==== Front Rev Bras Ginecol Obstet Rev Bras Ginecol Obstet 10.1055/s-00030576 RBGO Gynecology & Obstetrics 0100-7203 1806-9339 Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil 33254264 10.1055/s-0040-1715140 200055 Original Article Obstetrics/High Risk Prenancy New Benefits of Hydroxychloroquine in Pregnant Women with Systemic Lupus Erythematosus: A Retrospective Study in a Tertiary Centre http://orcid.org/0000-0003-4161-6461 Abd Rahman Rahana 1 http://orcid.org/0000-0001-6243-4961 Min Tun Kyaw 1 http://orcid.org/0000-0001-8447-004X Kamisan Atan Ixora 1 http://orcid.org/0000-0003-1459-1844 Mohamed Said Mohd Shahrir 2 http://orcid.org/0000-0001-8423-707X Mustafar Ruslinda 2 http://orcid.org/0000-0002-9463-8050 Zainuddin Ani Amelia 1 1 Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia 2 Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia Address for correspondence Rahana Abd Rahman, PhD Universiti Kebangsaan Malaysia Medical CentreJalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala LumpurMalaysiadrrahana@ppukm.ukm.edu.my 30 11 2020 11 2020 1 11 2020 42 11 705711 24 2 2020 29 6 2020 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ) 2020 The Author(s). https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective  To determine pregnancy outcomes in women with systemic lupus erythematosus (SLE) who were treated with hydroxychloroquine in a tertiary center. Methods  A retrospective study involving pregnant women with SLE who had antenatal follow-up and delivery in between 1 January 2007 and 1 January 2017. All participants were retrospectively enrolled and categorized into two groups based on hydroxychloroquine treatment during pregnancy. Results  There were 82 pregnancies included with 47 (57.3%) in the hydroxychloroquine group and 35 (42.7%) in the non-hydroxychloroquine group. Amongst hydroxychloroquine users, there were significantly more pregnancies with musculoskeletal involvement ( p  = 0.03), heavier mean neonatal birthweight ( p  = 0.02), and prolonged duration of pregnancy ( p  = 0.001). In non-hydroxychloroquine patients, there were significantly more recurrent miscarriages ( p  = 0.003), incidence of hypertension ( p  = 0.01) and gestational diabetes mellitus ( p  = 0.01) and concurrent medical illness ( p  = 0.005). Hydroxychloroquine use during pregnancy was protective against hypertension ( p  = 0.001), and the gestational age at delivery had significant effect on the neonatal birthweight ( p  = 0.001). However, duration of the disease had a significant negative effect on the neonatal birthweight ( p  = 0.016). Conclusion  Hydroxychloroquine enhanced better neonatal outcomes and reduced adverse pregnancy outcomes and antenatal complications such as hypertension and diabetes. Keywords hydroxychloroquine systemic lupus erythematosus pregnancy ==== Body pmcIntroduction Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, affecting women primarily in their reproductive age. It is one of the main causes of maternal mortality in women between 15 and 24 years old. 1 The incidence of SLE varies from as low as 2.35 (per 100.000 persons-year) to as high as 8.1 in Taiwan. 2 3 In Malaysia, there is lack of national data, but the incidence in tertiary centers in Kuala Lumpur and Sarawak were 424 over 17 months and 633 over 12 months, respectively. 4 5 Diagnosis is made based on clinical features combined with laboratory findings according to the Systemic Lupus International Collaborating Clinics (SLICC) and the American College of Rheumatology Criteria for Classification of SLE. 6 7 Systemic lupus erythematosus activities are suppressed with nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive medication, or short courses of corticosteroids. There are associated risks of multiple organs damage due to the disease itself, or the medications used, specifically corticosteroids. 