Hydroxychloroquine

Exposed non-exposed studies (cohort)

Study Country
Study period
Population source Exposure definition Non-exposure definition Sample size Rmk
Al Arfaj, 2010 Saudi Arabia
1980 - 2006
All pregnancies in patients with Systemic lupus erythematosus (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).
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.
Buchanan, 1996 United Kingdom
Not specified
Patients with systemic lupus erythematosus (SLE) or related conditions who attended this clinic during pregnancy. Pregnancies who had taken hydroxychloroquine (HCQ). unexposed, sick
Pregnancies who had attended the clinic with lupus pregnancy were drawn randomly from the same database.
36 / 53 22 were exposed to HCQ 200mg/day and 14 to 400 mg/day at some point during gestation. The mean duration of exposure to HCQ in pregnancy was 28.4 (SD10-75) weeks.
Chakravarty, 2005 USA
1991 - 2001
All the pregnant patients with Systemic lupus erythematosus (SLE) who were seen at the Hospital. Pregnant patients that received hydroxychloroquine. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant patients that not received hydroxychloroquine. (This is a subgroup of exposure among the whole exposed group considered in the study).
13 / 50
Cimaz, 2007 Italy
1999 - 2000
Babies born from mothers with connective tissue diseases. Babies born from mothers 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 mothers receiving low-dose aspirin during pregnancy.
14 / 6
Clowse, 2006 USA
1987 - 2002
Women with systemic lupus erythematosus (SLE) Hydroxychloroquine (HCQ) throughout pregnancy. unexposed, sick
No hydroxychloroquine (HCQ) within the 3 months prior to or during 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.
Colvin, 2010 Australia
2002 - 2005
All birth events in Western Australia (WA). 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 (not otherwise specified)
All other births (those births to women dispensed a Pharmaceutical Benefits Scheme (PBS) medicine or not).
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.
Cooper (controls exposed to TNF-I), 2014 USA
1995 - 2007
Women with inflammatory arthropathies, those with systemic lupus erythematosus, and those with inflammatory bowel disease who filled prescriptions for immunosuppressive or corticosteroids during pregnancy. 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).
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.
Cooper (controls unexposed, sick), 2014 USA
1995 - 2007
Women with inflammatory arthropathies, those with systemic lupus erythematosus, and those with inflammatory bowel disease who filled prescriptions for immunosuppressive or corticosteroids during pregnancy. Prescription for hydroxychloroquine (in the absence of methotrexate fetal exposure) during the first trimester of pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Women with immune-mediated diseases treated with immunosuppressive medications in the 180 days before, but not during, pregnancy.
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.
Costedoat-Chalumeau, 2003 France
1993 - 2002
Pregnant women with connective tissue disease (CTD) who had been monitored regularly at the Pitié-Salpétrière Hospital before becoming pregnant. 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.
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.
Diav-Citrin, 2013 Israel
1998 - 2006
Women who contacted the Israeli Teratology Information Service (TIS). Pregnant women exposed to hydroxychloroquine (HCQ). unexposed (not otherwise specified)
Women among those who contacted the Israeli TIS during pregnancy being exposed to agents known not to be teratogenic.
114 / 455 Additional medications for the rheumatic disease were taken in 79.8% of the HCQ group.
Do, 2020 USA
2000 - 2017
Pregnant women with Systemic lupus erythematosus (SLE) aged 18 years or older who delivered after 20 weeks at Lucile Packard Children’s Hospital at Stanford. Hydroxychloroquine (HCQ)-exposed pregnancies. unexposed, sick
Hydroxychloroquine (HCQ)-unexposed pregnancies.
53 / 76
Frassi, 2004 Italy
Not specified
Pregnancies in women suffering from connective tissue diseases (CTD). Pregnancies in women treated with hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women not exposed to hydroxychloroquine (HCQ).
76 / 80
Howren, 2020 Canada
2002 - 2012
An Rheumatic diseases (RD) pregnancy study cohort that included women with RA, systemic autoimmune rheumatic diseases (SARDs), and other RD including ankylosing spondylititis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). At least one prescription of hydroxychloroquine filled during perinatal windows of interest, i.e 90 days post conception for malformations and from conception to delivery for SGA. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies in women with RD without filled prescriptions for conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs; e.g. hydroxychloroquine, methotrexate) during aforementioned perinatal windows of interest;
114 / 6064
Kalok, 2019 Malaysia
2007 - 2014
Pregnant women with Systemic lupus erythematosus (SLE) in the institution. Hydroxychloroquine received in pregnancy. (Other treatments could also be received). unexposed, sick
No hydroxychloroquine during pregnancy. (Other treatments could be received).
26 / 45
Khamashta, 1996 England
The past 7 years
Lupus patients. Pregnancies in patients with hydroxychloroquine (HCQ) exposure. unexposed, sick
Patients who had attended the clinic with lupus pregnancy but without exposure to hydroxychloroquine (HCQ).
36 / 53 Although accurate assessment of vision in infants is difficult, no evidence of visual disturbance was so far clinically observed in the babies of patients exposed to HCQ in utero.
Langen, 2014 USA
2001 - 2009
All pregnancies complicated by Rheumatoid arthritis (RA) delivered at the institution. Women with 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 prednisone only near the time of conception. (This is a subgroup of exposure among the whole exposed group considered in the study).
13 / 15 HCQ was discontinued in 7/13 pregnancies upon discovery of pregnancy (but long half life).
Leroux, 2015 France
2001 - 2011
