TNF-alpha inhibitors

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
Agosti
2015 		Italy
Not specified
retrospective cohort 		Not specified Children who were exposed in utero to anti-TNFalfa agents. unexposed, sick
Non-exposed children born to women with the same disease. 		during pregnancy (anytime or not specified) 24 / 24 Exposures: 20 exposed to etanercept, 3 to adalimumab, 1 to certolizumab.
Not specified.
Broms (Controls exposed to other treatments)
2020 		Denmark, Finland and Sweden
2006 - 2013
population based cohort retrospective 		A population-based study based on nationwide medical birth registers, patient registers, and registers of prescribed drugs, Women who filled prescriptions for Anti-TNF agent (ETA, IFX, ADA, CZP, or GOL) within 90 days before their LMP until delivery. exposed to other treatment, sick
Women who filled prescriptions for Nonbiologic systemic treatment (mainly azathioprine, corticosteroids, sulfasalazine, anti-malarials, and methotrexate) within 90 days before their LMP until delivery. 		3 months (or more) before pregnancy or during pregnancy, during pregnancy (anytime or not specified) 1027 / 9393
The national prescribed drug registers. Information was also identified from the National Patient Register (Denmark), from the register for biologic treatment (Finland) and from the ARTIS and PsoReg registers (Sweden).
Broms (Controls unexposed, disease free)
2020 		Denmark, Finland and Sweden
2006 - 2013
population based cohort retrospective 		A population-based study based on nationwide medical birth registers, patient registers, and registers of prescribed drugs, Women who filled prescriptions for Anti-TNF agent (ETA, IFX, ADA, CZP, or GOL) within 90 days before their LMP until delivery. unexposed, disease free
The general population (women without the diseases of interest and without treatment). 		3 months (or more) before pregnancy or during pregnancy 1027 / 1623483
The national prescribed drug registers. Information was also identified from the National Patient Register (Denmark), from the register for biologic treatment (Finland) and from the ARTIS and PsoReg registers (Sweden).
Bröms a (Controls unexposed, disease free)
2016 		Denmark and Sweden
2004/6 - 2012
population based cohort retrospective 		National danish and swedish population-based health registers: the national medical birth registers, patient registers, and registers on prescribed drugs Women who had filled prescriptions for etanercept, infliximab, adalimumab, certolizumab-pegol, or golimumab within 90 days before and 90 days after their last menstrual period. unexposed, disease free
Women without disease or TNF treatment (ie, the general population). 		3 months or more before pregnancy or1st trimester 683 / 1250192 EXPOSURE: ETN (50.4%), INF (22.8%), ADA (23.6%), CER (0.3%), GOL (0.6%), combinations (2.3%).
The national registers on prescribed drugs. Anti-TNF treatment also identified from visits recorded in the patient register covering all Danish hospitals using a specific treatment code (Denmark) or from the ARTIS and PsoReg registers (Sweden).
Bröms a (Controls unexposed, sick)
2016 		Denmark and Sweden
2004/6 - 2012
population based cohort retrospective 		National danish and swedish population-based health registers: the national medical birth registers, patient registers, and registers on prescribed drugs Women who had filled prescriptions for etanercept, infliximab, adalimumab, certolizumab-pegol, or golimumab within 90 days before and 90 days after their last menstrual period. unexposed, sick
Women with chronic inflammatory disease but no anti-TNF treatment. 		3 months or more before pregnancy or1st trimester 683 / 21549 EXPOSURE: ETN (50.4%), INF (22.8%), ADA (23.6%), CER (0.3%), GOL (0.6%), combinations (2.3%). Controls: Corticosteroids (7.7%); anti-inflammatory treatments (20.8%: AZA, mercaptopurine, cyclosporine, acitretin, mycophenolate...); MTX (0.2%).
The national registers on prescribed drugs. Anti-TNF treatment also identified from visits recorded in the patient register covering all Danish hospitals using a specific treatment code (Denmark) or from the ARTIS and PsoReg registers (Sweden).
