Hydroxychloroquine (All indications except Antiphospholipid Syndrom)

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
Abd Rahman
2020 		Malaysia
2007 - 2017
retrospective cohort 		A tertiary hospital that is a referral center for rheumatology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. Hydroxychloroquine (HCQ) use during pregnancy in Systemic Lupus Erythematosus (SLE) patients. unexposed, sick
No hydroxychloroquine (HCQ) use during pregnancy in Systemic Lupus Erythematosus (SLE) patients. 		during pregnancy (anytime or not specified) 47 / 35
The data collected included drugs used prior to pregnancy and patients were classified based on their hydroxychloroquine use during pregnancy (Not Otherwise Specified).
Al Arfaj
2010 		Saudi Arabia
1980 - 2006
retrospective cohort 		A retrospective cohort of pregnancies with SLE managed at King Khalid University Hospital, Riyadh. Pregnancies exposed to prednisolone and hydroxychloroquine. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies exposed to prednisolone only. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 69 / 222 The group of exposure 'None' was defined as 'All medications were discontinued upon confirmation of pregnancy' => Due to the long half-life of HCQ it cannot be used as unexposed group. The same for the group 'HCQ stopped' before pregnancy.
Treatments were recorded from medical charts.
Andersson (Controls exposed to corticosteroides)
2021 		Denmark
1996 - 2016
population based cohort retrospective 		Historical registry–based cohort with linkage of individual-level data between different nationwide registries using the unique personal identification number assigned to all inhabitants in Denmark. Pregnant women with a filled prescription for hydroxychloroquine during the considered time windows of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with a filled prescription for oral Glucocorticoids (H02AB) during the considered time windows of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). 		1st trimester, during pregnancy (anytime or not specified) 293 / 293 The medians for number of redeemed tablets and tablet strengths were 40 tablets (IQR, 20–40) and 250 mg (IQR, 250–250) for chloroquine and 100 tablets (IQR, 100–100) and 200 mg (IQR, 200–250) for hydroxychloroquine.
Information on prescription drug use was obtained through the Registry of Medicinal Product Statistics, which holds information on all redeemed prescriptions from all Danish pharmacies.
Andersson (Controls unexposed, NOS)
2021 		Denmark
1996 - 2016
population based cohort retrospective 		Historical registry–based cohort with linkage of individual-level data between different nationwide registries using the unique personal identification number assigned to all inhabitants in Denmark. Pregnant women with a filled prescription for hydroxychloroquine during the considered time windows of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnant women with no filled prescriptions for a 4-aminoquinoline drug (i.e chloroquine or hydroxychloroquine) during the respective pregnancy-exposure time windows as well as in the 6 months prior to pregnancy onset. 		1st trimester, during pregnancy (anytime or not specified) 303 / 303 The medians for number of redeemed tablets and tablet strengths were 40 tablets (IQR, 20–40) and 250 mg (IQR, 250–250) for chloroquine and 100 tablets (IQR, 100–100) and 200 mg (IQR, 200–250) for hydroxychloroquine.
Information on prescription drug use was obtained through the Registry of Medicinal Product Statistics, which holds information on all redeemed prescriptions from all Danish pharmacies.
Baalbaki
2020 		USA
2006 - 2013
retrospective cohort 		The University of Alabama at Birmingham, USA. Pregnant patients with Systemic Lupus Erythematosus (SLE) treated with Hydroxychloroquine during pregnancy. unexposed, sick
Pregnant patients with Systemic Lupus Erythematosus (SLE) not treated with Hydroxychloroquine during pregnancy. 		during pregnancy (anytime or not specified) 47 / 30 Patients with multifetal gestations and prenatally diagnosed congenital anomalies were excluded. In addition, patients with confirmed antiphospholipid syndrome and on anticoagulation were also excluded.
Individual maternal and neonatal medical records were reviewed, and data were abstracted and entered into a constructed database. Duration of medication use was collected.