Pregnant women with Systemic lupus erythematosus (SLE) who delivered after 22 weeks at Bordeaux University Hospital (France). Pregnant patients who received Hydroxychloroquine (HCQ) throughout the pregnancy. unexposed, sick
Pregnant patients that did not take Hydroxychloroquine (HCQ) neither in the six months prior nor during 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
Levy, 2001 Brazil
Not specified
Pregnant patients diagnosed with systemic lupus erythematosus (SLE) or biopsy-proven discoid lupus erythematosus (DLE) for more than 1 year. Pregnant patients received hydroxychloroquine beginning between 8 and 18 weeks of pregnancy (average of 11 weeks for both groups). unexposed, sick
Pregnant patients received placebo beginning between 8 and 18 weeks of pregnancy (average of 11 weeks for both groups).
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.
Mekinian, 2016 France
2010 - 2014
Patients with clinical obstetrical criteria (Sydney): ≥3 early miscarriages less than 10 weeks of gestation; (2) intrauterine fetal death ≥10 weeks of gestation; (3) preeclampsia, prematurity <34 weeks of gestation related to placental insufficiency; (4) absence of inherited thrombophilia and of conventional APL. Pregnancies in patients under hydroxychloroquine during pregnancy (patients with non-conventional APS; non-APL group and confirmed APS). unexposed, sick
Pregancies in patients not under hydroxychloroquine during pregnancy (patients with non-conventional APS; non-APL group and confirmed APS).
12 / 462 474 pregnancies in patients: 261 pregnancies which occurred in 65 patients with non-conventional APS ; 81 pregnancies of confirmed APS patients and 132 pregnancies of 31 patients from non-APL group.
Mekinian, 2015 Europe
Not specified
Pregnancies in patients with Antiphospholipid syndrome (APS) or asymptomatic antiphospholipid (aPL) carriers. Pregnancies treated by hydroxychloroquine in patients with APS or asymptomatic aPL carriers, in addition to conventional APS treatment). unexposed, sick
Pregnancies in patients with confirmed APS treated by conventional APS treatment (aspirin and low-molecular weighted heparin) without hydroxychloroquine.
35 / 25
Mollerach, 2019 Argentina
2000 - 2014
All pregnant women with anti-Ro/La-positive antibodies in the laboratory registries (This is a subgroup of population among the whole population considered in the study) Pregnancy in women treated with hydroxychloroquine (200– 400 mg/day) during all their pregnancy. unexposed, sick
Pregnancy in women without hydroxychloroquine during pregnancy.
14 / 48
Moroni, 2016 Italy
2006 - 2013
Pregnant patients with lupus nephritis with a counselling visit within 3 months before the beginning of pregnancy. Outcomes of women treated with hydroxychloroquine at conception. unexposed, sick
Outcomes of women not treated with hydroxychloroquine at conception.
37 / 36
Ruffatti, 2018 20 centres (Italy, France, Spain, Russia, Poland, Argentina, UK, Israel, Emirates, Austria, Portuga)
1999 - 2016
Patients with primary antiphospholipid syndrome (PAPS) were retrospectively enrolled in the study. Administration of Hydroxychloroquine (HCQ) daily, in addition to conventional therapy (prophylactic or therapeutic doses of heparin and low-dose aspirin). exposed to other treatment, sick
Administration of low dose steroid, in addition to conventional therapy (prophylactic or therapeutic doses of heparin and low-dose aspirin).
94 / 36
Sciascia, 2016 United Kingdom
2008 - 2014
All the pregnancies in women with persisting antiphospholipid antibodies (aPL). Pregnancies in women with aPL treated with hydroxychloroquine (HCQ) for at least 6 months prior to pregnancy and continued throughout gestation unexposed, sick
Pregnancies in women with aPL not treated with hydroxychloroquine (HCQ) during pregnancy.
51 / 119 In 26 pregnancies women received HCQ 200 mg twice daily, and in 25 pregnancies women received HCQ 200 mg once daily.
Seo, 2019 Republic of Korea
1995 - 2018
Women with Systemic lupus erythematosus (SLE) who were managed at the rheumatology center in the author's institution, a tertiary care university hospital and referral center. Pregnancies exposed to Hydroxychloroquine (HCQ) throughout the index pregnancy. unexposed, sick
Pregnancies not exposed to Hydroxychloroquine (HCQ) within three months before pregnancy or during pregnancy.
80 / 71
Tincani, 2005 Italy
Not specified
Pregnancies in women suffering from connective tissue diseases (CTD). Pregnancies in women treated with hydroxychloroquine (HCQ). unexposed, sick
Pregnancies in women not exposed to hydroxychloroquine (HCQ).
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.
Viktil, 2012 Norway
2004 - 2007
Singleton pregnancies in women receiving at least 1 prescription during the study period. 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, Azathioprine, Methotrexate, Etanercept, Leflunomide, Adalumimab, or Anakinra) from 3 months prior to pregnancy to delivery.
58 / 1458 Analysis performed on anti-rheumatic drugs as a whole, no individual analyse for each substance. Raw data (number of exposed pregnancies and malformations) were available in the text and were used for this meta-analysis.
Vroom (controls exposed to sulfasalazine), 2009 United Kingdom
1992 - 2006
All women who were permanently registered (in GPRD) with their practice and aged 11-49 at the pregnancy end-date. 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.
-9 / -9
Vroom (controls unexposed, disease free), 2009 United Kingdom
1992 - 2006
All women who were permanently registered (in GPRD) with their practice and aged 11-49 at the pregnancy end-date. 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
-9 / 583447
Ye, 2017 China
2011- 2016
Recurrent spontaneous abortion (RSA) patients with Antiphospholipid syndrome (APS) who underwent regular prenatal examinations and delivered at Peking University Third Hospital. Prednisone (10 mg/d), Hydroxychloroquine (0.2 g bid), Low‐dose aspirin (LDA) (75 mg/d) taken from the 6th day of the menstrual cycle, then subcutaneous injection of LWMH (5000 U/d). During pregnancy, prednisone, LDA and LMWH stopped at different gestational age. unexposed, sick
Low‐dose aspirin (LDA) and low‐molecular‐weight heparin (LMWH) combination therapy taken with the same usage as former.
126 / 141

