ICSI vs IVF: A Trial of 824 Women Found No Benefit Without Severe Male Factor
Last updated: January 2026
Journal Club #3. We read the latest fertility research so you don’t have to.
The Paper
“IVF versus ICSI in patients without severe male factor infertility: a randomized clinical trial”
Berntsen S, Zedeler A, Nohr B, et al. Nature Medicine, 2025;31(6):1939–1948.
Read the full paper on PubMed →
DOI: 10.1038/s41591-025-03621-x | Trial registration: NCT04128904
Why This Matters
ICSI costs $1,000 to $2,500 on top of a standard IVF cycle. It was developed for severe male factor infertility: cases where sperm can’t penetrate the egg on their own. That indication is clear.
The problem: ICSI is now used in over 70% of IVF cycles worldwide. Only about 30% of those cycles involve male factor infertility. Clinics routinely add ICSI as a default, often without explaining why. Patients rarely question it because it sounds like “the better version.”
This trial asked the obvious question. If your partner’s sperm is normal or only mildly impaired, does ICSI actually improve your chance of having a baby?
824 women. Six Danish public fertility clinics. Randomized. The answer: no.
Study Design
A multicenter, open-label randomized controlled trial across 6 public fertility clinics in Denmark. 824 women in their first IVF cycle were randomized: 414 to ICSI, 408 to conventional IVF. All had normal or non-severely decreased sperm quality. Enrollment ran from November 2019 to December 2022 with follow-up through December 2023.
Every transfer was a single embryo transfer. Roughly 96% were at blastocyst stage. Stratified by site and maternal age. Analyzed by intention to treat.
Key Findings
Live birth rates: ICSI did not improve outcomes
| Outcome | ICSI | Conventional IVF | Relative Risk (95% CI) |
|---|---|---|---|
| Cumulative live birth (ITT) | 43.2% (179/414) | 47.3% (193/408) | 0.91 (0.79–1.06) |
| Cumulative live birth (per-protocol) | 43.0% | 49.2% | 0.87 (0.75–1.02) |
| Live birth after first transfer | 26.6% | 31.6% | N/A |
The point estimates all favor conventional IVF. Not statistically significant, but the direction is consistent: ICSI performed the same or worse across every measure.
Fertilization: conventional IVF was significantly better
| ICSI | Conventional IVF | P value | |
|---|---|---|---|
| Fertilization rate | 53.5% (1,940/3,628) | 58.1% (1,983/3,412) | < 0.001 |
| Total fertilization failure | 4.8% (20/414) | 3.7% (15/408) | N/A |
Conventional IVF fertilized a higher proportion of eggs. This matters because more fertilized eggs means more embryos to select from, more to freeze, and more chances per retrieval cycle.
More embryos in the IVF group
| ICSI | Conventional IVF | |
|---|---|---|
| Day 5 high-quality blastocysts | 779 total (median 1, IQR 0–3) | 886 total (median 2, IQR 0–3) |
| Total cryopreserved embryos | 742 | 862 |
| Remaining at 12 months | 383 (32.9%) | 484 (37.0%) |
The conventional IVF group had 120 more cryopreserved embryos. Those are future transfer attempts without another egg retrieval. In a field where every frozen embryo represents thousands of dollars in avoided stimulation costs, that difference adds up.
The subgroup finding that matters most
Women aged 32 or younger showed a negative effect from ICSI. The number needed to harm was 9: for every 9 women under 32 who received ICSI instead of conventional IVF, one fewer had a baby.
Women with a normal ovarian response (10 to 15 oocytes retrieved) also did significantly worse with ICSI.
No significant differences appeared for sperm morphology, AMH levels, or treatment indication.
Safety was equivalent
No differences in gestational diabetes, preeclampsia, preterm birth, congenital malformations, or birth weight between the two groups.
What This Means for Patients
You can ask your clinic why ICSI is recommended. If your partner’s sperm analysis is normal or only mildly abnormal, this trial says conventional IVF produces equivalent or better results. “We always do ICSI” is not a clinical indication. It’s a billing practice. Some clinics add ICSI the way restaurants add a service charge: quietly and by default, hoping you won’t ask what it’s for.
The cost is real. At $1,000 to $2,500 per cycle, ICSI over three cycles adds $3,000 to $7,500 for a procedure that this trial shows provides no benefit without severe male factor. For patients traveling to Spain or Czech Republic partly to save money, paying for unnecessary ICSI erases some of that saving.
Younger women should pay particular attention. The NNH of 9 for women under 32 is striking. This is a well-powered subgroup analysis from a randomized trial, not a post-hoc fishing expedition. If you’re under 32 with normal sperm parameters, the data suggests ICSI may actively reduce your chances.
More embryos means more options. Conventional IVF produced more high-quality blastocysts and more frozen embryos in this trial. Each frozen embryo is a potential future transfer without another stimulation cycle. The math favors the less expensive procedure.
Limitations
- Open-label design: clinicians knew which procedure they performed. This is unavoidable (you can’t blind an embryologist to whether they’re injecting sperm), but it could influence decisions about embryo culture or selection.
- All 6 clinics were Danish public facilities. Results may differ in private clinics with different lab protocols, patient populations, or quality standards.
- The trial excluded severe male factor, so it does not address ICSI’s original and established indication.
- Subgroup analyses (age, ovarian response) are hypothesis-generating, not confirmatory. The NNH of 9 for younger women needs replication in a trial powered for that specific question.
Practical Takeaway
Before your next cycle, ask your clinic one question: “Based on my partner’s semen analysis, is there a specific clinical reason to use ICSI over conventional IVF?” If the answer is a vague reference to “better results” or “it’s what we always do,” you now have a randomized trial of 824 women published in Nature Medicine that says otherwise.
ICSI was a genuine breakthrough for severe male factor infertility. Using it on everyone else is an expensive habit, not medicine.
This is part of EuroFertile’s Journal Club. Summaries of recent fertility research, written for patients, not doctors. Browse all research summaries →
Comparing clinics for your first cycle? Get matched to clinics in your budget → | Estimate your costs →