HA-ICSI may slightly reduce miscarriage risk in IVF, but live birth and pregnancy rates show little difference

Rationale Assisted reproductive technologies (ART), including in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), combine an egg and sperm outside the body 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 hypothesised to improve the likelihood that structurally intact and mature sperm with high DNA integrity are selected. Strategies include selection according to surface charge; sperm apoptosis; sperm birefringence; magnetic‐activated cell sorting; ability to bind to hyaluronic acid; microfluidic selection; and sperm morphology under ultra‐high magnification. This is an update of a Cochrane review first published in 2014 and updated in 2019. Objectives To evaluate the benefits and harms of advanced sperm selection techniques on assisted reproductive technologies (ART) outcomes. Search methods We conducted a systematic search of electronic databases (CENTRAL via the Cochrane Register of Studies Online, MEDLINE, and Embase) for relevant randomised controlled trials (RCTs). We handsearched the reference lists of included studies and similar reviews. The search was conducted on 24 February 2025. Eligibility criteria We included randomised controlled trials (RCTs) comparing advanced sperm selection techniques versus standard IVF or ICSI, or versus another advanced sperm selection technique. We excluded studies on intracytoplasmic morphologically selected sperm injection (IMSI), as they are the subject of a separate Cochrane review. Due to increasing concerns about untrustworthy data in health research, we carried out the Trustworthiness in Randomised Controlled Trials (TRACT) assessment for all eligible studies. Outcomes Our primary outcomes were live birth and miscarriage per woman randomly assigned. Secondary outcomes included clinical pregnancy per woman randomly assigned, miscarriage per clinical pregnancy, and foetal abnormalities. Risk of bias Two review authors independently assessed the risk of bias in included studies using the Cochrane RoB 2 tool. Any disagreements were resolved by a third review author. Synthesis methods Two review authors independently assessed study eligibility and extracted data. Any disagreements were resolved by a third review author. We consulted study investigators to answer queries. Risk ratios (RRs) were calculated with 95% confidence intervals (CIs). We combined studies' data using the fixed‐effect model. We evaluated the certainty of the evidence using GRADE methods. Included studies We found one new study to include in this updated review. We also removed four previously included studies as we had concerns about the trustworthiness of their data. Therefore, in this update, we included five RCTs (3752 women). Our assessment of the certainty of evidence ranged from very low to moderate. The main limitations in the evidence were performance bias and attrition bias. The outcome of foetal abnormalities was not reported in the included studies. Synthesis of results Hyaluronic acid selected sperm‐intracytoplasmic sperm injection (HA‐ICSI) versus ICSI One RCT evaluated the effects of HA‐ICSI versus ICSI on live birth. HA‐ICSI may result in no difference or a slight increase in live birth per woman randomly assigned: there was a 25% chance of live birth with ICSI versus 24% to 31% with HA‐ICSI (RR 1.09, 95% CI 0.97 to 1.24; I² not applicable; 1 study, 2772 participants; low‐certainty evidence). Two RCTs reported on miscarriage. HA‐ICSI probably slightly decreases miscarriage per woman randomly assigned: 7% chance of miscarriage with ICSI versus 3% to 6% chance with HA‐ICSI (RR 0.59, 95% CI 0.44 to 0.80; I² = 0%; 2 studies, 3327 participants; moderate‐certainty evidence) and per clinical pregnancy: 18% chance of miscarriage with ICSI compared to 8% to 15% chance with HA‐ICSI (RR 0.60, 95% CI 0.45 to 0.80; I² = 0%; 2 studies, 1207 participants; moderate‐certainty evidence). Two RCTs reported on clinical pregnancy. There may be little or no difference between groups: 37% chance of pregnancy with ICSI versus 33% to 40% chance with HA‐ICSI (RR 0.98, 95% CI 0.90 to 1.07; I² = 0%; 2 studies, 3327 participants; low‐certainty evidence). HA‐ICSI versus SpermSlow One RCT compared two advanced sperm selection techniques: HA‐ICSI versus SpermSlow. The certainty of the evidence is very low. We are uncertain about the relative effects of these techniques on live birth (RR 1.13, 95% CI 0.64 to 2.01; 1 study, 100 participants), miscarriage (per woman (RR 0.80, 95% CI 0.23 to 2.81; 1 study, 100 participants) and per clinical pregnancy (RR 0.76, 95% CI 0.24 to 2.44; 1 study, 41 participants)), and clinical pregnancy (RR 1.05, 95% CI 0.66 to 1.68; 1 study, 100 participants). Zeta potential sperm selection versus ICSI One RCT evaluated zeta potential sperm selection versus ICSI. The certainty of the evidence is very low. We are uncertain of the effect of zeta potential sperm selection on live birth (RR 2.48, 95% CI 1.34 to 4.56; 1 study, 203 participants), miscarriage (per woman (RR 0.74, 95% CI 0.17 to 3.23; 1 study, 203 participants) and per clinical pregnancy (RR 0.41, 95% CI 0.10 to 1.68; 1 study, 62 participants)), and clinical pregnancy (RR 1.80, 95% CI 1.16 to 2.80; 1 study, 203 participants). Microfluidic Sperm Sorting (MFSS) versus ICSI One RCT evaluated MFSS versus ICSI. The certainty of the evidence is very low. We are uncertain of the effect of MFSS on live birth (RR 1.10, 95% CI 0.68 to 1.76; 1 study, 122 participants), miscarriage (per woman (RR 1.20, 95% CI 0.39 to 3.72; 1 study, 122 participants) and per clinical pregnancy (RR 1.08, 95% CI 0.37 to 3.11; 1 study, 55 participants)), and clinical pregnancy (RR 1.12, 95% CI 0.75 to 1.65; 1 study, 122 participants). Authors' conclusions The evidence suggests that use of HA‐ICSI may make no difference to or may slightly increase live‐birth rate and probably slightly reduces miscarriage rate. We do not know the effect of the other advanced sperm selection techniques on live birth or miscarriage, or clinical pregnancy, principally because of the very low certainty of the evidence. Further high‐quality studies, including awaited data from 19 ongoing studies, are required to evaluate whether any of these advanced sperm selection techniques can be recommended for use in routine practice. Funding This Cochrane review had no dedicated funding. Registration Original review (2014) DOI: 10.1002/14651858.CD010461.pub2 PICOs PICOs Population Intervention Comparison Outcome