Man vs. nature: Who will choose the fittest sperm?

Since its arrival in 1992, intracytoplasmic sperm injection (ICSI) has proven to be a breakthrough technique that improves outcomes in male factor infertility. However, ICSI has been used increasingly in nonmale factor infertility despite the lack of evidence for this clinical application. According to the Center for Disease Control’s Assisted Reproductive Technology Data, ICSI insemination use ranged from 68.4% for those aged >40 years to 80.5% for those aged <35 years in in vitro fertilization cycles performed in the United States in 2020, rates much higher than the prevalence of male factor infertility. A recent large retrospective study demonstrated that ICSI does not improve cumulative live birth rate (CLBR) and had significant added costs compared with conventional insemination (CI) in cycles without a male factor infertility diagnosis (1Iwamoto A. Van Voorhis B.J. Summers K.M. Sparks A. Mancuso A.C. Intracytoplasmic sperm injection vs. conventional in vitro fertilization in patients with non-male factor infertility.Fertil Steril. 2022; 118: 465-472Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). The CLBR for those that underwent ICSI was 60.9% compared with 64.3% for CI. Similarly, analysis of cycles using preimplantation genetic testing for aneuploidy (PGT-A) showed no difference in CLBR with 64.7% for ICSI and 69.0% for CI (1Iwamoto A. Van Voorhis B.J. Summers K.M. Sparks A. Mancuso A.C. Intracytoplasmic sperm injection vs. conventional in vitro fertilization in patients with non-male factor infertility.Fertil Steril. 2022; 118: 465-472Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). The estimated added cost per cycle performed with ICSI was $1,500, with an estimated $44,689,500 charged to patients cumulatively over 2 years in the United States, without any added benefit. In this current retrospective study, Patel et al. (2Patel K. Vaughan D.A. Rodday A.M. Penzias A. Sakkas D. Compared with conventional insemination, intracytoplasmic sperm injection provides no benefit in cases of nonmale factor infertility as evidenced by comparable euploidy rate.Fertil Steril. 2023; 120: 277-286Abstract Full Text Full Text PDF Scopus (1) Google Scholar) asked if euploidy rates determined using PGT-A differ between ICSI and CI in nonmale factor infertility cases. On a basic level, this study examines whether there are differences in euploidy rates when a sperm is chosen by man through a simple microscopic technique vs. the complex physiologic processes of natural selection and fertilization. Fertilization rate and the number of embryos biopsied were also assessed. Although the number of retrieved oocytes and embryos biopsied was similar among the ICSI and CI groups (15.01 vs. 14.85, 4.36 vs. 4.34), the fertilization rate per oocyte retrieved was significantly lower in the ICSI group (0.64 vs. 0.66, P=.04) and the number of euploid embryos per cycle was also significantly lower (1.8 vs. 2.0, P<.01). For the primary study outcome, before correcting for all confounding factors, the proportion of euploid embryos per embryo biopsied was significantly lower with ICSI (0.47 vs. 0.52) with a euploid rate ratio of 0.89 (P<.01). However, after adjusting the data for the PGT reference laboratory used, no significant difference in euploidy rate was seen (relative risk: 0.97; 95% confidence interval: 0.94, 1.00; P=.07). The investigators appropriately took the PGT reference laboratory into consideration given the recent literature indicating different yields of euploid embryos on the basis of the genetic testing laboratory used (3Bardos J. Kwal J. Caswell W. Jahandideh S. Stratton M. Tucker M. et al.Reproductive genetics laboratory may impact euploid blastocyst and live birth rates: a comparison of 4 national laboratories' PGT-A results from vitrified donor oocytes.Fertil Steril. 2023; 119: 29-35Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Preimplantation genetic testing for aneuploidy is the most current, validated genetic testing technique for embryos, yet it has limitations, with variations in biopsy technique and algorithmic differences between laboratories affecting outcomes. Although the aneuploidy rates were not statistically significant after adjustment for laboratory, this trend toward lower euploidy rates after ICSI is a concerning outcome that could reach significance with larger numbers. Mosaic embryos were not reported and categorized as abnormal along with aneuploid embryos, and only “normal” embryos were considered eligible for transfer on the basis of copy number cutoffs established by the respective genetic testing laboratory. This is one limitation because mosaic embryos, especially low-level or segmental ones, are being considered a lesser priority but eligible for transfer in many centers because of the potential for live births. It would also have been informative to know whether the percentage of embryos biopsied on days 5, 6, or 7 was similar between groups because aneuploidy rates increase the longer embryos are in culture (4Tong J. Niu Y. Wan A. Zhang T. Comparison of day 5 blastocyst with day 6 blastocyst: evidence from NGS-based PGT-A results.J Assist Reprod Genet. 2022; 39: 369-377Crossref PubMed Scopus (6) Google Scholar). The finding of an increased fertilization rate with CI may be because of natural selection that enables the best-quality sperm to fertilize the egg compared with ICSI. Alternatively, ICSI requires a fully mature metaphase II oocyte at the time when it is performed, thus decreasing the “pool” of eligible oocytes to be inseminated. With CI, some initially immature eggs may mature with a longer time in culture and ultimately fertilize, leading to the higher fertilization rates seen in this study. Strengths of the study include a large sample size from a high-quality in vitro fertilization program with experienced practitioners and investigators. Limitations of the study population include the definition of male factor infertility and the requirement of at least one embryo for biopsy, thereby excluding those with failed fertilization. The definition of nonmale factor infertility as >4 million total motile sperm per mL, although justified in the article, may not be the criteria used by other clinics and therefore limit the broad clinical application of these findings. Reporting the failed fertilization rates may have been helpful, given that this is a common justification for routine use of ICSI. Given the lack of high-quality evidence that ICSI decreases failed fertilization rates specifically in nonmale factor cases, we suspect this would not have changed the recommendations to limit use of ICSI in these circumstances. Although the risk of birth defects is low, it may be increased using ICSI, which continues to be supported in the recent literature (5Luke B. Brown M.B. Wantman E. Forestieri N.E. Browne M.L. Fisher S.C. et al.The risk of birth defects with conception by ART.Hum Reprod. 2021; 36: 116-129Crossref PubMed Scopus (41) Google Scholar). Overall, their findings indicate that ICSI is not advantageous for yielding euploid embryos and may be detrimental. Future studies, including randomization to the two insemination techniques and testing through a single laboratory, may be helpful in clarifying these findings. This study adds to the growing body of literature that ICSI should be pursued only when indicated in male factor cases and may lead to adverse outcomes when more widely used. With the reduced euploidy rates, lack of improved pregnancy rates, increased cost, and increased risk of birth defects, the evidence strongly suggests that ICSI is contraindicated in nonmale factor infertility cases unless required for genetic testing of embryos or when cryopreserved gametes are used. Until new evidence or techniques emerge, the selection of the best sperm for fertilization is best left to nature in most cases. Compared with conventional insemination, intracytoplasmic sperm injection provides no benefit in cases of nonmale factor infertility as evidenced by comparable euploidy rateFertility and SterilityVol. 120Issue 2PreviewTo evaluate whether differences in euploidy rates exist between intracytoplasmic sperm injection (ICSI) and conventional insemination (CI) in nonmale factor infertility cases. Full-Text PDF