Association of hydroxychloroquine use with pregnancy outcomes in euthyroid TPOAb-positive women with unexplained recurrent pregnancy loss: a retrospective cohort study

Recurrent pregnancy loss (RPL) is a multifactorial disease. Approximately 40–60% of cases remain unexplained and are classified as unexplained recurrent pregnancy loss (URPL). Thyroid autoimmunity (TAI), particularly thyroid peroxidase antibody (TPOAb) positivity, has been implicated in adverse reproductive outcomes even in euthyroid women, while the optimal management of this population remains controversial. Hydroxychloroquine (HCQ), an immunomodulatory agent, has shown potential benefits in autoimmune-related reproductive disorders, but its role in euthyroid TPOAb-positive URPL remains unclear. This retrospective cohort study included 1720 euthyroid women with URPL treated at Sun Yat-sen Memorial Hospital between 2012 and 2023. Logistic regression models were used to evaluate (i) the association between TPOAb positivity and pregnancy outcomes in the overall cohort, and (ii) the association between HCQ use and outcomes within the TPOAb-positive subgroup. Primary outcomes were early miscarriage and live birth. Secondary outcomes among live births included preterm birth, low birth weight (LBW), and fetal growth restriction (FGR). Multivariable models adjusted for relevant confounders, and additional propensity score–based analyses were performed to further address potential confounding. Subgroup analyses were conducted stratified by maternal age. Among the overall cohort, TPOAb positivity was independently associated with an increased risk of early miscarriage (OR (95% CI): 1.34 (1.09–1.65), P = 0.006) and a decreased likelihood of live birth (OR (95% CI): 0.76 (0.62–0.93), P = 0.009). Among women with live births, TPOAb positivity was associated with higher risks of LBW (OR (95% CI): 1.76 (1.06–2.95), P = 0.029) and FGR (OR (95% CI): 3.03 (1.33–7.56), P = 0.011). Within the TPOAb-positive subgroup, HCQ use was associated with a lower risk of early miscarriage (OR (95% CI): 0.55 (0.39–0.76), P < 0.001) and a higher likelihood of live birth (OR (95% CI): 1.74 (1.25–2.42), P = 0.001), with consistent effects across age strata. HCQ use was not significantly associated with preterm birth, LBW, or FGR among live births. These associations remained broadly consistent in propensity score–based analyses. In euthyroid women with URPL, TPOAb positivity is associated with increased risks of miscarriage, reduced live birth, and adverse fetal growth outcomes (LBW and FGR). HCQ use in TPOAb-positive women is associated with a lower risk of early miscarriage and a higher likelihood of live birth, suggesting that HCQ may be associated with improved outcomes in this biologically defined subgroup and supports further evaluation in prospective studies and randomized trials.