Does Intracytoplasmic Sperm Injection Outperform Conventional In Vitro Fertilization in Couples Without Severe Male Factor Infertility? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

ICSI showed no live birth edge over standard IVF in 1,438 couples without severe male infertility

Journal: Human Reproduction | Published: 2026-07-01 | Type: Systematic Review, Meta-Analysis | PMID: 42172285 Authors: Kayimu Kailibinuer, Fu Yu, Yuan Yi, Tian Tian, Liu Fang, Gao Jiayi (Peking University Third Hospital); Berntsen Sine, Vomstein Kilian (Copenhagen University Hospital Fertility Clinic); Vuong Lan N. (University of Medicine and Pharmacy, Ho Chi Minh City); Ho Tuong M. (My Duc Hospital, Ho Chi Minh City) Funding/COI: Funded by Chinese national science grants and Peking University Third Hospital, with no funder role in design or analysis. Several co-authors disclose speaker, consulting, or grant income from Merck, Merck Sharp & Dohme, Ferring, Gedeon Richter, IBSA, Astra Zeneca, Cook Medical, Novo Nordisk, Organon, and others.

Summary

This meta-analysis pooled six RCTs to ask whether ICSI, originally developed for severe male infertility, actually helps couples who don't have that problem. It doesn't. Live birth and cumulative live birth rates were statistically indistinguishable between ICSI and conventional IVF, despite ICSI's routine use across a much broader patient population than it was designed for.

Claims

• Live birth rate: 32.8% (ICSI) vs 34.5% (cIVF), pooled RR 0.96 (95% CI 0.85-1.09), 4 studies, N=1,438, GRADE high-quality evidence
• Cumulative live birth rate: 43.2% vs 47.4%, pooled RR 0.92 (95% CI 0.84-1.01), 3 studies, N=1,911, GRADE high-quality evidence
• Preterm birth: 4.6% vs 6.0%, pooled RR 0.77 (95% CI 0.59-1.00), P=0.0447, 3 studies, N=222
• No significant differences detected on any other fertility or pregnancy outcome measured

Study Quality

The review searched ten databases, including Chinese-language sources (Wan Fang, CNKI) frequently omitted from Western meta-analyses, with no language restriction and a search window through May 2025. Only RCTs comparing outcomes per couple were included, screening out studies that analyzed per-oocyte data (a common unit-of-analysis error in this literature) or lacked randomization. Risk of bias was assessed with Cochrane RoB2, and study trustworthiness with the TRACT checklist, a response to a wave of fabricated or unreliable RCTs surfacing in reproductive medicine. GRADE rated the live birth and cumulative live birth evidence as high quality. The protocol was prospectively registered (CRD42023479967).

That said, the two primary outcomes rest on only four and three trials respectively, with moderate heterogeneity (I2 37% and 41%). The preterm birth finding is the shakiest number in the paper: three trials, 222 total patients, a confidence interval that tops out at exactly 1.00, and a p-value (0.0447) that would flip to non-significant with trivial changes in the data.

Red Flags

• The headline "reduced preterm birth" result is built on 222 patients and a p-value barely under 0.05, with a CI upper bound sitting right at the null
• Cumulative live birth RR (0.92) has a CI (0.84-1.01) that only just crosses 1, making the "no difference" conclusion less airtight than the high-quality GRADE label implies
• Multiple co-authors report ongoing financial relationships with major fertility drug manufacturers (Merck, Ferring, Gedeon Richter, MSD), though these are disclosed and not tied to ICSI equipment or a specific product being tested
• Authors themselves flag limited subgroup-specific data and heterogeneity in how outcomes were measured across trials

Strengths

• Ten-database search with no language restriction, capturing Chinese-language RCTs often missed by English-only reviews
• Restricted to true per-couple randomized comparisons, avoiding a known statistical pitfall (per-oocyte analysis) that inflates apparent effect sizes in this field
• Applied a dedicated trustworthiness screen (TRACT) on top of standard risk-of-bias tools, relevant given recent scrutiny of fabricated trials in reproductive medicine
• Prospectively registered protocol and GRADE-rated evidence quality

Verdict

This is a methodologically careful meta-analysis tackling a real practice problem: ICSI is used far more often than the evidence for non-severe-male-factor cases justifies, and this pooled analysis of six RCTs finds no live birth advantage to show for it. The primary findings are well-supported by a solid search strategy and trial-quality screening, though the secondary preterm birth result is thin enough (222 patients, p=0.045) that it shouldn't be read as more than a hypothesis worth testing further.