| 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 |
|---|---|---|---|---|---|---|---|---|
|
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 Adalimumab within 90 days before their LMP until delivery. (This is a subgroup of exposure among the whole exposed group considered in the study). |
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 | 257 / 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). | ||||||||
|
Bröms (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 adalimumab within 90 days before and 90 days after their last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Women without disease or TNF treatment (ie, the general population). |
3 months or more before pregnancy or1st trimester | 161 / 1250192 | Primary analyse on Anti-TNF, with individual result by substance (n=161 ADA). | |
| 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). | ||||||||
|
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 Adalimumab within 90 days before their LMP until delivery. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
The general population (women without the diseases of interest and without treatment). |
3 months (or more) before pregnancy or during pregnancy | 257 / 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 (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 adalimumab within 90 days before and 90 days after their last menstrual period. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Women with chronic inflammatory disease but no anti-TNF treatment. |
3 months or more before pregnancy or1st trimester | 161 / 21549 | Primary analyse on Anti-TNF, with individual result by substance (n=161 ADA). 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). | ||||||||
|
Casanova 2013 |
Spain Not specified retrospective cohort |
Inflammatory bowel disease (IBD) Units from 24 Spanish hospitals | Pregnancies in IBD patients on adalimumab 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 | 16 / 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 (Controls unexposed, disease free) 2019 |
USA and Canada 2004 - 2016 prospective cohort |
The MotherToBaby pregnancy study conducted by the Organization of Teratology Information Specialists (OTIS). | Pregnant women with a diagnosis of rheumatoid arthritis or Crohn’s Disease who received at least one dose of adalimumab in the first trimester. |
unexposed, disease free
Pregnant women have a rheumatic disease or an inflammatory bowel disease, no treatment with a monoclonal antibody medication in pregnancy. |
at least 1st trimester | 257 / 225 | ||
| Pregnant women completed up to three telephone interviews during pregnancy, including data on on all medications (prescription, over-the-counter) used/administered during pregnancy. | ||||||||
|
Chambers (Controls, sick) 2019 |
USA and Canada 2004 - 2016 prospective cohort |
The MotherToBaby pregnancy study conducted by the Organization of Teratology Information Specialists (OTIS). | Pregnant women with a diagnosis of rheumatoid arthritis or Crohn’s Disease who received at least one dose of adalimumab in the first trimester. |
unexposed, sick
Pregnant women with a diagnosis of rheumatoid arthritis or Crohn’s Disease who not used adalimumab at any time during pregnancy. |
at least 1st trimester | 257 / 120 | Unexposed group: exposure to another anti-TNF-α medication:18/120 (15%). Sensitivity analyse excluding women from the disease-matched unexposed group with anti-TNF-α medication in pregnancy, produced similar results (data not shown). | |
| Pregnant women completed up to three telephone interviews during pregnancy, including data on on all medications (prescription, over-the-counter) used/administered during pregnancy. | ||||||||
|
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 Adalimumab 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 | 2 / 36 | ||
| 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 Adalimumab 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 | 2 / 32 | 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. | ||||||||
|
Hoxha 2017 |
Italia 2008 - 2015 prospective cohort |
Four Rheumatology Units (Belluno, Padua, Trento and Udine) | Pregnancies in patients which were treated with Adalimumab at conception/ 1st trimester [anti-TNFa therapy was discontinued between 7th-11th weeks of gestations (WG)]. (This is a subgroup of exposure among the whole exposed group considered in the study). |
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 | 5 / 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). Raw individual data provided for each substance and used for the meta-analysis. | |
| A form including information on biological agents exposure, the concomitant use of disease modifying antirheumatic drugs was filled out by the treating rheumatologist. | ||||||||
|
Hyrich 2006 |
United Kingdom Until 2005 retrospective cohort |
The British Society for Rheumatology Biologics Register (BSRBR) | Patients who were directly exposed to adalimumab at the time of conception. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Patients who electively discontinued their anti-TNFa therapy prior to conceiving (range 1–10 months before conception). |
1st trimester | 3 / 9 | All but 2 etanercept patients discontinued their during the first trimester of pregnancy. | |
| The British Society for Rheumatology Biologics Register (BSRBR) database was searched for all reports of pregnancy. Details on exposure to disease-modifying antirheumatic drugs (DMARDs) and biologic drugs were collected using standardized forms. | ||||||||
|
Langen 2014 |
USA 2001 - 2009 retrospective cohort |
Perinatal database of a tertiary care referral hospital. | Women with adalimumab only 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 | 1 / 15 | Co-exposure Prednisolone, plaquenil and etanercept (discontinuation of Plaquenil and etanercept). | |
| Data were collected from review of medical records and included medication use. | ||||||||
|
Schnitzler (Unexposed control, disease free) 2011 |
Belgium 1994 - 2007 prospective cohort |
Cohort at the University Hospital in Leuven | Pregnant IBD patients treated with ADA within 3 months prior to conception and/or during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
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 | 7 / 56 | Main analysis: pregnancies with IFX (n=35) or ADA (n =7), but for malformations, raw data provided for each substance and used for this meta-analysis. | |
| 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 ADA within 3 months prior to conception and/or during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnancies after diagnosis of IBC but prior to start ADA treatment. |
3 months (or more) before pregnancy or during pregnancy | 7 / 78 | Main analysis: pregnancies with IFX (n=35) or ADA (n =7), but for malformations, raw data provided for each substance and used for this meta-analysis. | |
| 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 Adalimumab within 3 months prior to conception and/or during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, sick
Pregnant IBD patients not treated with anti-TNF therapy. |
3 months (or more) before pregnancy or during pregnancy | 42 / 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. | ||||||||
|
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 Adalumimab from 3 months prior to pregnancy to delivery. (This is a 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 | 3 / 1458 | 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 Adalumimab from 3 months prior to pregnancy to delivery. (This is a 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 | 3 / 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 (Unexposed controls, disease free) 2018 |
USA 2011 - 2015 retrospective cohort (claims database) |
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 Adalimumab during the preconception and/or gestational periods. (This is a subgroup of exposure among the whole exposed group considered in the study). |
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) | 108 / 14596 | Primary analysis performed on the group of TNFi, but raw data related to serious infections provided by type of TNFi and used in this meta-analysis. | |
| The MarketScan commercial database is a large prospective US database of >230 million subjects containing drug prescription claims. | ||||||||
|
Vinet (Unexposed controls, sick) 2018 |
USA 2011 - 2015 retrospective cohort (claims database) |
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 Adalimumab during the preconception and/or gestational periods. (This is a subgroup of exposure among the whole exposed group considered in the study). |
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). |
during pregnancy (anytime or not specified) | 108 / 2476 | Primary analysis performed on the group of TNFi, but raw data related to serious infections provided by type of TNFi and used in this meta-analysis. | |
| The MarketScan commercial database, 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 ADA at any time during the first 12 weeks after the last menstrual period (LMP). (This is a subgroup of exposure among the whole exposed group considered in the study). |
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 | 172 / 1532 | Analyses were performed for the group of 5 TNF-α inhibitors (172 ADA, 7 CZP, 140 ETA, 3 GOL and 168 IFX). Raw data were provided for major malformations and used for the meta-analysis. | |
| Data on exposure (including both prescription and over-the-counter) were collected 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. | ||||||||
| Study | Country Study period Study design |
Data source | Case | Control | Exposition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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