Buchanan
1996 		United Kingdom
Not specified
retrospective cohort 		The Lupus Pregnancy Clinic, London. Pregnancies who had attended the clinic with lupus pregnancy and who had taken hydroxychloroquine (HCQ). unexposed, sick
Pregnancies who had attended the clinic with lupus pregnancy were drawn randomly from the same database. 		during pregnancy (anytime or not specified) 36 / 53 22 were exposed to HCQ 200mg/day and 14 to 400 mg/day at some point during gestation. Mean duration of HCQ in pregnancy: 28.4weeks. Total overlapping between Khamashta 1996 and Buchanan 1996, with some additional outcomes in Buchanan 1996 (=> kept).
Medical records (dose of hydroxychloroquine and duration of exposure in pregnancy).
Canti
2021 		Italy
2003 - 2019
prospective cohort 		The ‘Pregnancy at risk’ multidisciplinary outpatient clinic of San Raffaele Hospital, Milan, Italy. Pregnancies in women with systemic lupus erythematosus (SLE) treated with hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women with systemic lupus erythematosus (SLE) who did not receive hydroxychloroquine (HCQ). 		throughout pregnancy 45 / 29 HCQ: 300mg/day throughout pregnancy. Treatment with corticosteroids, low dose aspirin, and low molecular weight heparin during pregnancy was similar in the two groups (with higher dose of prednisolone in HCQ-). AZA in 21% unexposed and 40% in HCQ.
Patients were then monitored with regular visits every month from preconception counseling to delivery and post-partum.
Chakravarty
2005 		USA
1991 - 2001
retrospective cohort 		Stanford University Hospital and Lucile Packard Children’s, Palo Alto, California. Pregnant patients with Systemic lupus erythematosus (SLE) that received hydroxychloroquine. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant patients with Systemic lupus erythematosus (SLE) that not received hydroxychloroquine. (This is a subgroup of exposure among the whole exposed group considered in the study). 		during pregnancy (anytime or not specified) 13 / 50 21% of the patients were taking hydroxychloroquine (mean dose, 364 mg daily).
Review of the medical records. At each prenatal visit, data were abstracted regarding changes in medications.
Chambers (Controls unexposed, disease free)
2022 		Canada and USA
2004 - 2018
prospective cohort 		MotherToBaby / Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Study (members of the OTIS Collaborative Research Group) Women with diagnoses of various autoimmune diseases exposed to hydroxychloroquine at any dose and for any indication from the first day of the last menstrual period to the end of pregnancy. unexposed, disease free
Healthy women without autoimmune diseases (and no hydroxychloroquine during pregnancy). 		at least 1st trimester 279 / 279 The average daily dose of HCQ per treatment week was 324.8 mg per day, with a range of 100 mg to 800 mg per day.
Women enrolled in the study completed up to 3 prenatal interviews. Interviewers captured the following detailed information: all prescription and over-the-counter medications, including dosages, dates, and indications. Information on exposures was abstracted also from medical records.
Chambers (Controls unexposed, sick)
2022 		Canada and USA
2004 - 2018
prospective cohort 		MotherToBaby / Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Study (members of the OTIS Collaborative Research Group) Women with diagnoses of various autoimmune diseases exposed to hydroxychloroquine at any dose and for any indication from the first day of the last menstrual period to the end of pregnancy. unexposed, sick
Women with diagnoses of various autoimmune diseases not exposed to hydroxychloroquine at any time during pregnancy. 		at least 1st trimester 279 / 279 The average daily dose of HCQ per treatment week was 324.8 mg per day, with a range of 100 mg to 800 mg per day.
Women enrolled in the study completed up to 3 prenatal interviews. Interviewers captured the following detailed information: all prescription and over-the-counter medications, including dosages, dates, and indications. Information on exposures was abstracted also from medical records.
