Re-evaluating low-molecular-weight heparin use in recurrent missed miscarriage: current evidence and future directions

BACKGROUND: Recurrent missed miscarriage (RMM) is heterogenous and emotionally burdensome. Low-molecular-weight heparin (LMWH) plus low-dose aspirin improves live-birth rates in women with obstetric antiphospholipid syndrome (APS), but the value of the use of LMWH in APS-negative RMM with and without confirmed coagulation disorders remains controversial, and optimal dosing frequency is uncertain. METHODS: We performed a narrative synthesis of randomised controlled trials (notably ALIFE and ALIFE2), Cochrane systematic reviews, pharmacokinetic studies, and national/international guidelines (RCOG, ESHRE). Emphasis was placed on live-birth outcomes, trial design limitations (including inclusion of chromosomally abnormal losses), pharmacokinetics relevant to once-daily (OD) versus twice-daily (BD) regimens, and safety/tolerability data. RESULTS: Robust evidence supports LMWH plus low-dose aspirin in improving live-birth rates in women with APS. In APS-negative populations, randomised controlled trials and meta-analyses show no reproducible live-birth benefit; interpretation is limited by clinical heterogeneity, underpowering and failure to exclude chromosomally abnormal losses, which account for up to half of early miscarriages. Notably, these trials almost exclusively used once-daily LMWH. Pharmacokinetic data indicate that twice-daily dosing yields more stable anti-Xa levels than once-daily dosing; however, this is a pharmacokinetic rationale only, and no adequately powered trial has tested whether it improves clinical outcomes. CONCLUSIONS: Routine LMWH for APS-negative RMM is not supported outside clinical trials. Key knowledge gaps include the effect of pre-randomisation genetic stratification (euploid-only cohorts), directly comparing OD vs BD LMWH regimens, and incorporation of patient-centred and health-economic outcomes. Well-designed, adequately powered trials with genetic and phenotypic enrichment and embedded pharmacokinetic sub-studies are required to resolve clinical equipoise.