8 The survival rate and quality of life have significantly improved due to the advancement in disease management, leading to increasing numbers of successful pregnancies. These pregnancies are high-risk due to the associated fetal and maternal morbidity and mortality such as preeclampsia, intrauterine fetal loss, preterm delivery, intrauterine growth restriction (IUGR) and low birthweight. 9 During pregnancy, there is a risk of relapse as demonstrated by several published papers. 10 11 This can occur antenatally, as well as several months following delivery. 12 Women with lupus nephritis have a higher risk of relapse during pregnancy with worsening renal function despite aggressive therapy. Additionally, active disease of < 6 months prior to pregnancy is known to be the strongest predictor in disease flare and associated with worse pregnancy outcomes. 13 The mainstay of treatment in SLE consists of corticosteroids, low dose aspirin, and disease modifying anti-rheumatic drugs (DMARDs) such as hydroxychloroquine (HCQ). Hydroxychloroquine is an antimalarial drug that possesses anti-inflammatory and immunomodulatory properties via different molecular pathways. 14 Among the beneficial clinical effects is reduction in cholesterol and glucose levels as well as anti-thrombosis. More importantly, it plays a central role in the management of SLE due to reduction in disease flare associated with its use. 15 16 Other benefits of HCQ are prolongation of pregnancy and reduction in the rate of fetal growth restriction without teratogenic effects or long-term morbidities to the offspring. 17 18 In view of the various benefits of HCQ, the present study aimed to demonstrate the effects of HCQ in pregnant women with SLE. Methods We conducted a retrospective cohort study in a tertiary hospital that is a referral center for rheumatology from 1 January 2007 till 1 January 2017. Ethics approval was obtained from the hospital research and ethic committee (FF-2017–433). Patient Involvement The study population included pregnant women with SLE who fulfilled the criteria based on the Systemic Lupus International Collaborating Clinics (SLICC) and the American College of Rheumatology Criteria for Classification of SLE. 6 7 All of these women had antenatal management and deliveries in the tertiary center. Those who had antenatal care and/or delivered elsewhere were excluded. Patients were classified based on their HCQ use during pregnancy. The gestational age of the pregnancies was determined based on the 1 st trimester dating scan. The data collected included demographic data such as age, ethnicity and parity, clinical characteristics of women with SLE such as association with antiphospholipid antibody, disease duration, organ involvement, disease activity at conception, concurrent medical illness, drugs used prior to pregnancy and the pregnancy outcomes, which included antenatal complications, pregnancy duration, birthweight, neonatal Apgar score, neonatal intensive care unit (NICU) admission and mode of delivery. Activity during pregnancy was recorded using the SLE Pregnancy Disease Activity Index (SLEPDAI). Disease flare was defined as per Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI). 19 20 Remission of disease was considered as absence of symptoms, signs and abnormal serology with or without maintenance treatment and low dose steroids (5mg or less). 21 Miscarriage was defined as fetal loss < 24 weeks of gestation. Recurrent miscarriage is defined as ≥ 3 consecutive pregnancy losses before 24 weeks. 