Digging deeper: sperm selection with hyaluronic acid now linked to sperm DNA quality and reduced risk of miscarriage

Published 09 May 2022

Analysis of data from the 2019 HABSelect trial now finds that selection of sperm cells for ICSI based on their binding to hyaluronic acid was indeed associated with a real reduction in miscarriage rate, especially in women over 35. HA-based selection of sperm for ICSI could now be considered a part of the treatment plan for older female patients, say authors.

A follow-up analysis of data from the 2019 HABSelect trial, which compared live birth outcomes from ICSI with sperm cells selected for binding to hyaluronic acid (dubbed physiological ICSI, or PICSI) and routinely selected sperm cells, has found that a reduction in miscarriage risk from PICSI - originally reported as a possible chance finding – was a consistent and real feature of hyaluronic acid selection.(1,2) In response to several modelling studies applied to the data, the authors now report that ‘our evidence points to the effect being bona fide and that a male factor, most likely a genotoxic sperm DNA defect, may be responsible for up to one-third of miscarriages’.

This beneficial effect of HA sperm selection appeared most pronounced in ‘older’ women, whose live birth rates were found comparable with those of younger women, ‘most likely a result of better avoidance of sperm with damaged DNA’. Thus, the investigators now report ‘improved live birth outcomes among older couples’ and propose that poor sperm quality, as reflected in lower levels of HA-binding score, ‘probably contributed to the depression of all gestational outcomes including live births in the HABSelect trial’.

That original study had run from 2014 to 2017 and included 2752 couples from whom ‘surplus’ sperm samples used in the control (ICSI) and intervention (PICSI) arms of the trial were frozen for later assessment of DNA quality (DNAq) to detect any pathological sperm-mediated factor mitigated by prior HA-binding/selection. Thus, this ‘mechanistic’ analysis of sperm samples, which had been initially assessed when fresh for concentration, motility and HA-binding, included measurements of sperm DNA integrity using a variety of assays.

The analysis first showed that female age was a clear indicator for clinical pregnancy and live birth, but the ‘mitigating’ effect of PICSI appeared to reduce the impact of female ageing. Thus, while the original HABSelect trial had found no overall benefit on LBRs from PICSI, here there was a benefit in women over the age of 35. Interestingly, when the data were applied to several models for predicting clinical outcome, all of them retained either some aspect of sperm DNAq or male age.

In their discussion the authors describe hyaluronic acid as a ‘constituent’ of substrates for adhesion by many cell types, including sperm. It’s this binding function which lies behind the (albeit controversial) development of hyaluronan-enriched embryo transfer media (‘glue’) as an aid to implantation in IVF. The authors report that ‘a similar principle is applied to the immobilization and capture of sperm for ICSI, including solid-state PICSI’, and adding: ‘HA-based sperm selection processes were justified on the grounds that HA-binding sperm are demonstrably more mature, have higher motility and better indices of good DNAq.’ Now, based on their results the authors propose that the reduction in miscarriage rate in the trial’s PICSI arm was linked to the more successful avoidance of sperm cells for injection with a defect in their DNA, especially in older women.

Of course, there were miscarriages in the PICSI arm of the trial, but the authors recognise other factors – notably aneuploidy – ‘not restricted to sperm’. However, based on this subsequent data analysis, they propose that a sperm DNA defect may be responsible ‘for up to one-third of miscarriages’. ‘No other detail of the data offers an alternative explanation.’ And thus, as an ever increasing patient age seems likely to ‘dominate’ ICSI in the future, they propose that HA-based selection of sperm for ICSI ‘could be considered as part of their treatment plan’.

These upbeat conclusions, however, are less emphatic than those of a Cochrane review, which in 2019 had only two RCTs to compare the effects of PICSI vs ICSI.(3) In this analysis, LBRs were exactly comparable, although the authors did suggest that HA binding ‘may reduce miscarriage’.

1. Miller D, Pavitt S, Sharma V, et al. Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial. Lancet 2019; 393: 416-422.
2. West R, Coomarasamy A, Frew L, et al. Sperm selection with hyaluronic acid improved live birth outcomes among older couples and was connected to sperm DNA quality, potentially affecting all treatment outcomes. Hum Reprod 2022;
3. Lepine S, McDowell S, Searle LM, et al. Advanced sperm selection techniques for assisted reproduction. Cochrane Database of Systematic Reviews 2019, Issue 7. CD010461. doi:10.1002/14651858.CD010461.pub3.

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