Mechanisms and roles of hydroxychloroquine in pregnancy in rheumatic diseases

ABSTRACT

Introduction: Hydroxychloroquine (HCQ), originally an antimalarial drug, is currently used to treat multiple disorders, especially rheumatic diseases. Given its good efficacy and safety, HCQ is widely administered in pregnant patients. However, the safety profile of HCQ during pregnancy remains controversial due to limited research. In addition, HCQ has been reported to reduce preeclampsia in patients with systemic lupus erythematosus (SLE) and could potentially alleviate the symptom of preeclampsia. However, the clinical profile and molecular mechanism of HCQ in preeclampsia is yet to be fully understood.

Method: We reviewed the literature on HCQ treatment in pregnancy with rheumatic diseases and preeclampsia in PubMed and Web of Science. We also discussed the safety of long-term therapy with HCQ during pregnancy.

Results: HCQ mainly modulates autoimmune response through inhibition of lysosomal function, toll-like receptor (TLR) signalling, nicotinamide adenine dinucleotide phosphate-mediated oxidative stress and autophagy. Benefits of HCQ in treating rheumatic diseases, including antiphospholipid syndrome, rheumatoid arthritis and Sjogren’s syndrome during pregnancy, has been demonstrated in clinics. In particular, multiple clinical guidelines recommend HCQ as an indispensable therapeutic drug for pregnant patients with SLE. Additionally, it may potentially function in preeclampsia to improve clinical symptoms.

Conclusion: HCQ is effectively used for rheumatic diseases during pregnancy. The benefits of HCQ treatment in rheumatic diseases outweigh the risk of adverse reactions it induces in pregnant women.

CLINICAL IMPACT

What is New

• This presentation summarised the latest advanced role, mechanism, treatment and safety of hydroxychloroquine (HCQ) in rheumatic diseases during pregnancy.
• Meanwhile, we discussed the application prospects of HCQ in preeclampsia.

Clinical Implications

• To provide the pharmaceutical perspective on the effect and safety of HCQ in pregnancy, aiming to help clinicians use HCQ or any other anti-rheumatic drugs more reasonably and safely in the treatment of pregnant women.

With the prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, hydroxychloroquine (HCQ) has once again come into public attention due to its potential therapeutic role in COVID-19. HCQ is a classic antimalarial drug that belongs to the 4-aminoquinoline phospholipase A2 inhibitors. It was first introduced in 1955 and quickly gained popularity in the treatment of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and other rheumatic diseases. Apart from its immunomodulatory function, the effect of HCQ has extended to antiviral, hypolipidaemic, hypoglycaemic and antithrombosis, as well as anti-malignancies (Fig. 1).¹ Due to its good efficacy, safety profile and low cost, HCQ is now commonly administered as a single agent or in combination with other immunosuppressants during pregnancy to treat rheumatic diseases.²

Fig. 1. Benefits of HCQ in various diseases.

Rheumatic diseases occur primarily in females of childbearing years, including SLE, APS, rheumatoid arthritis (RA) and Sjogren’s syndrome (SS). HCQ predominantly alleviates the symptoms of typical rheumatic diseases, particularly skin problems and joint pain, by reducing the inflammatory response in patients. Since pregnant women with rheumatic diseases are always considered to be at higher possibility of pregnancy complications and adverse pregnancy outcomes (APOs), they should require more intensive observation and prompt pharmacotherapy. With the development and use of HCQ in clinical therapy, recent research has generally recognised the benefit of HCQ in improving pregnancy outcomes and its safety profile in pregnant women with rheumatic disorders.

Although the application of HCQ in reproductive immunity has become a new research hotspot, the molecular mechanism is not yet entirely understood. This review primarily focused on the mechanism and clinical treatment of HCQ in pregnancy with rheumatic diseases, such as SLE, APS, SS and RA. It also discussed the relevance and potential use of HCQ in preeclampsia. Finally, we further presented our opinion on the safety of pregnant patients taking HCQ for rheumatic disorders. Keywords such as “rheumatic disease” OR “rheumatism” OR “antiphospholipid antibody syndrome” OR “Sjogren’s syndrome” OR “rheumatoid arthritis” OR “systemic lupus erythematosus” OR “preeclampsia” AND “hydroxychloroquine” AND “pregnancy” OR “gestation” were used in the literature search in PubMed and Web of Science. We also checked reference lists for relevant publications, recent reviews and editorials.

