Randomized allocation of oocytes to IVF or ICSI for IVF-naïve cases with unexplained infertility in an IVF-ICSI Split protocol favors ICSI to optimize live birth outcomes

John Lui  Yovich; Jason Lee  Conceicao; Nicole  Marjanovich; Rachel  Wicks; Jesmine  Wong; Peter Michael  Hinchliffe

doi:10.30574/gscbps.2021.17.3.0346

Authors

John Lui Yovich Department of Pharmacy and Biomedical Sciences, Curtin University Perth, Western Australia, Australia 6845.
Jason Lee Conceicao PIVET Medical Centre Perth, Western Australia, Australia 6007.
Nicole Marjanovich PIVET Medical Centre Perth, Western Australia, Australia 6007.
Rachel Wicks PIVET Medical Centre Perth, Western Australia, Australia 6007.
Jesmine Wong PIVET Medical Centre Perth, Western Australia, Australia 6007.
Peter Michael Hinchliffe PIVET Medical Centre Perth, Western Australia, Australia 6007.

DOI:

https://doi.org/10.30574/gscbps.2021.17.3.0346

Keywords:

Assisted reproduction treatments (ART), vitro fertilization [IVF], Intracytoplasmic sperm injection [ICSI], Single embryo transfer (SET), Frozen embryo transfer (FET), Live birth productivity rate (LBPR)

Abstract

In assisted reproduction treatments (ART), applying the ICSI method for fertilization of oocytes rather than traditional IVF method, is regarded as controversial for two reasons, namely utility and safety. Our study examines an IVF-ICSI Split model for couples with unexplained infertility, where male factor is meticulously excluded and ART is conducted by a strict algorithm, a commitment to blastocyst culture, along with single embryo transfers and a high commitment to cryopreservation. From 242 treatment cycles, 3346 oocytes recovered (13.8 per OPU) were randomly allocated to IVF or ICSI and the fertilization rates standardized to the number of 2PNS arising from each group applying the metaphase II oocyte number identified for the ICSI group, as the denominator for both groups. The fertilization rates were significantly higher overall for ICSI (83.2% vs 65.4%; p<0.0001), being most pronounced for women under 40 years. The resultant embryos had equivalent implantation rates in both fresh ET and frozen (FET) cycles with no significant differences in pregnancy rates, miscarriage rates or live birth outcomes indicating equivalent embryo quality. However, there were significantly higher numbers of ICSI-generated embryos cryopreserved and subsequent FET procedures showed higher live birth rates (21 births vs 6 births; p<0.005) and potential livebirths (214 births vs 104 births; p<0.0001). No congenital fetal abnormalities were detected in any of the 199 babies delivered during the study period to December 2020, neither IVF-generated nor ICSI-generated. Whilst the data strongly favors ICSI, there were 2 women (from 26 with fertilization in one arm only) who demonstrated fertilization only in the IVF arm of the study. We conclude that the IVF-ICSI Split model should be undertaken on all IVF-naïve women with unexplained infertility to determine the appropriate fertilization mode, albeit ICSI will be safely preferred for >90% of cases.

Metrics

Metrics Loading ...

References

Edwards R, Bavister B, Steptoe, P. (1969). Early stages of fertilization In vitro of human oocytes matured In vitro. Nature, 221, 632–635.

Steptoe PC, Edwards RG. (1978). Birth after the re-implantation of a human embryo. Lancet, 2(8085), 366.

Yovich JL, Craft IL. (2018). Founding pioneers of IVF: Independent innovative researchers generating livebirths within 4 years of the first birth. Reprod Biol, 18, 317-323.

Yovich JL. (2020). Founding pioneers of IVF Update: Independent innovative researchers generating livebirths within 4 years of the first birth. Reprod Biol, 20, 111-113.

Craft I, Yovich J. (1979). Implications of embryo transfer. Lancet, ii, 642-643.

Yovich JL, Matson PL. (1989). The influence of infertility aetiology on the outcome of in-vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT) treatments. Int J Fertil, 35, 26-33.