Carman - Etanercept (Controls unexposed, disease free)
2017 		USA
1995 - 2012
retrospective cohort (claims database) 		Claims‐based data from a large US health plan research database affiliated with Optum (ORD) Pregnant women diagnosed with chronic inflammatory arthritis (cIA) or Psoriasis (PsO) treated with etanercept during pregnancy. unexposed, disease free
General population comparator group without chronic inflammatory arthritis (cIA) or Psoriasis (PsO) or TNFi treatment (ETN, adalimumab, certolizumab, golimumab, or infliximab). 		during pregnancy (anytime or not specified) 337 / 1685 Addition of Chronic Inflammatory Arthritis (n=256) and Psoriasis (n=81) patients and their respective control group (n=1280 and 405).
The ETN‐exposure was defined as having at least one administration or pharmacy dispensing during pregnancy. Provider‐administered drug exposures were identified using procedure codes for injections or infusions pharmacy dispensing claims.
Carman - Etanercept (Controls unexposed, sick)
2017 		USA
1995 - 2012
retrospective cohort (claims database) 		Claims‐based data from a large US health plan research database affiliated with Optum (ORD) Pregnant women diagnosed with chronic inflammatory arthritis (cIA) or Psoriasis (PsO) treated with etanercept during pregnancy. unexposed, sick
Pregnant women diagnosed with chronic inflammatory arthritis (cIA) or Psoriasis (PsO) not treated with any TNFi (ETN, adalimumab, certolizumab, golimumab, or infliximab). 		during pregnancy (anytime or not specified) 337 / 2861 Addition of Chronic Inflammatory Arthritis (n=256) and Psoriasis (n=81) patients and their respective control group (n=1512 and 1349).
The ETN‐exposure was defined as having at least one administration or pharmacy dispensing during pregnancy. Provider‐administered drug exposures were identified using procedure codes for injections or infusions pharmacy dispensing claims.
Casanova
2013 		Spain
Not specified
retrospective cohort 		Inflammatory bowel disease (IBD) Units from 24 Spanish hospitals Pregnancies in IBD patients on anti-TNF-α during pregnancy or during the 3 months before conception. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancies in IBD patients which did not receive thiopurines or anti-TNF-α drugs either during pregnancy or the 3 months before conception. (84% exposed to 5-Aminosalicylates and/or steroids). 		3 months (or more) before pregnancy or during pregnancy 66 / 318 Primary aim: evaluate the safety of thiopurines and anti-TNF-α during conception and pregnancy in IBD patients. Exposed population divided in 2 groups: A) thiopurines alone; B) anti-TNF-α drugs (IFX, ADA, and CZB) with or without concomitant thiopurines.
Data were obtained from the review of medical records and an interview with the patient when additional information was necessary was conducted. Collected data including data on drugs received during 3 months before conception and during pregnancy.
Chambers - Adalimumab (Controls unexposed, disease free)
2017 		USA and Canada
2004 - 2014
prospective cohort 		OTIS (Organization of Teratology Information Specialists) Pregnant women who had been treated with adalimumab in pregnancy for Rheumatoid arthritis (RA) or Crohn’s Disease (CD). unexposed, disease free
Pregnant women non diseased and unexposed to adalimumab. 		at least 1st trimester 257 / 225 Chambers 2017: related to the 2 indications: RA et CD. Chambers 2017 included rather than Burmester 2017 (the latest Short Communication published) because it concerns only RA.
Not specified. Women in the USA or Canada were enrolled in pregnancy prior to 20 weeks’ gestation.
Chambers - Adalimumab (Controls unexposed, sick, ADA only)
2017 		USA and Canada
2004 - 2014
prospective cohort 		OTIS (Organization of Teratology Information Specialists) Pregnant women who had been treated with adalimumab in pregnancy for Rheumatoid arthritis (RA) or Crohn’s Disease (CD). unexposed, sick
Pregnant women disease-matched not treated with adalimumab. 		at least 1st trimester 257 / 120 Chambers 2017: related to the 2 indications: RA et CD. Chambers 2017 included rather than Burmester 2017 (the latest Short Communication published) because it concerns only RA.
Not specified.