Mechanism of action of HCQ

The exact mechanism of how HCQ regulates immune function has not been entirely delineated. HCQ has been reported to function mainly in rheumatic diseases through versatile immunomodulatory and anti-inflammatory responses, with additional roles such as antiplatelet and antioxidant effects.³ In general, HCQ could exert therapeutic effects via modulating different cellular signals, especially the inhibition of endolysosomal activities, innate inflammatory signalling pathways, oxidative stress and thrombosis (Fig. 2).

Fig. 2. Major mechanisms of HCQ.

Inhibition of lysosomal function

Due to its hydrophobicity and alkalescence, HCQ disperses quickly into acidic lysosomes across cell membranes. It accumulates in lysosomal compartments, stabilises cell membrane and decreases the functions of acidic proteases, thereby increasing the pH of acidic subcellular compartments. Meanwhile, alteration in acid enzyme activity reduces the formation and transport of major histocompatibility class II complex molecules, leading to suppression of antigen presentation and autoimmune responses. Furthermore, HCQ disrupts autophagy, a lysosomal-dependent degradation process that degrades damaged cytoplasmic materials and organelles to maintain cell homeostasis.¹

Inhibition of toll-like receptor (TLR)-mediated innate immune response

HCQ inhibits several typical inflammatory pathways, particularly the signalling mediated by TLRs. TLRs expressed primarily by immune cells are significant receptors in the innate immune system, and mediate the induction of inflammatory cytokine genes. TLR3, TLR7 and TLR9 of the innate immune system are present in the intracellular compartments like endosomes. TLR3 mainly induced the expression of type I interferon (IFN) and IFN-inducible genes via TRIF/IRF3. Sensitive to synthetic imidazoquinoline-like molecules, TLR7 triggered the induction of type I IFN and inflammatory cytokines via the myeloid differentiation primary-response protein 88 (MyD88)- and nuclear factor-kappaB (NF-κB)-dependent pathways. TLR9, activated by DNA in the endosome of immune cells, leads to the robust production of IFN. HCQ prefers to interact with TLR3, TLR7 and TLR9, and specifically blocks the activation of these receptors that mediate inflammatory pathways and cytokines. Therefore, it prevents the activation of these receptors that mediate inflammatory pathways and cytokines.³

Suppression of other signalling pathways

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs)—exclusive enzyme complexes in the generation of reactive oxygen species (ROS) —are involved in numerous proinflammatory signalling cascades. HCQ has been proven to alleviate NOX-mediated production of TNF-α and IL-1β by directly blocking the translocation of gp91phox.⁴ It also protects the endothelium by suppressing NADPH and activating extracellular signal-regulated kinase 5 (ERK5),⁴ because overproduction of ROS is the main cause of vascular endothelial dysfunction. With regard to second messenger-mediated signal transduction, HCQ impairs the expression and secretion of immune cytokines and factors in T- and B-cells by interfering with intracellular Ca²⁺ mobilisation.⁵

In addition, before low molecular weight heparin was widely applied in clinical practice, HCQ was used to prevent pulmonary embolism after arthroplasty for its potential antithrombotic effect. Its anticoagulant and antithrombotic effects have gradually been recognised with the use of HCQ in treating diverse diseases. Belizna et al. found HCQ dose dependently reduced collagen-induced platelet aggregation and platelet α-granule release. It suppresses platelet aggregation via adenosine diphosphate (ADP)  inhibition and inhibits the release of arachidonic acid caused by activated platelets.⁶

HCQ treatment in pregnancy with rheumatic diseases

Systemic lupus erythematosus (SLE)

