Heparin for assisted reproduction.
Author(s): Akhtar MA(1), Sur S, Raine-Fenning N, Jayaprakasan K, Thornton JG, Quenby S.
Affiliation(s): Author information:
(1)Clinical Reproductive Medicine Unit, University Hospitals, Coventry &
Warwickshire NHS Trust, Clifford Bridge Road, Coventry, UK.
Publication date & source: 2013, Cochrane Database Syst Rev. , 8:CD009452
BACKGROUND: Heparin 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.
OBJECTIVES: To investigate whether the administration of heparin around the time
of implantation (peri-implantation heparin) improves clinical outcomes in
subfertile women undergoing assisted reproduction.
SEARCH METHODS: A 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(published, unpublished, in press, and in progress).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 CRITERIA: All 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 ANALYSIS: Two 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 RESULTS: Three 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' CONCLUSIONS: The 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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