Chambers - Etanercept
2015 		USA and Canada
2005 - 2012
prospective cohort 		OTIS (Organization of Teratology Information Specialists) Pregnancy outcomes in women treated with Etanercept. A total of 344 women received ETA in the first trimester; and 51% used ETA in the third trimester. unexposed, sick
Pregnancy outcomes in disease-matched (DM) women. 		at least 1st trimester 370 / 164 There were no significant differences between groups in prenatal or postnatal growth, rates of serious or opportunistic infections, or developmental concerns on the ASQ. No malignancies were reported.
Women were followed up with multiple telephone interviews and medical record review.
Chaparro
2018 		Multicenter European countries
1999 - 2014
retrospective cohort 		A retrospective multicenter cohort study of children born to women diagnosed with IBD identified by practitioners specialized in IBD Children from mothers with IBD treated with anti- TNFα drugs either in monotherapy or in combination with thiopurines at any time during pregnancy or during the 3 months before conception. unexposed, sick
Children from mothers with IBD not treated with anti-TNFα drugs or thiopurines at any time during pregnancy or during the 3 months before conception. 		3 months (or more) before pregnancy or during pregnancy 388 / 453 Exposure: Infliximab (n = 223), Adalimumab (n = 164), Certolizumab pegol (n = 1): First trimester : 353 (91%); Second trimester : 345 (89%); Thrid trimester: 148 (38%).
Practitioners specialized in IBD identified women who received or did not receive anti-TNFα drugs for IBD during their pregnancy. Data (including medical treatment during conception, pregnancy...) were obtained from the medical records and the mothers were asked in case of missing data.
Cooper
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) Prescription for one of tumor necrosis factor inhibitor (TNFi) (in the absence of methotrexate fetal exposure) during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women with immune-mediated diseases treated with immunosuppressive medications in the 180 days before, but not during, pregnancy. 		1st trimester 56 / 171 Births in which the mother received prescriptions during the first trimester for medications thought to be teratogenic (valproic acid, chemotherapy medications, lithium misoprostol, and warfarin) were excluded.
The Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases.
De Lima
2018 		The Netherlands
2014 - 2017
prospective cohort 		Outpatient clinic at the Erasmus University Medical Center Rotterdam, a tertiary health centre Children born to mothers with IBD treated with anti-TNF during part of the pregnancy or the entire pregnancy. exposed to other treatment, sick
Children born to mothers with IBD not treated with anti-TNF, but any other IBD medication was permitted. 		at least 1st trimester, during pregnancy (anytime or not specified) 15 / 12 Women in the study group were treated with anti-TNF alpha during pregnancy, at least until the end of the second trimester. Exposure: IFX (n=8); ADA (n=7)
Data on medication were collected before pregnancy and during each visit at our IBD outpatient clinic, bi-monthly during pregnancy by an experienced IBD physician.
De Lima (Controls unexposed, disease free)
2016 		The Netherlands
2008 - 2014
prospective cohort 		2 prospective cohorts of the same region: a single centre clinical cohort study conducted at the Erasmus University Medical Center Rotterdam (exposed) and Generation R (control) Children born to IBD mothers, exposed to anti-TNF in utero (exposure at least during the 1st trimester and continued during 2nd and/or 3rd trimester). unexposed, disease free
Children born to non-IBD mothers not treated with anti-TNF as recruited from the Generation R cohort. 		1st and 2nd trimester, during pregnancy (anytime or not specified) 83 / 804 In part this cohort consists of patients from a previously published cohort (Zelinkova et al., 2013). Exposed group included: Stop group (Anti-TNF stopped after T1 and before 25 GW) and Continue group (anti-TNF not stopped or stopped after 30 GW).
At this specialised outpatient clinic, an experienced gastroenterologist counsels and treats patients with IBD before pregnancy and bimonthly during pregnancy. At every visit, data on medication use was recorded.
De Lima (Treatment stopped during pregnancy, sick)
2016 		The Netherlands
2008 - 2014
prospective cohort 		A single prospective centre clinical cohort study conducted at the Erasmus University Medical Center Rotterdam (exposed) Children born to IBD mothers exposed to anti-TNF in utero at least during the first trimester and continued at least until GW 30 (continue group). unexposed, sick
Children born to IBD mothers exposed to anti-TNF in utero at least during the first trimester and discontinued before week 25 (stop group). 		1st and 2nd trimester 32 / 51 In part this cohort consists of patients from a previously published cohort (Zelinkova et al., 2013). Exposed group divided by 2: Stop group (Anti-TNF stopped after T1 and before 25 GW) versus continue group (anti-TNF not stopped or stopped after 30 GW).
