Improving outcomes of after fertilization failure with intracytoplasmic sperm injection: the role of differentiating oocyte-related and sperm-related oocyte activation deficiency

Abstract

The paper by Cheung et al. in this month’s Fertility and Sterility establishes an interesting clinical pathway for patients who have had complete fertilization failure or very poor fertilization rates after in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) (1Cheung S.C. Xie P. Parrella A. Keating D. Rosenwaks Z. Palermo G.D. Identification and treatment of men with PLCζ-defective spermatozoa.Fertil Steril. 2020; 114: 535-544Scopus (7) Google Scholar). Although complete fertilization failure occurs rarely, in ∼1%–3% of couples undergoing IVF/ICSI, subsequent fertilization and pregnancy rates are lower without careful consideration of the clinical scenario (2Vanden Meerschaut F. Nikiforaki D. Heindryckx B. de Sutter P. Assisted oocyte activation following ICSI fertilization failure.Reprod Biomed Online. 2014; 28: 560-571Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). The main cause of fertilization failure after ICSI is thought to be oocyte activation deficiency (OAD), which can be due to oocyte-related factors or sperm-related factors (2Vanden Meerschaut F. Nikiforaki D. Heindryckx B. de Sutter P. Assisted oocyte activation following ICSI fertilization failure.Reprod Biomed Online. 2014; 28: 560-571Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Studies have shown that artificial oocyte activation (AOA) can be helpful in this situation, but it is most effective in couples who have clear sperm-related OAD (3Bonte D. Ferrer-Buitrago M. Dhaenens L. Popovic M. Thys V. de Croo I. et al.Assisted oocyte activation significantly increases fertilization and pregnancy outcome in patients with low and total failed fertilization after intracytoplasmic sperm injection: a 17-year retrospective study.Fertil Steril. 2019; 112: 266-274Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The tests used historically to identify sperm-related OAD have not made an easy transition to being clinically useful. For example, the mouse oocyte activation test (MOAT) is cumbersome and of unclear clinical utility owing to differences in the murine and human oocyte. Moreover, AOA is not without potential risks (2Vanden Meerschaut F. Nikiforaki D. Heindryckx B. de Sutter P. Assisted oocyte activation following ICSI fertilization failure.Reprod Biomed Online. 2014; 28: 560-571Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Although it appears that children born with the use of ICSI and AOA have normal obstetrical and developmental outcomes, the results are still early and sample sizes are limited. Cheung et al. ask what we can do to differentiate which couples will respond well to AOA and which will not. The spermatozoa release phospholipase zeta (PLCζ) into the oocyte, which triggers calcium oscillations and thus oocyte activation (4Yu Y. Saunders C.M. Lai F.A. Swann K. Preimplantation development of mouse oocytes activated by different levels of human phospholipase C zeta.Hum Reprod. 2008; 23: 365-373Crossref PubMed Scopus (45) Google Scholar). The authors’ PLCζ assay allows them to separate couples into those with mainly oocyte-related factors versus sperm-related factors and tailor their subsequent therapy to this. It was also shown to be concordant with MOAT results and genetic testing. Whereas AOA has been shown to be associated with better outcomes in those with clear sperm-related OAD, data are sparse on what can be done to improve outcomes of oocyte-related OAD. In those couples who did not show any abnormalities in PLCζ, Cheung et al. had the women undergo a superovulation protocol aimed at optimizing oocyte maturity. The literature suggests that successful fertilization depends in part on cytoplasmic and nuclear maturation of the oocyte (5Combelles C.M. Morozumi K. Yanagimachi R. Zhu L. Fox J.H. Racowsky C. Diagnosing cellular defects in an unexplained case of total fertilization failure.Hum Reprod. 2010; 25: 1666-1671Crossref PubMed Scopus (39) Google Scholar). Those patients who did not follow a superovulation protocol were offered an assisted gamete treatment (AGT) protocol, either AGT-initial or -revised depending on the protocol. This led to significantly higher fertilization and clinical pregnancy rates compared with the couples’ previous treatment cycles. AGT was associated with higher rates of fertilization (42.1% vs. 9.1%; P<.05) and clinical pregnancy (36% vs. 0%; P<.05). Also in the 52 couples with oocyte-related OAD who underwent IVF with ICSI with a superovulation protocol, AGT was associated with higher rates of fertilization (59% vs. 2.1%; P<.0001) and clinical pregnancy (28.6% vs. 0%; P<.00010), with no difference in fertilization rate but a significantly higher clinical pregnancy rate with the use of the AGT-revised protocol compared with the AGT-initial protocol. The relative success of the authors’ protocol regarding fertilization and clinical pregnancy rates is promising. It remains to see if these results can be replicated in other centers and what the long-term outcomes are for children born from these assisted reproductive technologies. Identification and treatment of men with phospholipase Cζ–defective spermatozoaFertility and SterilityVol. 114Issue 3PreviewTo identify and treat the gamete responsible for complete fertilization failure with intracytoplasmic sperm injection (ICSI) using a newly proposed assisted gamete treatment (AGT). Full-Text PDF Open Access