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HABSelect Clinical trial

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Background

Oocyte quality is now recognised as an important determinant of successful pregnancy outcome as donor eggs from younger women seem able to compensate for lower fertility in older women. It is probable, however, that future advances in ART are likely to more speedily benefit from procedures that target selection of higher quality sperm regardless of parental age. While offering universal benefits to the fertility field overall, this approach would offer particular promise for older couples (notably where the female is aged >37 years) and whose oocytes are less efficient at repairing DNA damage in their partners’ sperm. These couples are hitherto challenging to treat with current fertility technologies and have the poorest live birth outcomes but they are also the fastest growing group requesting treatment. The relationship of sperm selection, integrity of DNA and pregnancy outcome is precisely what the HABSelect study is designed to evaluate. A successful conclusion of the study will help provide a more consistent and efficient procedure for ICSI sperm selection which complies with and extends on NICE’s recently called review on fertility guidance (http://www.nice.org.uk/guidance/cg156).


In 2008, almost 40,000 couples in the UK alone were treated with assisted reproduction technologies (ART), comprising 50,687 IVF cycles and this number is set to rise in the coming years. Currently, live birth rates (LBRs) for ART are at an average of 24% per treatment cycle although live birth rates (per couple) are higher at 32% because couples normally receive an average of ~1.3 treatment cycles. While it is estimated that more than two thirds of naturally conceived pregnancies end in failure, we may not have reached the limit for improvements in LBR following ART. For all ART procedures, including intracytoplasmic sperm injection (ICSI), the embryologist seeks to use the best sperm available. Selection is aided by semen ‘washing’ techniques using density gradient centrifugation (DGC) that can enrich for sperm with high motility and good morphology (WHO Manual, 2010). In contrast with standard in vitro fertilisation (IVF) where the egg is the final arbiter for selection, ICSI is dependent on the relatively subjective judgement of the andrologist or embryologist to choose the ‘right’ single sperm for each egg. Various studies have shown clear inverse relationships between the burden of DNA damaged sperm in the ejaculate and clinical pregnancy (CPR) or live birth (LBR) rates in standard IVF but this relationship is less obvious with ICSI cycles. We recently reported reductions in levels of sperm DNA fragmentation following density gradient washing of semen. However, while the values from washed semen were reduced, they were still over twice as high in the non-pregnant (~50%) versus pregnant (~23%) cohorts. These and other data suggest that sperm with poor DNA quality persist in washed sperm preparations from fertile and infertile men and unlike IVF, where there is a natural selection by the egg, ICSI could be particularly vulnerable to a poor choice of sperm. By eliminating abnormal sperm from the sample preparation for ICSI, success rates should rise accordingly. Paternal and maternal genomic integrity must be equally important determinants of successful pregnancy outcome, so to achieve a high LBR in ICSI, the embryologist must have the tools for selecting sperm with either undamaged DNA or with levels of DNA damage that are not beyond the capacity of the egg’s natural ability to repair. Alternatively, there may be forms of genotoxic DNA damage in the sperm nucleus that are not detected by existing assays, do not prevent fertilisation by either standard IVF or ICSI based procedures but can compromise embryo development and result in higher rates of miscarriage.

Sperm that bind to hyaluronic acid seem to be of a higher quality in relation to cytoplasmic maturity and nuclear integrity (low levels of DNA fragmentation) and so selecting sperm for ICSI using prior hyaluronic acid binding may be an effective way of treating male infertility. The HABSelect trial aims to test this hypothesis in a multi-centre clinical trial that will also examine sperm DNA fragmentation in relation to the trial outcomes (pregnancy and live birth). The trial is in progress.

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