At this specialised outpatient clinic, an experienced gastroenterologist counsels and treats patients with IBD before pregnancy and bimonthly during pregnancy. At every visit, data on medication use was recorded.
De Lorenzo (Controls unexposed, disease free)
2020 		Italy
2009 - 2017
retrospective cohort 		The Clinic for Pregnancy and Autoimmunity at the San Raffaele University Hospital, Milan, Italy. Children born to mothers with autoimmune diseases on Anti-TNF therapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Children born to healthy mothers. 		at least 1st trimester 12 / 36 Exposed group: addition of children exposed in utero to Etanercept, Adalimumab, Infliximad and Certolizumab.
Data were collected retrospectively during paediatric consultations.
De Lorenzo (Controls unexposed, sick)
2020 		Italy
2009 - 2017
retrospective cohort 		The Clinic for Pregnancy and Autoimmunity at the San Raffaele University Hospital, Milan, Italy. Children born to mothers with autoimmune diseases on Anti-TNF therapy during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Children born to mothers with autoimmune diseases not treated with Biologic disease-modifying anti-rheumatic drugs (bDMARDs). 		at least 1st trimester 12 / 32 Exposed group: addition of children exposed in utero to Etanercept, Adalimumab, Infliximad and Certolizumab. Unexposed: 13 of 32 neonates were born to mothers under no immunosuppressive, 15 to HCQ, 1 to AZA and 3 to both AZA and HCQ.
Data were collected retrospectively during paediatric consultations.
Desai
2017 		USA
2000 - 2010
retrospective cohort (claims database) 		Medicaid Analytical eXtract files and Optum Clinformatics files: 1 public and 1 private heatlh insurance programs, respectively Pregnant women treated with TNF inhibitors for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. exposed to other treatment, sick
Pregnant women treated with non-biologic agents for immunosuppressive drugs for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. 		during pregnancy (anytime or not specified) 776 / 816 Two control groups: steroids, non-biologic agents. The control group 'non-biologic agents' was retained because patients should be closer than patients with TNFa inhibitors.
Pharmacy dispensing databases of health insurances.
Diav-Citrin (Controls exposed to other treatments)
2014 		Israel
2002 - 2011
prospective cohort 		Israeli Teratology Information Service (TIS) Pregnant women counseled for TNF-a-antagonists (infliximab, etanercept, or adalimumab) exposure. exposed to other treatment, sick
Pregnant women with similar autoimmune diseases not treated with anti-TNF-a medications during pregnancy (either treated with medications other than anti-TNF-a excluding methotrexate, or untreated during pregnancy). 		1st trimester 83 / 86 Analyses were performed for the group of 3 TNF-α inhibitors (35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnan- cies). Indication: various immune mediated disease.
Details of exposure were collected during pregnancy, at the initial contact with the TIS and before pregnancy outcome was known, using a structured questionnaire.
Diav-Citrin (Controls unexposed, disease free)
2014 		Israel
2002 - 2011
prospective cohort 		Israeli Teratology Information Service (TIS) Pregnant women counseled for TNF-a-antagonists (infliximab, etanercept, or adalimumab) exposure. unexposed, disease free
Pregnant women counseled for non-teratogenic exposure (Pregnancies of women who have chronic diseases were not included in the non-teratogenic-exposed group (unexposed control)). 		1st trimester 83 / 341 Analyses were performed for the group of 3 TNF-α inhibitors (35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnan- cies). Indication: various immune mediated disease.
Details of exposure were collected during pregnancy, at the initial contact with the TIS and before pregnancy outcome was known, using a structured questionnaire.
