| 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 |
|---|---|---|---|---|---|---|---|---|
|
Alami 2017 |
France 1989 - 2012 prospective cohort |
TERAPPEL database shared by several French Regional PharmacoVigilance Centers (CRPVs), France. | Pregnant women who had been exposed to Azathioprine at least during the organogenesis period (from 4 to 12 weeks after last menstrual period (LMP)) and if follow-up data on pregnancy outcome were available. |
unexposed, sick
Pregnant women randomly selected in the same registry who had been exposed at least during the organogenesis period to another drug or immunosuppressant used for the same indication (such as mesalazine, corticosteroids, sulfasalazine, hydroxychloroquine or beta interferon). |
at least 1st trimester | 124 / 124 | Mycophenolate not included in the control group. Preterm and LBW not reported because comparison of AZA (at least T3, including T1) versus AZA T1 => not adequate. Control group considered as 'unexposed sick' because co-exposures are in both groups. | |
| Data were obtained by structured telephone interviews within 22 weeks after the Last Menstrual Period (i.e. before the level II ultrasound scan). | ||||||||
|
Angelberger 2011 |
Austria 1999 - 2007 retrospective cohort |
Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria. | Offsprings of inflammatory bowel disease (IBD) patients receiving azathioprine (AZA) during pregnancy and breastfeeding. |
unexposed, sick
Offsprings of inflammatory bowel disease (IBD) patients without any immunosuppressive therapy during pregnancy and breastfeeding. |
during pregnancy (anytime or not specified) | 15 / 15 | Azathioprine dosage: once a day in the morning (median dose 150 mg/d; range: 100–250 mg/d). | |
| Azathioprine and all other therapies of mothers were documented at each visit at the department and registered in a local pregnancy-registry. | ||||||||
|
Ban (Controls unexposed, disease free) 2014 |
United Kingdom 1990 - 2010 retrospective cohort (claims database) |
UK database of primary care: The Health Improvement Network (a nationally representative UK database of primary care records containing medical diagnoses, events, and drug prescriptions). | Children of women with inflammatory bowel disease (IBD) with a prescription for azathioprine/6-mercaptopurine in the first trimester (between 4 weeks before a woman’s estimated conception date and 12 weeks after). |
unexposed, disease free
Children of women without inflammatory bowel disease (IBD). |
1st trimester | 149 / 384811 | ||
| Among mothers with IBD, all prescriptions for 5-aminosalicylates, azathioprine/6-mercaptopurine, or corticosteroids (including both oral and rectal corticosteroids) were extracted from their primary care electronic health records. | ||||||||
|
Ban (Controls unexposed, sick) 2014 |
United Kingdom 1990 - 2010 retrospective cohort (claims database) |
UK database of primary care: The Health Improvement Network (a nationally representative UK database of primary care records containing medical diagnoses, events, and drug prescriptions). | Children of women with inflammatory bowel disease (IBD) with a prescription for azathioprine/6-mercaptopurine in the first trimester (between 4 weeks before a woman’s estimated conception date and 12 weeks after). |
unexposed, sick
Children of women with inflammatory bowel disease (IBD) without prescription for azathioprine/6-mercaptopurine. |
1st trimester | 149 / 1554 | Control group considered as 'unexposed sick' because co-exposures are possible in both groups. Patients with IBD with prescription during 1st trimester of pregnancy for steroids (n=209; 12.3%), 5-aminosalicylates (n=551; 32.4%). | |
| Among mothers with IBD, all prescriptions for 5-aminosalicylates, azathioprine/6-mercaptopurine, or corticosteroids (including both oral and rectal corticosteroids) were extracted from their primary care electronic health records. | ||||||||
|
Bröms (Crohn’s disease, stable disease) 2014 |
Sweden 2006 - 2010 population based cohort retrospective |
Swedish Medical Birth Register, National Patient Register and the Prescribed Drug Register. | Infants of women with stable Crohn’s disease (CD) having filled at least 1 prescription of thiopurines (azathioprine or 6-mercaptopurine). (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed, disease free
Infants of women without Ulcerative colitis (UC) nor Crohn’s disease (CD). |
during pregnancy (anytime or not specified) | -9 / 467057 | Authors provided 4 exposed group (Crohn*2; Ulcerative*2) versus the same comparator => only 1 used: this one with higher exposures (Crohn disease: n=262, no further details according to disease activity) and stable disease to limit impact of illness. | |
| Filled drug prescriptions as recorded in the Prescribed Drug Register by date of dispensing, drug name, and preparation according to the Anatomical Therapeutic Chemical classification. | ||||||||
|
Casanova 2013 |
Spain Not specified. retrospective cohort |
Medical records of Inflammatory bowel disease (IBD) units from 24 Spanish hospitals. | Pregnancies developed with the Inflammatory bowel disease (IBD) patient on thiopurines (azathioprine or mercaptopurine) alones 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 nflammatory bowel disease patients which did not receive thiopurines nor anti-TNF 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 | 187 / 318 | Exposed population divided in 2 groups: A) thiopurines alone; B) anti-TNF-α drugs (IFX, ADA, and CZB) with or without concomitant thiopurines. Women who had another disease that may affect the course of pregnancy were excluded. | |
| 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 (during each trimester of pregnancy). | ||||||||
|
Cleary (Controls unexposed, NOS) 2009 |
Sweden 1995 - 2007 population based cohort retrospective |