Cimaz
2007 		Italy
1999 - 2000
retrospective cohort 		A cohort of babies born from mothers who were followed in two pregnancy autoimmune centers, Brescia and Milan, Italy. Babies born from patients receiving Hydroxychloroquine (alone or in association) during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Babies born from patients who did not receive immunosuppressants during pregnancy and take low-dose aspirin during pregnancy. 		during pregnancy (anytime or not specified) 14 / 6
Not specified.
Clowse
2006 		USA
1987 - 2002
prospective cohort 		The Hopkins Lupus Pregnancy Cohort, USA. Pregnant women with systemic lupus erythematosus (SLE) with Hydroxychloroquine (HCQ) throughout pregnancy. unexposed, sick
Pregnant women with systemic lupus erythematosus (SLE) without hydroxychloroquine (HCQ) within the 3 months prior to or during pregnancy. 		at least 1st trimester, throughout pregnancy 56 / 163 Similar rates of azathioprine and prednisolone use among women who took HCQ and those who never took HCQ. Due to long half-life of HCQ, the group who stopped HCQ before or during 1st trimester of pregnancy cannot be considered as unexposed to HCQ.
At the first visit, the patient’s lupus and obstetric history and medications taken prior to and during pregnancy were recorded. At each subsequent visit, generally every 4–6 weeks throughout pregnancy, medications were recorded.
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. Hydroxychloroquine 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 26 / 106048 Category D or X medicines also studied. Total nb of unexposed: 106048=106 074-26. 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.
Cooper (controls exposed to TNF-I)
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 hydroxychloroquine (in the absence of methotrexate or TNF-I fetal exposure) during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Prescription for tumor necrosis factor inhibitors (TNF-I) (in the absence of methotrexate or hydroxychloroquine fetal exposure) during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). 		1st trimester 194 / 56 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.
Cooper (controls unexposed, sick)
2014 		USA
1995 - 2007
retrospective cohort (claims database) 		Health databases of 3 geographically diverse health plans (Tennessee Medicaid, Kaiser Permanente Northern California, and Kaiser Permanente Southern California) Pregnant women with immune-mediated diseases with prescription for hydroxychloroquine (in the absence of methotrexate or TNF-I 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
Pregnant women with immune-mediated diseases treated with immunosuppressive medications in the 180 days before, but not during, pregnancy. 		1st trimester 194 / 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.
Costedoat-Chalumeau
2003 		France
1993 - 2002
prospective cohort 		The Pitié-Salpétrière Hospital Pregnancies in women treated with Hydroxychloroquine (HCQ) continued throughout gestation (and at least 6 months prior to pregnancy). unexposed, sick
Pregnancies in women who had not been treated with HCQ for at least 6 months prior to conception. 		throughout pregnancy 133 / 70 Women received HCQ 200 mg twice daily (122 pregnancies), or HCQ 200 mg once daily (11 pregnancies). Other treatments (in HCQ exposed and unexposed groups) included prednisone, aspirin 100 mg/day, LMW heparin, AZA, and iv immunoglobulin.
Pregnancies who received treatment in the author's hospital (not otherwise specified).
Diav-Citrin
2013 		Israel
1998 - 2006
prospective cohort 		Israeli Teratology Information Service (TIS). Pregnant women exposed to hydroxychloroquine (HCQ). unexposed (general population or NOS)
Pregnant women exposed to agents known not to be teratogenic. 		at least 1st trimester 114 / 455 Additional medications for the rheumatic disease were taken in 79.8% of the HCQ group. The median daily dose [interquartile range (IQR) between the 25 and 75th percentiles] of HCQ was 300 mg (200–400).
Details of exposure were collected during pregnancy, at the initial contact to the TIS and before pregnancy outcome was known, using a structured questionnaire. After delivery, HCQ and other exposures were ascertained.
Do
2020 		USA
2000 - 2017
retrospective cohort 		The Stanford STARR (STAnford medicine Research data Repository) database, Lucile Packard Children’s Hospital at Stanford, USA. Hydroxychloroquine (HCQ)-exposed pregnancies. unexposed, sick
Hydroxychloroquine (HCQ)-unexposed pregnancies. 		during pregnancy (anytime or not specified) 53 / 76
By medical chart review, exposure was based on mention in physician notes in the medication list or plan at the earliest prenatal visit.