Drechsel
2020 		Not specified
2007 - 2018
prospective cohort 		The Juvenile idiopathic arthritis (JIA) registry Biologics in Paediatric Rheumatology (BiKeR) and its follow-up registry, Juvenile arthritis Methotrexate/Biologics long-term Observation (JuMBO). Pregnancies with maternal TNF inhibitors only exposure. unexposed, sick
Pregnancies unexposed to disease modifying antirheumatic drug (DMARD). 		1st trimester 21 / 85 Addition of Etanercept only and other TNFi only. Major congenital anomalies were classified according to the guidelines of the European Surveillance of Congenital Anomalies.
Patients were asked to participate in a structured telephone interview about their pregnancies. Patients were contacted at the first notification of pregnancy.
Duricova
2019 		Czech Republic
2007 – 2016
retrospective cohort 		3 Centers of Inflammatory bowel disease (IBD) and general pediatricians’ offices Children (≥12 months of age) born to mothers with IBD (2007–2016) treated with anti-TNF-alpha during pregnancy in 3 centers in the Czech Republic. unexposed, disease free
Unexposed children of non-IBD mothers undergoing mandatory check-ups at general pediatricians’ offices. 		during pregnancy (anytime or not specified) 72 / 69 Exposure: infliximab or adalimumab.
Information on IBD women, including type of diagnosis, details of anti-TNF-alpha treatment, and concomitant medication, was obtained from the patients’ medical files.
Fu - Etanercept
2019 		China
2014 - 2017
randomized controlled trial 		The Weifang people's hospital. Women administered basic treatment (heparin, aspirin, prednisone, cyclosporine) and etanercept (daily s.c. administration at a dosage of 25 mg from the end of menstruation until the occurrence of menstruation or to the end of the 10th week of gestation). unexposed, sick
Women administered basic treatment (heparin, aspirin, prednisone, cyclosporine) and placebo (daily with s.c. saline solution at the same dosage and same time). 		1st trimester 95 / 93
The patients were randomized assigned to the two arms of the study, by means of a computer-generated randomization number sequence.
Hoxha
2017 		Italy
2008 - 2015
prospective cohort 		Four Rheumatology Units (Belluno, Padua, Trento and Udine) Pregnancies in patients which were treated with anti-TNFa agents at conception/ 1st trimester [anti-TNFa therapy was discontinued between 7th-11th weeks of gestations (WG)). unexposed, sick
Pregnancies in women withdrawn anti-TNFa prior to conception [anti-TNFa therapy was discontinued between one to six months prior to conception, following the leaflet recommendations]. 		1st trimester 24 / 11 Primary analyse concerned AntiTNFa group, which was further categorized into those exposed to ETN (n=17), ADA (n=5) or CZP (n=2) at conception; and 3 paternal exposures (ETN).
A form including information on biological agents exposure, the concomitant use of disease modifying antirheumatic drugs was filled out by the treating rheumatologist.
Komoto
2016 		Japan
2008 - 2014
retrospective cohort 		A multicenter, cross-sectional study, among 18 collaborating hospitals, members of the Japanese Research Committee for Inflammatory Bowel Disease. Pregnancies in women exposed to anti-tumor necrosis factor drugs (anti-TNF) therapy only (no thiopurine therapy). unexposed, sick
Pregnancies in women exposed to neither anti-tumor necrosis factor drugs (anti-TNF) or thiopurine therapy. 		during pregnancy (anytime or not specified) 24 / 31
From the medical records, therapy was collected. Each patient was given a questionnaire to answer.
Langen
2014 		USA
2001 - 2009
retrospective cohort 		Perinatal database of a tertiary care referral hospital. Women with infliximab, adalimumab or etanercept near the time of conception. (Addition of pregnancies exposed to infliximab, adalimumab or etanercept). 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 4 / 15 Addition of pregnancies exposed to infliximab, adalimumab or etanercept (discontinued upon discovery of pregnancy).
Data were collected from review of medical records and included medication use.
Lichtenstein - infliximab
2018 		North America
1999 - 2012
prospective cohort 		TREAT Registry (The Crohn’s Therapy, Resource, Evaluation, and Assessment Tool) Pregnancy in CD patients treated with infliximab (at least one infliximab infusion), ≤ 365 days before the pregnancy outcome date. exposed to other treatment, sick
Pregnancy in CD patients treated with non-biologic CD treatments only (such as azathioprine, methotrexate, 6-mercaptopurine, prednisone, and antibiotics or narcotic analgesics). 		3 months (or more) before pregnancy or during pregnancy, 3 months or more before pregnancy or1st trimester 106 / 106 2 analyses: IFX gestational exposure (≤365 days before the pregnancy outcome date) and IFX pre-gestational exposure (>365 days before the pregnancy outcome date => NOT REPORTED here).