Yovich JL. (2019). Indications and Techniques of In vitro fertilization. In: 40 years after In vitro fertilization: state of the art and new challenges (ed: Jan Tesarik). Cambridge Scholars Publishing, Lady Stephenson Library, Newcastle upon Tyne, UK, 25-75.

Yovich JL, Stanger JD, Kay D, Boettcher B. (1984). In-vitro fertilization of oocytes from women with serum antisperm antibodies. Lancet, ii, 369-370.

Yovich JL, Stanger JD. (1984). The limitations of in-vitro fertilization from males with severe oligospermia and abnormal sperm morphology. J In vitro Fert Embryo Transfer, 1(3), 172-179.

Mahadevan M, Baker G. (1984). Assessment and preparation of semen for In vitro fertilization. In C. Wood et al (eds). Clinical In vitro Fertilization. Springer-Verlag Berlin Heidelberg, Ch7, 83-97.

Yovich JL, Stanger JD, Yovich JM. (1985). Management of oligospermic infertility by in-vitro fertilization. In: In vitro Fertilization and Embryo Transfer. Seppälä M, Edwards RG. (Eds). Ann NY Acad Sci, 442, 276-286.

Yovich JM, Edirisinghe WR, Cummins JM, Yovich JL. (1988). Preliminary results using pentoxifylline in a PROST program for severe male factor infertility. Fertil Steril, 50, 179-181.

Yovich JM, Edirisinghe WR, Cummins JM, Yovich JL. (1990). Influence of pentoxifylline in severe male factor infertility. Fertil Steril, 53(4), 715-722.

Yovich JL. (1993). Pentoxifylline: actions and applications in assisted reproduction. Hum Reprod, 8, 1786-91.

Malter HE, Cohen J. (1989). Partial zona dissection of the human oocyte: a non-traumatic method using micromanipulation to assist zona pellucida penetration. Fertil Steril, 51(1), 139-148.

Ng SC, Bongso A, Sathananthan H, Chan CL, Wong PC, Hagglund L, Ratnam SS. (1988). Pregnancy after transfer of sperm under zona. Lancet, 2: 790.

Edirisinghe WR, Junk SM, Yovich JM, Bootsma B, Yovich JL. (1995). Sperm stimulants can improve fertilization rates in male-factor cases undergoing IVF to the same extent as micromanipulation by partial zona dissection (PZD) or sub-zonal sperm insemination (SUZI): a randomized controlled study. J Assist Reprod Genet, 12(5), 312-318.

Ng SC, Bongso TA, Liow SL, Edirisinghe R, Ratnam SS. (1992). Micro-insemination sperm transfer (MIST) and its application to male subfertility: current strategies to improve results. Ann Acad Med Singa, 21(4), 561-564.

Palermo G, Joris H, Devroey P, Van Steirteghem AC. (1992). Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet, 340(8810), 17-18.

Yovich JL, Edirisinghe WR, Apted SI, Yovich JM. (1993). Pregnancy from microinjected epididymal spermatozoa. Med J Aust, 159, 71-72.

Yovich JL. (1993). Individualization of sperm preparations. J Assist Reprod Genet, 10, 247-250.

Matson PL, Yovich JM, Edirisinghe WR, Junk SM, Yovich JL. (1995). An argument for the past and continued use of pentoxifylline in assisted reproductive technology. Hum Reprod, 10, suppl 1, 67-71.

Molina LCP, Luque GM, Balestrini PA, Marin-Briggiler, CI, Romarowski A, Buffone MG. (2018). Molecular basis of human sperm capacitation. Front Cell Dev Biol, 6, 1-72.

Holt WV, Fazeli A. (2015). Do sperm possess a molecular passport? Mechanistic insights into sperm selection in the female reproductive tract. Molecular Hum Reprod, 21, 491-501.

De Jonge C. (2005). Biological basis for human capacitation. Hum Reprod Update, 2005, 11(3), 205-214.

De Jonge C. (2017). Biological basis for human capacitation – revisited. Hum Reprod Update, 23(3), 289-299.

