From the literature

Nature Medicine volume 31, pages1939–1948 (2025)

IVF versus ICSI in patients without severe male factor infertility: a randomized clinical trial

Berntsen S, Zedeler A, Nøhr B, Petersen MR, Grøndahl ML, Andersen LF, Løssl K, Løkkegaard E, Englund AL, Gabrielsen AV, Prætorius L, Behrendt-Møller I, Thuesen LL, Vomstein K, Lauritsen MP, Trajcevski AI, Skipper DF, Westergaard D, Pinborg A, Nielsen HS, Freiesleben NLC.

Background

Intracytoplasmic sperm injection (ICSI) has become widely used in assisted reproductive technologies (ART), even in the absence of male factor infertility. While ICSI was initially developed for severe male infertility, its routine use has expanded, raising questions about its comparative efficacy, safety, and cost-effectiveness in normozoospermic populations.

Objective

To evaluate whether ICSI offers any advantage over conventional in vitro fertilization (IVF) in terms of live birth rates among couples without severe male factor infertility undergoing their first ART cycle.

Methods

• Design: Multicenter, prospective, randomized controlled trial (RCT)
• Population: 1,064 couples with no severe male factor infertility undergoing their first ART cycle
• Randomization: 1:1 allocation to either IVF or ICSI
• Primary Outcome: Live birth after the first embryo transfer (fresh or frozen)
• Secondary Outcomes: Fertilization rate, implantation rate, pregnancy loss, cumulative live birth rate, embryo quality, and perinatal outcomes

Key Inclusion Criteria

• Women aged <40 years
• Normal or mild male factor infertility (total motile sperm count >2 million)
• No previous IVF or ICSI treatment

Key Findings

1. Primary Outcome – Live Birth After First Transfer

• IVF Group: 30.9% live birth rate
• ICSI Group: 27.1% live birth rate
• Risk Ratio (RR): 1.14 (95% CI: 0.94–1.38)
• Conclusion: No statistically significant difference in live birth rate after the first transfer between IVF and ICSI.

2. Cumulative Live Birth Rate

• IVF: 43.2%
• ICSI: 39.8%
• Not significantly different between groups.

3. Fertilization Rates

• Higher in IVF group: Mean fertilization rate 66.7% (IVF) vs. 64.0% (ICSI)
• Statistically significant: p < 0.01

4. Embryo Quality

• No difference in the proportion of good-quality blastocysts

5. Perinatal Outcomes

• No difference in gestational age, birth weight, or incidence of adverse events such as preterm birth or neonatal intensive care unit (NICU) admissions.

Subgroup Analyses

• Male Factor: No differential benefit of ICSI over IVF in couples with mild male infertility.
• Oocyte Yield: Results are consistent across strata of retrieved oocyte numbers.
• Center-Specific Effects: Findings consistent across participating fertility clinics.

Conclusions

• ICSI does not improve live birth outcomes compared to IVF in couples without severe male factor infertility.
• Routine use of ICSI in these populations may represent overuse without clinical benefit, potentially increasing costs and procedural complexity without improving outcomes.

Clinical Implications

• Supports the return to evidence-based selection of fertilization technique.
• Suggests IVF should be the default first-line method for non-severe male infertility cases.
• Aligns with growing concerns about the over-medicalization of ART in low-risk populations.

Strengths of the Study

• Large sample size and randomized design
• Real-world clinical settings (multicenter)
• Intention-to-treat analysis
• Clinically relevant outcomes (live birth, embryo quality, safety)

Limitations

• Single-country study (Denmark); generalizability may vary
• Excluded older women and severe male factor cases
• Did not assess long-term child health outcomes

Key Takeaway

ICSI should not be routinely used in ART cycles where there is no severe male factor infertility, as it does not improve the likelihood of live birth and may unnecessarily increase healthcare resource utilization.