Patient data were collected at registry enrollment by gastroenterologists and then semi-annually (January, July), including medication use, concomitant CD medication use; and the number of infliximab infusions before, during, and after pregnancy.
Luu
2018 		France
2011 - 2015
retrospective cohort (claims database) 		French Health Insurance database (SNIIRAM - Système National Inter Régimes d’Assurance Maladie). Pregnancies in women with inflammatory bowel disease (IBD) exposed to anti-TNFα. exposed to other treatment, sick
Pregnancies in women with inflammatory bowel disease (IBD) not exposed to anti-TNFα (but treated with other treatments). 		3rd trimester, during pregnancy (anytime or not specified) 1457 / 9818 Exposure: Infliximab or adalimumab accounted for 54.9% and 43.3% of anti-TNFα use and 223 exposed women (15.3%) were concomitantly treated with thiopurines, mainly azathioprine (88.8%).
Data were extracted from the SNIIRAM database that includes the database containing all prescriptions for expensive drugs fully reimbursed by the national health insurance and the reimbursement data for out-of-hospital drug purchases with the Presentation Identifer Code codes.
Moens (Controls exposed to Vedolizumab)
2020 		Europe
2009 - 2018
retrospective cohort 		A retrospective multicentre (n = 29) observational study from nine countries (Belgium, Denmark, France, Germany, Ireland, Israel, Serbia, Sweden and The Netherlands). Pregnancies exposed to anti‐TNF. exposed to other treatment, sick
Pregnancies exposed to Vedolizumab. 		at least 1st trimester 186 / 79 At conception, 84 (45%) were on infliximab (IFX) monotherapy, 101 (54%) on ADM monotherapy and the remaining patient (0.5%) initiated ADM treatment during the first trimester. Three (4%) women initiated VDZ treatment after conception.
Information from Vedolizumab pregnancies was collected through a structured electronic case report form (CRF) that had to be filled out by the treating gastroenterologist, including dose and duration of VDZ therapy, other IBD medications during pregnancy.
Moens (Controls unexposed, sick)
2020 		Europe
2009 - 2018
retrospective cohort 		A retrospective multicentre (n = 29) observational study from nine countries (Belgium, Denmark, France, Germany, Ireland, Israel, Serbia, Sweden and The Netherlands). Pregnancies exposed to Anti-TNF. unexposed, sick
Pregnancies that were not exposed to biologics nor to immunomodulatory drugs. 		at least 1st trimester 186 / 184 At conception, 84 (45%) were on infliximab (IFX) monotherapy, 101 (54%) on ADM monotherapy and the remaining patient (0.5%) initiated ADM treatment during the first trimester.
Information from Vedolizumab pregnancies was collected through a structured electronic case report form (CRF) that had to be filled out by the treating gastroenterologist, including dose and duration of VDZ therapy, other IBD medications during pregnancy.
Schnitzler (Controls unexposed, disease free)
2011 		Belgium
1994 - 2007
prospective cohort 		Cohort at the University Hospital in Leuven Pregnant IBD patients treated with IFX or ADA within 3 months prior to conception and/or during pregnancy who delivered at the University Hospital in Leuven. unexposed, disease free
Matched pregnancies of healthy women out of the Flemish population who delivered at the University Hospital in Leuven. 		3 months (or more) before pregnancy or during pregnancy 42 / 56 Exposure: 35 pregnancies with IFX; 7 pregnancies with ADA. The first trimester (T1) was defined as the time period from last menstruation until week 13.5, T2 > 13.5 weeks until week 26.5, and T3 > 26.5 weeks until week 40.
Patients were treated with IFX or with ADA in our IBD unit at the University Hospital in Leuven and were prospectively followed.