Frassi
2004 		Italy
Not specified
prospective cohort 		Not specified Pregnancies in women treated with hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women not exposed to hydroxychloroquine (HCQ). 		during pregnancy (anytime or not specified) 76 / 80
Not specified
Gernaat (Controls unexposed, disease free)
2022 		Sweden
2006 - 2016
population based cohort retrospective 		Swedish population-based study (including the population-based Swedish Lupus Linkage (SLINK) cohort, Total Population Register and the Swedish Medical Birth Register (MBR)).) Pregnant women with Systemic Lupus Erythematosus (SLE) which received at least 1 Hydroxychloroquine (HCQ) dispensation during 6 months before or any time during pregnancy. unexposed, disease free
Pregnant women randomly sampled from the general population without Systemic Lupus Erythematosus (SLE). 		3 months (or more) before pregnancy or during pregnancy 287 / 4644
The nationwide Prescribed Drug Register (PDR) includes all pharmacy-dispensed prescription medications.
Gernaat (Controls unexposed, sick)
2022 		Sweden
2006 - 2016
population based cohort retrospective 		Swedish population-based study (including the population-based Swedish Lupus Linkage (SLINK) cohort, Total Population Register and the Swedish Medical Birth Register (MBR)).) Pregnant women with Systemic Lupus Erythematosus (SLE) which received at least 1 Hydroxychloroquine (HCQ) dispensation during 6 months before or any time during pregnancy. unexposed, sick
Pregnant women with Systemic Lupus Erythematosus (SLE) which not received any Hydroxychloroquine (HCQ) dispensation before or during pregnancy. 		3 months (or more) before pregnancy or during pregnancy 287 / 408
The nationwide Prescribed Drug Register (PDR) includes all pharmacy-dispensed prescription medications.
Haase
2020 		Germany
Not specified.
prospective cohort 		Heinrich-Heine-University Düsseldorf, Policlinic of Rheumatology and Hiller Research Unit, Düsseldorf, Germany. Pregnancies in women with Systemic Lupus Erythematosus (SLE) under hydroxychloroquine (HCQ) treatment from 1st trimester. unexposed, sick
Pregnancies of women with Systemic Lupus Erythematosus (SLE) without hydroxychloroquine (HCQ) therapy. 		during pregnancy (anytime or not specified) 77 / 107 Overlapping: results for preeclampsia not reported here because specifically studied in an other study using the same dataset (Haase 2020b) and giving more details.
Not specified.
Haase
2021 		Germany
1995 - 2019
prospective cohort 		Heinrich-Heine-University Düsseldorf, Policlinic of Rheumatology and Hiller Research Unit, Düsseldorf, Germany. Pregnancies in women with Systemic Lupus Erythematosus (SLE) under hydroxychloroquine (HCQ) treatment from 1st trimester. unexposed, sick
Pregnancies of women with Systemic Lupus Erythematosus (SLE) without hydroxychloroquine (HCQ) therapy. 		during pregnancy (anytime or not specified) 82 / 108 Number of exposures to hydroxychloroquine (HCQ) = sum of HCQ only and Low dose Aspirin (LDA).
Not specified.
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 hydroxychloroquine 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. 		1st trimester, during pregnancy (anytime or not specified) 114 / 6064 Systemic auto-immune rheumatic diseases (SARDs), and other RD including ankylosing spondylititis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA)
PharmaNet captures complete information on all drug prescriptions dispensed including drug identification number, dispensation date, dispensation quantity, dosage, and duration.
