Use of anticoagulants to improve pregnancy outcomes in couples positive for M2 haplotype: A systematic review

•Our comprehensive review shows potential benefits of anticoagulants in M2 haplotype positive couples in improving pregnancy outcomes.•Studies included, highlight significant association between ANXA5 and various placental mediated pregnancy complications (PMPC), offering insights for targeted interventions.•Growing understanding of the role of ANXA5 in placental pathology and mechanism of Low Molecular Weight Heparin (LMWH) in PMPC reduction pave the way for optimistic prospects in tailored treatment approaches. Placental mediated pregnancy complications (PMPC) are common, often recurring, and pose a significant health risk to mother and fetus. Evidence suggests that the hypercoagulable state associated with many PMPC, could reflect reduced expression of Annexin 5 (ANXA5), a naturally occurring anticoagulant protein in placental tissue. The ANXA5 M2 haplotype is a genetic variant, which results in reduced expression of ANXA5 protein. M2 haplotype carrier couples may therefore be at increased risk of PMPC. Evidence regarding the effectiveness of anticoagulation to prevent PMPC is inconsistent. Furthermore, studies have not selected or stratified for M2 haplotype carriers, in whom there is a predisposition to hypercoagulability, to assess the effectiveness of anticoagulation, which may vary from those without the M2 haplotype. The aim of this study was to systematically review the current evidence to assess whether anticoagulant treatment improves pregnancy outcomes in couples positive for M2 haplotype. The review was registered on PROSPERO (CRD42022343943). A comprehensive literature search was performed using MEDLINE, Embase and Cochrane collaboration databases from inception to January 2023. Two reviewers assessed the articles for eligibility and extracted the data simultaneously. Primary outcome was successful pregnancy and live birth. Secondary outcomes included PMPC (implantation failure, miscarriage, pre-eclampsia, preterm birth and fetal growth restriction). From a pool of 410 references, 10 were selected for full text review, of which three studies (a post hoc analysis of a randomised controlled trial, cohort study and a case report) were included in this review. Included studies comprised of 223 individuals, 129 of whom who received anticoagulation treatment after testing positive for M2 haplotype. The studies collectively showed an improvement in pregnancy outcomes in M2 haplotype positive individuals however, given the heterogeneity of studies,