Swedish population register : Medical Birth Register, Register of Birth Defects and the Hospital Discharge Register. | Women who reported taking Azathioprine (AZA) at the first antenatal care visit (defined as early pregnancy). |
unexposed (general population or NOS)
All women with a delivery in the study period who did not report taking azathioprine at the first antenatal care visit. |
early pregnancy | 476 / 1163554 | For outcomes LBW, preterm and SGA : only singleton infants are counted. For malformations all births are considered. For outcomes other than malformations, numbers vary because of missing values. Indication of AZA use in exposed group is IBD for >60%. | |
| Medication exposures in early pregnancy are collected prospectively at the first antenatal care visit on a standard form used throughout the country : use of medication, when, what dose. Medication names are semiautomatically converted to ATC. | ||||||||
|
Cleary (Controls unexposed, sick) 2009 |
Sweden 1995 - 2007 population based cohort retrospective |
Swedish Medical Birth Register, Register of Birth Defects and the Hospital Discharge Register. | Infants of women who reported taking Azathioprine (AZA) at the first antenatal care visit (defined as early pregnancy). |
unexposed, sick
Infants of women with a delivery in the study period who did not report AZA use, but reported medications specifically used in IBD (ATC codes A07EA [corticosteroids acting locally], A07EC02 [mesalazine], A07EC03 [olsalazine], or A07EC04 [balsalazide]); (untreated IBD pregnant women not included). |
early pregnancy | 481 / 1739 | For outcomes LBW, preterm and SGA : only singleton infants are counted. For malformations all births are considered. For outcomes other than malformations, numbers vary because of missing values. Indication of AZA use in exposed group is IBD for >60%. | |
| Medication exposures in early pregnancy are collected prospectively at the first antenatal care visit on a standard form used throughout the country : use of medication, when, what dose. Medication names are semiautomatically converted to ATC. | ||||||||
|
Coelho (Controls exposed to 5-ASA) 2011 |
France 2004 - 2007 retrospective cohort |
Cohort CESAME (observational cohort that enrolled consecutive patients with inflammatory bowel disease (IBD)). | Pregnancies in women with inflammatory bowel disease (IBD) exposed to thiopurines alone. |
exposed to other treatment, sick
Pregnancies in women with inflammatory bowel disease (IBD) receiving aminosalicylates alone. |
during pregnancy (anytime or not specified) | 57 / 67 | No info on deaths inclusion in congenital anomalies. Results based on livebirths. It was not possible to take the full group B as a control group because authors give % and it is not possible to retrieve accurately numerators/denominators. | |
| Information (medications, smoking and alcohol consumption, obstetric history) was recorded on website forms by the gastroenterologists belonging to the CESAME panel. Data were collected retrospectively for the year 2005 and prospectively from 1 January 2006 until 1 January 2007. | ||||||||
|
Coelho (Controls unexposed, sick) 2011 |
France 2004 - 2007 retrospective cohort |
Cohort CESAME (observational cohort that enrolled consecutive patients with inflammatory bowel disease (IBD)). | Pregnancies in women with inflammatory bowel disease (IBD) exposed to thiopurines alone. |
unexposed, sick
Pregnancies in women with inflammatory bowel disease (IBD) not receiving any medication. |
during pregnancy (anytime or not specified) | 57 / 45 | Deaths are not counted in congenital anomalies (i.e. therapeutic abortion, intrauterine deaths). | |
| Information was recorded on website forms by the gastroenterologists belonging to the CESAME panel. Data were collected retrospectively for the year 2005 and prospectively from 1 January 2006 until 1 January 2007. | ||||||||
|
Colvin 2010 |
Australia 2002 - 2005 retrospective cohort (claims database) |
Linkage between administrative records of medicines dispensed in pregnancy (Pharmaceutical Benefits Scheme (PBS) and health administrative data. | Azathioprine dispensed from 14 days after the last menstrual period (LMP) to the end of first trimester or to the end of the pregnancy event. (This is a subgroup of exposure among the whole exposed group considered in the study). |
unexposed (general population or NOS)
All other births (those births to women dispensed a Pharmaceutical Benefits Scheme (PBS) medicine or not). |
1st trimester | 29 / 106045 | Category D or X medicines also studied. Total nb of unexposed: 106045=106074-29. Birth defect: structural or functional abnormality. Most minor defects are not recorded in the BDR. Of all cases, about 90% have at least one major birth defect. | |
| The national Pharmaceutical Benefits Scheme, with around 80% of prescriptions dispensed in Australia. | ||||||||
|
Dejaco 2005 |
Austria 2000 - 2003 prospective cohort |
Not specified | Pregnancies in women affected with Inflammatroy bowel disease (IBD) treated with azathioprine, 6-mercaptopurine or thioguanine. |
unexposed, sick
Pregnancies in women affected with Inflammatroy bowel disease (IBD) but without immunosuppressive therapy. |
during pregnancy (anytime or not specified) | 33 / 35 | ||
| Not specified. | ||||||||
|
Francella 2003 |
USA Late 1950s - 1997 retrospective cohort |
A database of more than 2800 patients with Inflammatory Bowel Disease (IBD) from a private practice of one of the authors, Mount Sinai Hospital Medical Center, New York, USA. | Women with Inflammatory Bowel Disease (IBD) who took 6-mercaptopurine (6-MP) throughout the entire pregnancy. |
unexposed, sick
Women with Inflammatory Bowel Disease (IBD) who took 6-mercaptopurine (6-MP) and stopped the drug prior to conception or patients who had pregnancies prior to treatment with 6-MP (sum of group A and C). |
throughout pregnancy | 15 / 132 | Unexposed= pregnancies in female from group A and C=132. All patients had been treated with 6-MP, and none were treated with azathioprine. Infections indexed in neonatal infection because they occurred at 3 and 6 months. | |
