Selection of sperm for Assisted Reproductive Treatment by prior hyaluronic acid binding: increasing live birth outcomes and reducing miscarriage rates (Hyaluronic Acid Binding Sperm Selection; HABSelect).

Lead Research Organisation: University of Leeds

Abstract

Male infertility accounts for almost half of all referrals to the infertility clinic for help in having a baby. In many cases, the man’s sperm are present but unable to fertilise his partner’s egg. There are numerous reasons why this might happen but providing the sperm are of good quality, it is possible to inject them directly into the egg and for pregnancies to be achieved as a result. Unfortunately, although this method is very successful at fertilising the egg and achieving a viable pregnancy, it is estimated that less than a quarter of all fertilised eggs, once transferred into the womb, will implant and develop normally. The reasons for this are not obvious but evidence suggests that we are still not very good at choosing the best sperm for injection and that this is clearly an issue that needs attention. Recently, a new method for sperm selection has been developed where preliminary tests suggest it may help improve pregnancy outcomes. The method relies on selecting sperm by their ability to stick to a naturally occurring substance ‘Hyaluronan’ that is normally found close to the surface of the egg. This material can be coated on to a special plate and if the man’s sperm is allowed to swim or flow over the material, the ‘best’ of them will be 'captured' by sticking to the coating and then can easily be picked for injection. Scientists are not sure why this method works or indeed what it is about the sperm which do stick to the material are better than those that don't. The purpose of this research is therefore twofold. Firstly, we hope to introduce the method into UK clinics to show that it can indeed improve success rates for couples where the man is infertile. This will be the largest ever test carried out so far in the world. Secondly, we want tofind more about what makes ‘sticky’ sperm different and what these difference might be. It is possible that simple changes in the way we pick sperm like the one being tested in this study could improve the couples’ chance of achieving a pregnancy successfully with minimal assistance from the fertility clinic. The introduction of the new sperm selection method into clinics may offer a simple and inexpensive way of increasing the chances of achieving a successful pregnancy and a desired positive impact on the couples seeking infertility treatment.

Technical Summary

RESEARCH DESIGN: Patients randomized into two equally sized groups for sperm selection by either Hyaluronan binding (PICSI) or standard polyvinylpyrrolidone (PVP). POPULATION: Patients undergoing IntraCytoplasmic Sperm Injection (ICSI) procedures for male factor infertility at the IVF units in 10 UK centres (Leeds, Sheffield, Manchester, Dundee, Liverpool, London Guy's, London Barts, Birmingham, Aberdeen and Southampton). PLANNED INTERVENTIONS: Men recruited into the study will be assessed for sperm hyaluronan binding using a proprietary assay kit (Hydak HBA slide). A single sperm will be injected directly into the egg following capture by PICSI or PVP. The clinical embryologist will monitor formation of pronuclei and cell division. High-grade embryos will be transferred into recipient partners and the management of the patient will then return to the clinical consultant for follow-up. ASSESSMENT AND FOLLOW-UP: Efficacy determined by comparison of outcomes from PICSI and PVP-selected sperm as follows: Biochemical pregnancy (BP) at 7 days post embryo transfer (pET); Ultrasound detection of fetal sac and/or heartbeat at 6-8 weeks (CP); Live birth rate (LBR) at > or =37 weeks (reported per first cycle and per couple). Safety will be assessed at all times during follow up by recording miscarriage and preterm labour rates throughout. Patient (and fetal) safety will be closely monitored and clear trial stopping criteria will be in place. PROPOSED SAMPLE SIZE: With 90% power (p=0.05), a minimum of 3266 couples (1633 in each arm) is required to detect a 5% improvement in LBR (24% - 29% per cycle), falling to 852 couples (426 in each arm) at 10.0% improvement. We aim to recruit 3730 couples into the study over 24 months. STATISTICAL ANALYSIS: Descriptive statistics will be recorded for Biochemical (BPR), Clinical (CPR), Live Birth (LBR) rates and pregnancy loss. Statistical tests will look for significant differences between the control and interventional trial arms for each of these outcome measures in relation to rates of DNA fragmentation and chromatin compaction of sperm in (i) high v low Hyaluronan Binding Score (BPS); (ii) CPR, LBR and pregnancy loss. Structural equation modelling will be used to probe these relationships for evaluation of mechanism. TIMETABLE: 6 months set up, recruitment is estimated at 1864 PA (40% of total eligible ICSI patients over 10 centres), requiring 24 months. Mechanistic evaluation will take 24 months running concurrently. Follow up for 10 months to include capture of Live Birth Data. Study completed , main outcomes analysed and final report available at 42 months.