By Robert W. Rebar, MD

Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: The data from a recent study suggest that at least some men whose fathers had male-factor infertility and were born as a result of ICSI also may suffer from male-factor infertility.

SOURCE: Belva F, Bonduelle M, Roelants M, et al. Semen quality of young adult ICSI offspring: The first results. Hum Reprod 2016; doi:10.1093/humrep/dew245.

Intracytoplasmic sperm injection (ICSI) is used widely as a part of in vitro fertilization (IVF) to help infertile couples in which the male partner has poor semen characteristics (i.e., typically low sperm count or motility) build a family. First used in 1991, the Belgian group pioneering its use has now examined the reproductive health of a cohort of 54 young adult ICSI men compared to 57 spontaneously conceived men of approximately the same age. The ICSI males included in this cohort were conceived with the use of ICSI because of severe male-factor infertility in their fathers. There was no difference in mean testicular volume between the ICSI men and the spontaneously conceived controls. After adjustment for several confounders (including age, body mass index, genital malformations, time from ejaculation to semen analysis, and period of abstinence), sperm concentration was almost doubled in spontaneously conceived peers compared to ICSI men (ratio 1.9; 95% confidence interval [CI], 1.1-3.2), and a two-fold lower total sperm count (ratio 2.3; 95% CI, 1.3-4.1) and total motile sperm count (ratio 2.12; 95% CI, 1.2-3.2) were found in ICSI men compared to the controls. In addition, ICSI men were almost three times more likely to have sperm concentrations lower than the accepted lower normal value of 15 million/mL (adjusted odds ratio [AOR], 2.7; 95% CI, 1.1-6.7) and four times more likely to have total sperm counts below 39 million (AOR, 4.3; 95% CI, 1.7-11.3).

COMMENTARY

The use of ICSI together with IVF has revolutionized the treatment of men with impaired spermatogenesis and permitted them to bear children. More recently, ICSI has become widely used even in normal men as a part of IVF. However, the long-term effect of ICSI on subsequent reproductive function in men conceived with ICSI is still unknown. It is important to note that this study involved ICSI men whose fathers had severe male-factor infertility.

The Belgian group has been following the male offspring of fathers with diminished spermatogenesis born as a result of ICSI for several years. They previously reported normal pubertal development,1 normal inhibin B as a marker of Sertoli cell function,2 and normal levels of salivary testosterone as an indicator of Leydig cell function.3 Even with the data reported in this study, we cannot conclude whether ICSI males will have diminished fertility.

It is possible that the subset of men with abnormal spermatogenesis and chromosomal abnormalities are those most likely to have sons born via ICSI who also will have abnormal spermatogenesis. It is known that infertile men have a higher prevalence of chromosomal abnormalities than fertile men, with several microdeletions of the Y chromosome now recognized.4 Y-chromosomal microdeletions, especially of the AZFc (azoospermia factor c) region, are the most frequently diagnosed cause of impaired spermatogenesis, with a prevalence of 6% in severely oligozoospermic men and a prevalence of 10% in azoospermic men.5-7 As expected, transmission of Y-chromosomal deletions from father to son through ICSI has been reported.7 Men with these deletions who successfully father children as a result of ICSI generally are not deterred by the prospect of having a son with the same difficulties with reproduction.

There is little doubt that the Belgian group will continue to follow this cohort and also will report on the use of ICSI in other circumstances involving men with normal spermatogenesis. Proposed indications for the use of ICSI in the literature now include unexplained infertility, poor quality oocytes retrieved in IVF cycles, low oocyte yield in IVF, advanced maternal age, prior fertilization failure with conventional insemination in IVF, routine use in all IVF cycles, use in IVF cycles that involve preimplantation genetic testing (PGT), fertilization after in vitro maturation (IVM) of immature oocytes as a part of IVF, and fertilization with use of cryopreserved oocytes.8 In the CDC’s 2014 National Summary Report of IVF, the percentage of oocyte retrievals using ICSI in those cycles without male infertility ranged from 67% among patients younger than age 35 years to 78% among those older than age 44 years.9 Overall, 56% of all ICSI procedures were performed in cycles without a diagnosis of male-factor infertility. The rationale for the use of ICSI even in the absence of a male factor is avoiding fertilization failure in IVF cycles.

In a Committee Opinion, the Practice Committees of the American Society for Reproductive Medicine and of the Society for Assisted Reproductive Technology concluded that there are no data to support the routine use of ICSI with IVF for non-male factor infertility.8 Further, they noted that more than 30 couples would need to undergo ICSI unnecessarily to prevent one failed fertilization during IVF. The committees also concluded that ICSI might be beneficial in cycles with PGT, IVM, or cryopreserved oocytes, but additional studies are warranted to determine if such is the case. ICSI for low oocyte yield and advanced maternal age has not improved clinical outcomes. Finally, the committees concluded that the safety and cost (which is not trivial) of ICSI in the setting of non-male factor infertility must be considered.

So what does this particular study tell us and what does it portend for the future? The data reported by the Belgian group suggest that at least some of the men whose fathers had male-factor infertility and were born as a result of ICSI may well suffer from male-factor infertility. Whether ICSI affects the reproductive health of men born after ICSI whose fathers were entirely normal remains to be determined. Having said that, it is difficult to envision that ICSI will increase male-factor infertility in the offspring of normal males. I chose to focus on this paper for this review because of the frequency with which ICSI is utilized together with IVF.

REFERENCES

  1. Belva F, Roelants M, Painter R, et al. Pubertal development in ICSI children. Hum Reprod 2012;27:1156-1161.
  2. Belva F, Bonduelle M, Painter RC, et al. Serum inhibin B concentrations in pubertal boys conceived by ICSI: First results. Hum Reprod 2010;25:2811-2814.
  3. Belva F, Bonduelle M, Schiettecatte, et al. Salivary testosterone concentrations in pubertal ICSI boys compared with spontaneously conceived boys. Hum Reprod 2011;26:438-441.
  4. Ferlin A, Raieu F, Gatta V, et al. Male infertility: Role of genetic background. Reprod Biomed Online 2007;14:734-735.
  5. Maurer B, Simoni M. Y chromosome microdeletion screening in infertile men. J Endocrinol Invest 2000;23:664-670.
  6. Oliva R, Margarit E, Ballesca JL, et al. Prevalence of Y chromosome microdeletions in oligospermic and azoospermic candidates for intracytoplasmic sperm injection. Fertil Steril 1998;70:506-510.
  7. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 1999;14:1722-1726.
  8. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Intracytoplasmic sperm injection (ICSI) for non-male factor infertility: A committee opinion. Fertil Steril 2012;98:1395-1399.
  9. 2014 ART National Summary Report. Centers for Disease Control and Prevention. Available at: www.cdc.gov/art/reports. Accessed Jan. 17, 2017.