Clinical efficacy of hyaluronate-containing embryo transfer medium in IVF/ICSI treatment cycles: a cohort study

Abstract

STUDY QUESTION Does the duration of embryo exposure to hyaluronic acid (HA) enriched medium improve the rate of live birth events (LBEs)? SUMMARY ANSWER The use of embryo transfer (ET) medium rich in HA improves LBE (a singleton or twin live birth) regardless of the duration of exposure evaluated in this study, but does not alter gestation or birthweight (BW). WHAT IS KNOWN ALREADY HA-enriched medium is routinely used for ET in ART to facilitate implantation, despite inconclusive evidence on safety and efficacy. STUDY DESIGN, SIZE, DURATION A cohort study was performed evaluating clinical treatment outcomes before and after HA-enriched ET medium was introduced into routine clinical practice. In total, 3391 fresh ET procedures were performed using low HA and HA-rich medium in women undergoing publicly funded IVF/ICSI treatment cycles between May 2011 and April 2015 were included in this cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 1018 ET performed using low HA medium were compared with 1198, and 1175 ET following exposure to HA-rich medium for 2–4 h (long HA exposure) or for 10–30 min (short HA exposure), respectively. A multiple logistic regression analysis was used to compare clinical outcomes including BW, gestational age and sex ratios between groups, whilst adjusting for patient age, previous attempt, incubator type and the number of embryos transferred. MAIN RESULTS AND THE ROLE OF CHANCE The use of HA-rich medium for ET was positively and significantly associated with improved clinical pregnancy rate and LBE, for both exposure durations: long HA (odds ratio (OR) = 1.21, 95% CI: 0.99–1.48), short HA (OR = 1.32, 95% CI: 1.02–1.72) and pooled OR = 1.26, 95% CI: 1.03–1.54, relative to the use of low HA medium. A comparative analysis of the risks of early pregnancy loss following long HA exposure (OR = 0.76, 95% CI: 0.54–1.06), short HA exposure (OR = 0.84, 95% CI: 0.54–1.30) and late miscarriage (OR = 0.88, 95% CI: 0.51–1.53) (OR = 1.41, 95% CI 0.72–2.77), were lower and not statistically significant. Similarly, ordinary regression analysis of the differences in BW at both HA exposures; pooled OR = −0.9 (−117.1 to 115.3), and adjusted BW between both HA cohorts; pooled OR = −13.8 (−106.1 to 78.6) did not show any differences. However, a difference in gestational age (pooled OR −0.3 (−3.4 to 2.9)) and sex ratio (pooled OR 1.43 (0.95–2.15)) were observed but these were not statistically significant relative to low HA medium. LIMITATIONS, REASONS FOR CAUTION The strength of a randomized treatment allocation was not available in this evaluation study, therefore effects of unmeasured or unknown confounding variables cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS The result of this large cohort study strengthens the case for using HA-rich medium routinely at transfer, while adding the important clinical information that duration of exposure may not be critical. The composition and effects of commercial IVF culture media on success rate and safety remains a major controversy despite increasing calls for transparency and evidence-based practice in ART. Nonetheless, the lack of differences in BW and gestational age observed in this study were reassuring. However, an appraisal of clinical outcomes and appropriate research investigations are required for the continuous evaluation of efficacy and safety of HA. STUDY FUNDING/COMPETING INTEREST(S) T.A. is funded by a Clinical Doctoral Research Fellowship (CDRF) grant (reference: ICA-CDRF-2015-01-068) from the National Institute for Health Research (NIHR). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The authors declare no conflict of interest.

Effect of Hyaluronic Acid-Enriched Media in Embryo Implantation

“…The success of implantation depends on embryo competence during development and the receptiveness of uterus in a repetitive, cyclical manner during the consecutive and synchronized interactions between the embryo and endometrium [ 1 ]. Embryo implantation is successful at the blastocyst stage when the weak apposition occurs for the blastocyst, which is then attached to the surface of the endometrial epithelium, followed by trophoblast invasion through the epithelium into the endometrial stroma [ 2 , 3 ].…”

“…An inflated concentration of hyaluronan improves in-vitro growth and the number of cells in bovine embryos by increasing the viscosity of the culture medium. They also discovered that embryos cultivated with hyaluronan supplementation had greater survival rates following freezing [ 1 - 3 , 10 , 11 ]. Onestep with increased hyaluronic acid concentration can be used successfully as a macromolecule in a medium used for embryo transfer which gives outcome in high pregnancy and implantation rates in a recent study [ 12 ].…”

“…Embryos should be in the medium for at least 10 minutes before being transferred, according to the manufacturer [2]. The effect of varied exposure times was explored in the study summarized in some studies [1][2][3].…”

“…For the success of in-vitro fertilization (IVF), embryo implantation is an important factor. A clinical pregnancy rate is usually 40-50% for embryo implantation in IVF [ 1 ]. There are many possible reasons for the failure of embryo transfer, such as endometrium thickness, its receptivity, defects in the embryo, and hereditary factor [ 1 ].…”

“…A clinical pregnancy rate is usually 40-50% for embryo implantation in IVF [ 1 ]. There are many possible reasons for the failure of embryo transfer, such as endometrium thickness, its receptivity, defects in the embryo, and hereditary factor [ 1 ]. The composition of the culture medium used for embryo transfer is a major factor in implantation.…”