SLE is an autoimmune rheumatic disease presented with multiple organ injury. Although the pathogenesis of SLE remains incompletely understood, the autoimmune attack theory may be the essential hypothesis so far. Pregnancy with SLE increases the obstetric risk of APOs, such as preterm birth, intrauterine growth restriction and preeclampsia.² Generally, therapy for SLE aims to alleviate immune damage in cells, tissues and organs. HCQ benefits SLE from diverse perspectives, particularly through amelioration of systemic symptoms as well as improvement in musculoskeletal and cutaneous mucosal performance. Apart from HCQ-moderate inflammatory response, HCQ obviously decreased the possibility of thrombosis in SLE. Another advantage of HCQ is its potential role in preventing severe complications. It reduces the incidence of diabetes in a dose-dependent manner, as shown in a study of HCQ treatment with 200 mg/day for 1.8 years in SLE patients.⁷ HCQ may also be beneficial for osteoporosis, a common complication in SLE patients, by increasing spinal bone mineral density, especially in women receiving prolonged steroid therapy. HCQ-treated group showed a trend towards lower prednisone dosage and reduced the occurrence of preeclampsia and preterm delivery in pregnant women with lupus.^8,9 HCQ treatment during pregnancy also significantly decreased flares during pregnancy and postpartum. Substantial evidence suggests that lupus activity and symptoms in pregnant women could be alleviated by HCQ without any risk to the fetus.^10-12 Significantly, most studies currently indicate that HCQ treatment in SLE women throughout pregnancy remarkably improved birth outcomes, in contrast to pregnant lupus mothers who did not take HCQ.^10,13-15 It also reduced recurrent miscarriages, the occurrence of hypertension, gestational diabetes and pregnancy complications.¹⁶ Based on these findings (Table 1), HCQ should be continued during pregnancy. This is also supported by many clinical guidelines from different countries. A Chinese guideline for pregnancy with SLE suggests that HCQ reduces the activity and recurrence of SLE in pregnant women, improves pregnancy outcomes, and even benefits for the prevention of preeclampsia and neonatal heart block, without harmful effects on newborns.¹⁷ HCQ plus low molecular weight heparin plus low-dose aspirin (LDA) is more suitable than HCQ in addition to LDA or glucocorticoid or Ig for pregnant patients undergoing SLE with antiphospholipid antibodies (aPL) and recurrent pregnancy loss, according to the Latin American group for the study of lupus (GLADEL).¹⁸ Practice guidelines of the British society for rheumatology (BSR) and the British health professionals in rheumatology recommend HCQ for all pregnant SLE patients, with the exception of contraindications.^19,20 The 2020 American College of Rheumatology (ACR) practice guideline strongly advises all SLE women to take HCQ during pregnancy if possible, showing that HCQ is beneficial to the outcomes of both mothers and fetuses.²¹ Furthermore, the European League Against Rheumatism (EULAR) suggests that pregnancies with SLE should be treated with HCQ at a maintenance dose to stabilise the condition and improve pregnancy outcomes. However, the dose of HCQ should not exceed 5 mg/kg/real of body weight (BW) (Table 2).²²

Table 1. Clinical studies on HCQ treatment in pregnant women suffering from SLE.

Table 2. Recommendations of guidelines for HCQ therapy in pregnant women with SLE.

Antiphospholipid syndrome (APS)

APS, characterised by thrombotic events and pathological pregnancies, is an autoimmune disorder that is more likely to lead to unfavourable pregnancy outcomes. Although low-dose aspirin and heparin treatment for pregnant women with APS has increased the live birth rate by approximately 70%, HCQ has commonly been administered as an adjunctive medication for the treatment of APS-related thrombosis.²³ It decreases the combination of aPL-β2GP1 complex and platelet aggregation by suppressing aPL-activated overexpression of GPIIb/IIIa on the platelet membrane.²³ Treatment of HCQ in patients with aPL during pregnancy increased the live birth rate (67% HCQ group versus [vs] 57% control group, P=0.05) and decreased the prevalence of aPL-related pregnancy morbidity and complication (2% vs 10.9%, P=0.05).²⁴ Emerging clinical studies also showed that treatment with 200–400 mg HCQ in refractory APS pregnant women could improve the pregnancy outcome, like lower rates of pregnancy loss, live birth and pregnancy complications (Table 3).^25-27 A retrospective study of 194 pregnant primary APS patients revealed that high dose HCQ (400 mg) and initiation prior to pregnancy were linked to a higher live birth rate in contrast to a low dose (200 mg) and treatment only during pregnancy.²⁷ To our knowledge, HCQ is currently not included in the standard therapy of primary APS, but it definitely benefits the refractory cases, involving refractory obstetrical APS. EULAR recommends the addition of HCQ in the first trimester may be conducive to APS patients with pregnancy, despite receiving a combination of LDA and heparin.²⁸ The other compelling clinical guideline has recommended HCQ used routinely alone or adding to therapeutic schemes for pregnant women with refractory APS or who experience recurrent complications,²⁹ with a safe dose of 200–400 mg.