Huybrechts (Controls unexposed, NOS)
2021 		USA
2000 - 2015
retrospective cohort (claims database) 		The Medicaid Analytic eXtract composed of all patients enrolled in Medicaid, and the IBM MarketScan Research Database composed of a nationally representative sample of patients with employer-provided health insurance. Pregnant women that filled a prescription for Hydroxychloroquine during the first trimester of pregnancy (defined as the date of the last menstrual period to day 90 of pregnancy). unexposed (general population or NOS)
Pregnant women without a prescription for Hydroxychloroquine for 3 months before the start of pregnancy to the end of the first trimester of pregnancy 		1st trimester 2045 / 3198589 Estimates were consistent between the 2 cohorts, therefore pooled estimations were reported. The risk of malformations among the HCQ- exposed women was the same regardless of whether women had concomitant exposure to steroids.
Database of prescriptions filled on an outpatient basis.
Huybrechts (Controls unexposed, sick)
2021 		USA
2000 - 2015
retrospective cohort (claims database) 		The Medicaid Analytic eXtract composed of all patients enrolled in Medicaid, and the IBM MarketScan Research Database composed of a nationally representative sample of patients with employer-provided health insurance. Pregnant women that filled a prescription for Hydroxychloroquine during the first trimester of pregnancy (defined as the date of the last menstrual period to day 90 of pregnancy). unexposed, sick
Pregnant women with a recorded diagnosis of autoimmune rheumatic disorders without a prescription for Hydroxychloroquine for 3 months before the start of pregnancy to the end of the first trimester of pregnancy 		1st trimester 2045 / 21679 Estimates were consistent between the 2 cohorts, therefore pooled estimations were reported. The risk of malformations among the HCQ- exposed women was the same regardless of whether women had concomitant exposure to steroids.
Database of prescriptions filled on an outpatient basis.
Kroese
2017 		Netherlands
2000 - 2015
retrospective cohort 		The University Medical Center (UMC) Utrecht, Netherlands. Pregnancies in women with systemic lupus erythematosus (SLE) that used hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women with systemic lupus erythematosus (SLE) that not used hydroxychloroquine (HCQ). 		during pregnancy (anytime or not specified) 30 / 80 Terminated pregnancies due to social reasons were not included in this study. The dose of hydroxychloroquine used in the pregnancies was 200 mg/day (16 pregnancies) or 400 mg/day (14 pregnancies).
Data were retrieved from patient medical files, from an intern systemic lupus erythematosus (SLE) registry, and from an in-house obstetric registry.
Langen
2014 		USA
2001 - 2009
retrospective cohort 		Perinatal database of a tertiary care referral hospital, Stanford University, USA. Women with Rheumatoid arthritis (RA) and hydroxychloroquine 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 Rheumatoid arthritis (RA) and 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 13 / 15 HCQ was discontinued in 7/13 pregnancies upon discovery of pregnancy (but long half life).
Data were collected from review of medical records and included medication use.
Leroux
2015 		France
2001 - 2011
retrospective cohort 		A descriptive and retrospective cohort study of pregnant women delivered at Bordeaux University Hospital (France). Pregnant patients with Systemic lupus erythematosus (SLE) who received Hydroxychloroquine (HCQ) throughout the pregnancy. unexposed, sick
Pregnant patients with Systemic lupus erythematosus (SLE) that did not take Hydroxychloroquine (HCQ) neither in the six months prior nor during pregnancy. 		throughout pregnancy 41 / 77 HCQ was administered at a single dose of 400mg/day for all of the patients. No significant difference was found between the two groups for other drugs given during pregnancy (prednisone, LMWH, azathiprine, low dose acetylsalicylic acid).
Reviewing of medical records for identification of medication exposures administered before, during the pregnancy, and postpartum.
Levy
2001 		Brazil
Not specified
randomized controlled trial 		A double-blind and placebo-controlled study, Rio de Janeiro, Brazil. Pregnant patients with Lupus erythematosus (systemic or discoid) that received hydroxychloroquine beginning between 8 and 18 weeks of pregnancy (average of 11 weeks for both groups). unexposed, sick
Pregnant patients with Lupus erythematosus (systemic or discoid) that received placebo beginning between 8 and 18 weeks of pregnancy (average of 11 weeks for both groups). 		2nd and/or 3rd trimester 10 / 10 Delivery age and Apgar scores were higher in the HCQ group (not stat signif). All the children achieved percentiles > 50 for height and weight and achieved satisfactory cognitive development and were able to perform activities expected for their ages.
