Adherence compounds in embryo transfer media for assisted reproductive technologies

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, I(2) = 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, I(2) = 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, I(2) = 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, I(2) = 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.

Conflict of interest statement

The Biotechnology Research Institute has an affiliation with KODE Biotech Ltd, which has licensed to ORIGIO/MediCult the rights for modifying human embryos with KODE constructs, including those that may contain hyaluronic acid.

Neil Johnson is involved in research into lipiodol and its possible properties for enhancement of endometrial receptivity to implantation.

Figures

1

Study flow diagram.

2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

4

Funnel plot of comparison: 3 Embryo transfer in medium enriched with hyaluronic acid versus medium devoid of, or with a lower concentration of, hyaluronic acid, outcome 3.14 Clinical pregnancy rate.

5

Forest plot of comparison: 1 High hyaluronic acid versus low/no hyaluronic acid, outcome: 1.1 Live birth rate.

6

Forest plot of comparison: 1 High versus low or no hyaluronic acid, outcome: 1.16 Adverse event rate.

7

Forest plot of comparison: 2 Fibrin sealant versus no fibrin sealant, outcome: 2.1 Clinical pregnancy rate (per randomly assigned couple).

8

Forest plot of comparison: 2 Fibrin sealant versus no fibrin sealant, outcome: 2.2 Adverse event rate (per randomly assigned couple).

1.1

Comparison 1 High versus low or no hyaluronic acid, Outcome 1 Live birth rate.

1.2

Comparison 1 High versus low or no hyaluronic acid, Outcome 2 Live birth rate (grouped by timing of intervention).

1.3

Comparison 1 High versus low or no hyaluronic acid, Outcome 3 Live birth rate (grouped by frozen‐thawed or fresh embryos).

1.4

Comparison 1 High versus low or no hyaluronic acid, Outcome 4 Live birth rate (grouped by oocyte donation).

1.5

Comparison 1 High versus low or no hyaluronic acid, Outcome 5 Live birth rate (grouped by exposure time to HA).

1.6

Comparison 1 High versus low or no hyaluronic acid, Outcome 6 Live birth rate (grouped by embryo transfer policy).

1.7

Comparison 1 High versus low or no hyaluronic acid, Outcome 7 Live birth rate (grouped by participant prognosis).

1.8

Comparison 1 High versus low or no hyaluronic acid, Outcome 8 Clinical pregnancy rate.

1.9

Comparison 1 High versus low or no hyaluronic acid, Outcome 9 Clinical pregnancy rate (grouped by timing of intervention).

1.10

Comparison 1 High versus low or no hyaluronic acid, Outcome 10 Clinical pregnancy rate (grouped by frozen‐thawed or fresh embryos).

1.11

Comparison 1 High versus low or no hyaluronic acid, Outcome 11 Clinical pregnancy rate (grouped by oocyte donation).

1.12

Comparison 1 High versus low or no hyaluronic acid, Outcome 12 Clinical pregnancy rate (grouped by exposure time to HA before transfer).

1.13

Comparison 1 High versus low or no hyaluronic acid, Outcome 13 Clinical pregnancy rate (grouped by participant prognosis).

1.14

Comparison 1 High versus low or no hyaluronic acid, Outcome 14 Clinical pregnancy rate (grouped by embryo transfer policy).

1.15

Comparison 1 High versus low or no hyaluronic acid, Outcome 15 Multiple pregnancy rate.

1.16

Comparison 1 High versus low or no hyaluronic acid, Outcome 16 Adverse event rate.

1.17

Comparison 1 High versus low or no hyaluronic acid, Outcome 17 Implantation rate.

2.1

Comparison 2 Fibrin sealant versus no fibrin sealant, Outcome 1 Clinical pregnancy rate (per randomly assigned couple).

2.2

Comparison 2 Fibrin sealant versus no fibrin sealant, Outcome 2 Adverse event rate (per randomly assigned couple).

2.3

Comparison 2 Fibrin sealant versus no fibrin sealant, Outcome 3 Implantation rate (per embryos transferred).