Table 3. Clinical studies on HCQ treatment in pregnant women with APS.

Sjogren’s syndrome (SS)

SS occurs more predominantly in women than in men, with a female-to-male ratio of about 9:1. Women with SS are likely to experience more complicated pregnancies than healthy women.²⁹ Although the therapeutic benefit of HCQ in classic SS symptoms remain controversial, there is research illustrating that HCQ alleviates oral domain symptoms and several indicators like unstimulated salivary flow rate (uSFR), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and immunoglobulin M (IgM) as well as immunoglobulin A (IgA) in general patients. Regarding the research on pregnant patients, a retrospective study included 109 pregnant women as control group and 26 pregnancies with SS group showed HCQ were used in 15 patients (57.7%) and may also help ameliorate obstetric outcomes.³⁰ In 853 autoimmune pregnancies with 49 SS patients, HCQ therapy decreased preeclampsia (19.8% vs 8.91%, P<0.001), early-onset preeclampsia (7.78% vs 2.51%, P=0.007) and pregnancy loss (2.99% vs 0.56%, P=0.036) significantly. Forty-two (85.71%) of 49 SS patients had taken HCQ.³¹ On the contrary, Ballester C et al. found there was no premature delivery or low birth weight percentile child in primary SS pregnant patients with HCQ.³² However, the insufficient number of HCQ group (n=6) limited the evaluation of the possible beneficial effects of HCQ. Several reports also indicated that there is no association between HCQ and a good pregnancy outcome in SS,^33,34 but these findings need to be confirmed in larger sample size studies (Table 4). Furthermore, both EULAR and Sjogren’s Syndrome Foundation suggested that first-line therapy for SS should concentrate on symptom relief, with HCQ (200 mg/day) to treat musculoskeletal pain treatment.^35,36 They also recommended assessing the benefits and risks for patients during pregnancy. BSR also advised the administration of HCQ (6 mg/kg) in SS, especially in patients with skin and joint lesions or fatigue symptoms. Besides, it was mentioned that HCQ might be continued throughout pregnancy and breastfeeding.³⁷

Table 4. Clinical studies of HCQ therapy in pregnancy with SS.

Rheumatoid arthritis (RA)

RA is a long-term inflammatory joint disorder with a variable progression. Historically, methotrexate (MTX), sulfasalazine, leflunomide, HCQ or chloroquine (CQ) are referred to as disease-modifying anti-rheumatic drugs (DMARDs), generally used in RA. Regrettably, although considerable reviews have established that HCQ is appropriate for pregnant patients with mild and moderate RA, we found few clinical studies on the effectiveness of HCQ treatment in pregnant patients with RA. However, the potential role of HCQ has been widely studied in general patients with RA. Combination of MTX with HCQ in RA treatment was more efficient than MTX alone.³⁸ According to the 2021 ACR guideline, HCQ is more appropriate than other DMARDs in the therapy of DMARDs-naive patients with mild RA.³⁹ EULAR recommends HCQ to be considered only in a particular circumstance when the other DMARDs failed or with MTX and sulfasalazine.⁴⁰ Furthermore, the Asia Pacific League of Associations for Rheumatology notes HCQ can only be used in combination with other DMARDs in patients with RA, primarily considering its possible metabolic and cardiovascular benefits.⁴¹ Thus, reviews summarise and conclude that HCQ is beneficial for RA patients with a mild or moderate disease during pregnancy and suggest continuing treatment in these patients who were willing to conceive. Regarding the guideline recommendation for RA pregnant patients, recommendations for medication therapy in pregnancy just points out HCQ did not increase the occurrence of congenital malformations and can be used throughout pregnancy with rheumatic diseases.¹⁹ HCQ efficiency on pregnant women with RA should be further studied.