22 Gestational age was considered preterm if < 37 weeks of gestation and term if at ≥ 37 weeks. Intrauterine growth restriction was defined as fetal weight < 10 th percentile for gestational age. Apgar score < 7 after 5 minutes of birth was considered abnormal. The diagnostic of antenatal complications such as gestational diabetes was made based on modified glucose tolerance test (MGTT) of ≥ 5.6 mmol/l for fasting and ≥ 7.8 mmol/l for 2 hours postprandial. 23 Hypertensive disease in pregnancy included gestational hypertension and preeclampsia with or without existing secondary hypertension. Preeclampsia was defined based on criteria by the International Society for the Study of Hypertension in Pregnancy (ISSHP). 24 The demographic data included mean maternal age, ethnicity and parity. The clinical characteristics of the study population were presence or absence of antiphospholipid antibodies, mean disease duration, system involvement, history of recurrent miscarriages, concurrent medical illness, steroids use pre and during pregnancy and immunosuppressive drugs use pre and during pregnancy. The main outcome measures were the pregnancy outcomes consisting of antenatal complications, particularly hypertensive disease in pregnancy and gestational diabetes mellitus, mean duration of pregnancy, rate of fetal loss at ≥ 24 weeks, gestational age at birth, mean birthweight, rate of intrauterine growth restriction, mode of delivery, neonatal Apgar score at 5 minutes and NICU admission. Statistics Data analysis was performed using IBM SPSS Statistics for Windows, Version 23 (IBM Corp., Armonk, NY, USA). Categorical variables were reported as frequency in percentage, and quantitative variables as mean and standard deviation (SD). The pregnancy outcome was tested with univariate analysis using the chi-squared and the Fischer exact test. A p-value  < 0.05 was considered statistically significant. Multivariate analysis was done using logistic regression to identify the efficacy of HCQ on maternal outcomes and neonatal complications. Results A total of 92 pregnancies were screened, 10 were excluded, and the remaining 82 were categorized into 2 groups; HCQ ( n  = 47) and non-HCQ user ( n  = 35). Table 1 demonstrates that there were no significant differences in the mean age (32.03 versus 31.5, p  = 0.82), ethnicity ( p  = 0.99) and parity ( p  = 0.12). The majority of patients were multiparous Malay women. Table 1 Demographic data of women with systemic lupus erythematosus grouped by hydroxychloroquine usage ( n  = 82) HCQ n = 47 (57.3%) Non HCQ n = 35 (42.7%) OR (95%CI) p-value Mean age ± SD (years old) 32.03 ± 3.92 31.50 ± 3.54 0.82 a Ethnicity, n (%) 0.99 b   Malay 35 (74.5) 26 (74.3)   Chinese 9 (19.1) 7 (20.0)   Indian 3 (6.4) 2 (5.7) Parity, n (%) 0.47 (0.18–1.21)   Primipara 20 (42.6) 9 (25.7) 0.12 c   Multipara 27 (57.4) 26 (74.3) Abbreviations: CI, confidence interval; HCQ, hydroxychloroquine; OR, odds ratio; SD, standard deviation. a Student’s t -test. b Contingency coefficient, df = 2. c Chi-square test. Table 2 showed that most of the patients in both groups had SLE without antiphospholipid antibody and this was not statistically significant ( p  = 0.11). The 2 groups were similar in mean disease duration (7.06 versus 6.57, p  = 0.44) and use of immunosuppressive drugs prior to ( p  = 0.46) and during pregnancy ( p  = 0.26). There were significantly more patients in the HCQ group who had musculoskeletal involvement ( p  = 0.03). In the non-HCQ group, the rate of recurrent miscarriages was significantly higher (0% vs 17.1%, p  = 0.003) with concurrent medical illnesses such as secondary hypertension, chronic kidney disease, thyroid, heart disease and idiopathic thrombocytopenic purpura (14.9% versus 42.9%, p  = 0.005). Patients in the HCQ group used significantly more steroids prior to pregnancy (95.7% versus 82.9%, p  = 0.05), but during pregnancy both groups were similar ( p  = 0.22). There