Patients were randomized to receive Hydroxychloroquine (HCQ) or placebo during pregnancy. HCQ or identical placebo capsules were dispensed and replaced at subsequent visits until 12 weeks after delivery.
Liu
2021 		China
2004 - 2019
retrospective cohort 		Delivery records of the Peking University First Hospital in Beijing, China. Pregnancies with Systemic lupus erythematosus (SLE) that received Hydroxychloroquine throughout the pregnancy or immediately after the diagnosis of SLE during pregnancy. unexposed, sick
Pregnant women with Systemic lupus erythematosus (SLE) that did not take HCQ 3 months before implantation or during pregnancy. 		during pregnancy (anytime or not specified) 53 / 66
The hospital’s electronic medical discharge reports were used. Medication exposures were collected.
Louthrenoo
2021 		Thailand
1993 - 2017
retrospective cohort 		The Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand. Pregnancies in lupus erythematosus (SLE) patients that used Hydroxychloroquine during pregnancy. unexposed, sick
Pregnancies in systemic lupus erythematosus (SLE) patients that not used Hydroxychloroquine during pregnancy. 		during pregnancy (anytime or not specified) 43 / 47 Nb of exposures and non exposures extracted from Table 4.
Review of the medical records.
Mollerach
2019 		Argentina
2000 - 2014
retrospective cohort 		Electronic medical records of patients seen at the Hospital Italiano de Buenos Aires. Pregnancy in women with anti-Ro/La-positive antibodies treated with hydroxychloroquine (200– 400 mg/day) during all their pregnancy. unexposed, sick
Pregnancy in women with anti-Ro/La-positive antibodies without hydroxychloroquine during pregnancy. 		throughout pregnancy 14 / 48 From the group of mothers who consumed hydroxychloroquine during all their pregnancy, nine consumed 400 mg/day of hydroxychloroquine whereas five consumed 200 mg/day.
Review of electronic medical records of patients.
Moroni
2016 		Italy
2006 - 2013
prospective cohort 		A multicenter, prospective, observational study designed by “The Pregnancy Study Group” of the Italian Society of Nephrology. Outcomes of women with lupus nephritis treated with hydroxychloroquine at conception. unexposed, sick
Outcomes of women with lupus nephritis not treated with hydroxychloroquine at conception. 		during pregnancy (anytime or not specified) 37 / 31
Data about history and therapy of Systemic Lupus Erythematosus (SLE), lupus nephritis were recorded from medical records. Women were seen at least once a month up to the 24th week of gestation and every two weeks from the 24th week up to delivery.
Poh
2020 		Singapore
2000 - 2016
retrospective cohort 		Singapore General Hospital, a tertiary referral centre in Singapore. Use of Hydroxychloroquine during pregnancy in systemic lupus erythematosus (SLE) patients. unexposed, sick
No use of Hydroxychloroquine during pregnancy in systemic lupus erythematosus (SLE) patients. 		during pregnancy (anytime or not specified) 40 / 63 OR not reported because aberrant value ((OR 0, CI 0–0.054)) and raw data not available to calculate OR.
Not specified.
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 with Hydroxychloroquine exposure during pregnancy (continued throughout pregnancy and breastfeeding in almost all cases). unexposed, sick
Pregnancies without Hydroxychloroquine exposure during pregnancy. 		throughout pregnancy 149 / 135 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.