Potential use of HCQ in preeclampsia

Preeclampsia (PE) is an obstetric complication leading to high neonatal and maternal morbidity and mortality. Rheumatic diseases tend to increase the incidence of preeclampsia. Since HCQ is generally used for thrombosis prevention, anti-inflammation and anti-oxidation in rheumatic diseases, the researchers investigated whether HCQ directly plays a preventive role in preeclampsia, which has similar standard features and pathophysiology to SLE.^8,42 In terms of molecule mechanism, endothelial dysfunction is one of the most persuasive opinions on preeclampsia development. Researchers preliminarily speculate that HCQ may benefit PE by suppressing oxidative stress and inflammatory mediators like cytokines, chemokines and cell adhesion molecules (i.e. intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), which could result in endothelial damage.⁴² Generally, HCQ restores NOX availability and disrupts vascular ROS overproduction induced by NADPH oxidase. HCQ also mitigated endothelial injury of PE by inhibiting the release of TNF-α and VCAM-1 as well as ICAM-1 to keep monocyte from adhering to the endothelium.⁴² Despite HCQ being the major medication in the treatment of pregnancy with SLE, no randomised controlled trials (RCTs) and observational studies have been conducted to report the efficiency of HCQ treatment in preeclampsia women without rheumatoid diseases. Previous clinical studies only focused on the treatment of HCQ in preeclampsia induced by rheumatoid disorders. Rector et al. indicated no statistically significant correlation between HCQ and preeclampsia in either nulliparous or multiparous lupus pregnancies.⁴³ Conversely, it reported that HCQ treatment in pregnant women with autoimmune diseases reduced the occurrence of preeclampsia.²⁴ A meta-analysis including 709 HCQ-treated pregnancies and 1055 pregnancies without HCQ showed that the additional use of HCQ apparently decreased the total risk of preeclampsia in pregnancies with SLE by 46%, but it had no effect on the incidence of preeclampsia for APS/aPLs patients.⁴⁴ In parallel with that conclusion, Liu et al. summarised that treatment with 200–400 mg of HCQ daily significantly lowered the incidence of preeclampsia in autoimmune disorders.⁹ Therefore, the clear efficiency of HCQ in preeclampsia induced by rheumatic diseases needs more evidence from further RCTs and large-scale prospective cohort studies. Next, more basic and clinical studies should examine the benefit of HCQ treatment in preeclampsia patients without rheumatic diseases.

Safety of HCQ therapy during pregnancy

Drug safety during pregnancy is a significant consideration for medical treatment. HCQ is an oral medication that is rapidly and completely absorbed from the upper intestinal tract.³ It is primarily metabolised into N-desethylhydroxychloroquine in the liver via cytochrome P450 enzymes.³ A large apparent volume of distribution leads to an elimination half-life of approximately 40 to 60 days.³ Since creatinine clearance is not associated with the response to HCQ bioavailability, dosage adjustment is not necessary in patients with renal insufficiency. Notably, HCQ readily crosses the placenta with the ratio of fetal concentration to maternal concentration being 1.04.⁴⁵ Various adverse reactions of HCQ have been found, of which ocular, skin and cardiac toxicity represent the most potential, especially when long-term therapy and large doses are used.⁴⁵ A small number of investigations indicate that HCQ treatment during pregnancy may be associated with ocular damage in fetuses.^46,47 This is debatable because normal newborns are likely to have malformations and these are just a few cases in the control group. A cohort study proposed the risk of malformations in first trimester pregnancy was slightly increased by HCQ, showing an adjusted relative risk (RR) of 1.26.⁴⁸ A clinical trial showed 5 of 45 (11%) infants exposed to 400 mg HCQ in utero had a prolonged corrected QT interval of more than 2 standard deviation (SD), without other symptoms.⁴⁹ Meanwhile, numerous clinical studies recently consider HCQ has no harmful effect on fetal outcomes (Table 5). In a retrospective study, 14 mothers who received HCQ treatment for an average of 7.2 months during their pregnancies at an average dose of 317 mg reported that their newborns’ visual acuity was normal with no ophthalmological abnormalities.⁵⁰ The conclusion was also confirmed by a study that included 90 women and 133 pregnancies treated with 200 mg HCQ per day (11 pregnancies) or twice daily (122 pregnancies).⁵¹ Reynolds et al. showed no significant differences in the incidence of congenital malformations or intrauterine growth restriction, regardless of whether children were exposed to HCQ in utero or not.⁵² Additionally, HCQ treatment did not increase the risk of spontaneous abortion or preterm delivery, birth defects and low birth weight, compared to the control group without HCQ.^2,13,53,55 This is consistent with data from an RCT of 115 pregnant women with mild SARS-CoV-2 infection, which found no obvious differences in the occurrence of adverse pregnancy outcomes and newborns with health problems at birth between the HCQ group and the control.⁵⁶ A meta-analysis comprising 3948 immune-disordered pregnancies, of which 1617 patients were in the HCQ group and 2331 in the control group, revealed that there was no significant correlation between HCQ and adverse fetal outcomes and congenital malformation.⁸ Although the safety evidence of HCQ during pregnancy in clinical studies remains insufficient to evaluate teratogenicity, most researchers insist that the benefits of HCQ treatment in pregnant women could outweigh the potential risks in the clinic.⁵⁷ Furthermore, we discover the amount of HCQ in these articles, which showed no effect on fetal safety, varies approximately from 200 to 400 mg during pregnancy. Huybrechts et al. showed that a daily dose of ≥400 mg HCQ in the first-trimester had a higher risk of malformations than <400 mg daily (RR 1.33 vs 0.95).⁴⁸ Therefore, the possibility of the HCQ side reactions occurring may be dose dependent. This is verified by a consensus from the Netherlands, which states that HCQ treatment at a dose of 200–400 mg/day during pregnancy and lactation may be safe for pregnant women.⁵⁸ EULAR also announced that the recommended dose of less than 5 mg/kg carries a low risk of toxicity in pregnant SLE patients.²²

