Methotrexate (Post-conception)

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
Cooper (Controls exposed to other treatment, sick)
2014 		USA
1995 - 2007
retrospective cohort (claims database) 		Health databases of 3 geographically diverse health plans (Tennessee Medicaid, Kaiser Permanente Northern California, and Kaiser Permanente Southern California) Singleton birth in women with immune-mediated diseases treated with first-trimester exposure to methotrexate. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton birth in women with immune-mediated diseases treated with first-trimester exposure to immunosuppressive medications. 		1st trimester 23 / 379 Women receiving methotrexate may have filled prescriptions for other immunosuppressive medications. Immunosuppressive medications as Tumor necrosis factor inhibitors, Hydroxychloroquine, gold, sulfasalazine, leflunomide, azathioprine, and minocycline.
The Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases.
Cooper (Controls unexposed, sick)
2014 		USA
1995 - 2007
retrospective cohort (claims database) 		Health databases of 3 geographically diverse health plans (Tennessee Medicaid, Kaiser Permanente Northern California, and Kaiser Permanente Southern California) Singleton birth in women with immune-mediated diseases treated with first-trimester exposure to methotrexate. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Singleton birth in women with immune-mediated diseases treated with immunosuppressive medications in the 180 days before, but not during pregnancy. 		1st trimester 23 / 171 Women receiving methotrexate may have filled prescriptions for other immunosuppressive medications.
The Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases.
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.
Viktil (Controls exposed to other treatment, sick)
2012 		Norway
2004 - 2007
population based cohort retrospective 		Two nationwide health registers, the Norwegian Prescription Database (NorPD) and the Medical Birth Registry of Norway (MBRN) Singleton pregnancies whose mothers were dispensed methotrexate from 3 months prior to conception until labour. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton pregnancies whose mothers were dispensed other anti-rheumatic drugs (Prednisolone, NSAIDs, Sulfasalazine, Hydroxychloroquine, Azathioprine, Leflunomide, Etanercept, Adalumimab, or Anakinra) from 3 months prior to pregnancy to delivery. 		3 months (or more) before pregnancy or during pregnancy 8 / 1453 Only the first pregnancy for each parent during the study period was included. Some of the women received more than one of the drugs in the study period.
The Norwegian Prescription Database (NorPD). All prescribed drugs dispensed from Norwegian pharmacies were recorded from 3 months prior to conception until labour and for men during 3 months prior to conception.
Viktil (Controls unexposed NOS)
2012 		Norway
2004 - 2007
population based cohort retrospective 		Two nationwide health registers, the Norwegian Prescription Database (NorPD) and the Medical Birth Registry of Norway (MBRN) Singleton pregnancies whose mothers were dispensed methotrexate from 3 months prior to conception until labour. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Singleton pregnancies whose mothers didn't received an anti-rheumatic drugs in the period 3 months prior to conception until labour. 		3 months (or more) before pregnancy or during pregnancy, at least 1st trimester 8 / 154976 Only the first pregnancy for each parent during the study period was included. Some of the women received more than one of the drugs in the study period.
The Norwegian Prescription Database (NorPD). All prescribed drugs dispensed from Norwegian pharmacies were recorded from 3 months prior to conception until labour and for men during 3 months prior to conception.
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. 		at least 1st trimester 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. 		at least 1st trimester 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 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.
Vinet
2013 		Canada
1996 - 2008
nested case control 		The Régie de l'assurance maladie du Québec (RAMQ) physician billing and the Maintenance et exploitation des données pour l'étude de la clientèle hospitalière (MED-ECHO). Women having an induced abortion (at the index date). Age-matched controls selected at random from all subjects who entered the cohort on the same month and year as the case and who were born within 12 months of the case birthdate. Exposure was defined as having filled at least 1 prescription for methotrexate as recorded in the RAMQ prescription database. 3 months (or more) before pregnancy or during pregnancy 112 / 5855 Some women were also exposed to anti-TNF agents. Spontaneous abortions may be increased in women receiving MTX, consequently resulting in a lower induced abortion rate.
Either one procedure code and/or a diagnostic code for induced abortion present in the MED_ECHO hospitalization and/ or RAMQ billing databases.

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

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