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Use of hydroxychloroquine during pregnancy in patients with systemic lupus erythematosus (SLE) is associated with a reduced risk for preeclampsia, according to a recent nationwide cohort study. A population-based analysis from Sweden found that women with SLE taking hydroxychloroquine had about half the risk for preeclampsia compared with those not taking it, but there was no clear association between hydroxychloroquine use and preterm birth risk.

“These findings suggest possibly favorable, or at least not harmful, associations between hydroxychloroquine and preeclampsia and preterm delivery in pregnancies in women with SLE, supporting the current recommendations for hydroxychloroquine treatment during pregnancy in these patients,” wrote Ngoc V. Nguyen, MPH, a PhD candidate at the Karolinska Institutet in Stockholm, Sweden, and his colleagues in The Lancet Rheumatology.

“[Hydroxychloroquine] may actually reduce the risk of preeclampsia,” Nguyen told Medscape Medical News.

Joshua Copel, MD, a professor of obstetricis, gynecology, and reproductive sciences and of pediatrics at Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News the findings show that “hydroxychloroquine certainly doesn’t seem to cause an increased risk for spontaneous preterm birth, and it probably reduces the risk for preeclampsia or at least delays the onset of preeclampsia.”

The researchers used the Swedish Medical Birth Register to identify all 959 singleton pregnancies among 685 women with SLE in Sweden between January 2007 and December 2022. Using the Prescribed Drug Register, they determined which patients had received at least two dispensations between 3 months before pregnancy through the end of the first trimester.

Among the 42% of pregnancies that were nulliparous, 43% were exposed to hydroxychloroquine and 57% were unexposed. Among the other 58% of pregnancies that were parous, 40% were exposed and 60% were unexposed. Patients had an average age of 32 years and an average first-trimester BMI ranging from 23.7 to 24.9 across the different groups. They had been diagnosed with lupus for 5.4-6.8 years, and rates of prior miscarriages ranged from 19% to 38% across the groups.

Preeclampsia occurred in 11% of exposed and 13% of unexposed nulliparous pregnancies and in 5% of exposed and 6% of unexposed parous pregnancies. Preterm birth occurred in 19% of exposed and 15% of unexposed nulliparous pregnancies and in 12% of exposed and 12% of unexposed parous pregnancies.

After adjustment for confounders, these numbers translated to an overall 49% reduced risk for preeclampsia in those exposed to hydroxychloroquine (95% CI, 0.31-0.79; P = .003). Stratified by parity, however, the 59% preeclampsia risk reduction in nulliparous pregnancies exceeded the threshold for statistical significance (95% CI, 0.33-1.08; P = .085). The 44% reduction in parous pregnancies was significant (95% CI, 0.22-0.89; P = .02).

Questions Remain

Though these findings “add to a growing body of evidence suggesting hydroxychloroquine may help lower the risk of preeclampsia,” Nguyen told Medscape Medical News, “it’s worth noting that not all studies have shown statistically significant effects [potentially because of] how hydroxychloroquine use was defined, how well patients adhered to it, or whether key factors like BMI and smoking were accounted for.”

Alfred Kim, MD, PhD, an associate professor of rheumatology at Washington University Medicine in St. Louis, told Medscape Medical News that hydroxychloroquine “has a well-established antithrombotic property,” as seen with antiphospholipid syndrome, and “preeclampsia is a prothrombotic condition due to substantial endothelial dysfunction, driving complement and coagulation cascade activation.”

“It is not completely clear how hydroxychloroquine attenuates thrombosis, though,” Kim said. “There are nice data suggesting that hydroxychloroquine inhibits platelet activation and thrombus formation, both of which can promote a preeclamptic state.”

Other possibilities, Nguyen added, include antioxidant activity, improved placental perfusion, and stabilization of endothelial function, any of which could also, in theory, reduce the risk for preterm birth in certain cases.

However, this study found no association with preterm birth overall (risk ratio [RR], 0.95; 95% CI, 0.67-1.34; P = .76), in nulliparous births (RR, 1.1; P = .69), or in parous births (RR, 0.75; P = .28).

Adherence Barriers Present Challenges

Grégoire Martin de Frémont, Gaëlle Guettrot-Imbert, and Nathalie Costedoat-Chalumeau of Paris City University in Paris wrote in an accompanying editorial in The Lancet Rheumatology that “by suggesting a beneficial effect on preeclampsia, the rigorous and valuable findings reported by the authors provide an additional rationale for the use of hydroxychloroquine in all pregnant women with SLE, as currently recommended.”

They add, however, that “obstacles to its optimal use persist, including drug unavailability, lack of prescription, and, in many cases, patients’ reluctance to take it.”

Kim agreed that many barriers remain to hydroxychloroquine adherence during pregnancy. “Sometimes it’s due to the patient not fulfilling the prescription, whether this is due to cost — which is typically not an issue with hydroxychloroquine — to inadequate comprehension due to low literacy, cognitive issues, language or visual barriers to a lack of trust in the medication or the medical team prescribing hydroxychloroquine,” Kim said.

Nguyen agreed that the challenge of adherence is complex, with hurdles that include misinformation about safety, mixed messages from providers, and challenges such as age, disease severity, or pill burden.

“Our study might help chip away at some of these barriers by offering strong evidence for benefit, not just safety. If we can reframe hydroxychloroquine as something that’s protective during pregnancy — not just ‘safe enough’ — that might help patients feel more comfortable and providers more proactive,” he said.

The research was funded by the US National Institutes of Health and the Ingegerd Johansson Donation. The authors reported no disclosures. Costedoat-Chalumeau reported grants from UCB and Roche and honoraria from Bristol Myers Squibb.

Copel serves on the advisory board for Janssen Pharmaceuticals, Nuvo, SimHawk, and Pulsenmore; receives royalties from Elsevier and UpToDate; and owns a company that manufactures prenatal vitamins.

Kim receives royalties from Kypha Inc.; sponsored research agreements with AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, and Novartis; and has done consulting or speaking for AbbVie, Amgen, Atara Biotherapeutics, Aurinia Pharmaceuticals, Cargo Tx, Exagen Diagnostics, GlaxoSmithKline, Genentech/Roche, Hinge Bio, Invivyd, Johnson & Johnson, UpToDate, and Zenas BioPharma.

Tara Haelle is a science/health journalist based in Dallas.