Table 5. Clinical studies on the safety of HCQ treatment during pregnancy.

CONCLUSION

Undoubtedly, HCQ is extensively used as a safe modulator in pregnant women with rheumatic diseases. Based on previous evidence, there is less risk of adverse fetal outcomes when treated with HCQ at a dose below 400 mg. However, there are insufficient prospective studies and no large-scale RCTs on the efficacy and safety of HCQ in rheumatic diseases. Currently, a multicentre, double-blind, prospective clinical trial called HIBISCUS is ongoing in order to investigate HCQ safety and whether additional treatment with HCQ improves the fetal outcomes in a population of patients with primary APS.⁵⁹ HYPATIA, another international multicentre RCT, is also underway to explore the effectiveness of HCQ in improving pregnancy outcomes in patients with persistently positive aPL, as well as its safety.⁶⁰ With its low cost, HCQ might be an extremely valuable adjunct to the treatment of rheumatic diseases during pregnancy.

REFERENCES

1. Ferreira PMP, de Sousa RWR, Ferreira JRO, et al. Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms. Pharmacol Res 2021;168:105582.
2. Chambers CD, Johnson DL, Xu R, et al. Birth Outcomes in Women Who Have Taken Hydroxycholoroquine During Pregnancy: A Prospective Cohort Study. Arthritis Rheumatol 2022;74:711-24.
3. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020;16:155-66.
4. Müller-Calleja N, Manukyan D, Canisius A, et al. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis 2017;76:891-7.
5. Izquierdo JH, Bonilla-Abadía F, Cañas CA, et al. Calcium, Channels, Intracellular Signaling and Autoimmunity. Reumatol Clín 2014;10:43-7.
6. Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev 2015;14:358-62.
7. Kroese SJ, de Hair MJH, Limper M, et al. Hydroxychloroquine Use in Lupus Patients during Pregnancy Is Associated with Longer Pregnancy Duration in Preterm Births [published correction appears in J Immunol Res 2022;9783521]. J Immunol Res 2017;2017:2810202.
8. Chen YM, Lin CH, Lan TH, et al. Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dose-dependent manner: a population-based cohort study. Rheumatology (Oxford) 2015;54:1244-9.
9. Liu Y, Wei Y, Zhang Y, et al. Hydroxychloroquine significantly decreases the risk of preeclampsia in pregnant women with autoimmune disorders: a systematic review and meta-analysis. Clin Rheumatol 2023;42:1223-35.
10. Alle G, Guettrot-Imbert G, Larosa M, et al. Hydroxychloroquine levels in pregnancy and materno-fetal outcomes in systemic lupus erythematosus patients. Rheumatology (Oxford) 2024;keae302.
11. Levy RA, Vilela VS, Cataldo MJ, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 2001;10:401-4.
12. Braga A, Barros T, Faria R, et al. Systemic lupus erythematosus and pregnancy: A retrospective single-center study of 215 pregnancies from Portugal. Lupus 2021;30:2165-75.
13. Leroux M, Desveaux C, Parcevaux M, et al. Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus 2015;24:1384-91.
14. Balevic SJ, Cohen-Wolkowiez M, Eudy AM, et al. Hydroxychloroquine Levels throughout Pregnancies Complicated by Rheumatic Disease: Implications for Maternal and Neonatal Outcomes. J Rheumatol 2019;46:57-63.
15. Canti V, Scarrone M, De Lorenzo R, et al. Low incidence of intrauterine growth restriction in pregnant patients with systemic lupus erythematosus taking hydroxychloroquine. Immunol Med 2021;44:204-10.
16. Abd Rahman R, Min Tun K, Kamisan Atan I, et al. New Benefits of Hydroxychloroquine in Pregnant Women with Systemic Lupus Erythematosus: A Retrospective Study in a Tertiary Centre. Rev Bras Ginecol Obstet 2020;42:705-11.