| Verification of 6-mercaptopurine (6-MP) exposure was achieved by review of each patient’s individual medical records. | ||||||||
|
Goldstein 2007 |
Israel, Canada, and Europe (Germany, Finland, the Netherlands and Italy) 2001 - 2004 prospective cohort |
7 Teratogen Information Services (TISs) : Zerifin (Israel), Berlin (Germany), Toronto (Canada), Helsinki (Finland), Bilthoven (The Netherlands), Jerusalem (Israel), Padova (Italy). | Pregnant women taking Azathioprine during pregnancy. |
unexposed (general population or NOS)
Pregnant women taking a drug with no teratogenic effect (such as acetaminophen, amoxicillin, prenatal vitamins, or allergy medications) or who were not exposed to drugs. |
at least 1st trimester | 189 / 230 | AZA group: 45% (n = 85) took AZA only, 38.6% (n = 73) took AZA together with another potential teratogen (mostly systemic corticosteroids) and 16% (n=30) took AZA with other nonteratogenic treatments. T1: 98%; entire pregnancy: 68%. | |
| Data were collected at the time of exposure, before the pregnancy outcome was known. Information collected included Azathioprine dose and use of other treatments, teratogenic or potentially teratogenic (under current debate in the medical literature). | ||||||||
|
Howren 2020 |
Canada 2002 - 2012 retrospective cohort (claims database) |
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. | Pregnancies in women with Rheumatic diseases (RD) with at least one prescription of azathioprine filled during the critical windows of interest (90 days post conception for malformations and from conception to delivery for small-for-gestational-age). |
unexposed, sick
Pregnancies in women with Rheumatic diseases (RD) without filled prescriptions for conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs; e.g. hydroxychloroquine, methotrexate) during aforementioned perinatal windows of interest. |
during pregnancy (anytime or not specified) | 23 / 6064 | ||
| PharmaNet captures complete information on all drug prescriptions dispensed including drug identification number, dispensation date, dispensation quantity, dosage, and duration. | ||||||||
|
Jolving 2021 |
Denmark 1995 - 2015 population based cohort retrospective |
Danish Medical Birth Registry, Danish National Patient Register, Danish National Prescription Register, Civil Registration System. | All children born to women who filled at least one prescription with thiopurines (azathioprine (AZA)/mercaptopurine) in a period of up to 3 months prior to conception and/or during pregnancy. |
unexposed (general population or NOS)
All live-born children from the study population, who were not exposed in utero to thiopurines, that is the mothers had no filled prescriptions for thiopurines within 3 months before conception or during pregnancy. |
3 months (or more) before pregnancy or during pregnancy | 1047 / 1307731 | For congenital malformations: overlapping with Langagergaard 2007 who used a more appropriate exposure period => Langagergaard 2007 was entered rather than Jolving 2021. | |
| Prescription of thiopurines were extracted from the Danish National Prescription Register using Anatomical Therapeutic Chemical (ATC) classification. | ||||||||
|
Kanis 2017 |
The Netherlands 2008 - 2016 prospective cohort |
Erasmus University Medical Center (Rotterdam, The Netherlands). | Patients inflammatory bowel disease (IBD) using a thiopurine during conception. |
unexposed, sick
Patients with inflammatory bowel disease (IBD) not using thiopurine during pregnancy. |
during pregnancy (anytime or not specified) | 146 / 263 | Totally overlapped by Kanis 2021 except for outcomes spontaneous abortions, allergies and eczema, therefore only these outcomes reported here. | |
| Before pregnancy, patients were counseled on inflammatory bowel disease (IBD) medication use, during pregnancy, data regarding medication adherence were collected. | ||||||||
|
Kanis 2021 |
The Netherlands 1999 - 2018 retrospective cohort |
All 56 Dutch hospitals with a gastroenterology department, the Netherlands. | Women with inflammatory bowel disease (IBD) using a thiopurine during pregnancy (no anti-tumour necrosis factor-α (anti-TNF-α)). |
unexposed, sick
Women with inflammatory bowel disease (IBD) not using a thiopurine nor anti-tumour necrosis factor-α (anti-TNF-α). |
at least 1st trimester, during pregnancy (anytime or not specified), throughout pregnancy | 240 / 564 | One mother used methotrexate until pregnancy week 6, all others discontinued 3–6 months prior to conception. Overall, 91% of children exposed to a thiopurine were exposed during the entire pregnancy and only 3 were not exposed during the 1st trimester. | |
| Medication use during pregnancy was retrieved during a telephonic interview with mothers and information was later verified in their medical chart. | ||||||||
|
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 thiopurine therapy only (no anti-tumor necrosis factor drugs (anti-TNF)). |
unexposed, sick
Pregnancies in women exposed to neither anti-tumor necrosis factor drugs (anti-TNF) or thiopurine therapy. |
during pregnancy (anytime or not specified) | 7 / 31 | ||
| From the medical records, therapy was collected. Each patient was given a questionnaire to answer. | ||||||||
|
Koslowsky 2019 |
Israel 2011 - 2015 prospective cohort |
Medical Records of Shaare-Zedek Medical Center, Jerusalem. | Women with a diagnosis of inflammatory bowel diseases (IBD) exposed to thiopurines throughout the entire pregnancy. (Patients exposed to steroids or biologics were excluded from the study). |
unexposed, sick
Women with a diagnosis of inflammatory bowel diseases (IBD) and no thiopurine exposure during pregnancy. (Patients exposed to steroids or biologics were excluded from the study). |
throughout pregnancy | 21 / 13 | Primary outcome is anemia in neonates. Patients exposed to steroids or biologics were excluded from the study. | |
