USE OF METHOTREXATE IN PREGNANCY

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(Date of issue: April 2016, Version: 1.1)

This is a UKTIS monograph for use by health care professionals. For case-specific advice please contact UKTIS on 0344 892 0909. To report an exposure please download and complete a pregnancy reporting form. Please encourage all women to complete an online reporting form.

A corresponding patient information leaflet on methotrexate use in pregnancy is available at www.medicinesinpregnancy.org.

Summary

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 intrauterine 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 in 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 embropathy. 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 spontaneous abortion rates were increased approximately twofold in women exposed to low dose methotrexate in early pregnancy compared to non-exposed women in both a disease-matched and healthy control group. 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 reported in, but not exclusive to, methotrexate embryopathy, with some of these infants having been exposed to doses reportedly as low as 7.5mg/week. However, a single small cohort study found no evidence that congenital malformation rates following gestational methotrexate exposure in the treatment of maternal autoimmune illness were significantly higher compared to those within a disease-matched control group, although rates were increased in comparison to healthy unexposed pregnancies. A single case-control study also provided no convincing evidence of an association between gestational low-dose methotrexate exposure and congenital malformation in the infant. Conclusions regarding the etiology of the birth defects described in the case reports are limited by concurrent medication exposures and lack of comprehensive genetic testing to rule out other diagnoses. A single study has assessed impact on fetal weight and gestation. Mean birth weights and gestational age at delivery 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, and 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 spontaneous abortion, 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. Data from inadvertent conception within six months of treatment do not provide strong evidence that methotrexate exposure is associated with increased rates of spontaneous abortion or congenital malformation in the infant but are limited both in quantity and methodologically. Additionally, almost all of the reported cases relate to methotrexate treatment for autoimmune illness, where doses were likely to have been significantly lower than those used to 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 and there is therefore 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. If women choose to continue their pregnancy, additional fetal monitoring is advised including detailed fetal anomaly scans and assessment 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.

This document is regularly reviewed and updated. Only use full UKTIS monographs downloaded directly from TOXBASE.org to be sure you are using the most up-to-date version. The summaries of these monographs are openly available on UKTIS.org.

This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to health care professionals at www.toxbase.org.

If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.

If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.

Disclaimer: Every effort has been made to ensure that this monograph was accurate and up-to-date at the time of writing, however it cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes of the measures recommended. The final decision regarding which treatment is used for an individual patient remains the clinical responsibility of the prescriber. This material may be freely reproduced for education and not for profit purposes within the UK National Health Service, however no linking to this website or reproduction by or for commercial organisations is permitted without the express written permission of this service. This document is regularly reviewed and updated. Only use UKTIS monographs downloaded directly from TOXBASE.org or UKTIS.org to ensure you are using the most up-to-date version.