17. National Clinical Research Center for Dermatologic and Immunologic Diseases; National Clinical Research Center for Obstetrics and Gynecology; Chinese Research Committee of Pregnancy and Reproduction in Autoimmune Rheumatic Diseases; Chinese Rheumatism Data Center, et al. Zhonghua Nei Ke Za Zhi 2022;61:1184-205.
18. Pons-Estel BA, Bonfa E, Soriano ER, et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR). Ann Rheum Dis 2018;77:1549-57.
19. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford) 2016;55:1693-7.
20. Gordon C, Amissah-Arthur MB, Gayed M, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology (Oxford) 2018;57:e1-e45.
21. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol 2020;72:529-56.
22. Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736-45.
23. Schreiber K, Hunt BJ. Pregnancy and Antiphospholipid Syndrome. Semin Thromb Hemost 2016;42:780-8.
24. Sciascia S, Hunt BJ, Talavera-Garcia E, et al. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol 2016;214:273.e1-273.e8.
25. Mekinian A, Lazzaroni MG, Kuzenko A, et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study. Autoimmun Rev 2015;14:498-502.
26. Gerde M, Ibarra E, Mac Kenzie R, et al. The impact of hydroxychloroquine on obstetric outcomes in refractory obstetric antiphospholipid syndrome. Thromb Res 2021;206:104-10.
27. Ruffatti A, Tonello M, Hoxha A, et al. Effect of Additional Treatments Combined with Conventional Therapies in Pregnant Patients with High-Risk Antiphospholipid Syndrome: A Multicentre Study. Thromb Haemost 2018;118:639-46.
28. Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76:476-85.
29. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296-304.
30. Barros T, Braga J, Abreu MI, et al. Sjögren’s syndrome and pregnancy: a Portuguese case-control study. Reumatologia 2022;60:311-7.
31. Ye S, Zhao X, Liu Y, et al. The use of hydroxychloroquine in pregnancy and its effect on perinatal outcomes in a population with autoimmune abnormalities. Clin Rheumatol 2023;42:1137-50.
32. Ballester C, Grobost V, Roblot P, et al. Pregnancy and primary Sjögren’s syndrome: management and outcomes in a multicentre retrospective study of 54 pregnancies. Scand J Rheumatol 2017;46:56-63.
33. Fierro JJ, Prins JR, Verstappen GM, et al. Preconception clinical factors related to adverse pregnancy outcomes in patients with systemic lupus erythematosus or primary Sjögren’s syndrome: a retrospective cohort study. RMD Open 2023;9:e003439.
34. Priori R, Gattamelata A, Modesti M, et al. Outcome of pregnancy in Italian patients with primary Sjögren syndrome. J Rheumatol 2013;40:1143-7.
35. Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies. Ann Rheum Dis 2020;79:3-18.
36. Carsons SE, Vivino FB, Parke A, et al. Treatment Guidelines for Rheumatologic Manifestations of Sjögren’s Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain. Arthritis Care Res (Hoboken). 2017;69:517-27.
37. Price EJ, Rauz S, Tappuni AR, et al. The British Society for Rheumatology guideline for the management of adults with primary Sjögren’s Syndrome [published correction appears in Rheumatology (Oxford). 2017;56:1828]. Rheumatology (Oxford) 2017;56:e24-e48.
38. Russell MD, Dey M, Flint J, et al. British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford) 2023;62:e48-e88.
39. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2021;73:924-39.
40. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82:3-18.