| The patients’ characteristics were collected from clinical files and a completed questionnaire. The doses and duration of thiopurines were documented prospectively. | ||||||||
|
Langagergaard (Controls unexposed, NOS) 2007 |
Denmark 1996 - 2001 population based cohort retrospective |
Danish population registries, Fertility Database, Danish Medical Birth Registry, Danish Hospital Discharge Registry, Danish Prescription database and Danish Civil Registration System. | Children born from women who filled prescriptions for azathioprine or mercaptopurine (AZA/6-MP) in the period from 30 days before conception (i.e. the first day in the last menstruation) until birth. |
unexposed (general population or NOS)
Matched children born from women who did not fill prescriptions for any kind of reimbursable medication during the 3 months prior to conception and the ensuing pregnancy. |
1st trimester, throughout pregnancy | 76 / 1274 | The women were classified according to exposure during two gestational stages: (i) the ‘early pregnancy’ group: from 30 days before conception to the end of the first trimester; (ii) The ‘entire pregnancy’ group: during the 1st through the 3rd trimesters. | |
| Exposition to a medication before or during pregnancy was based on the Danish Prescription database (using the ATC classification system). | ||||||||
|
Langagergaard (Controls unexposed, sick) 2007 |
Denmark 1996 - 2001 population based cohort retrospective |
Danish population registries, Fertility Database, Danish Medical Birth Registry,Danish Hospi- tal Discharge Registry, Danish Prescription database | Children born from women who filled prescriptions for azathioprine or mercaptopurine (AZA/6-MP) in the period from 30 days before conception (i.e. the first day in the last menstruation) until birth. |
unexposed, sick
Children born from women who were treated with azathioprine or mercaptopurine before pregnancy (3 months before conception), but not during pregnancy. |
1st trimester, throughout pregnancy | 76 / 174 | The women were classified according to exposure during two gestational stages: (i) the ‘early pregnancy’ group: from 30 days before conception to the end of the first trimester; (ii) The ‘entire pregnancy’ group: during the 1st through the 3rd trimesters. | |
| Exposition to a medication before or during pregnancy was based on the Danish Prescription database (using the ATC classification system). | ||||||||
|
Lazzaroni 2020 |
Italy 1987 - 2014 retrospective cohort |
Medical records of two Italian centers (Brescia, Milano). | Pregnancies in women with Systemic Lupus Erythematosus (SLE) treated with Azathioprine. |
unexposed, sick
Pregnancies in women with Systemic Lupus Erythematosus (SLE) not treated with Azathioprine (NOS). |
during pregnancy (anytime or not specified) | 27 / 65 | Control group considered as 'unexposed sick' because co-exposures are possible in both groups. Most of the patients were treated with corticosteroids during pregnancy (78.2%), hydroxychloroquine (HCQ) was prescribed in half of the pregnancies (51.1%). | |
| Data regarding therapy prescribed during pregnancy were retrospectively retrieved from medical charts from the two centers and collected in a common database. | ||||||||
|
Mahadevan 2021 |
USA 2007 - 2019 prospective cohort |
The Pregnancy in Inflammatory bowel disease And Neonatal Outcomes (PIANO) study, that enrolled pregnant women with Inflammatory Bowel Disease at 30 U.S. centers. | Use of thiopurines (azathioprine or 6-mercaptopurine) (but no biologics: anti-TNF, anti-integrin, anti-IL 12/23) in the 3 months prior to last menstrual period or at any time during pregnancy. |
unexposed, sick
No use of azathioprine nor biologics in the 3 months prior to last menstrual period or any time during pregnancy (includes mesalamine, corticosteroids, and antibiotics). |
3 months (or more) before pregnancy or during pregnancy | 242 / 379 | Neurodevelopment outcomes were not extractable because there is no information on dispersion for the control group (only delta? in exposed group and none in unexposed group). | |
| Information was collected on medication use prior to conception, during pregnancy, and for 1 year postpartum through questionnaires at each trimester of pregnancy, at the end of the pregnancy, 4, 9, and 12 months post-delivery, and once a year up to the age of 18 years of age. | ||||||||
|
Marder 2013 |
United States of America 2008 - 2010 retrospective cohort |
Hospital record of University of Michigan, Ann Arbor, MI, USA and Michigan Lupus Cohort. | Women with systemic lupus erythematosus (SLE) exposed to azathioprine during pregnancy. |
unexposed, sick
Women with systemic lupus erythematosus (SLE) not exposed to of azathioprine during pregnancy (NOS). |
during pregnancy (anytime or not specified) | 13 / 47 | No Mycophenolate mofetil exposure in infants with Developmental Delay/special educational service utilization. Control group considered as 'unexposed sick' because co-exposures are possible in both groups. | |
| Medication use at conception and during pregnancy were recorded by a structured interview of the mother with a study team member, as well as medical record review (full medical records were available for 70% of the pregnancies). | ||||||||
|
Meyer 2025 |
France 2010 - 2021 population based cohort retrospective |
The EPI-MERES registry, which identifies pregnancies in the Système National des Données de Santé (SNDS) and the French national health data system, France. | Children exposed in utero to thiopurines (azathioprine, mercaptopurine) during 1st trimester of pregnancy born of women with inflammatory bowel disease (IBD). |
unexposed, sick
Children unexposed in utero to either thiopurines or anti-TNF during 1st trimester of pregnancy born of women with inflammatory bowel disease (IBD). |
