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Meta-Analysis
. 2020 Sep 2;9(9):CD007421.
doi: 10.1002/14651858.CD007421.pub4.

Hyaluronic acid in embryo transfer media for assisted reproductive technologies

Devorah Heymann  1 , Liat Vidal  2 , Yuval Or  1   3 , Zeev Shoham  1   3   4
Affiliations
Meta-Analysis

Hyaluronic acid in embryo transfer media for assisted reproductive technologies

Devorah Heymann et al. Cochrane Database Syst Rev. .

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 (ARTs), adherence compounds such as hyaluronic acid (HA) 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 adding adherence compounds to embryo transfer media could improve pregnancy outcomes, including improving live birth and decreasing miscarriage, in women undergoing assisted reproduction.

Search methods: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO electronic databases on 7 January 2020 for randomised controlled trials that examined the effects of adherence compounds in embryo transfer media on pregnancy outcomes. Furthermore, we communicated with experts in the field, searched trials registries, checked reference lists of relevant studies, and conference abstracts were handsearched.

Selection criteria: Only truly randomised controlled trials comparing embryo transfer media containing functional concentrations of adherence compounds to media with no or low adherence compound concentrations were included.

Data collection and analysis: Two review authors selected trials for inclusion according to the above criteria, after which the same two review authors independently extracted data for subsequent analysis. Statistical analysis was performed according to the guidelines developed by Cochrane. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We used GRADE methods to assess the overall quality of evidence for the main comparisons.

Main results: We analysed 26 studies with a total of 6704 participants. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity. Compared to embryos transferred in media containing no or low (0.125 mg/mL) HA, the addition of functional (0.5 mg/mL) HA concentrations to the transfer media probably increases the live birth rate (RR 1.21, 95% CI 1.1 to 1.31; 10 RCTs, N = 4066; I² = 33%; moderate-quality evidence). This suggests that if the chance of live birth following no HA addition in media is assumed to be 33%, the chance following HA addition would be between 37% and 44%. The addition of HA may slightly decrease miscarriage rates (RR 0.82, 95% CI 0.67 to 1.00; 7 RCTs, N = 3091; I² = 66%; low-quality evidence). Nevertheless, when only studies with low risk of bias were included in the analysis, there was no conclusive evidence of a difference in miscarriage rates (RR 0.96, 95% CI 0.75 to 1.23; N = 2219; I² = 36%). Adding HA to transfer media probably results in an increase in both clinical pregnancy (RR 1.16, 95% CI 1.09 to 1.23; 17 studies, N = 5247; I² = 40%; moderate-quality evidence) and multiple pregnancy rates (RR 1.45, 95% CI 1.24 to 1.70; 7 studies, N = 3337; I² = 36%; moderate-quality evidence). We are uncertain of the effect of HA added to transfer media on the rate of total adverse events (RR 0.86, 95% CI 0.40 to 1.84; 3 studies, N = 1487; I² = 0%; low-quality evidence).

Authors' conclusions: Moderate-quality evidence shows improved clinical pregnancy and live birth rates with the addition of HA as an adherence compound in embryo transfer media in ART. Low-quality evidence suggests that adding HA may slightly decrease miscarriage rates, but when only studies at low risk of bias were included in the analysis, the results were inconclusive. HA had no clear effect on the rate of total adverse events. The increase in multiple pregnancy rates may be due to combining an adherence compound and transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

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Conflict of interest statement

No declarations of interest to declare.

Figures

1
1
Study flow diagram.
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Funnel plot of comparison: 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
5
Forest plot of comparison: high hyaluronic acid versus low/no hyaluronic acid, outcome: 1.1 Live birth rate.
6
6
Forest plot of comparison: Fibrin sealant versus no fibrin sealant, outcome: 2.1 Clinical pregnancy rate (per randomly assigned couple).
7
7
Forest plot of comparison: Fibrin sealant versus no fibrin sealant, outcome: 2.2 Adverse event rate (per randomly assigned couple).
1.1
1.1. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 1: Live birth rate
1.2
1.2. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 2: Live birth rate (grouped by timing of embryo transfer)
1.3
1.3. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 3: Live birth rate (grouped by frozen‐thawed or fresh embryos)
1.4
1.4. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 4: Live birth rate (grouped by exposure time to HA)
1.5
1.5. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 5: Live birth rate (grouped by embryo transfer policy)
1.6
1.6. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 6: Live birth rate (grouped by participant prognosis)
1.7
1.7. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 7: Miscarriage
1.8
1.8. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 8: Clinical pregnancy rate
1.9
1.9. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 9: Clinical pregnancy rate (grouped by timing of embryo transfer)
1.10
1.10. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 10: Clinical pregnancy rate (grouped by frozen‐thawed or fresh embryos)
1.11
1.11. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 11: Clinical pregnancy rate (grouped by exposure time to HA before transfer)
1.12
1.12. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 12: Clinical pregnancy rate (grouped by embryo transfer policy)
1.13
1.13. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 13: Clinical pregnancy rate (grouped by participant prognosis)
1.14
1.14. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 14: Multiple pregnancy rate
1.15
1.15. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 15: Implantation rate
1.16
1.16. Analysis
Comparison 1: High versus low or no hyaluronic acid, Outcome 16: Total adverse event rate
2.1
2.1. Analysis
Comparison 2: Fibrin sealant versus no fibrin sealant, Outcome 1: Clinical pregnancy rate (per randomly assigned couple)
2.2
2.2. Analysis
Comparison 2: Fibrin sealant versus no fibrin sealant, Outcome 2: Adverse event rate (per randomly assigned couple)
2.3
2.3. Analysis
Comparison 2: Fibrin sealant versus no fibrin sealant, Outcome 3: Implantation rate (per embryos transferred)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to studies excluded from this review

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References to ongoing studies

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