Suarez SS, Ho H-C. (2003). Hyperactivation of mammalian sperm. Cell Mol Biol, 49(3), 351-356.

Yovich JM, Edirisinghe WR, Yovich JL. (1994). Use of the acrosome reaction to ionophore challenge test (ARIC) in managing patients in an assisted reproduction programme. Fertil Steril, 61, 902-910.

Sosa CM, Pavarotti MA, Zanetti MN, Zoppino FCM, De Blas GA, Mayorga LS. (2015). Kinetics of human sperm acrosomal exocytosis. Mol Hum Reprod, 21(3), 244-254.

Flesch FM, Gadella BM. (2000). Dynamics of the mammalian sperm plasma membrane in the process of fertilization. Biochimica et Biophysica Acta, 1469, 197-235.

Gadella B. (2012). Dynamic regulation of sperm interactions with the zona pellucida prior to and after fertilisation. Reprod Fert Develop, 25(1), 26-37.

Tosti E, Menezo Y. (2016). Gamete activation: basic knowledge and clinical applications. Hum Reprod Update, 22(4), 420-439.

Yeste M, Jones C, Amdani SN, Patel S, Coward K. (2016). Oocyte activation deficiency: a role for an oocyte contribution? Hum Reprod Update, 22(1), 23-47.

Kashir J, Nomikos M, Swann K, Lai FA. (2015). PLC-zeta or PAWP: revisiting the putative mammalian sperm factor that triggers egg activation and embryogenesis. Mol Hum Reprod, 21(5), 383-388.

Simerly CR, Takahashi D, Jacoby E, Castro C, Hartnett C, Hewitson L, Navara C, Shatten G. (2019). Fertilization and cleavage axis differ in primates conceived by conventional (IVF) versus intracytoplasmic sperm injection (ICSI). Sci Rep, 9, 15282.

Avidor-Reiss T, Mazur M, Fishman EL, Sindhwani P. (2019). The role of sperm centrioles in human reproduction – the known and the unknown. Front Cell Dev Biol, 7(188), 1-15.

Sanchez AD, Feldman JL. (2017). Microtubule-organising centers: from the centrosome to non-centrosomal sites. Current Opinion in Cell Biology, 44, 93-101.

Jaroudi K, Al-Hassan S, Al-Sufayan H, Al-Mayman H, Qeba M, Coskun S. (2003). Intracytoplasmic sperm injection and conventional In vitro fertilization are complementary techniques in management of unexplained infertility. J Assist Reprod Genet, 20(9), 377–381.

Vitek WS, Galarraga O, Klatsky PC, Robins JC, Carson SA, Blazar AS. (2013). Management of the first In vitro fertilization cycle for unexplained infertility: a cost-effectiveness analysis of split In vitro fertilization-intracytoplasmic sperm injection. Fertil Steril, 100(5), 1381–1388.

Yovich JL, Mustafa KB, Marjanovich N, Yovich SJ, Keane KN. (2016). IVF-ICSI Split insemination reveals those cases of unexplained infertility benefitting from ICSI even when the DNA fragmentation index is reduced to 15% or even 5%. Androl Gynecol: Curr Res, 4(1), 1-7.

Yovich JL, Conceicao JL, Marjanovich N, Ye Y, Hinchliffe PM, Dhaliwal SS, Keane KN. (2018). An ICSI rate of 90% minimizes complete failed fertilization and provides satisfactory implantation rates without elevating fetal abnormalities. Reprod Biol, 18, 301-311.

Sauerbrun-Cutler M-T, Huber WJ 3rd, Has P, Shen C, Hackett, Alvero R, Wang S. (2020). Is intracytoplasmic sperm (ICSI) better than traditional In vitro fertilization (IVF): confirmation of higher blastocyst rates per oocyte using a split insemination design? J Assist Reprod Genet, 37(7), 1661-1667.