Seo
2019 		Republic of Korea
1995 - 2018
retrospective cohort 		Data of the rheumatology center, a tertiary care university hospital and referral center, Korea. Pregnancies in Systemic lupus erythematosus (SLE) patients exposed to Hydroxychloroquine (HCQ) throughout the index pregnancy. unexposed, sick
Pregnancies in Systemic lupus erythematosus (SLE) patients not exposed to Hydroxychloroquine (HCQ) within three months before pregnancy or during pregnancy. 		throughout pregnancy 80 / 71
Retrospective study (probably medical records, not clearly specified).
Tang
2022 		China
2003 - 2021
retrospective cohort 		Peking University First Hospital, Beijing, China. Patients with biopsy-proven IgA nephropathy and prescription of Hydroxychloroquine at any time during pregnancy. unexposed, sick
Patients with biopsy-proven IgA nephropathy, without prescription of Hydroxychloroquine at any time during pregnancy. 		during pregnancy (anytime or not specified) 25 / 63 All patients enrolled in this study discontinued renin–angiotensin–aldosterone system inhibitors therapy when pregnancy was planned or detected.
Review of medical records from the IgA nephropathy registration database at Peking University First Hospital. Utilization of Hydroxycloroquine during pregnancy was identified using prescription records of Hydroxycloroquine dispensing any time during pregnancy.
Tincani
2005 		Italy
Not specified
prospective cohort 		Not specified Pregnancies in women suffering from connective tissue diseases (CTD), treated with hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women suffering from connective tissue diseases (CTD), not exposed to hydroxychloroquine (HCQ). 		during pregnancy (anytime or not specified) 76 / 80 Review provided data published in scientific literature, including a study previously published by authors (Frassi 2004), with 3 additional outcomes: preterm, spontaneous abortions and stillbirths that were reported here; with protocol of Frassi 2004.
Not specified
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 Hydroxychloroquine 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 58 / 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 Hydroxychloroquine 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 58 / 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).
Vroom (controls exposed to sulfasalazine)
2009 		United Kingdom
1992 - 2006
retrospective cohort (claims database) 		The General Practice Research Database (GPRD). Women that was prescribed hydroxychloroquine at any time between 3 months before and 3 months after pregnancy (then analyzes performed according to trimester of pregnancy). (This is a subgroup of exposure among the whole exposed group considered in the study) exposed to other treatment, sick
Women that was prescribed sulfasalazine. 		1st trimester, 2nd trimester, 3rd trimester -9 / -9
Prescription database, the General Practice Research Database (GPRD).
Vroom (controls unexposed, disease free)
2009 		United Kingdom
1992 - 2006
retrospective cohort (claims database) 		The General Practice Research Database (GPRD). Women that was prescribed hydroxychloroquine at any time between 3 months before and 3 months after pregnancy (then analyzes performed according to trimester of pregnancy). (This is a subgroup of exposure among the whole exposed group considered in the study) unexposed, disease free
The general population not prescribed Disease Modifying Antirheumatic Drugs in pregnancy (DMARDs) during pregnancy 		1st trimester, 2nd trimester, 3rd trimester -9 / 583447
Prescription database, the General Practice Research Database (GPRD).

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
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.
Bérard
2021 		Canada
1998 - 2015
nested case control 		The population-based Quebec Pregnancy Cohort. Pregnancies resulted in a premature delivery, or a low birth weight, or a small for gestational age, or a major congenital malformation. Pregnancies not resulted in the studied outcome (premature delivery, or a low birth weight, or a small for gestational age, or a major congenital malformation). The study medication prescription fillings were identified from the Quebec prescription drug insurance database (prescribed over- the-counter medications were also included), using timing of exposure determined by the dispensed date and duration of treatment. 1st trimester, during pregnancy (anytime or not specified) 23991 / 207084 Within the study population: 15,032 pregnancies resulted in a premature delivery; 11,606 low birthweight; 22,280 small for gestational age newborns and 23,991 major malformations.
The Régie de l’assurance maladie du Québec (RAMQ): diagnoses, medical procedures, socio-economic status. The Quebec birth certificates database (ISQ): patient socio-demographics, gestational age, birth weight). The MedEcho: in-hospital diagnoses and procedures, gestational age.
