The effect of hyaluronic acid in embryo transfer media in donor oocyte cycles and autologous oocyte cycles: a systematic review and meta-analysis

Abstract

STUDY QUESTION Does the addition of hyaluronic acid (HA) to embryo transfer medium improve pregnancy outcomes in both autologous and oocyte donation IVF cycles? SUMMARY ANSWER The best available evidence indicates that the addition of HA to embryo transfer medium is clinically beneficial in cycles with autologous oocytes. WHAT IS KNOWN ALREADY There is a known clinical benefit of HA addition to embryo transfer media but it is not known if HA affects donor and autologous oocyte cycles differently. STUDY DESIGN, SIZE, DURATION A systematic review with meta-analysis was performed. The Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL via Cochrane Register of Studies Online (CRSO), MEDLINE, Embase and PsycINFO electronic databases (until 8 January 2020) were searched for randomized controlled trials (RCTs) examining the effect of HA in embryo transfer medium on pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS RCTs with separate donor and autologous oocyte data that compared embryo transfer medium with functional HA concentrations (0.5 mg/ml) to those containing no or low HA concentrations (0.125 mg/ml) were included. Two review authors independently selected trials for inclusion, extracted data and assessed the included studies using the Cochrane risk of bias assessment tool. Pooled risk ratios and 95% CIs were calculated. A summary of findings table was generated using Grading of Recommendations, Assessment, Development and Evaluation criteria. Judgements about evidence quality were justified and incorporated into the reported results for each outcome. MAIN RESULTS AND THE ROLE OF CHANCE Fifteen studies, totalling 4686 participants, were analysed. In autologous oocyte cycles, live birth increased from 32% to 39% when embryo transfer media contained functional HA concentrations (risk ratio (RR) 1.22, 95% CI 1.11–1.34; nine studies, 3215 participants, I2 = 39%, moderate-quality evidence (number needed to treat (NNT) 14). HA-enriched media increased clinical pregnancy and multiple pregnancy rates by 5% and 8%, respectively (RR 1.11, 95% CI 1.04–1.18; 13 studies, 4014 participants, I2 = 0%, moderate-quality evidence, NNT 21) and (RR 1.49, 95% CI 1.27–1.76; 5 studies, 2400 participants, I2 = 21%, moderate-quality evidence, number needed to harm 13). Conversely, in donor oocyte cycles, HA addition showed little effect on live birth and clinical pregnancy (RR 1.12 95% CI 0.86–1.44; two studies, 317 participants, I2 = 50%, low-quality evidence) and (RR 1.06, 95% CI 0.97–1.28; three studies, 351 participants, I2 = 23%, low-quality evidence). There was insufficient available information on multiple pregnancy in donor oocyte cycles and on total adverse effects in both groups to draw conclusions. LIMITATIONS, REASONS FOR CAUTION There were limited studies with separate data on donor oocyte cycles and limited information on oocyte quality. Additionally, one-third of the included studies did not include the main outcome, live birth rate. WIDER IMPLICATIONS OF THE FINDINGS There is a moderate level of evidence to suggest that functional HA concentration in embryo transfer medium increases clinical pregnancy, live birth and multiple pregnancy rates in IVF cycles using autologous oocytes. This effect was not seen in donor oocyte cycles, indicating either intrinsic differences between donor and autologous oocytes or lack of statistical power. The combination of HA addition to transfer media in cycles using autologous oocytes and a single embryo transfer policy might yield the best combination, with higher clinical pregnancy and live birth rates without increasing the chance of multiple pregnancies. STUDY FUNDING/COMPETING INTEREST(S) No financial assistance was received. The authors have no competing interests. REGISTRATION NUMBER N/A.

Good practice recommendations on add-ons in reproductive medicine

“… Heymann etal. (2022) later summarized the data separately for donor oocyte cycles and autologous oocyte cycles and concluded that, in donor oocyte cycles, HA addition showed little effect on LBR (RR 1.12; 95% CI 0.86 to 1.44; 2 RCTs; n = 317; I 2 = 50%; low-quality evidence) and CPR (RR 1.06; 95% CI 0.97 to 1.28; 3 RCTs; n = 351; I 2 = 23%; low-quality evidence).…”

HB‐EGF‐loaded nanovesicles enhance trophectodermal spheroid attachment and invasion

“…Indeed, we show that hTSC NV HBEGF and NVs, enriched in these molecules, are effective supplements for promoting endometrial adhesion to trophectodermal cells and trophectodermal invasion into Matrigel (Figure 5). For example, they may be paired with clinically available supplements such as EmbryoGlue, a viscous embryo transfer media which minimises embryo mobility [111,112], supports embryo health [113], and which hyaluronan content promotes interactions with CD44 [114], purported to enhance implantation [112,115] and live birth [116][117][118][119] rates by 7%-9%. Like gelatin methacryloyl-rich hydrogels [120][121][122], they may serve to prolong the stability and function of NVs.…”

Rapid generation of functional nanovesicles from human trophectodermal cells for embryo attachment and outgrowth

“…Currently, a clinically available supplement beneficial to both embryo and endometrium is EmbryoGlue, a viscous, hyaluronan-rich media purported to marginally increase implantation [166,167] and live birth [168][169][170][171] rates by 7%-9% by minimising embryo mobility [167,172], supporting embryo health [173], and promoting initial embryo-endometrial attachment via hyaluronate-CD44 interaction [81]. Given its viscosity, EmbryoGlue may function similarly to gelatin methacryloyl-rich hydrogels used to prolong the stability and function of EVs [174][175][176], without immobilising the implanting embryo.…”