Yovich JL, Conceicao JL, Wong J, Marjanovich N, Wicks R, Hinchliffe PM. (2021). Fertilization by ICSI generates a higher number of live births than IVF in a pioneer facility applying >90% single blastocyst-stage embryo transfers. GSC Biological and Pharmaceutical Sciences, 15(01), 087-103.

Yovich JL, Puzey A, De Atta R, Roberts R, Reid S, Grauaug A. (1982). In-vitro fertilization pregnancy with early progestagen support. Lancet, ii, 378-379.

Yovich JL. (2019). Monitoring the stimulated IVF cycle. In: How to Prepare the Egg and Embryo to Maximise IVF Success. (Eds: Gabor T Kovacs, Anthony J Rutherford, David K Gardner). Cambridge University Press, Cambridge, 94-120.

Yovich J, Stanger J, Hinchliffe P. (2012). Targeted gonadotrophin stimulation using the PIVET algorithm markedly reduces the risk of OHSS. Reprod Biomed Online, 24(3), 281-292.

Yovich JL, Alsbjerg B, Conceicao JL, Hinchliffe PM, Keane KN. (2016). PIVET rFSH dosing algorithms for individualized controlled ovarian stimulation enables optimized pregnancy productivity rates and avoidance of ovarian hyperstimulation syndrome. Drug Des Devel Ther, 10, 2561–2573.

Yovich JL, Keane KN, Borude G, Dhaliwal SS, Hinchliffe PM. (2018). Finding a place for corifollitropin within the PIVET FSH-dosing algorithms. Reprod Biomed Online, 36(1), 47-58.

Yovich JL, Hinchliffe PM, Lingam S, Srinivasan S, Keane KN. (2018). Adjusting the PIVET rFSH dosing algorithm for the biosimilar Bemfola product. J Fertil In vitro IVF Worldw Reprod Med Genet Stem Cell Biol, 5: 3.

Kuwayama M, Vajta G, Kato O, Leibo SP. (2005). Highly efficient vitrification method for cryopreservation of human oocytes. Reprod Biomed Online, 11, 300-308.

Newman JE, Paul RC, Chambers GM. (2020). Assisted Reproductive Technology in Australia and New Zealand 2018; National Perinatal Epidemiology and Statistics Unit, the University of New South Wales: Sydney, Australia, 1–83.

Your IVF Success Estimator. (2020). Find an Australian IVF clinic. Australian & New Zealand Assisted Reproduction Database. University of New South Wales: Sydney, Australia.

WHO. (2010). WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva: World Health Organization, 270pp.

Stanger JD, Vo L, Yovich JL, Almahbobi G. (2010). Hypo-osmotic swelling test identifies individual spermatozoa with minimal DNA fragmentation. Reprod Biomed Online, 20, 474-484.

Yovich JL, Katz D, Jequier AM. (2018). Sperm recovery for men with spinal cord injury: vasal flush is the preferred method for an-ejaculatory males. J Fertil In vitro IVF Worldw Reprod Med Genet Stem Cell Biol, 6(1), 1-6.

Jequier AM. (2011). Physical agents, toxins and drugs: their effect upon male fertility. In: Male Infertility. A Clinical Guide. Cambridge University Press. Second Edition, 197-208.

Yovich JL, Hinchliffe PM. (2021). A 10-year perspective on the utility of three adjuvants often used in IVF: growth hormone, melatonin and DHEA. Reprod Med, 2, 155-162.

Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. (2015). Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA, 313(3), 255-63.

Ludwig M, al-Hasani S, Küpker W, Bauer O, Diedrich K. (1997). A new indication for an intracytoplasmic sperm injection procedure outside the cases of severe male factor infertility. Eur J Obstet Gynecol Reprod Biol, 75(2), 207-210.

Ou YC, Lan KC, Huang FJ, Kung FT, Lan TH, Chang SY. (2010). Comparison of In vitro fertilization versus intracytoplasmic sperm injection in extremely low oocyte retrieval cycles. Fertil Steril, 93, 96–100.

Gozlan I, Dor A, Farber B, Meirow D, Feinstein S, Levron J. (2007). Comparing intracytoplasmic sperm injection and In vitro fertilization in patients with single oocyte retrieval. Fertil Steril, 87, 515–518.

