Advanced sperm selection techniques for assisted reproduction

Review question

We sought to determine if any advanced sperm selection techniques used for assisted reproduction, except for ultra-high magnification, alter the rates of live birth, clinical pregnancy, miscarriage, or foetal abnormalities.

Background

In vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI) is a commonly used treatment for subfertile couples. It is thought that the selection of high-quality sperm may improve outcomes for these couples. Advanced sperm selection techniques use complex methods to select healthy, mature, and structurally sound sperm for fertilisation. Despite the use of these techniques in many centres worldwide, their effectiveness is unclear.

Study characteristics

We included eight randomised controlled trials (a type of study in which participants are assigned to one of two or more treatment groups using a random method) with a total of 4147 women. Four studies evaluated sperm selection by their ability to bind to hyaluronic acid during the ICSI process (HA-ICSI) against ICSI. One study compared HA-ICSI versus SpermSlow. One study compared HA-ICSI versus magnetic-activated cell sorting (MACS) versus ICSI. Three studies compared MACS versus ICSI. One study compared sperm selection by surface charge Zeta potential versus ICSI. Six of the included studies reported rates of live birth; seven reported clinical pregnancy; six reported miscarriage per clinical pregnancy and per woman randomly assigned; and none reported on foetal abnormalities.

Key results

The current evidence suggests that advanced sperm selection strategies in assisted reproductive technologist (ART) may not result in an increase in the likelihood of live birth. The only sperm selection technique that potentially increases live birth and clinical pregnancy rates is Zeta sperm selection, yet these results were of very low quality and derived from a single study, therefore we are uncertain of the effect. There is low-quality evidence that HA-ICSI decreases miscarriage rates when compared with ICSI. We are uncertain whether the other sperm selection techniques alter clinical pregnancy or miscarriage rates. No studies reported on foetal abnormalities, and further studies of suitable quality are required before any of these advanced sperm selection techniques can be recommended for use in clinical practice.

Evidence quality

The evidence gathered was of very low to low quality. The main limitations were imprecision associated with low numbers of participants or events and high risk of performance bias. Data on important clinical outcomes such as foetal abnormalities were absent.

Authors' conclusions: 

The evidence suggests that sperm selected by hyaluronic acid binding may have little or no effect on live birth or clinical pregnancy but may reduce miscarriage. We are uncertain of the effect of Zeta sperm selection on live birth, clinical pregnancy, and miscarriage due principally to the very low quality of the evidence for this intervention. We are uncertain of the effect of the other selection techniques on live birth, miscarriage, or pregnancy.

Further high-quality studies, including the awaited data from the identified ongoing studies, are required to evaluate whether any of these advanced sperm selection techniques can be recommended for use in routine practice.

Read the full abstract...
Background: 

Assisted reproductive technologies (ART) including in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), combine gametes to enhance the probability of fertilisation and pregnancy. Advanced sperm selection techniques are increasingly employed in ART, most commonly in cycles utilising ICSI. Advanced sperm selection techniques are proposed to improve the chance that structurally intact and mature sperm with high DNA integrity are selected for fertilisation. Strategies include selection according to surface charge; sperm apoptosis; sperm birefringence; ability to bind to hyaluronic acid; and sperm morphology under ultra-high magnification. These techniques are intended to improve ART outcomes.

Objectives: 

To evaluate the effectiveness and safety of advanced sperm selection techniques on ART outcomes.

Search strategy: 

We conducted a systematic search of electronic databases (Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online, MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL); trials registers (ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform); conference abstracts (Web of Knowledge); and grey literature (OpenGrey) for relevant randomised controlled trials (RCTs). We handsearched the reference lists of included studies and similar reviews. The search was conducted in June 2018.

Selection criteria: 

We included RCTs comparing advanced sperm selection techniques versus standard IVF, ICSI, or another technique. We excluded studies of intracytoplasmic morphologically selected sperm injection (IMSI), as they are subject to a separate Cochrane Review. Primary outcomes measured were live birth and miscarriage per woman randomly assigned. Secondary outcome measures included clinical pregnancy per woman randomly assigned. Secondary adverse events measured included miscarriage per clinical pregnancy and foetal abnormality.