1st trimester | 5223 / 28827 | Thiopurines were generally azathioprine (95.1% of births exposed to thiopurines) and rarely mercaptopurine (5.0%). When available data excluding exposure to combination therapy was used. | |
| The Système National des Données de Santé (SNDS) that contains comprehensive outpatient (drugs, procedures) and inpatient (expensive drugs dispensed information. | ||||||||
|
Meyer a (Controls exposed to Anti-TNF) 2021 |
France 2010 - 2018 retrospective cohort (claims database) |
The French national health database, SNIIRAM, France. | All children born from women with inflammatory bowel disease (IBD) who were dispensed azathioprine/mercaptopurine (without co-exposure to anti-TNF) during pregnancy or during the previous 2 month. |
exposed to other treatment, sick
All children born from women with inflammatory bowel disease (IBD) who were dispensed anti-TNF monotherapy (infliximab, adalimumab, golimumab, certolizumab) (without co-exposure to thiopurines) during pregnancy or during the previous 2 month. |
during pregnancy (anytime or not specified) | 3392 / 3399 | If available, use of Sensitivity results 'during pregnancy, narrower def of exposure', rather than '2 months before and/or pregnancy'. Otherwise, primary analysis used because similar results were obtained. Overlapping with Meyer 2021b: infections only. | |
| Drugs dispensed before or during pregnancy were recorded in the French national health data system (Système National des Données de Santé (SNDS)). | ||||||||
|
Meyer a (Controls unexposed, sick) 2021 |
France 2010 - 2018 retrospective cohort (claims database) |
The French national health database, SNIIRAM, France. | All children born from women with inflammatory bowel disease (IBD) who were dispensed azathioprine/mercaptopurine (without co-exposure to anti-TNF) during pregnancy or during the previous 2 month. |
unexposed, sick
All children born from women with inflammatory bowel disease (IBD) who were not dispensed or administered at hospital azathioprine/mercaptopurine nor anti-TNF 2 months before or during pregnancy. |
during pregnancy (anytime or not specified) | 3392 / 18954 | If available, use of Sensitivity results 'during pregnancy, narrower def of exposure', rather than '2 months before and/or pregnancy'. Otherwise, primary analysis used because similar results were obtained. Overlapping with Meyer 2021b: infections only. | |
| Drugs dispensed before or during pregnancy were recorded in the French national health data system (Système National des Données de Santé (SNDS)). | ||||||||
|
Meyer b (Controls exposed to Anti-TNF) 2021 |
France 2010 - 2018 retrospective cohort (claims database) |
The French national health database, SNIIRAM, France. | All children born from women with inflammatory bowel disease (IBD) who were dispensed azathioprine/mercaptopurine (without co-exposure to anti-TNF) during pregnancy or during the previous 2 month. |
exposed to other treatment, sick
All children born from women with inflammatory bowel disease (IBD) who were dispensed anti-TNF monotherapy (infliximab, adalimumab, golimumab, certolizumab) (without co-exposure to thiopurines) during pregnancy or during the previous 2 month. |
during pregnancy (anytime or not specified) | 3554 / 3525 | If available, use of Sensitivity results 'during pregnancy, narrower def of exposure', rather than '2 months before and/or pregnancy'. Otherwise, primary analysis used because similar results were obtained. | |
| Drugs dispensed before or during pregnancy were recorded in the French national health data system (Système National des Données de Santé (SNDS)). | ||||||||
|
Meyer b (Controls unexposed, sick) 2021 |
France 2010 - 2018 retrospective cohort (claims database) |
The French national health database, SNIIRAM, France. | All children born from women with inflammatory bowel disease (IBD) who were dispensed azathioprine/mercaptopurine (without co-exposure to anti-TNF) during pregnancy or during the previous 2 month. |
unexposed, sick
All children born from women with inflammatory bowel disease (IBD) who were not dispensed or administered at hospital azathioprine/mercaptopurine nor anti-TNF 2 months before or during pregnancy. |
during pregnancy (anytime or not specified) | 3554 / 19811 | If available, use of Sensitivity results 'during pregnancy, narrower def of exposure', rather than '2 months before and/or pregnancy'. Otherwise, primary analysis used because similar results were obtained. | |
| Drugs dispensed before or during pregnancy were recorded in the French national health data system (Système National des Données de Santé (SNDS)). | ||||||||
|
Nguyen 2019 |
International 2005 - 2016 prospective cohort |
The Multiple Sclerosis (MS) Base Registry is a large, international observational cohort study, with long-term prospectively collected data. | Pregnancies in Relapsing-Remitting Multiple Sclerosis (RRMS) patients occurring during Azathioprine therapy. (This is a subgroup of exposure among the exposed group considered in the study). |
unexposed, sick
Pregnancies in Relapsing-Remitting Multiple Sclerosis (RRMS) patients not exposed to disease-modifying therapies (DMTs) (pregnancy occurring within a year of DMT discontinuation or without DMT exposure in the prior year). |
during pregnancy (anytime or not specified) | 4 / 886 | ||
| Data in the MSBase registry, including prospective pregnancy data, is entered in real time or near real time, as part of routine clinical visits. Information collected included: disease-modifying therapies exposure before and during pregnancy. | ||||||||
|
Nguyen_IBD (Controls exposed to TNFi) 2025 |
Sweden 2007 - 2022 population based cohort retrospective |
The Swedish National Patient Register (NPR), the Swedish Medical Birth Register and the Prescribed Drug Register. | Inflammatory bowel disease (IBD) pregnancies with at least 1 dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
exposed to other treatment, sick
