Leflunomide - Medication and Pregnancy KB

Leflunomide

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
Chambers (Unexposed control, disease free) 2010	USA and Canada 1999 - 2009 prospective cohort	Organization of Teratology Information Specialists (OTIS)	Pregnant women with a diagnosis of rheumatoid arthritis (RA) or juvenile rheumatoid arthritis (JRA) who took at least one dose of leflunomide (for any length of time) during the first trimester of pregnancy.	unexposed, disease free A comparison group of healthy pregnant women without a diagnosis of RA, JRA, or any other autoimmune disease, including type 1 or type 2 diabetes mellitus, and without exposure to any known human teratogen, including isotretinoin, anticonvulsants, and large quantities of alcohol.	1st trimester	64 / 78	2 OTIS articles NOT the same data. Cassina 2012 included women which did not meet the strict criteria of Chambers 2010 (enrolled > 20 GW, indication other than RA, or LEF discontinued within 2 years prior to conception but no elimination confirmation).
Chambers (Unexposed control, disease free) 2010	USA and Canada 1999 - 2009 prospective cohort	Organization of Teratology Information Specialists (OTIS)	Each woman completed 2 or 3 structured telephone interviews during pregnancy that included exposures. Each woman was provided with a diary in which she kept a record of any additional exposures that might occur before delivery. Medical records were examined for additional exposure data.		1st trimester	64 / 78
Chambers (Unexposed control, sick) 2010	USA and Canada 1999 - 2009 prospective cohort	Organization of Teratology Information Specialists (OTIS)	Pregnant women with a diagnosis of rheumatoid arthritis (RA) or juvenile rheumatoid arthritis (JRA) who took at least one dose of leflunomide (for any length of time) during the first trimester of pregnancy.	unexposed, sick A disease-matched comparison group of pregnant women with a diagnosis of RA or JRA who did not take leflunomide at any time during pregnancy and did not have exposure to any other known teratogenic agent.	1st trimester	64 / 108	2 OTIS articles NOT the same data. Cassina 2012 included women which did not meet the strict criteria of Chambers 2010 (enrolled > 20 GW, indication other than RA, or LEF discontinued within 2 years prior to conception but no elimination confirmation)
Chambers (Unexposed control, sick) 2010	USA and Canada 1999 - 2009 prospective cohort	Organization of Teratology Information Specialists (OTIS)	Each woman completed 2 or 3 structured telephone interviews during pregnancy that included exposures. Each woman was provided with a diary in which she kept a record of any additional exposures that might occur before delivery. Medical records were examined for additional exposure data.		1st trimester	64 / 108
Karadag 2013	Turkey 2004 - 2012 retrospective cohort	Hospital files	Female patients whose leflunomide was interrupted after detection of pregnancy.	unexposed, sick Female patients whose leflunomide was interrupted before pregnancy.	early pregnancy	3 / 13
Karadag 2013	Turkey 2004 - 2012 retrospective cohort	Hospital files	Hospital files were used for selecting patients who used leflunomide before or during pregnancy.		early pregnancy	3 / 13
Langen 2014	USA 2001 - 2009 retrospective cohort	Perinatal database of a tertiary care referral hospital.	Women with leflunomide near the time of conception. (This is a subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Women with prednisone only near the time of conception. (This is a subgroup of exposure among the whole exposed group considered in the study).	at least 1st trimester	2 / 15	Leflunomide was discontinued in the 2 pregnancies upon discovery of pregnancy.
Langen 2014	USA 2001 - 2009 retrospective cohort	Perinatal database of a tertiary care referral hospital.	Data were collected from review of medical records and included medication use.		at least 1st trimester	2 / 15
Viktil (Controls exposed to other treatments) 2012	Norway 2004 - 2007 population based cohort propective	Two nationwide health registers, the Norwegian Prescription Database (NorPD) and the Medical Birth Registry of Norway (MBRN)	Women with dispensation of Leflunomide from 3 months prior to pregnancy to delivery (subgroup of exposure among the whole exposed group considered in the study).	exposed to other treatment, sick Women with dispensation of other anti-rheumatic drugs (Prednisolone, NSAIDs, Sulfasalazine, Hydroxychloroquine, Etanercept, Adalimumab, Methotrexate, Leflunomid, or Anakinra) from 3 months prior to pregnancy to delivery.	3 months or more before pregnancy or1st trimester	2 / 1459	Analysis performed on anti-rheumatic drugs as a whole, no individual analyse for each substance. Raw data (number of exposed pregnancies and malformations) were available in the text and were used for this meta-analysis.
Viktil (Controls exposed to other treatments) 2012	Norway 2004 - 2007 population based cohort propective		Prescriptions were recorded from 3 months prior to conception until labour from the Norwegian Prescription Database (NorPD).		3 months or more before pregnancy or1st trimester	2 / 1459
Viktil (Controls unexposed, NOS) 2012	Norway 2004 - 2007 population based cohort propective	Two nationwide health registers, the Norwegian Prescription Database (NorPD) and the Medical Birth Registry of Norway (MBRN)	Women with dispensation of Leflunomide from 3 months prior to pregnancy to delivery (subgroup of exposure among the whole exposed group considered in the study).	unexposed (general population or NOS) Singleton pregnancies whose mothers did not received an anti-rheumatic drugs in the period 3 months prior to conception until labour.	3 months or more before pregnancy or1st trimester	2 / 154976	Analysis performed on anti-rheumatic drugs as a whole, no individual analyse for each substance. Raw data (number of exposed pregnancies and malformations) were available in the text and were used for this meta-analysis.
Viktil (Controls unexposed, NOS) 2012	Norway 2004 - 2007 population based cohort propective		Prescriptions were recorded from 3 months prior to conception until labour from the Norwegian Prescription Database (NorPD).		3 months or more before pregnancy or1st trimester	2 / 154976

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
Bérard 2018	Canada 1998 - 2015 nested case control	Quebec Pregnancy Cohort (QPC)	Spontaneous abortions (before the 22nd GW) or Singleton liveborns with malformations (exclusion of minor and chromosomal abnormalities) or prematurity (<37th GW) or LBW (<2500g).	Pregnancies ending without the considered adverse outcome.	The Quebec Prescription Drug Insurance database (drug name, start date, dosage, duration).	1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified)	14368 / 129948	Within the study cohort, 4 separate case–control analyses were conducted. Analyses of spontaneous abortions: all pregnancies; analyses of malformations, prematurity and LBW: only singleton liveborns. 1st trimester: 0–14 completed weeks of gestation.
Bérard 2018	Canada 1998 - 2015 nested case control	Quebec Pregnancy Cohort (QPC)	The medical service database (RAMQ: diagnoses, medical procedures, socio- economic status of women), the Hospital Records database (MedEcho: diagnoses and procedures, gestational age) and the Quebec Statistics database (ISQ: patient sociodemographic, birth weight).				14368 / 129948

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

master protocol