was a significantly lower prevalence of hypertension (6.4% versus 42.9%, p  = 0.01) and gestational diabetes (0% versus 14.3%, p  = 0.01) in the HCQ group. In the HCQ-treated group, the majority of patients (85.1%) were treated for > 6 months prior to pregnancy (results not shown). Table 2 Clinical characteristics of women with systemic lupus erythematosus grouped by hydroxychloroquine usage ( n  = 82) HCQ n = 47 Non HCQ n = 35 OR (95%CI) p-value Presence of antiphospholipid antibody, n (%) 0.11 a   No 36 (76.6) 21 (60.0)   Yes 11 (23.4) 14 (40.0) Mean disease duration ± SD (years) 7.06 ± 4.24 6.57 ± 3.56 0.44 a System involvement, n (%) Musculoskeletal 29 (61.7) 13 (37.1) 2.63 (1.06–6.51) 0.03 c Lupus nephritis 23 (48.9) 22 (62.9) 0.54 (0.22–1.33) 0.18 c Hematology 24 (51.1) 12 (34.3) 2.09 (0.85–5.18) 0.11 c CNS 0 3 (8.6) 0.91 (0.83–1.01) 0.07 c Recurrent miscarriage, n (%) 0 6 (17.1) 0.83 (0.71–0.96) 0.003 c Concurrent medical illness, n (%) 7 (14.9) 15 (42.9) 0.23 (0.08–0.66)   Secondary hypertension 2 (4.3) 6 (15.8) 0.005 c   Chronic kidney disease 0 4 (10.5)   Thyroid disease 1 (2.1) 2 (5.3)   Heart disease 1 (2.1) 5 (13.2) ITP 2 (4.3) 1 (2.6) Steroids use pre pregnancy, n (%) 45 (95.7) 29 (82.9) 0.05 b   5–10 mg 32 (71.1) 20 (68.9)   10–20 mg 5 (11.1) 4 (13.9)   >   20 mg 8 (17.8) 5 (17.2) Steroids use during pregnancy, n (%) 45 (95.7) 31 (88.6) 0.22 b   5–10 mg 28 (62.2) 19 (61.3)   10–20 mg 11 (24.4) 7 (22.6)   > 20 mg 6 (13.6) 5 (16.1) Immunosuppressive drugs prepregnancy, n(%) 23(48.9) 20(57.1) 0.46 b   Azathioprine 16 (34.0) 13 (37.1)   Cyclosporin A 7 (14.9) 2 (5.7)   Both 0 4 (11.4) Immunosuppressive drugs during pregnancy, n (%) 25 (53.2) 23 (67.7) 0.26 b   Azathioprine 17 (36.2) 18 (51.4)   Cyclosporin A 6 (12.8) 2 (5.7)   Both 2 (4.3) 3 (8.6) Abbreviations: CI, confidence interval; CNS, central nervous system; HCQ, hydroxychloroquine; OR, odds ratio; SD, standard deviation; ITP, idiopathic thrombocytopenic purpura. a Student's t -test. b contingency coefficient, df = 2. c Chi-square test, difference expressed in odds ratio (95% CI), ITP-idiopathic thrombcytopenic purpura. The numbers of term live births and miscarriages were similar between the 2 groups ( Table 3 ). The mean duration of pregnancy was significantly longer in the HCQ group (36.74 versus 34.79, p  = 0.001) leading to a significantly heavier mean birthweight (2.52 versus 2.13, p  = 0.02). There were no significant differences in fetal loss after 24 completed weeks, rate of live birth and miscarriages, newborns' Apgar score, NICU admission, mode of delivery and indications for cesarean section between the two groups. The most frequent indication for cesarean section in the non-HCQ and HCQ groups was preeclampsia (33.3%) and fetal distress (41.2%), respectively. However, more preterm delivery was found in the non-HCQ group, but it was not statistically significant (23.4% versus 40.0%, p  = 0.25). Furthermore, IUGR was less frequent in the HCQ group (16.7% versus 35.7%, p  = 0.08). Table 3 Pregnancy outcome of women with systemic lupus erythematosus grouped by hydroxychloroquine usage ( n  = 82) HCQ n = 47 Non HCQ n = 35 OR (95% CI) p value Antenatal complication   Hypertension in pregnancy 3 (6.4) 15 (42.9) 0.09 (0.02–0.35) 0.01 c Gestational diabetes mellitus 0 5 (14.3) 0.86 (0.75–0.98) 0.01 c Mean duration of pregnancy ± SD (week) 36.74 ± 2.01 34.79 ± 4.21 0.001 a Fetal loss ≥ 24 weeks, n (%) 2 (5.3) 2 (7.1) 0.72 (0.09–5.47) 0.75 c Gestational age at birth, n (%) 0.25 b   Term livebirth (≥ 37 weeks) 26 (55.3) 14 (40.0)   Preterm livebirth (< 37 weeks) 11 (23.4) 14 (40.0)   Miscarriage (< 24 weeks) 10 (21.3) 7 (20.0) Mean birthweight (kg) ± SD (range) 2.52 ± 0.56 2.13 ± 0.79 0.02 a Intrauterine growth restriction, n (%) 6 (16.7) 10 (35.7) 0.36 (0.11–1.16) 0.08 c Mode of delivery, n (%)   Vaginal 18 (47.9) 13 (43.3) 0.91 b   Assisted vaginal 3 (7.9) 2 (6.7) Caesarean section 17 (44.7) 15 (50.0) Apgar score   ≥ 7 in 5 minutes 34 (94.4) 22 (78.6) 0.22 (0.04–1.17)   < 7 in 5 minutes 2 (5.6) 6 (21.4) 0.06 c NICU admission 4 (11.1) 5 (19.2) 0.53 (0.13–2.18) 0.37 c Indication for LSCS 0.53 b   Preeclampsia 2 (11.8) 5 (33.3)   Fetal Distress 7 (5.9) 2 (13.3)   Worsening Lupus 1 (5.9) 2 (13.3)   Failed IOL/ Poor Progress 2 (11.8) 2 (13.3)   Maternal Request/ Refuse TOS 4 (23.5) 1 (6.7)   Breech 1 (5.9) 1 (6.7) Abbreviations: CI, confidence interval; HCQ, hydroxychloroquine; IOL, induction of labor; LSCS; lower segment caesarean section; NICU, neonatal intensive care unit; OR, odds ratio; SD, standard deviation; TOS, trial of scar. a Student's t -test. b Contingency coefficient, df = 2. c Chi-squared test, difference expressed in odds ratio (95% CI). Two multivariate logistic regression analyses for preeclampsia and neonatal birthweight were performed ( Table 4 ). We included usage of HCQ ( p  = 0.001), maternal age ( p  = 0.63), concurrent medical illness ( p  = 0.58), immunosuppressive treatment ( p  = 0.06), and lupus nephritis ( p  = 0.58), which were risk factors for preeclampsia. The usage of HCQ was still statistically significant ( p  = 0.001), with HCQ treatment in pregnancy being independently protective against preeclampsia. Associated factors such as usage of HCQ ( p  = 0.67), maternal age ( p  = 0.33), concurrent medical illness ( p  = 0.21), immunosuppressive treatment ( p  = 0.98), lupus nephritis ( p  = 0.45), gestational age at delivery ( p  = 0.001) and duration of SLE ( p  = 0.016) were included for neonatal birthweight. The gestational age at delivery ( p  = 0.001) was a significant associated factor for neonatal birthweight and, in contrast, duration of SLE ( p  = 0.016) had a significant negative effect. Table 4 Multivariate models assessing the association between hydroxychloroquine usage and preeclampsia (Model I) and neonatal birthweight (Model II) incorporating potential confounders as covariates Multivariate Model I Multivariate Model II aOR (95% CI) p-value aß (95% CI) p-value HCQ usage 0.08 (0.02–0.36) 0.001 0.002 (−0.45–0.45) 0.67 Maternal age (years old) 1.04 (0.88–1.23) 0.63 0.01 (−0.02–0.03) 0.33 Concurrent medical illness 0.65 (0.15–2.91) 0.58 −0.12 (−0.30–0.07) 0.21 Immunosuppressive treatment 4.48 (0.92–21.88) 0.06 0.002 (−0.17–0.17) 0.98 Lupus nephritis 1.53 (0.34–6.77) 0.58 0.07 (−0.11–0.24) 0.45 Gestational age at delivery (week) – 0.19 (0.16–0.21) 0.001 Duration of SLE (years) – −0.03 (−0.05 to −0.01) 0.016 Abbreviations: CI, confidence interval; HCQ, hydroxychloroquine; OR, odds ratio; SD, standard deviation; SLE, systemic lupus erythematosus. Discussion The present study demonstrated the effects of HCQ regarding the pregnancy outcome in a single tertiary center. It is also a form of evaluation on the quality of care for women with SLE during pregnancy. This 10-year data has shown that despite the recommendation to continue HCQ treatment throughout pregnancy, there were a considerable number of women who were not treated. The main reasons were worry regarding its use in pregnancy and gastrointestinal upset. This was despite the knowledge that the use of HCQ in SLE had been established to be safe and beneficial. Although long-term use at high dosage may be associated with retinopathy, this can be avoided by ensuring the use of the optimum lowest dosage. The main positive effect of continuing HCQ in pregnancy is reduction in the incidence of flares, which led to longer pregnancy duration resulting in higher birthweight. 11 25 Additionally, women with positive anti-Ro/La antibodies benefited from the 64.5% reduction in the recurrence of neonatal congenital heart block in those with previous affected pregnancies. 