Braga
2021 		Portugal
1993 - 2019
nested case control 		The Obstetrics Department and the Immunology Clinical Unit of the tertiary university hospital, Porto, Portugal. Pregnancy with Adverse pregnancy outcome (APO) defined as the occurrence of miscarriage, stillbirth, fetal growth restriction, preterm, or the development of hypertensive disorders of pregnancy Normal pregnancy (i.e, without Adverse pregnancy outcome (APO)). Before conception, hydroxychloroquine was introduced when possible (Not Otherwise Specified). during pregnancy (anytime or not specified) 89 / 126
Maternal and fetal outcomes were assessed (Not Otherwise Specified).
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 (Not Otherwise Specified). 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 (Not Otherwise Specified).
Howley - BDS study
2021 		USA
1976 - 2015
case control 		The Slone Epidemiology Center Birth Defects Study (BDS), a large, multisite, case–control study. Infants with any major birth defect. Liveborn infants without birth defects identified from study hospitals and birth certificates in the same catchment areas as case participants. Women were asked about medications taken. Data were maternal self-reported up to 6 months after delivery via in-person interviews. 3 months (or more) before pregnancy or during pregnancy, early pregnancy 29838 / 12868 Reported indications included systemic lupus erythematosus (n = 19), rheumatoid arthritis (n = 11), psoriatic arthritis (n = 1), other rheumatic diseases (...), connective tissue disorder (n = 1), fibromyalgia (n = 1), and unknown indication (n = 4).
Review of discharge records or registry data at participating hospitals or birth defect registries.
Howley - NBDPS study
2021 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS), large, multisite, case–control study. Pregnancies affected by one or more of 30 categories of major structural birth defects, excluding those attributed to a known chromosomal or single-gene abnormality. Live births without major birth defects randomly selected from hospital records or birth certificates in the same time period and geographic area as the cases. Women were asked about medications taken. Data were maternal self-reported up to 24 months after delivery via computer-assisted telephone interviews. 3 months (or more) before pregnancy or during pregnancy, early pregnancy 31468 / 11614 Reported indications included systemic lupus erythematosus (n = 19), rheumatoid arthritis (n = 11), psoriatic arthritis (n = 1), other rheumatic diseases (...), connective tissue disorder (n = 1), fibromyalgia (n = 1), and unknown indication (n = 4).
Cases were ascertained through birth defects surveillance programs in 10 states (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah). Clinical geneticists reviewed cases to determine eligibility for the overall study and to classify cases.
Kiatkongchuchai
2020 		Thailand
2012 - 2018
nested case control 		Rajavithi hospital, Muang, Thailand. Systemic Lupus Erythematosus (SLE) pregnant patients with preeclampsia. Systemic Lupus Erythematosus (SLE) pregnant patients without preeclampsia Current medication used were collected (Not Otherwise Specified). during pregnancy (anytime or not specified) -9 / -9 Raw data not provided (Abstract).
Not specified.
Placais
2019 		France
2011 - 2015
case control 		A French monocentric study conducted at Jean-Verdier Hospital. Patients consulting for obstetrical morbidity (early recurrent miscarriage, intrauterine death; intra-uterine growth restriction; preeclampsia, eclampsia prematurity). Patients without fetal loss/obstetrical complication. Not specified. during pregnancy (anytime or not specified) 83 / 16
Not specified.
Zhang
2022 		China
2014 - 2020
nested case control 		Single-center, retrospective study conducted at the rheumatology clinic of the Meizhou People’s Hospital of the Southern China. Using the hospital electronic database, the medical records of patients were comprehensively reviewed to collect the type of current medications. during pregnancy (anytime or not specified) 59 / 64 Hydroxychloroquine was prescribed to patients with a dose of 100 to 400 mg daily.
Using the hospital electronic database, the medical records of patients were comprehensively reviewed to collect clinical information (pregnancy and neonatal outcomes).

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

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