Heparin for assisted reproduction

Review Question

Researchers in the Cochrane Collaboration reviewed the evidence about the effect of heparin administered around the time of implantation on clinical outcomes in subfertile women undergoing assisted reproduction.

Background

Heparin is a class of blood thinning drug that is used in the prevention and treatment of blood clots. It has been suggested that heparin may improve the intrauterine environment in subfertile women, by increasing growth factors to improve attachment of the embryo to the lining of the womb. The result could be an improvement in live birth rates during assisted reproduction.

Study Characteristics

Three studies with 386 participants were included in the review. All participants were subfertile women undergoing assisted reproduction. Their characteristics differed across studies. One study included women having their first IVF cycle, with no blood clotting disorder. Another study included women with at least one blood clotting disorder. The third study included women with at least two previous unsuccessful assisted reproduction treatment cycles. In all cases a daily injection of low molecular weight heparin was given to women from the time of egg collection or embryo transfer during assisted reproduction. Control groups received placebo or no treatment. There were no issues with source of funding in any of the studies. The evidence is current to May 2013.

Key Results

It is unclear whether peri-implantation heparin in assisted reproduction treatment (ART) cycles improves live birth and clinical pregnancy rates in subfertile women. Although there was some suggestion of benefit, this disappeared when an alternative method of analysis was used. Heparin had side effects such as bruising and bleeding, but no conclusions could be drawn regarding its safety because none of the studies reported comparative data on adverse effects. The evidence does not justify the use of heparin except in well-designed clinical research trials. Such trials are a priority.

Quality of Evidence

The evidence was of low or very low quality, mainly due to imprecision, inconsistency and inadequate reporting of advere events. Further well-designed randomised controlled trials with larger sample sizes are needed to clarify the possible role of heparin in assisted reproduction.

Authors' conclusions: 

It is unclear whether peri-implantation heparin in assisted reproduction treatment (ART) cycles improves live birth and clinical pregnancy rates in subfertile women, as the evidence was sensitive to choice of statistical model and no benefit was apparent when a random effects model was used. Side effects have been reported with use of heparin and no firm conclusions can be drawn regarding its safety. Our results do not justify the use of heparin in this context, except in 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 non-systemic application of heparin during ART.

Read the full abstract...
Background: 

Heparin as an adjunct in assisted reproduction (peri-implantation heparin) is given at or after egg collection or at embryo transfer. Heparin has been advocated to improve embryo implantation and clinical outcomes.  It is proposed that heparin may enhance 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 strategy: 

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. 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 low molecular weight heparin (LMWH) during IVF/ICSI was given at or after egg collection or at embryo transfer in these studies. The characteristics of the participants differed across studies. One included women having their first IVF cycle, with no blood clotting disorder; another included women with at least one blood clotting disorder and the third included women who had undergone at least two previous unsuccessful ART cycles.

Our findings differed according to choice of statistical model. When we used a fixed effect analysis, the evidence suggested that peri-implantation heparin was associated with an improvement in live birth rate compared with placebo or no heparin (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.07 to 2.90, three studies, 386 women, I2 = 51%, very low quality evidence) and also an improvement in the clinical pregnancy rate (OR 1.61, 95% CI 1.03 to 2.53, three studies, 386 women, I2 = 29%, low quality evidence). However when a random effects model was used there was no longer a difference between the groups for either live birth (OR 1.85, 95% CI 0.80 to 4.24) or clinical pregnancy (OR 1.66, 95% CI 0.94 to 2.90). Moreover there was high heterogeneity (I2 = 51%) for the analysis of live birth.

Adverse events were poorly reported in all the included studies. Events such as bleeding, and thrombocytopenia were reported in women receiving heparin and affected 5-7% of women in the heparin group in one study. However no studies reported data suitable for analysis and so no firm conclusions could be drawn regarding adverse effects.

The main limitations in the evidence were inconsistency, imprecision and inadequate reporting of adverse events.

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