Schnitzler (Unexposed control, sick)
2011 		Belgium
1994 - 2007
prospective cohort 		Cohort at the University Hospital in Leuven Pregnant IBD patients treated with IFX or ADA within 3 months prior to conception and/or during pregnancy who delivered at the University Hospital in Leuven. unexposed, sick
Pregnancies after diagnosis of IBC but prior to IFX treatment. 		3 months (or more) before pregnancy or during pregnancy 42 / 78 Exposure: 35 pregnancies with IFX; 7 pregnancies with ADA. The first trimester (T1) was defined as the time period from last menstruation until week 13.5, T2 > 13.5 weeks until week 26.5, and T3 > 26.5 weeks until week 40.
Patients were treated with IFX or with ADA in our IBD unit at the University Hospital in Leuven and were prospectively followed.
Seirafi
2014 		France and Belgium
2009 - 2010
retrospective cohort 		GETAID (Groupe d’Etude Thérapeutique des Affections du Tube Digestif) centres and CESAME registry Pregnant IBD patients under anti-TNF therapy (IFX, ADA or CTZ) within 3 months prior to conception and/or during pregnancy. unexposed, sick
Pregnant IBD patients not treated with anti-TNF therapy. 		3 months (or more) before pregnancy or during pregnancy 133 / 99 Design seems to be a retrospective cohort rather than a case–control study as mentioned by authors. Exposures: IFX (n=86), ADA (n=42) or CTZ (n=5). Anti-TNFs were preventively discontinued before GW 30 in 73% of patients having completed their pregnancy.
Inclusion: patient records from hospital IBD units and patients were contacted by phone when data were missing. During pregnancy, information collected included dose and duration of anti-TNFs and concomitant treatments.
Verstappen
2011 		United Kingdom
Not specified
prospective cohort 		The British Society for Rheumatology Biologics Register (BSRBR) Pregnancies in patients treated with one of the three available anti-TNF therapies (adalimumab (ADA), etanercept (ETA) and infliximab (INF)) at time of conception (but no MTX or LEF). unexposed, sick
Pregnancies in patients with active rheumatoid arthritis (RA) exposed to Anti-TNF therapy prior to conception or never exposed to Anti-TNF therapy, but receiving non-biological disease-modifying antirheumatic drugs. Addition of the 2 control groups. 		early pregnancy 50 / 59 4 groups according to anti-TNF exposure: (1) anti-TNF and to methotrexate and/or leflunomide at conception (n=21); (2) anti-TNF at conception (n=50); (3) anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (n=10).
Data available at recruitment. Follow-up information (include any changes to treatment) is collected from medical records. All reports of pregnancies are followed up with an additional questionnaire (patient reports) which includes data on exposure to biological agents at the time of conception.
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 Etanercept or Adalimumab from 3 months prior to pregnancy to delivery. (Addition of 2 subgroups 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 40 / 1421 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.
Prescriptions were recorded from 3 months prior to conception until labour from the Norwegian Prescription Database (NorPD).
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 Etanercept or Adalimumab from 3 months prior to pregnancy to delivery. (Addition of 2 subgroups 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 40 / 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.
Prescriptions were recorded from 3 months prior to conception until labour from the Norwegian Prescription Database (NorPD).
Vinet (Controls unexposed, disease free)
2018 		USA
2011 - 2015
retrospective cohort 		The RA Mothers and Outcomes in Offspring in the United States (PAROUS) cohort and the MarketScan commercial databases. Children born of rheumatoid arthritis (RA) women with ≥1 filled prescription of TNFi during during the preconception and/or gestational periods. unexposed, disease free
Children born to non-RA mothers without TNFi exposure (i.e., no prescription filled or infusion procedure claim within the preconception and gestational periods). 		during pregnancy (anytime or not specified) 380 / 14596
The MarketScan commercial database is a large prospective US database of >230 million subjects containing drug prescription claims.
Vinet (Controls unexposed, sick)
2018 		USA
2011 - 2015
retrospective cohort 		Pregnancies in RA Mothers and Outcomes in Offspring in the United States (PAROUS) cohort and the MarketScan commercial databases. Children born of rheumatoid arthritis (RA) women with ≥1 filled prescription of TNFi during during the preconception and/or gestational periods. unexposed, sick
Children born of rheumatoid arthritis (RA) women without TNFi exposure (i.e., no prescription filled or infusion procedure claim within the gestational period and the 12 weeks preceding it). 		3rd trimester, during pregnancy (anytime or not specified) 380 / 2476
The MarketScan commercial database is a large prospective US database of >230 million subjects containing drug prescription claims.
