• Muhammad A Akhtar, Shyamaly Sur, Nick Raine-Fenning, Kannamannadiar Jayaprakasan, Jim G Thornton, and Siobhan Quenby.
• Clinical Reproductive Medicine Unit, University Hospitals, Coventry & Warwickshire NHS Trust, Clifford Bridge Road, Coventry, UK.
• Cochrane Db Syst Rev. 2013 Aug 17; 2013 (8): CD009452CD009452.

BackgroundHeparin as an adjunct in assisted reproduction (peri-implantation heparin) is given at or after egg collection or at embryo transfer during assisted reproduction. Heparin has been advocated to improve embryo implantation and clinical outcomes.  It has been proposed that heparin enhances the intra-uterine environment by improving decidualisation with an associated activation of growth factors and a cytokine expression profile in the endometrium that is favourable to pregnancy.ObjectivesTo investigate whether the administration of heparin around the time of implantation (peri-implantation heparin) improves clinical outcomes in subfertile women undergoing assisted reproduction.Search MethodsA comprehensive and exhaustive search strategy was developed in consultation with the Trials Search Co-ordinator of the Cochrane Menstrual Disorders and Subfertility Group (MDSG). The strategy was used in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). Relevant trials were identified from both electronic databases and other resources (last search 6 May 2013).Selection CriteriaAll randomised controlled trials (RCTs) were included where peri-implantation heparin was given during assisted reproduction. Peri-implantation low molecular weight heparin (LMWH) during IVF/ICSI was given at or after egg collection or at embryo transfer in the included studies. Live birth rate was the primary outcome.Data Collection And AnalysisTwo review authors independently assessed the eligibility and quality of trials and extracted relevant data. The quality of the evidence was evaluated using GRADE methods.Main ResultsThree RCTs (involving 386 women) were included in the review.Peri-implantation LMWH administration during assisted reproduction was associated with a significant improvement in live birth rate compared with placebo or no LMWH (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.07 to 2.90, three studies, 386 women, I(2) = 51%, very low quality evidence with high heterogeneity). There was also a significant improvement in the clinical pregnancy rate with use of LMWH (OR 1.61, 95% CI 1.03 to 2.53, three studies, 386 women, I(2) = 29%, very low quality evidence with low heterogeneity).However these findings should be interpreted with extreme caution as they were dependent upon the choice of statistical method: they were no longer statistically significant when a random-effects model was used.Adverse events were poorly reported in all included studies, with no comparative data available. However, LMWH did cause adverse effects including bruising, ecchymosis, bleeding, thrombocytopenia and allergic reactions. It appeared that these adverse effects were increased if heparin therapy was used over a longer duration.Authors' ConclusionsThe results of this Cochrane review of three randomised controlled trials with a total of 386 women suggested that peri-implantation LMWH in assisted reproduction treatment (ART) cycles may improve the live birth rate in women undergoing assisted reproduction. However, these results were dependent on small low quality studies with substantial heterogeneity, and were sensitive to the choice of statistical model. There were side effects reported with use of heparin, including bruising and bleeding, and no reliable data on long-term effects. The results do not justify this use of heparin outside well-conducted research trials.These findings need to be further investigated with well-designed, adequately powered, double-blind, randomised, placebo-controlled, multicentre trials. Further investigations could also focus on the effects of the local (uterine) and not systemic application of heparin during ART.

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