Methotrexate (Pre-conception only)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Howren
2020 		Canada
2002 - 2012
retrospective cohort 		Three administrative health data holdings in British Columbia (BC), Canada, namely Population Data BC, PharmaNet, and the BC Perinatal Database Registry (BCPDR), linked to create a population-based pregnancy cohort. Pregnant women with rheumatic diseases who filled at least one prescription of methotrexate in preconception (90 days prior to the date of conception) or during pregnancy (i.e., from conception to delivery). (This is a subgroup of exposure among the one considered). unexposed, sick
Pregnancies in women with rheumatic diseases without filled prescriptions for conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) during aforementioned perinatal windows of interest. 		1st trimester, during pregnancy (anytime or not specified), preconceptional for kinetic reason 24 / 6064 Each pregnancy can be exposed to more than one category of csDMARDs.
PharmaNet captures complete information on all drug prescriptions dispensed including drug identification number, dispensation date, dispensation quantity, dosage, and duration.
Matsui
2003 		Japan
1974 - 2000
retrospective cohort 		Chiba University Hospital, Japan Pregnancies in women initially treated with methotrexate for gestational trophoblastic tumor who conceived less than 6 months after completion of chemotherapy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in women initially treated with chemotherapy for gestational trophoblastic tumor who conceived more than 6 months after completion of chemotherapy. 		preconceptional for kinetic reason 4 / 115 17 (30.4%) of 56 patients initially given MTX had to be switched to other single-agent regimens due to the development of drug resistance and/or toxicity. Drug resistance was defined after at least three consecutive cycles of chemotherapy.
Patients with gestational trophoblastic tumor underwent chemotherapy at Chiba University Hospital.
Svirsky
2017 		Israel
2004 - 2014
retrospective cohort 		Medical records of Assaf Harofe Medical Center in Zerifin. Women treated with methotrexate injection(s) for ectopic pregnancy who subsequently conceived less than 6 months after treatment. unexposed, sick
Women treated with methotrexate injection(s) for ectopic pregnancy who subsequently conceived more than 7 months after treatment (between 7 to ≥24 months). 		preconceptional for kinetic reason 93 / 133 There is a two years overlap between this study and an earlier published study by the same author: Svirsky et al., 2009.
Medical records.
Svirsky
2009 		Israel
2000 - 2006
retrospective cohort 		Medical records of Assaf Harofeh Medical Center Women treated with intramuscular injection of methotrexate (MTX) 50mg/m2 in a single dose for ectopic pregnancy who conceived within 6 months from the last methotrexate (MTX) injection. unexposed, sick
Women treated with intramuscular injection of methotrexate (MTX) 50mg/m2 in a single dose) for ectopic pregnancy who postponed conception for more than 6 months after the last methotrexate (MTX) injection. 		preconceptional for kinetic reason 45 / 80 Index pregnancy is the one following MTX treatment. In two cases of twin pregnancy only the outcome of the first newborn was considered for statistical analysis.
Computerized medical records and a telephone questionnaire when medical records were insufficients. After reviewing the medical records, the women were divided into two groups (less or more than 6 months).
Weber-Schoendorfer (Controls exposed to other treatment, sick)
2014 		Worldwide (9 countries)
1994 - 2011
prospective cohort 		European Network of Teratology Information Services (ENTIS) and Organization of Teratology Information Specialists (OTIS). Pregnant women who were exposed to MTX only before conception (i.e., between 10 weeks prior to the last menstrual period and no more than 1 week plus 6 days after the last menstrual period) or after conception (i.e., ≥1 dose 2 weeks after the first day of the last menstrual period). exposed to other treatment, sick
Pregnant women with rheumatic/inflammatory diseases who did not take MTX during pregnancy or during the 12 weeks before conception. These women had either been treated with other immunomodulatory drugs or the physician had decided not to prescribe any of these drugs. 		preconceptional for kinetic reason 324 / 459 Number of total assessed post-conception MTX-exposed infants not reported for genetic birth defects (so not reported here).
Data on exposure were obtained via structured telephone interviews and/or mailed questionnaires completed by the mother and/or her physicians.
Weber-Schoendorfer (Controls unexposed, disease free)
2014 		Worldwide (9 countries)
1994 - 2011
prospective cohort 		European Network of Teratology Information Services (ENTIS) and Organization of Teratology Information Specialists (OTIS). Pregnant women who were exposed to MTX only before conception (i.e., between 10 weeks prior to the last menstrual period and no more than 1 week plus 6 days after the last menstrual period) or after conception (i.e., ≥1 dose 2 weeks after the first day of the last menstrual period). unexposed, disease free
Pregnant women identified through teratology information service centers during spontaneous consultations for other conditions or exposures. Not affected by rheumatic/inflammatory diseases and were not taking any immunomodulatory drugs during pregnancy. 		preconceptional for kinetic reason 324 / 1107 Number of total assessed post-conception MTX-exposed infants not reported for genetic birth defects (so not reported here).
Data on exposure were obtained via structured telephone interviews and/or mailed questionnaires completed by the mother and/or her physicians.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Dawson
2014 		USA
1997 - 2009
case control 		National Birth defects Prevention Study (NBDPS). Infants with major birth defects identified through population-based surveillance systems. Live-born infants with no major birth defects selected at random from the same ascertainment area as case infants. Computer-assisted telephone interview which included detailed questions concerning exposures that occurred from 3 months prior to conception through the end of the pregnancy. Mothers were interviewed between 6 weeks and 24 months after their EDD. 1st trimester, 2nd and/or 3rd trimester, 3 months (or more) before pregnancy or during pregnancy, preconceptional for kinetic reason 27623 / 10113 Infants with birth defects with a known etiology, including those with recognized chromosomal syndromes or single-gene disorders, are excluded. The indication for methotrexate use was not reported in most cases.
A clinical geneticist and a pediatrician trained in cardiology review the abstracted clinical records for each case infant. Clinical records for control infants were not available for review.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

master protocol

- About - Master protocol - Browse exposition - RSS - Made with in Lyon - Contact us - Privacy policy - Licence Creative Commons