Inflammatory bowel disease (IBD) pregnancies with at least 1 recorded use of tumor necrosis factor inhibitors (TNFi) during pregnancy (infliximab, adalimumab, or golimumab). |
during pregnancy (anytime or not specified) | 714 / 357 | Pregnancies with dual exposure during pregnancy were excluded to isolate the effect of thiopurines. Median time from the index thiopurine dispensation to ICP diagnosis was 28 and 29 weeks in SLE and IBD, respectively. | |
| Data on drug exposure were obtained from the Prescribed Drug Register, which contains information on all dispensations of prescribed drugs in pharmacies in Sweden | ||||||||
|
Nguyen_IBD (Controls unexposed, sick) 2025 |
Sweden 2007 - 2022 population based cohort retrospective |
The Swedish National Patient Register (NPR), the Swedish Medical Birth Register and the Prescribed Drug Register. | Inflammatory bowel disease (IBD) pregnancies with at least 1 dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
unexposed, sick
Inflammatory bowel disease (IBD) pregnancies without dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
1st trimester, during pregnancy (anytime or not specified) | 1924 / 3848 | Pregnancies with dual exposure during pregnancy were excluded to isolate the effect of thiopurines. Median time from the index thiopurine dispensation to ICP diagnosis was 28 and 29 weeks in SLE and IBD, respectively. | |
| Data on drug exposure were obtained from the Prescribed Drug Register, which contains information on all dispensations of prescribed drugs in pharmacies in Sweden | ||||||||
|
Nguyen_SLE (Controls exposed to TNFi) 2025 |
Sweden 2007 - 2022 population based cohort retrospective |
The Swedish National Patient Register (NPR), the Swedish Medical Birth Register and the Prescribed Drug Register. | Systemic lupus erythematosus (SLE) pregnancies with at least 1 dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
exposed to other treatment, sick
Systemic lupus erythematosus (SLE) pregnancies with at least 1 recorded use of tumor necrosis factor inhibitors (TNFi) during pregnancy (infliximab, adalimumab, or golimumab). |
during pregnancy (anytime or not specified) | -9 / -9 | Pregnancies with dual exposure during pregnancy were excluded to isolate the effect of thiopurines. Median time from the index thiopurine dispensation to ICP diagnosis was 28 and 29 weeks in SLE and IBD, respectively. | |
| Data on drug exposure were obtained from the Prescribed Drug Register, which contains information on all dispensations of prescribed drugs in pharmacies in Sweden | ||||||||
|
Nguyen_SLE (Controls unexposed, sick) 2025 |
Sweden 2007 - 2022 population based cohort retrospective |
The Swedish National Patient Register (NPR), the Swedish Medical Birth Register and the Prescribed Drug Register. | Systemic lupus erythematosus (SLE) pregnancies with at least 1 dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
unexposed, sick
Systemic lupus erythematosus (SLE) pregnancies without dispensation of azathiorpine or 6-mercaptopurine (L01BB02) from last menstrual period to one day before delivery or intrahepatic cholestasis of pregnancy (ICP). |
1st trimester, during pregnancy (anytime or not specified) | 297 / 594 | Pregnancies with dual exposure during pregnancy were excluded to isolate the effect of thiopurines. Median time from the index thiopurine dispensation to ICP diagnosis was 28 and 29 weeks in SLE and IBD, respectively. | |
| Data on drug exposure were obtained from the Prescribed Drug Register, which contains information on all dispensations of prescribed drugs in pharmacies in Sweden | ||||||||
|
Norgard 2020 |
Denmark 1995 - 2015 population based cohort retrospective |
The Medical Birth Registry, the National Patient Registry, the Nationwide Prescription Registry and the Central Personal Registration system. | Children exposed in utero to thiopurines (azathioprine/mercaptopurine) in a period of 3 months before conception or during pregnancy. |
unexposed (general population or NOS)
Children who were not exposed in utero for thiopurines in the period of 3 months before conception or during pregnancy. |
3 months (or more) before pregnancy or during pregnancy | 1048 / 1309961 | For preterm birth: Overlapping between Langagergaard 2007 and Norgard 2020. Data of Langagergaard 2007 were kept rather than those of Norgard 2020 because this latter use an inappropriate exposition period. | |
| Data on mothers’ use of thiopurines were retrieved from the Nationwide Prescription Registry and based on one or more filled prescriptions for azathioprin (using ATC system). | ||||||||
|
Norgard (Controls unexposed, NOS) 2003 |
Denmark 1991 - 2000 population based cohort retrospective |
The Danish Birth Registry (North Jutland County), Pharmaco-Epidemiological Prescription Database of North Jutland and the Hospital Discharge Registry. | Pregnancies exposed to azathioprine or mercaptopurine (‘early pregnancy’ group: prescriptions from 30 days before conception to the end of the first trimester; or 'entire pregnancy': during the first to the third trimesters). |
unexposed (general population or NOS)
All pregnant women who had not been prescribed any kind of reimbursed medicine from three months before conception to the end of pregnancy. |
throughout pregnancy | 10 / 19418 | Overlapping: Only perinatal deaths in results because the study is partially overlap by Langagergaard 2007 for preterm births, LBW and all congenial malformations (larger cohort in Langagergaard 2007). | |
| The population‐based Pharmaco‐Epidemiological Prescription Database of North Jutland was used to identify all pregnancies in which women had taken up prescriptions for azathioprine or mercaptopurine (using ATC system). | ||||||||
|
Norgard (Controls unexposed, sick) 2003 |
Danemark 1991-2000 population based cohort retrospective |
The Danish Birth Registry (North Jutland County), Pharmaco-Epidemiological Prescription Database of North Jutland and the Hospital Discharge Registry | Pregnancies exposed to azathioprine or mercaptopurine (‘early pregnancy’ group: prescriptions from 30 days before conception to the end of the first trimester; or 'entire pregnancy': during the first to the third trimesters). |