26 Obvious findings that were similar to other published data were that the use of HCQ was associated with reduction in recurrent miscarriages and prolongation of pregnancy, resulting in heavier neonatal birthweight. 25 27 The role of HCQ in recurrent miscarriages due to antiphospholipid antibodies in women with SLE has not been well established. Women with positive antiphospholipid antibodies have been shown to have increased risk of thrombosis due to disruption of annexin A5 binding, which is believed to lead to recurrent miscarriages. 28 In vitro and animal studies had demonstrated that HCQ administration was associated with reversal of this pathological process. 29 30 Likewise, published clinical studies showed similar results. 31 There were two new benefits of HCQ observed in our study population. Use of HCQ was associated with lower incidence of hypertensive disease and gestational diabetes. There is limited evidence on the role of HCQ in hypertension. Theoretically, both SLE and preeclampsia shared a similar pathophysiology. 32 In line with this, an in vitro model of preeclampsia had demonstrated that HCQ improved tumor necrosis factor-α (TNF-α)-induced endothelial dysfunction. 33 Additionally, in a mouse model of SLE, treatment with HCQ was associated with reduction in hypertension, improvement in endothelial dysfunction and organ damage. 34 Recently, Seo et al 35 have found a significantly lower incidence of preeclampsia in SLE women treated with HCQ during pregnancy. Similarly, Kroese et al 25 observed a nonsignificant lower incidence of preeclampsia and HELLP syndrome. Regarding gestational diabetes, there is growing evidence on the positive impact of HCQ on the disease. In line with our findings, several small studies have demonstrated the hypoglycemic and antidiabetic effect of HCQ. 16 More interestingly, the addition of HCQ to the first line oral hypoglycemic drugs or insulin in poorly controlled diabetics led to the improvement of HbA1c, fasting and postprandial glucose and dosage of insulin. 36 37 However, these were small studies. Hence, larger and longer duration of research is needed to establish the beneficial effects. The strength of the present study was the duration of review of 10 years. The limitations of our study were the small sample size, short duration of study period, incomplete information for some pregnancies and inability to evaluate disease activity prior and during pregnancy. Both physicians and obstetricians need to educate their patients regarding the importance of continuing HCQ to reduce maternal and perinatal complications. Conclusion More studies will be required to focus on hypertensive disease in pregnancy and gestational diabetes mellitus. Hydroxychloroquine may be a potential drug to improve the clinical outcomes of early onset severe preeclampsia or prevention against preeclampsia in women at high risk. Likewise, it may also be an adjunct therapy to improve the blood glucose control in diabetic patients during pregnancy, particularly in those who develop side effects with metformin. Acknowledgments We would like to thank all those who were involved indirectly or directly in the research. Contributions Conflict of Interests The authors have no conflict of interests to declare. Rahman R. A. has initiated the idea of the research, performed data analysis and the writing of the manuscript. Tun K. M. has performed data collection, data analysis and the writing of the manuscript. Both Said M. S. M. and Mustafar R. have assisted in the writing of the manuscript. Atan I. K. has performed the data analysis and assisted in the writing of the manuscript. Zainuddin A. A. has assisted in the writing of the manuscript. ==== Refs