Weber-Schoendorfer
2015 		Australia, Finland, France, Italy, The Netherlands, Turkey, Switzerland and the United Kingdom
1998 - 2013
prospective cohort 		European Network of Teratology information services (TIS) Pregnant women who had been exposed to more than one dose of one of the five approved TNF-α inhibitors (ADA, CZP, ETA, GOL and IFX) at any time during the first 12 weeks after the last menstrual period (LMP). unexposed, disease free
Pregnant women identified through spontaneous TIS consultations for other conditions or exposures such as hairdyeing, urinary tract infection, asthma or depression. 		1st trimester 495 / 1532 Analyses were performed for the group of 5 TNF-α inhibitors (172 ADA, 7 CZP, 140 ETA, 3 GOL and 168 IFX). Indications: IBD (48,1%) et RA (26,9%).
Data were collected on exposure (including both prescription and over-thecounter) from structured telephone or face-to-face interviews and/or mailed questionnaires obtained from both the mother and/or her physician(s) after oral informed consent.
Zbinden (rheumatoid arthritis)
2018 		Switzerland
2000 - 2016
prospective cohort 		The Centre for Pregnancy in Rheumatic Diseases at the Department of Rheumatology of the University Hospital of Bern and the University Hospital of Bern. Pregnancies in patients with rheumatoid arthritis exposed to Anti-TNF during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnancies in healthy women. 		during pregnancy (anytime or not specified) 28 / 70 In pregnancies of RA patients (n=96 pregnancies), TNFi treatment at any time during pregnancy was used in 29.2%.
All patients were seen at each trimester during pregnancy, with record of the current medication. The data from healthy pregnant women were recorded once: at the last trimester.
Zbinden b (axial spondyloarthritis)
2018 		Switzerland
2000 - 2016
prospective cohort 		The Centre for Pregnancy in Rheumatic Diseases at the Department of Rheumatology of the University Hospital of Bern and the University Hospital of Bern. Pregnancies in patients with in axial spondyloarthritis exposed to Anti-TNF during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnancies in healthy women. 		during pregnancy (anytime or not specified) 31 / 70 Among axSpA patients (n=78 pregnancies), 75.6% were on anti-rheumatic drugs during pregnancy, the most common being TNFi (39.7%).
All patients were seen at each trimester during pregnancy, with record of the current medication. The data from healthy pregnant women were recorded once: at the last trimester.

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
Bröms b
2016 		Sweden
2006 - 2010
case control 		Swedish national health registers: the Medical Birth Register, the Patient Register and the Prescribed Drug Register All women with CD or UC who gave birth to a live-born singleton infant before term. Randomly selected women with CD or UC who gave birth at a later gestational week than their matched case. Information on drug treatment was obtained from the Prescribed Drug Register, the Medical Birth Register and from medical charts. Exposure: 90 days before pregnancy or in first trimester. 3 months or more before pregnancy or1st trimester 237 / 239 Not the same outcomes than in Bröms(b) 2016 (Swedish AND Danish registers).
Review of medical charts of cases and controls from departments of obstetrics, gastroenterology and internal medicine nationwide for clinical data for the period starting from three months before pregnancy until delivery.
Vinet
2013 		Canada
1996 - 2008
case control 		A nested case–control study using administrative databases from Quebec Women having an induced abortion based either on 1 procedure code and/or diagnostic code for induced abortion present in the MED-E´CHO hospitalization and/or RAMQ billing databases 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 The RAMQ (Régie de l’assurance maladie du Québec) prescription database. during pregnancy (anytime or not specified) 112 / 5855 Primary analysis on MTX. Exposure to anti–tumor necrosis factor (anti-TNF) also investigated.
Induced abortion based either on 1 procedure code and/or diagnostic code for induced abortion present in the MED-E´CHO hospitalization and/or RAMQ billing databases.

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

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