Preconception Hydroxychloroquine Therapy Restores Placental Function and Improves Pregnancy Outcomes in Obstetric Antiphospholipid Syndrome

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Aims: Obstetric antiphospholipid syndrome (OAPS), a representative autoimmune disorder driven by antiphospholipid antibodies (aPLs), afflicts 30% of patients with refractory to conventional antithrombotic treatment. Hydroxychloroquine (HCQ) offers adjunctive potential, yet its mechanistic action and critical treatment timing remain undefined. This study establishes the preventive efficacy of preconception HCQ initiation (HCQ-pre) and deciphers its fundamental rescue pathways in OAPS. Results: Clinical data suggested a potential advantage of HCQ-pre compared to post-conception administration (HCQ-post) in optimizing pregnancy outcomes for patients with OAPS. Modeling the pathology of OAPS using human trophoblast organoids revealed that HCQ-pre effectively reverses aPLs-mediated trophoblast dysfunction: increasing cytotrophoblast proliferation (Ki67 + /TP63 + ) by 20% and restoring their differentiation into extravillous trophoblast (HLA-G + ) to 93% of control levels, while HCQ-post shows markedly limited efficacy. Mechanistically, HCQ-pre preemptively corrected aPLs-induced redox imbalance by rescuing hypoxia-inducible factor 1-alpha-mediated hypoxia and replenishing antioxidant mediators (NRF2/SOD2/GPX4) via Hippo/YAP and Wnt/β-catenin signaling. Murine OAPS models established that HCQ-pre restores placental perfusion (90% of control levels) by enhancing spiral artery remodeling—with diminished efficacy observed at post-conception administration—thereby attenuating hypoperfusion-induced hypoxic damage and improving pregnancy outcomes. Innovation and Conclusions: We redefine HCQ as a proactive placental resetter that neutralizes oxidative stress barriers preconception, thereby liberating trophoblast differentiation capacity. This work positions HCQ-pre as the critical intervention phase—a paradigm shift from reactive adjunct to preemptive root-cause interception, providing the mechanistic foundation for optimizing OAPS management through timely individualized prophylaxis. Antioxid. Redox Signal. 44, 748–769.

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