References 1 Yen E Y Singh R R Lupus-an unrecognized leading cause of death in young women: population-based study using nationwide death certificates 2000–2015 Arthritis Rheumatol 2018 70 08 1251 1255 10.1002/art.40512 29671279 2 Hermansen M L Lindhardsen J Torp-Pedersen C Faurschou M Jacobsen S Incidence of systemic lupus erythematosus and lupus nephritis in Denmark: a nationwide cohort study J Rheumatol 2016 43 07 1335 1339 10.3899/jrheum.151221 27134247 3 Chiu Y M Lai C H Nationwide population-based epidemiologic study of systemic lupus erythematosus in Taiwan Lupus 2010 19 10 1250 1255 10.1177/0961203310373780 20647248 4 Shaharir S S Hussein H Rajalingham S Said M SM Gafor A HA Mohd R Mustafar R Damage in the multiethnic Malaysian Systemic Lupus Erythematosus (SLE) Cohort: comparison with other cohorts worldwide PLoS One 2016 11 11 e0166270 10.1371/journal.pone.0166270 27846298 5 Teh C L Ling G R Aishah W S The Sarawak lupus cohort: clinical features and disease patterns of 633 SLE patients in a single tertiary centre from East Malaysia Rheumatol Int 2015 35 01 153 157 10.1007/s00296-014-3057-4 24906574 6 Hochberg M C Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1997 40 09 1725 10.1002/art.1780400928 7 Petri M Orbai A M Alarcón G S Gordon C Merrill J T Fortin P R Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012 64 08 2677 2686 10.1002/art.34473 22553077 8 Conti F Ceccarelli F Perricone C The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort Lupus 2016 25 07 719 726 10.1177/0961203315627199 26821965 9 Abdwani R Al Shaqsi L Al-Zakwani I Neonatal and obstetrical outcomes of pregnancies in systemic lupus erythematosus Oman Med J 2018 33 01 15 21 10.5001/omj.2018.04 29467994 10 The Hopkins Lupus Pregnancy Center Experience Petri M Howard D Repke J Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience Arthritis Rheum 1991 34 12 1538 1545 1670196 11 Eudy A M Siega-Riz A M Engel S M Franceschini N Howard A G Clowse M EB Petri M Effect of pregnancy on disease flares in patients with systemic lupus erythematosus Ann Rheum Dis 2018 77 06 855 860 10.1136/annrheumdis-2017-212535 29463519 12 Clowse M E Magder L Witter F Petri M Hydroxychloroquine in lupus pregnancy Arthritis Rheum 2006 54 11 3640 3647 10.1002/art.22159 17075810 13 Smyth A Oliveira G HM Lahr B D Bailey K R Norby S M Garovic V D A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis Clin J Am Soc Nephrol 2010 5 11 2060 2068 10.2215/CJN.00240110 20688887 14 Wallace D J Gudsoorkar V S Weisman M H Venuturupalli S R New insights into mechanisms of therapeutic effects of antimalarial agents in SLE Nat Rev Rheumatol 2012 8 09 522 533 10.1038/nrrheum.2012.106 22801982 15 Canadian Hydroxychloroquine Study Group A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus N Engl J Med 1991 324 03 150 154 10.1056/NEJM199101173240303 1984192 16 Hage M P Al-Badri M R Azar S T A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role Ther Adv Endocrinol Metab 2014 5 04 77 85 10.1177/2042018814547204 25343023 17 Leroux M Desveaux C Parcevaux M Julliac C Gouyon J B Dallay D Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study Lupus 2015 24 13 1384 1391 10.1177/0961203315591027 26082465 18 Levy R A Vilela V S Cataldo M J Ramos R C Duarte J L Tura B R Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study Lupus 2001 10 06 401 404 10.1191/096120301678646137 11434574 19 The Committee on Prognosis Studies in SLE Bombardier C Gladman D D Urowitz M B Caron D Chang C H Derivation of the SLEDAI. A disease activity index for lupus patients Arthritis Rheum 1992 35 06 630 640 10.1002/art.1780350606 1599520 20 Feld J Isenberg D Why and how should we measure disease activity and damage in lupus? Presse Med 2014 43 (6 Pt 2):e151 e156 10.1016/j.lpm.2014.03.002 24791651 