41. Lau CS, Chia F, Dans L, et al. 2018 update of the APLAR recommendations for treatment of rheumatoid arthritis. Int J Rheum Dis 2019;22:357-75.
42. de Moreuil C, Alavi Z, Pasquier E. Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage. Br J Clin Pharmacol 2020;86:39-49.
43. Rector A, Marić I, Chaichian Y, et al. Hydroxychloroquine in Lupus Pregnancy and Risk of Preeclampsia. Arthritis Rheumatol. Published online. 25 January 2024.
44. Hu Z, Gao R, Huang W, et al. Effect of Hydroxychloroquine on Lupus Activity, Preeclampsia and Intrauterine Growth Restriction in Pregnant Women with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis. J Clin Med 2023;12:485.
45. Louchet M, Sibiude J, Peytavin G, et al. Placental transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019. Am J Obstet Gynecol MFM 2020;2:100159.
46. Gaffar R, Pineau CA, Bernatsky S, et al. Risk of Ocular Anomalies in Children Exposed In Utero to Antimalarials: A Systematic Literature Review. Arthritis Care Res (Hoboken) 2019;71:1606-10.
47. Kim DA, Rho S. Peters Anomaly in One Premature Twin Following Hydroxychloroquine Exposure During Pregnancy: A Case Report. Korean J Ophthalmol 2023;37:273-4.
48. Huybrechts KF, Bateman BT, Zhu Y, et al. Hydroxychloroquine early in pregnancy and risk of birth defects. Am J Obstet Gynecol 2021;224:290.e1-290.e22.
49. Friedman DM, Kim M, Costedoat-Chalumeau N, et al. Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation. Circ Arrhythm Electrophysiol 2020;13:e008686.
50. Klinger G, Morad Y, Westall CA, et al. Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 2001;358:813-4.
51. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003;48:3207-11.
52. Reynolds JA, Gayed M, Khamashta MA, et al. Outcomes of children born to mothers with systemic lupus erythematosus exposed to hydroxychloroquine or azathioprine. Rheumatology (Oxford) 2023;62:1124-35.
53. Andersson NW, Skov L, Andersen JT. Fetal safety of chloroquine and hydroxychloroquine use during pregnancy: a nationwide cohort study. Rheumatology (Oxford) 2021;60:2317-26.
54. Bérard A, Sheehy O, Zhao JP, et al. Chloroquine and Hydroxychloroquine Use During Pregnancy and the Risk of Adverse Pregnancy Outcomes Using Real-World Evidence. Front Pharmacol 2021;12:722511.
55. Diav-Citrin O, Blyakhman S, Shechtman S, et al. Pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study. Reprod Toxicol 2013;39:58-62.
56. González R, Goncé A, Gil MDM, et al. Efficacy and safety of hydroxychloroquine for treatment of mild SARS-CoV-2 infection and prevention of COVID-19 severity in pregnant and postpartum women: A randomized, double-blind, placebo-controlled trial. Acta Obstet Gynecol Scand 2024;103:602-10.
57. Clowse MEB, Eudy AM, Balevic S, et al. Hydroxychloroquine in the pregnancies of women with lupus: a meta-analysis of individual participant data. Lupus Sci Med 2022;9:e000651.
58. Limper M, de Leeuw K, Lely AT, et al. Diagnosing and treating antiphospholipid syndrome: a consensus paper. Neth J Med 2019;77:98-108.
59. Belizna C, Pregnolato F, Abad S, et al. HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome. Autoimmun Rev 2018;17:1153-68.
60. Schreiber K, Breen K, Cohen H, et al. HYdroxychloroquine to Improve Pregnancy Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) Protocol: A Multinational Randomized Controlled Trial of Hydroxychloroquine versus Placebo in Addition to Standard Treatment in Pregnant Women with Antiphospholipid Syndrome or Antibodies. Semin Thromb Hemost 2017;43:562-71.