Case-control studies (cohort)

Study Country
Study period
Case Control Sample size Rmk
Lockshin, 2012 Seven study sites recruited
2003 - 2011
Patients who had any Adverse pregnancy outcomes (APOs), defined as an otherwise unexplained fetal demise after 12 weeks, neonatal death prior to discharge, associated with complications of prematurity, preterm delivery prior to 34 weeks because of gestational hypertension, preeclampsia or placental insufficiency, and small for gestational age (birth weight <5th percentile). Patients who had not Adverse pregnancy outcomes (APOs). 28 / 116 Control group: sick and healthy.
Placais, 2020 France
2011 - 2015
Patients consulting for obstetrical morbidity (early recurrent miscarriage, intrauterine death; intra-uterine growth restriction; preeclampsia, eclampsia prematurity) Patients without fetal loss/obstetrical complication. 83 / 16
Yelnik, 2016 USA, Canada, UK
2011 - 2015
Patients who had any Adverse pregnancy outcomes (APOs), defined as: fetal death after 12 weeks of gestation, neonatal death before hospital discharge due to complications of prematurity, preterm delivery before 36 weeks of gestation due to gestational hypertension, pre-eclampsia or placental insufficiency and small-for- gestational-age (SGA) neonate (birth weight, fifth percentile). Patients who had not Adverse pregnancy outcomes (APOs). 13 / 31

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