Swedish cohort study validates the safety of hydroxychloroquine in rheumatic disease during pregnancy

Recent studies on the safety of hydroxychloroquine (HCQ) during pregnancy, particularly in managing rheumatic disorders such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), have sparked debates. While HCQ has traditionally been considered safe for pregnant women with rheumatic diseases, concerns persist regarding its potential teratogenic effects, attributed to its ability to cross the placenta and interfere with DNA synthesis. 

In contrast to prior research, a study by Nguyen et al., published in Rheumatology (Oxford), sheds light on the safety of first-trimester HCQ exposure in pregnant individuals with prevalent SLE or RA. Utilizing Swedish nationwide registers, this population-based cohort study encompassed all singleton births from 2006 to 2021 among individuals with SLE or RA. The study included 1,007 births (453 exposed) in the SLE cohort and 2,500 births (144 exposed) in the RA cohort. The study findings revealed that first-trimester HCQ exposure was not significantly associated with an increased risk of major congenital malformations (MCM). In the SLE cohort, the MCM risks for the overall, exposed, and unexposed groups were 3.6%, 3.7%, and 3.4%, respectively. In the RA cohort, the corresponding figures were 4.4%, 5.6%, and 4.3%, respectively. Adjusted relative risks (RRs) ranged from 1.29 to 1.32, with small adjusted risk differences of 0.9% in SLE and 1.3% in RA. 

In contrast, a US-based study conducted in 2021 by Huybrechts et al. revealed a significantly higher rate of major congenital malformations among infants exposed to HCQ compared to unexposed infants. Analyzing data from 1,867 pregnancies with HCQ exposure and 19,080 unexposed pregnancies, the study found that even after accounting for confounding variables, the adjusted relative risk remained statistically significant, indicating an elevated risk. Additionally, the study highlighted that the risk varied depending on the HCQ dosage, with higher doses associated with an increased risk. These findings suggested a small but significant increase in the risk of congenital malformations among mothers with rheumatic diseases who used HCQ in the first trimester of pregnancy. 

The findings from this US study prompted action from regulatory bodies, including the European Medicines Agency (EMA), which swiftly updated its guidelines in February 2023. The EMA incorporated the significant association reported in the US study, replacing prior non-significant findings. This update sent ripples of concern throughout rheumatology societies, clinicians, patients, and policymakers, prompting a reevaluation of HCQ safety profile in pregnancy. 

However, a recent comprehensive meta-analysis conducted by Clowse et al. (2022) corroborated the safety of HCQ in pregnant women. According to the analysis, the use of HCQ did not significantly increase the risk of common adverse outcomes such as spontaneous abortion, prematurity, or intrauterine growth restriction. These findings support the perspective that the benefits of HCQ during pregnancy may outweigh potential risks, particularly concerning major congenital malformations. The study adds to the growing body of evidence suggesting the safety of HCQ use in managing SLE or RA during pregnancy. 

These findings provide reassurance, suggesting that the benefits of using HCQ during pregnancy for individuals with rheumatic diseases may outweigh any potential risks. However, the conflicting evidence highlights the complexity of the issue, emphasizing the importance of evidence-based decision-making in clinical practice. Healthcare providers stress the need for thorough risk-benefit assessments before prescribing HCQ during pregnancy. Effective communication between healthcare providers and pregnant individuals is essential to ensure informed decision-making and to optimize maternal and fetal health outcomes. 


  1. Huybrechts KF, Bateman BT, Zhu Y, Straub L, Mogun H, Kim SC, et al. Hydroxychloroquine early in pregnancy and risk of birth defects. Am J Obstet Gynecol. 2021 Mar;224(3):290.e1-290.e22.
  2. Clowse MEB, Eudy AM, Balevic S, Sanders-Schmidler G, Kosinski A, Fischer-Betz R, et al. Hydroxychloroquine in the pregnancies of women with lupus: a meta-analysis of individual participant data. Lupus Science & Medicine. 2022 Mar 1;9(1):e000651. 
  3. Russell MD, Dey M, Flint J, Davie P, Allen A, Crossley A, et al. British Society of Rheumatology guideline working group response to European Medicines Agency safety update on Hydroxychloroquine. Rheumatology (Oxford). 2023 Jul 31;63(2):e37–8. 
  4. Schreiber K, Giles I, Costedoat-Chalumeau N, Nelson-Piercy C, Dolhain RJ, Mosca M, et al. Global comment on the use of hydroxychloroquine during the periconception period and pregnancy in women with autoimmune diseases. Lancet Rheumatol. 2023 Sep;5(9):e501–6. 
  5. Nguyen NV, Svenungsson E, Dominicus A, Altman M, Hellgren K, Simard JF, et al. Hydroxychloroquine in lupus or rheumatoid arthritis pregnancy and risk of major congenital malformations: a population-based cohort study. Rheumatology (Oxford). 2024 Mar 13;keae168.