Background: Pregnancy failure and placenta mediated pregnancy complications affect N25% of pregnancies. Although there is biological plausibility for a procoagulantmechanism underlying some of these events, antithromboticintervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determinewhether this screening and LMWHtreatment normalized the outcome for ANXA5M2 positive couples.Thiswas a pragmatic study that aimed tomeasure the effectiveness of a testing (for theM2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments.Methods: Couples (N=77) with one or both partners ANXA5M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotypescreening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreenedand untreated couples undergoing assisted conception, from which 103 matched control couples were derived.The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence.Findings: The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both themore fertile comparison group (38.5%), and to the 103matched controls (33.0%). Significantlymore treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p =0.045).Interpretation: Pragmatic ANXA5M5 screening and treatmentwith LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcomefor treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although othermechanisms are possible. This study suggests that LMWH treatmentshould be started prior to clinical pregnancy.