In IVF, does transferring the embryo in media containing high concentrations of hyaluronic acid result in more live births?

What is IVF?

In vitro fertilisation (IVF) is a fertility treatment that helps people with fertility problems to have a baby. During IVF an egg from a woman's ovaries is fertilised with sperm in a laboratory. The egg can be placed in a dish with multiple sperm to fertilise it, or a single sperm can be injected directly into it (intracytoplasmic sperm injection; ICSI). The fertilised egg (an embryo) is then placed (implanted) into the woman's womb to grow and develop.

The embryo is transferred to the womb in a special transfer media, a solution containing compounds that help the embryo stick (adhere) successfully to the inside of the womb (implantation). Hyaluronic acid is a natural compound found in the body that acts as a binding and protective agent in tissues. It is often added to embryo transfer media to help implant the embryo.

Why we did this Cochrane Review

We wanted to find out whether using transfer media with high concentrations of adherence compounds for embryo transfer such as hyaluronic acid improves success in implanting embryos, resulting in more live births.


What did we do?

We searched for studies that investigated the use of embryo transfer media containing different concentrations of hyaluronic acid in IVF/ICSI.

We looked for randomised controlled studies in which the treatments received are decided at random, because these studies usually give the most reliable evidence about the effects of a treatment. We assessed the evidence by looking at how the studies were conducted, study sizes, and whether study findings were consistent.

Search date: we included evidence published up to January 2020.


What we found

We found 26 studies including 6704 women aged 27 to 35 years who underwent IVF/ICSI. These studies compared embryo transfer using media containing high concentrations of hyaluronic acid versus solutions containing no or low concentrations of hyaluronic acid.

We were interested in learning how the concentration of hyaluronic acid in the transfer solution affected the numbers of:

· live births;

· miscarriages (loss of pregnancy before 20 weeks' gestation);

· clinical pregnancies;

· multiple pregnancies; and

· adverse (unwanted) events.

What are the results of our review?

Embryo transfer using media with high concentrations of hyaluronic acid probably increases the number of live births compared with using solutions with low concentrations or no hyaluronic acid (10 studies). If transfer media with low concentrations or no hyaluronic acid have a 33% chance of resulting in a live birth, solutions with high concentrations increase the chance of a live birth to between 37% and 44%. There would probably be 1 additional live birth for every 14 embryos transferred in a high-concentration hyaluronic acid solution.

High concentrations of hyaluronic acid in the embryo transfer solution probably also increase the number of clinical pregnancies (17 studies) and the number of multiple pregnancies (7 studies).

Using transfer solutions containing high concentrations of hyaluronic acid may result in slightly fewer miscarriages (7 studies). But our analysis did not show a clear difference if we left out studies whose results varied widely.

Reported adverse events included ectopic pregnancies (when an embryo becomes implanted outside the womb) and abnormalities affecting the embryo or the foetus. Similar numbers of adverse events were reported for both types of transfer solution (high and low concentrations of hyaluronic acid): we found no evidence that the concentration of hyaluronic acid in the transfer solution affected the number of adverse events reported.

How reliable are these results?

We are moderately confident about our results for the numbers of live births, clinical pregnancies, and multiple pregnancies. Our results may change if further evidence becomes available.

We are less confident about the rate of miscarriage and the number of adverse events, because results for these varied widely. Our results are likely to change if further evidence becomes available.

Conclusions

Embryo transfer using solutions containing high concentrations of hyaluronic acid probably increases the number of live births in IVF/ICSI. Transfer solutions containing high concentrations of hyaluronic acid may slightly decrease the rate of miscarriage.


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.

Read the full 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 strategy: 

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).

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