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Randomized Controlled Trial
. 2025 Jun;31(6):1939-1948.
doi: 10.1038/s41591-025-03621-x. Epub 2025 Apr 11.

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

Sine Berntsen  1 , Anne Zedeler  1 , Bugge Nøhr  2 , Morten Rønn Petersen  3 , Marie Louise Grøndahl  2 , Lars Franch Andersen  4 , Kristine Løssl  3   5 , Ellen Løkkegaard  4   5 , Anne Lis Englund  6 , Anette Vestergaard Gabrielsen  7 , Lisbeth Prætorius  1 , Ida Behrendt-Møller  1 , Lea Langhoff Thuesen  1   5 , Kilian Vomstein  1   5 , Mette Petri Lauritsen  1 , Aleksandra Ivanoska Trajcevski  1 , Dea Frøding Skipper  8 , David Westergaard  8   9 , Anja Pinborg  3   5 , Henriette Svarre Nielsen  5   8 , Nina la Cour Freiesleben  10   11
Affiliations
Randomized Controlled Trial

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

Sine Berntsen et al. Nat Med. 2025 Jun.

Abstract

Intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (c-IVF) are widely used fertilization techniques in assisted reproduction, but their relative effectiveness in patients without severe male factor infertility remains debated. While ICSI's role in couples with severe male factor infertility is well established, its routine use in cases with normal or nonseverely decreased sperm quality is not evidence-based. Here we conducted the INVICSI study, an open-label, multicenter randomized controlled trial, to compare cumulative live birth rates (CLBR) as the primary outcome between ICSI and c-IVF in patients without severe male factor infertility. Between November 2019 and December 2022, 824 women undergoing their first IVF cycle were randomized to ICSI (n = 414) or c-IVF (n = 410) across six public fertility clinics in Denmark. The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group, yielding a risk ratio of 0.91 (95% confidence interval, 0.79-1.06). These findings demonstrate that ICSI does not improve CLBR compared to c-IVF and support c-IVF as the preferred first-line treatment for patients with normal or nonseverely decreased sperm quality. ICSI should be reserved for severe male factor infertility. ClinicalTrials.gov registration: NCT04128904 .

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE (International Committee of Medical Journal Editors) uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ . K.L., A.P., B.N. and K.V. have received scientific grants and personal payments/honoraria from Gedeon Richter, Ferring Pharmaceuticals and Merck. They have also received support for attending meetings from these companies. A.P. has additionally received consulting fees for lectures and presentations from Novo Nordisk, Cryos and Organon. A.L.E., L.P. and B.N. are on advisory boards for Ferring Pharmaceuticals. B.N. is also on the advisory board for Merck. N.l.C.F. has received scientific grants from Gedeon Richter, Merck and Cryos, and has received consulting fees from Merck and support for meetings from Gedeon Richter, Merck, Ferring Pharmaceuticals and IBSA (Institut Biochimique SA). E.L. received personal payments/honoraria for lectures and presentations from Pfizer and is on the advisory board for Astellas Pharma Nordic. M.L.G. has received scientific grants from Gedeon Richter, Cooper Surgical and Merck, as well as personal payments/honoraria for lectures and presentations from Merck. H.S.N. has received scientific grants from Freya Biosciences, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordisk Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Independent Research Fund Denmark and Ole Kirks Fond and has received personal payments/honoraria for lectures and presentations from Ferring Pharmaceuticals, Merck, AstraZeneca, Cook Medical, Gedeon Richter, Novo Nordisk and IBSA. S.B. received scientific grants from Gedeon Richter and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Fond. A.I.T. received support for attending meetings from Ferring Pharmaceuticals and Gedeon Richter. A.Z., M.R.P., L.F.A., A.V.G., I.B.-M., L.L.T., M.P.L., D.F.S. and D.W. declare no competing interests.

Figures

Fig. 1
Fig. 1. Trial profile.
Single asterisk indicates participants who were allocated to ICSI but received c-IVF by mistake. Double asterisk indicates participants who were allocated to c-IVF but received ICSI due to sperm count below 2 million progressively motile spermatozoa. ITT, intention-to-treat; PP, per-protocol.
Extended Data Fig. 1
Extended Data Fig. 1. CLBR and risk difference stratified by maternal age at randomization (LRT = 1.79 × 10−9).
The shaded area represents the 95% confidence interval, as estimated using ITT population (ICSI, n = 414; c-IVF, n = 408). CLBR, cumulative live birth rate; LRT, likelihood ratio test.
Extended Data Fig. 2
Extended Data Fig. 2. CLBR and risk difference stratified by ovarian response (LRT = 1.23 × 10−9).
The error bars represent the 95% confidence interval, as estimated using ITT population (ICSI, n = 414; c-IVF, n = 408). CLBR, cumulative live birth rate; LRT, likelihood ratio test.
See this image and copyright information in PMC

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