Adherence compounds in embryo transfer media for assisted reproductive technologies Edited (no change to conclusions)

Abstract

Abstract Background

This is an update of a Cochrane review first published in The Cochrane Library (2010, Issue 7).

To increase the success rate of assisted reproductive technologies (ART), adherence compounds such as hyaluronic acid (HA) and fibrin sealant have been introduced into subfertility management. Adherence compounds are added to the embryo transfer medium to increase the likelihood of embryo implantation, with the potential for higher clinical pregnancy and live birth rates.

Objectives

To determine whether embryo transfer media containing adherence compounds improved live birth and pregnancy rates in ART cycles.

Search methods

The Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE, EMBASE and PsycINFO electronic databases were searched (up to 13 November 2013) to look for publications that described randomised controlled trials on the addition of adherence compounds to embryo transfer media. Furthermore, reference lists of all obtained studies were checked, and conference abstracts were handsearched.

Selection criteria

Only truly randomised controlled trials comparing embryo transfer media containing functional (e.g. 0.5 mg/ml HA) concentrations of adherence compounds versus transfer media containing low or no concentrations of adherence compounds were included. The adherence compounds that were identified for evaluation were HA and fibrin sealant.

Data collection and analysis

Two review authors selected trials for inclusion according to the above criteria, after which two review authors independently extracted the data for subsequent analysis. Statistical analysis was performed in accordance with the guidelines developed by The Cochrane Collaboration.

Main results

Seventeen studies with a total of 3898 participants were analysed. One studied fibrin sealant, and the other 16 studied HA. No evidence was found of a treatment effect of fibrin sealant as an adherence compound. For HA, evidence of a positive treatment effect was identified in the six trials that reported live birth rates (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.17 to 1.69; six RCTs, N = 1950, I2 = 0%, moderate‐quality evidence). Furthermore, the 14 trials reporting clinical pregnancy rates showed evidence of treatment benefit when embryos were transferred in media containing functional concentrations of HA (OR 1.39, 95% CI 1.21 to 1.60; 14 RCTs, N = 3452, I2 = 46%, moderate‐quality evidence) as compared with low or no use of HA. The multiple pregnancy rate (OR 1.86, 95% CI 1.49 to 2.31; five RCTs, N = 1951, I2 = 0%, moderate‐quality evidence) was significantly increased in the high HA group, but no significant differences in adverse event rates were found (OR 0.74, 95% CI 0.49 to 1.12; four RCTs, N = 1525, I2 = 0%, moderate‐quality evidence).

Authors' conclusions

Evidence suggests improved clinical pregnancy and live birth rates with the use of functional concentrations of HA as an adherence compound in ART cycles. However, the evidence obtained is of moderate quality. The increase in multiple pregnancy rate may be the result of use of a combination of an adherence compound and a policy of transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

Author(s)

Stephan Bontekoe, Neil Johnson, Deborah Blake

Abstract

Plain language summary

Adherence compounds in embryo transfer media for assisted reproductive technologies

Cochrane review authors assessed the effect of the addition of adherence compounds in embryo transfer media on fertility outcomes.

Couples who have trouble getting pregnant are able to make use of fertility treatments such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). Over the years, much research has been performed to determine whether there are ways to increase the success rate of such treatments. One area of research has focused on the medium in which embryos are transferred back into the uterus. Adherence compounds have been added to the embryo transfer medium in attempts to increase the chance of the embryo adhering to the uterus, with a greater chance of pregnancy and the birth of a healthy newborn as a result. Many studies of these adherence compounds have been undertaken with some positive and negative results.

Seventeen randomised controlled trials (3898 participants) were included in the review. One studied fibrin sealant, and the other 16 studied HA. Investigators compared embryo transfer in a medium containing high versus low or no hyaluronic acid and in a medium containing fibrin sealant versus transfer in a medium with no fibrin sealant. Outcomes reported included live birth rates, clinical pregnancy rates, implantation rates, multiple pregnancy rates and other adverse events. The mean age of the women ranged from 27.5 to 35.7 years. The evidence gathered is current to November 2013.

Analysis of the 16 studies that were identified using functional concentrations of HA showed an increase in the chances of pregnancy and live birth (450 vs 367 per 1000) but also an increase in the chance of the more risky outcome of multiple pregnancy (282 vs 175 per 1000). This increase in multiple pregnancy rate may be the result of improved pregnancy outcomes due to the addition of the adherence compound and the policy of transferring more than one embryo back into the uterus.

Evidence obtained for these comparisons was of moderate quality. It is important to note that evidence of a higher delivery rate was not found in all analyses; however, it was found in the overall meta‐analysis. Based on the single identified study that used fibrin sealant, no evidence indicates that the addition of this compound to an embryo transfer medium improved pregnancy outcomes.

Author(s)

Stephan Bontekoe, Neil Johnson, Deborah Blake

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Moderate‐quality evidence suggests that adherence compounds such as hyaluronic acid are valuable in improving the success rate of assisted reproductive technologies such as in vitro fertilisation and intracytoplasmic sperm injection, with resultant evidence of an increase in the number of live births. An overall increase of 8% in the live birth rate was found with the addition of adherence compounds (0.5 mg/ml HA) to the embryo transfer medium (44.8% in the HA group and 36.7% in the control group), with the number needed to treat for beneficial outcome (NNTB) of 12.5. A treatment effect was noted for both early (day two to three) and late (day five) embryo transfers; this implies that the actual working mechanism of adherence compounds may not involve enhancement of adhesion per se. An increase in the multiple pregnancy rate was noted but is likely to be a consequence of both the effect of the adherence compound and a policy of transferring multiple embryos per treatment cycle. The addition of adherence compounds to a single embryo transfer policy might yield the best combination with higher clinical pregnancy rates and higher live birth rates as a result, and without increasing the chance of multiple pregnancies. With each incremental improvement in the in vitro fertilisation technique, a compounding effect on multiple pregnancy rates will further entrench the drive towards single embryo transfer.

Implications for research

The most important outcome measure that should be addressed is the live birth rate. Only six of the 16 studies included in this systematic review reported on this outcome measure. The lack of studies reporting on the number of live births may be a result of the large proportion of pregnancies that fail to progress to birth, or it may reflect the frequent practice of reporting studies before the last study participant has given birth, suggesting either inadequate reporting capabilities or an eagerness to publish. Other important outcome measures that have not been reported fully are multiple pregnancies and other adverse events such as miscarriages.

Further research on the actual working mechanism of adherence compounds might be useful. Additional studies of adherence compounds with single embryo transfer need to be undertaken. Also, randomised controlled trials on other potential adherence compounds should be performed in the future.

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