unexposed, sick
Women who used azathioprine or mercaptopurine before pregnancy, but not three months before pregnancy or during pregnancy. |
throughout pregnancy | 10 / 30 | Overlapping: Only perinatal deaths in results because the study is partially overlap by Langagergaard 2007 for preterm births, LBW and all congenial malformations (larger cohort in Langagergaard 2007). | |
| The population‐based Pharmaco‐Epidemiological Prescription Database of North Jutland was used to identify all pregnancies in which women had taken up prescriptions for azathioprine or mercaptopurine (using ATC system). | ||||||||
|
Reynolds 2022 |
United Kingdom 2007 - 2011 retrospective cohort |
10 hospital sites within the UK [Birmingham (3 sites), London (2 sites), Bath, Manchester, Blackburn, Sheffield and Southampton]. | Pregnancies in systemic lupus erythematosus (SLE) patients with Azathioprine exposure during pregnancy (continued throughout pregnancy and breastfeeding in almost all cases). |
unexposed, sick
Pregnancies in systemic lupus erythematosus (SLE) patients without Azathioprine exposure during pregnancy. |
throughout pregnancy | 86 / 198 | Only live-born children were included. 'As HCQ or AZA were continued throughout pregnancy and breastfeeding in almost all cases, exposure was combined into a single variable for each drug'. | |
| Retrospective data were collected using a previously piloted questionnaire, completed by women and by collection of maternal data via interview and reviewing the medical records. Pregnancy data collected included drug exposure at conception, during pregnancy, and during breastfeeding. | ||||||||
|
Schramm 2006 |
Germany Not specified. retrospective cohort |
Medical records of liver clinic at the University of Mainz and of the liver units of the Universities of Munich, Innsbruck, and Ulm. | Pregnancies in patient with Autoimmune Hepatitis exposed to azathioprine (at anytime during pregnancy). |
unexposed, sick
Pregnancies in patient with Autoimmune Hepatitis not exposed to azathioprine. |
during pregnancy (anytime or not specified) | 14 / 28 | 14 pregnancies exposed to azathioprine including 10 co-exposed to prednisolone. | |
| Review of medical records. | ||||||||
|
Selinger (Controls unexposed, disease free) 2023 |
United Kindgom 2014 - 2022 retrospective cohort |
The combined inflammatory bowel disease (IBD) Antenatal Clinic and Leeds Teaching Hospitals Leeds, UK | Thiopurine-exposed pregnancies in patients with inflammatory bowel disease (IBD), defined as any treatment with thiopurine during pregnancy. |
unexposed, disease free
Non-inflammatory bowel disease (IBD) patients without thiopurine exposure. |
throughout pregnancy | 111 / 386 | Thiopurine therapy was delivered dosed at 2–2.5 mg/kg bodyweight for azathioprine and 1–1.5 mg/ kg bodyweight for mercaptopurine. Dose adjustments were made if neutropenia occurred or in case of other side effects. | |
| Complete medication exposure was prospectively recorded at inflammatory bowel disease (IBD) antenatal clinic visits and therefore captured all IBD medication exposure. For controls, data was obtained from the electronic pregnancy medical records. | ||||||||
|
Selinger (Controls unexposed, sick) 2023 |
United Kindgom 2014 - 2022 retrospective cohort |
The combined inflammatory bowel disease (IBD) Antenatal Clinic and Leeds Teaching Hospitals Leeds, UK | Thiopurine-exposed pregnancies in patients with inflammatory bowel disease (IBD), defined as any treatment with thiopurine during pregnancy. |
unexposed, sick
Inflammatory bowel disease (IBD) patients without thiopurine exposure. |
throughout pregnancy | 111 / 275 | Thiopurine therapy was delivered dosed at 2–2.5 mg/kg bodyweight for azathioprine and 1–1.5 mg/ kg bodyweight for mercaptopurine. Dose adjustments were made if neutropenia occurred or in case of other side effects. | |
| Complete medication exposure was prospectively recorded at inflammatory bowel disease (IBD) antenatal clinic visits and therefore captured all IBD medication exposure. | ||||||||
|
Shim 2011 |
Australia 1996 - 2006 retrospective cohort |
ObstetriX Database and hospital records from Nepean Hospital, Westmead Hospital, and Royal North Shore Hospital in Sydney. | Births from women with inflammatory bowel disease (IBD) pregnant who reported taking azathioprine/6-mercaptopurine (AZA/6-MP) during their first antenatal visit (i.e. first trimester). |
unexposed, sick
Births from age-matched women with inflammatory bowel disease (IBD) pregnant who were not exposed to azathioprine/6-mercaptopurine (AZA/6-MP) before and during their pregnancy. |
throughout pregnancy | 19 / 74 | For LBW: OR provided by authors not reported because aberrant (1.00 (0.99-1.01)). All exposed to AZA/6-MP throughout pregnancy. None of the women in either group were treated with methotrexate, cyclosporine, ciprofloxacin, or biologic therapy. | |
| Medical records of eligible women were reviewed: medications used before and during pregnancy were recorded. Women reported taking medications during their first antenatal visit. | ||||||||
|
Tennenbaum 1999 |
France 1989 - 1995 retrospective cohort |
Database of three referral centers for inflammatory bowel disease (Rothschild, Saint-Lazare, Saint-Louis), Paris, France. | Pregnant women with inflammatory bowel disease that continued azathioprine during pregnancy. |
unexposed, sick
Pregnant women with inflammatory bowel disease without any treatment the 6 months before pregnancy. |
during pregnancy (anytime or not specified) | 12 / 52 | ||
| A postal questionnaire completed by the mother, including details on drugs related to IBD, 6 months before pregnancy and during pregnancy with details on the period of exposure during pregnancy. | ||||||||
|
Vestergaard 2024 |