Zhao J, Zhang N-Y, Xu Z-P, Chen L-J, Zhao X, Zeng H-M, Jiang Y-Q, Sun H-X. (2015). Effects of abnormal zona pellucida on fertilization and pregnancy in IVF/ICSI-ET. J Reprod Contraception, 26, 73-80.

O’Neill CL, Chow S, Rosenwaks Z, Palermo GD. (2018). Development of ICSI. Reproduction, 156, F51-F58.

Van der Westerlaken L, Helmerhorst F, Dieben S, Naaktgeboren N. (2005). Intracytoplasmic sperm injection as a treatment for unexplained total fertilization failure or low fertilization after conventional In vitro fertilization. Fertil Steril, 83, 612–617.

Vitek WS, Galarraga O, Klatsky PC, Robins JC, Carson SA, Blazar AS. (2013). Management of the first In vitro fertilization cycle for unexplained infertility: a cost-effectiveness analysis of split In vitro fertilization-intracytoplasmic sperm injection. Fertil Steril, 100(5), 1381–1388.

Ruiz A, Remohi J, Minguez Y, Guanes PP, Simon C, Pellicer A. (1997). The role of In vitro fertilization and intracytoplasmic sperm injection in couples with unexplained infertility after failed intrauterine insemination. Fertil Steril, 68(1), 171–173.

Yovich JL, Grudzinskas G. (1990). In vitro fertilization and embryo transfer (IVF-ET): current status (1988). In: The Management of Infertility, a manual of gamete handling procedures, Chapter 10. Heinemann Medical Books, Oxford. UK (ISBN 0 433 00160 7), 121–44.

Yovich JL. (2020). The effect of ICSI-related procedural timings and operators on the outcome. GSC Biological and Pharmaceutical Sciences, 11(01), 09-11.

Larbuisson A, Raick D, Demelenne S, Delvigne A. (2017). ICSI diagnostic: a way to prevent total fertilization failure after 4 unsuccessful IUI. Basic Clin Androl, 27(18), 1-5.

Harton GL, De Rycke M, Fiorentino F, Moutou C, SenGupta S, Traeger- Synodinos J, Harper JC. (2011). European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium. ESHRE PGD consortium best practice guidelines for amplification based PGD. Hum Reprod, 26(1), 33-40.

Yovich JL, Mariappen U, Hinchliffe PM, Dhaliwal SS, Keane KN. (2020). MPA given orally during the first trimester for threatened miscarriage carries no specific risk for foetal abnormalities albeit the rate is higher than non- threatened pregnancies. Reprod Biol, 20, 424-432.

Li Z, Wan AY, Bowman M, Hammarberg K, Farquar C, Johnson L, Safi N, Sullivan EA. (2018). ICSI does not increase the cumulative live birth rate in non-male factor infertility. Hum Reprod, 33(7), 1322-1330.

ASRM Practice Committee. (2012). Intracytoplasmic sperm injection (ICSI) for non-male factor infertility: a committee opinion. Fertil Steril, 98, 1395-1399.

American Society for Reproductive Medicine. (2020). Practice Committee for the Society of Assisted Reproductive technology. Intracytoplasmic sperm injection (ICSI) for non-male factor indications: a committee opinion. Fertil Steril, 114, 239-245.

Yovich JL, Keane KN. (2017). Assessing the male in fertility clinics - men undervalued, under-managed and undertreated. Trans Androl Urol, 6 (suppl 4), s624-s628.

Matson PL, Junk SM, Spittle JW, Yovich JL. (1998). Effect of antispermatozoal antibodies in seminal plasma upon spermatozoal function. International Journal of Andrology, 11(2), 101-106.

Mariappen U, Keane KN, Hinchliffe PM, Dhaliwal SS, Yovich JL. (2018). Neither male age nor semen parameters influence clinical pregnancy or live birth outcomes from IVF. Reprod Biol, 18, 324-329.