy.

Folic acid
Methotrexate is a folic acid antagonist. Reports of co-administration of folic acid with methotrexate in pregnancy are few, therefore there is insufficient evidence to state whether supplemental use of folic acid in pregnancy might prevent or ameliorate adverse fetal outcomes. However, in light of the established and theoretical risks of the detrimental effects of maternal folic acid deficiency on a developing fetus, high-dose folic acid supplementation (5mg/day) is recommended throughout pregnancy for all women taking methotrexate.

Advice and investigations
Exposure to high-dose methotrexate in early pregnancy confers a risk of severe embryopathy in the fetus and the option of termination of pregnancy should be discussed with the patient. For women with ongoing pregnancies, additional fetal monitoring is advised, including focussed fetal anomaly scans and close monitoring of fetal growth. Women should be made aware of the limitations of these investigations and that impaired neurodevelopment may occur in the absence of structural anomalies.

Where exposure to lower doses of methotrexate has occurred prior to conception, or in the treatment of maternal autoimmune disease or cancer, additional fetal monitoring is also advised, and women and their partners should be counselled about the lack of available data to facilitate quantification of risk of adverse pregnancy outcomes.

Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.