21 van Vollenhoven R Voskuyl A Bertsias G Aranow C Aringer M Arnaud M A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS) Ann Rheum Dis 2017 76 03 554 561 10.1136/annrheumdis-2016-209519 27884822 22 Royal College of Obstetricians and Gynaecologists The investigation and treatment of couples with recurrent first trimester and second trimester miscarriage [Internet] London RCOG 2011[cited 2019 Nov 17]. (Green-Top Guideline; no. 17). Available from:https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf 23 NICE National Institute for Health and Care Excellence Gestational diabetes: risk assessment, testing, diagnosis and management [Internet] 2019[cited 2020 Jan 20]. Available from:https://pathways.nice.org.uk/pathways/diabetes-in-pregnancy/gestational-diabetes-risk-assessment-testing-diagnosis-and-management 24 International Society for the Study of Hypertension in Pregnancy (ISSHP) Brown M A Magee L A Kenny L C Karumanchi S A McCarthy F P Saito S Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice Hypertension 2018 72 01 24 43 10.1161/HYPERTENSIONAHA.117.10803 29899139 25 Kroese S J de Hair M JH Limper M Hydroxychloroquine use in lupus patients during pregnancy is associated with longer pregnancy duration in preterm births J Immunol Res 2017 2017 2.810202E6 10.1155/2017/2810202 26 Izmirly P M Costedoat-Chalumeau N Pisoni C N Khamashta M A Kim M Y Saxena A Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus Circulation 2012 126 01 76 82 10.1161/CIRCULATIONAHA.111.089268 22626746 27 Sciascia S Hunt B J Talavera-Garcia E Lliso G Khamashta M A Cuadrado M J The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies Am J Obstet Gynecol 2016 214 02 2730 2.73E10 10.1016/j.ajog.2015.09.078 28 Rand J H Wu X X Quinn A S Taatjes D J The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis Lupus 2010 19 04 460 469 10.1177/0961203310361485 20353989 29 Rand J H Wu X X Quinn A S Ashton A W Chen P P Hathcock J J Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug Blood 2010 115 11 2292 2299 10.1182/blood-2009-04-213520 19965621 30 Albert C R Schlesinger W J Viall C A Mulla M J Brosens J J Chamley L W Abrahams V M Effect of hydroxychloroquine on antiphospholipid antibody-induced changes in first trimester trophoblast function Am J Reprod Immunol 2014 71 02 154 164 10.1111/aji.12184 24325143 31 Ruiz-Irastorza G Ramos-Casals M Brito-Zeron P Khamashta M A Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review Ann Rheum Dis 2010 69 01 20 28 10.1136/ard.2008.101766 19103632 32 Abd Rahman R DeKoninck P Murthi P Wallace E M Treatment of preeclampsia with hydroxychloroquine: a review J Matern Fetal Neonatal Med 2018 31 04 525 529 10.1080/14767058.2017.1289511 28142291 33 Rahman R Murthi P Singh H Gurushinghe S Mockler J Lim R Wallace E M The effects of hydroxychloroquine on endothelial dysfunction Pregnancy Hypertens 2016 6 04 259 262 10.1016/j.preghy.2016.09.001 27939463 34 Gómez-Guzmán M Jiménez R Romero M Sánchez M Zarzuelo M J Gómez-Morales M Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus Hypertension 2014 64 02 330 337 10.1161/HYPERTENSIONAHA.114.03587 24842914 35 Seo M R Chae J Kim Y M Cha H S Choi S J Oh S Roh C-R Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia Lupus 2019 28 06 722 730 10.1177/0961203319843343 30971164 36 Pareek A Chandurkar N Thomas N Viswanathan V Deshpande A Gupta O P Efficacy and safety of hydroxychloroquine in the treatment of type 2 diabetes mellitus: a double blind, randomized comparison with pioglitazone Curr Med Res Opin 2014 30 07 1257 1266 10.1185/03007995.2014.909393 24669876 37 Quatraro A Consoli G Magno M Caretta F Nardozza A Ceriello A Giugliano D Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug? Ann Intern Med 1990 112 09 678 681 10.7326/0003-4819-112-9-678 2110430