Data collection and analysis: 

Two review authors independently assessed study eligibility and risk of bias and extracted data. Any disagreements were resolved by consultation with a third review author. We consulted study investigators to resolve queries. Risk ratios (RRs) were calculated with 95% confidence intervals (CIs). We combined studies using a fixed-effect model. We evaluated the quality of the evidence using GRADE methods.

Main results: 

We included eight RCTs (4147 women). The quality of evidence ranged from very low to low. The main limitations were imprecision, performance bias, and attrition bias.

Hyaluronic acid selected sperm-intracytoplasmic sperm injection (HA-ICSI) compared to ICSI

Two RCTs compared the effects of HA-ICSI versus ICSI on live birth. The quality of the evidence was low. There may be little or no difference between groups: 25% chance of live birth with ICSI versus 24.5% to 31% with HA-ICSI (RR 1.09, 95% CI 0.97 to 1.23, 2903 women, I2 = 0%, low-quality evidence). Three RCTs reported on miscarriage. HA-ICSI may decrease miscarriage per woman randomly assigned: 7% chance of miscarriage with ICSI versus 3% to 6% chance with HA-ICSI (RR 0.61, 95% CI 0.45 to 0.83, 3005 women, I2 = 0%, low-quality evidence) and per clinical pregnancy: 20% chance of miscarriage with ICSI compared to 9% to 16% chance with HA-ICSI (RR 0.62, 95% CI 0.46 to 0.82, 1065 women, I2 = 0%, low-quality evidence). Four RCTs reported on clinical pregnancy. There may be little or no difference between groups: 37% chance of pregnancy with ICSI versus 34% to 40% chance with HA-ICSI (RR 1.00, 95% CI 0.92 to 1.09, 3492 women, I2 = 0%, low-quality evidence).

HA-ICSI compared to SpermSlow

One RCT compared HA-ICSI to SpermSlow. The quality of the evidence was very low. We are uncertain whether HA-ICSI improves live birth compared to SpermSlow (RR 1.13, 95% CI 0.64 to 2.01, 100 women) or clinical pregnancy (RR 1.05, 95% CI 0.66 to 1.68, 100 women). We are uncertain whether HA-ICSI reduces miscarriage per woman (RR 0.80, 95% CI 0.23 to 2.81, 100 women) or per clinical pregnancy (RR 0.76, 95% CI 0.24 to 2.44, 41 women).

Magnetic-activated cell sorting (MACS) compared to ICSI

One RCT compared MACS to ICSI for live birth; three reported clinical pregnancy; and two reported miscarriage. The quality of the evidence was very low. We are uncertain whether MACS improves live birth (RR 1.95, 95% CI 0.89 to 4.29, 62 women) or clinical pregnancy (RR 1.05, 95% CI 0.84 to 1.31, 413 women, I2 = 81%). We are also uncertain if MACS reduces miscarriage per woman (RR 0.95, 95% CI 0.16 to 5.63, 150 women, I2 = 0%) or per clinical pregnancy (RR 0.51, 95%CI 0.09 to 2.82, 53 women, I2=0)

Zeta sperm selection compared to ICSI

One RCT evaluated Zeta sperm selection. The quality of the evidence was very low. We are uncertain of the effect of Zeta sperm selection on live birth (RR 2.48, 95% CI 1.34 to 4.56, 203 women) or clinical pregnancy (RR 1.82, 95% CI 1.20 to 2.75, 203 women). We are also uncertain if Zeta sperm selection reduces miscarriage per woman (RR 0.73, 95% CI 0.16 to 3.37, 203 women) or per clinical pregnancy (RR 0.41, 95% CI 0.10 to 1.68, 1 RCT, 62 women).

MACS compared to HA-ICSI

One RCT compared MACS to HA-ICSI. This study did not report on live birth. The quality of the evidence was very low. We are uncertain of the effect on miscarriage per woman (RR 1.52, 95% CI 0.10 to 23.35, 78 women) or per clinical pregnancy (RR 1.06, 95% CI 0.07 to 15.64, 37 women). We are also uncertain of the effect on clinical pregnancy (RR 1.44, 95% CI 0.91 to 2.27, 78 women).

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