Denmark 2008 - 2022 retrospective cohort |
The Department of Hepatology and Gastroenterology outpatient clinic, Aarhus University Hospital (AUH), a tertiary inflammatory bowel disease (IBD) center, Denmark. | Pregnant women with inflammatory bowel disease (IBD) who receive treatment with thiopurines monotherapy (i.e without concomitant biologics). |
unexposed, sick
Pregnant women with inflammatory bowel disease (IBD) who did not receive treatment with thiopurines, biologics, or the 2 combined (treated with 5-ASA, corticosteroids, Budesonide or no medical treatment). |
3rd trimester, during pregnancy (anytime or not specified) | 111 / 372 | Concurrent usage of biologics and thiopurines was termed combination treatment. | |
| All data were obtained through review of medical records, and all data from both mothers and children were recorded prospectively in medical records from routine clinical care. Medication requiring a prescription was registered. | ||||||||
|
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 Azathioprine 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 | 101 / 1360 | 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 Azathioprine 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 | 101 / 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). | ||||||||
|
Yeaman (Controls mainly exposed to biologics) 2023 |
Canada 2013 - 2018 prospective cohort |
The inflammatory bowel disease (IBD) and Pregnancy Clinic, Canada. | Pregnant people with inflammatory bowel disease (IBD) with exposure to thiopurines. |
exposed to other treatment, sick
Pregnant people with inflammatory bowel disease (IBD) without exposure to thiopurines (but may have had exposure to biologic IBD treatments including anti-TNF, vedolizumab, and ustekinumab). |
during pregnancy (anytime or not specified) | 19 / 50 | 27/50 (54%) of the non-thiopurine IBD patients were on biologic monotherapy (infliximab, adalimumab, golimumab, ustekinumab, or vedolizumab) => Mainly exposed to biologics. | |
| The physicians in this clinic use a standardized clinical care pathway to ensure consistent patient education about the safety of medications. Medications are recorded at each visit; and pregnancy complications and pregnancy outcomes are captured using standardized questionnaires. | ||||||||
|
Yeaman (Controls unexposed, disease free) 2023 |
Canada 2013 - 2018 prospective cohort |
The inflammatory bowel disease (IBD) and Pregnancy Clinic, Canada. | Pregnant people with inflammatory bowel disease (IBD) with exposure to thiopurines. |
unexposed, disease free
Pregnant people without inflammatory bowel disease (IBD) and with no exposure to thiopurines nor other immunomodulators for any other indication. |
during pregnancy (anytime or not specified) | 19 / 37 | ||
| The physicians in this clinic use a standardized clinical care pathway to ensure consistent patient education about the safety of medications. Medications are recorded at each visit; and pregnancy complications and pregnancy outcomes are captured using standardized questionnaires. | ||||||||
| Study | Country Study period Study design |
Data source | Case | Control | Exposition | Exposition period | Sample size (exposed/unexposed) Or (case / control) |
Remarks | Risk of bias |
|---|---|---|---|---|---|---|---|---|---|
|
Andreoli 2022 |
Italy Not specified. nested case control |
Twenty four (24) centres affiliated with the Italian Society for Rheumatology (SIR), Italy. | Children with neurodevelopmental disorders (learning disabilities, attention deficiency and hyperactivity disorder, autism spectrum disorder). | Children without neurodevelopmental disorders (learning disabilities, attention deficiency and hyperactivity disorder, autism spectrum disorder). | Interviews conducted retrospectively, by means of a maternal self-reported questionnaire. | during pregnancy (anytime or not specified) | 11 / 288 | No overlapping with Lazzaroni 2020, not the same disease ('This paper focuses on the follow-up of children born to patients with RD, as the other themes have already been the subject of a previous paper'). | |
| Children’s follow-up made with a maternal self-reported questionnaire. Children’s diagnoses of Autoimmune diseases (AD) and/or neurodevelopmental disorders (ND) reported by the mothers were checked through a 2nd round of interview, and only cases certified by a medical specialist were considered. | |||||||||
|
Bröms 2016 |
Sweden 2006 - 2010 nested case control |
Swedish national health registers : Medical Birth Register, National Patient Register and the Prescribed Drug Register. | Singleton preterm births among women with Inflammatory bowel diseases (IBD). | Randomly selected Inflammatory bowel diseases (IBD) controls 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. | throughout pregnancy | 237 / 239 | For preterm: Overlap with Bröms 2014, which is not specifically designed for this outcome, used general population as control group, did not adjust for previous preterm and separate CD and UC women. => Bröms 2016 used rather than Broms 2014. | |
| Data related to prematurity was obtained from the Medical Birth Register (structured forms throughout pregnancy, delivery and the neonatal period). | |||||||||
|
He 2022 |
Japan 2013 - 2020 nested case control |
The Takayasu arteritis (TAK) cohort of Peking Union Medical College Hospital (PUMCH), China. | Pregnancies with adverse pregnancy outcomes. | Pregnancies without adverse pregnancy outcomes. | The therapeutic data before and after pregnancy in both TAK patients and controls were collected and analyzed (NOS). | during pregnancy (anytime or not specified) | 68 / 42 | ||
| The demographic, laboratory, imaging, and therapeutic data before and after pregnancy in both TAK patients and controls were collected and analyzed (NOS). | |||||||||
Risk of bias: : NA; : low; : moderate; : serious; : critical; : unclear;
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