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 Table of Contents  
EDITORIAL
Year : 2015  |  Volume : 2  |  Issue : 1  |  Page : 2-4

Routine use of intracytoplasmic sperm injection: How much is it evidence based?


Aberdeen Fertility Centre, Aberdeen Maternity Hospital, Foresterhill, Aberdeen, AB25 2ZL, UK

Date of Web Publication20-Apr-2016

Correspondence Address:
Abha Maheshwari
Aberdeen Fertility Centre, Aberdeen Maternity Hospital, Foresterhill, Aberdeen, AB25 2ZL
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-4285.180480

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How to cite this article:
Maheshwari A, Welsh DA. Routine use of intracytoplasmic sperm injection: How much is it evidence based?. Fertil Sci Res 2015;2:2-4

How to cite this URL:
Maheshwari A, Welsh DA. Routine use of intracytoplasmic sperm injection: How much is it evidence based?. Fertil Sci Res [serial online] 2015 [cited 2022 Oct 1];2:2-4. Available from: https://www.fertilityscienceresearch.org/text.asp?2015/2/1/2/180480

Intracytoplasmic sperm injection (ICSI) was first started in 1992 as a treatment for severe male factor infertility. [1] More than a decade later, 0 Jain and Gupta [2] explored the trends in the use of ICSI compared with the proportion of those with male factor. They found that the diagnosis of a male factor had remained static over the period but the use of ICSI had increased. In data published by the Human Embryology and Fertilization Authority (HFEA, UK), about half (52.6%) of fresh in vitro fertilization (IVF) treatments in 2013 involved ICSI; a similar proportion to that has been seen in recent years (2012: 53.1%; 2011: 53% - HFEA trends and figures 2013). In the USA, 67% of all treatments were ICSI in 2013, although the diagnosis of male factor was again reported in a much lower proportion of treatments.

(https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0).

It is, therefore, clear that ICSI has been used to treat other causes of infertility. In some clinics, almost 100% of IVF cases use ICSI as a method of fertilization. This raises the question whether ICSI should be used for reasons other than a male factor or even for all.


  Male factor infertility Top


ICSI was started as a fertilization technique for those with severe male factor infertility, i.e., those with severe oligoasthenospermia and those with surgically retrieved sperm. Its use has been expanded to those with male factor infertility, but what constitutes male factor infertility is always a matter of debate. Moreover, the diagnosis of what male factor is has changed over the years with changing WHO reference ranges for acceptable semen parameters [Table 1].
Table 1: Comparison of WHO reference range for semen parameters


Click here to view


In addition, morphology is determined by individual laboratories. Despite standardization, this analysis does vary widely among laboratories. Some laboratories do not rely on morphology to make decisions about ICSI since on the day of egg collection; there is no time to do appropriate morphology assessments.

As the threshold of what constitutes male factor has been lowered, the proportion of ICSI cycles should be lowered, but that is not the case.


  Unexplained infertility Top


Although randomized controlled trials have suggested no difference in the pregnancy rates if ICSI is routinely used in cases of unexplained infertility, [3],[4] later meta-analysis of observational data suggests that fertilization rates are higher with ICSI leading to more embryos, [5] greater utilization and hence theoretically, the possibility of higher cumulative live birth rates.

There is a wide variation in the rates quoted for total fertilization failure (TFF), 5-25%. TFF has devastating consequences. ICSI has been recommended routinely to prevent TFF. Best available evidence comes from meta-analysis of observational data, [5] which has inherent limitations. The pooled relative risk (RR) of TFF for well-defined unexplained infertility was significantly higher with conventional insemination (RR, 8.22, 95% confidence interval [CI] 4.44-15.23). Although this is statistically significant, CIs are very wide. Given the proportion of TFF is very low, existing randomized controlled trials are not powered to answer the question. [3] It has been calculated by the authors of this meta-analysis that one has to do five extra ICSI cycles to prevent one TFF in cases of unexplained infertility. However, ASRM Practice Committee reports 30 extra cases of ICSI are needed to be done to prevent one TFF.

Following TFF or low fertilization with IVF, ICSI is recommended. It has to be remembered that ICSI minimizes but does not eliminate the risk of TFF. The chance of TFF with ICSI is about 3%. However, that includes cases with severe male factor infertility. [6]

Others have suggested the use of spilt IVF/ICSI in cases of unexplained infertility. [7]


  Polycystic ovarian syndrome Top


In a single-center study, sibling oocytes were randomized to be inseminated either through ICSI or IVF. [8] There was a higher fertilization rate and lower TFF in those inseminated through ICSI. However, the unit of randomization was oocytes rather than women.

Newer indication for ICSI

As practice of IVF has evolved, ICSI has been used for other indications:

  • Frozen eggs: A higher proportion of women are freezing eggs due to social reasons. When they return for their treatment, it will need to be ICSI due to the stripping of the cumulus mass before freezing and zona hardening post thaw. A number of clinics are creating egg banks by freezing the donor eggs. This makes the process much simpler rather than trying to match donor and recipients. As these eggs are frozen, they will need ICSI even if sperm is entirely normal.
  • Long duration of infertility: It is thought that one of the contributing factors of the long duration of unexplained infertility is sperm/egg interaction. Some clinics do not wish to take any risk with this and resort to ICSI to minimize the risk of TFF. The evidence supporting this in the literature is currently nonexistent.
  • Low number of eggs: In a retrospective analysis of the 1014 patients that underwent 2819 consecutive cycles, it was suggested that ICSI may improve ongoing pregnancy rate in those who have a poor ovarian response as per ESHRE criteria. [9] However, this has the inherent limitations of retrospective data analysis. These findings have been contraindicated in the past by some, [10] but supported by others. [11] Hence, the jury is still out. The American Society of Reproductive Medicine does not support its use for this indication. [12]
  • Advanced maternal age: A higher proportion of women are presenting at advanced maternal age, where due to limited time and suspicion of thickened zona, ICSI has started to be the preferred mode of fertilization. There is no evidence that ICSI for advanced maternal age improves outcome. [12]
  • HIV-positive cases: To reduce the risk of transmission ICSI is recommended in cases where the male partner is HIV-positive (even with undetectable viral load).
  • In vitro maturation: It was initially thought that oocytes matured in vitro have hardened zona and will consequently need ICSI to facilitate fertilization. However, in a randomized trial of sibling oocytes, no difference was found in fertilization rates, utilization rates, and blastocyst formation rates in oocytes matured in vitro when either ICSI or IVF was used. [13]
Hence, the indications of ICSI have increased from just severe male factor infertility (without appropriate evidence) to the extent that this question is repeatedly asked whether we should do ICSI for all? There are advantages and disadvantages of doing ICSI routinely [Table 2].
Table 2: Advantages of intracytoplasmic sperm injection and in vitro fertilization


Click here to view



  Emerging techniques Top


It has been argued that sperm selection is better with IVF, as it is more natural. However there have been significant developments in the sperm selection methods such as IMSI [14] or hyaluron binding. [15] It may mean that the argument for a better selection of sperm has swung in favor of ICSI compared to IVF, but that has yet to be proven.


  Cost effectiveness Top


There is limited data reported in the literature to study the cost effectiveness, alongside clinical effectiveness of routine IVF versus ICSI only for nonmale factor only. ICSI does add additional costs over IVF. In a four center Dutch study, assessing costs of all procedures involved in IVF/ICSI, it was found that the cost of ICSI was 8.3% higher than IVF. [16] However, no cost effectiveness was studied. A cost-effectiveness modeling exercise revealed that split IVF/ICSI becomes the preferred approach as a result of higher cumulative live birth rate as compared to all IVF and the lesser cost per live birth compared to only ICSI. [7]


  Risk of congenital anomalies Top


There have been suggestions that ICSI is associated with higher incidence of congenital anomalies. Unfortunately, most of this data do not segregate the ICSI done for severe male factors over other causes. Reassurance about congenital abnormalities is provided by the fact that despite the increase in the use of ICSI across the world, there are no proportionately increased risks of congenital abnormalities.

Although concerns were raised, [17] meta-analysis did not show any difference in congenital anomalies in children born by ICSI when compared to IVF.


  Patient perceptions Top


There are no studies which have evaluated patient perceptions as to whether they would prefer to have IVF/ICSI when the diagnosis is nonmale factor and, after all, the information is given.


  Conclusions Top


The proportion of cases using ICSI is increasing with or without supporting evidence. The definition of male factor infertility is wooly at best. The indications of ICSI have widened to more than severe male factor alone. There is no good data on clinical and cost effectiveness of the use of ICSI for nonmale factor infertility, linked to an outcome of cumulative live birth rate.

The risk of congenital anomalies is increased in ICSI done for severe male factor cases, but there is no evidence that it is the same for nonmale factor.

Further research is needed in evaluating patient preferences and assessing long-term outcomes of children born as a result of ICSI done for nonmale factor infertility. This could be done through large registry data available in various countries. With newer methods of selecting sperm and more familiarity with ICSI techniques, an appropriately powered randomized controlled trial is needed for evaluating the clinical and cost effectiveness of ICSI for nonmale factor infertility. Outcome measures for this trial should go beyond clinical pregnancy rates and include cumulative live birth rates and long-term societal costs.

These studies are needed urgently; otherwise, we are on a slippery slope of ICSI for all, without appropriate evidence to back it up. So far, another example of changing practice in our field without evidence in an era of evidence-based medicine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340:17-8.  Back to cited text no. 1
    
2.
Jain T, Gupta RS. Trends in the use of intracytoplasmic sperm injection in the United States. N Engl J Med 2007;357:251-7.  Back to cited text no. 2
    
3.
Bhattacharya S, Hamilton MP, Shaaban M, Khalaf Y, Seddler M, Ghobara T, et al. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: A randomised controlled trial. Lancet 2001;357:2075-9.  Back to cited text no. 3
    
4.
Foong SC, Fleetham JA, O'Keane JA, Scott SG, Tough SC, Greene CA. A prospective randomized trial of conventional in vitro fertilization versus intracytoplasmic sperm injection in unexplained infertility. J Assist Reprod Genet 2006;23:137-40.  Back to cited text no. 4
    
5.
Johnson LN, Sasson IE, Sammel MD, Dokras A. Does intracytoplasmic sperm injection improve the fertilization rate and decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and meta-analysis. Fertil Steril 2013;100:704-11.  Back to cited text no. 5
    
6.
Goksan Pabuccu E, Sinem Caglar G, Dogus Demirkiran O, Pabuccu R. Uncommon but devastating event: Total fertilisation failure following intracytoplasmic sperm injection. Andrologia 2016;48:164-70.  Back to cited text no. 6
    
7.
Vitek WS, Galárraga O, Klatsky PC, Robins JC, Carson SA, Blazar AS. 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 2013;100:1381-8.  Back to cited text no. 7
    
8.
Hwang JL, Seow KM, Lin YH, Hsieh BC, Huang LW, Chen HJ, et al. IVF versus ICSI in sibling oocytes from patients with polycystic ovarian syndrome: A randomized controlled trial. Hum Reprod 2005;20:1261-5.  Back to cited text no. 8
    
9.
Maman E, Geva LL, Yerushalmi G, Baum M, Dor J, Hourvitz A. ICSI increases ongoing pregnancy rates in patients with poor response cycle: Multivariate analysis of 2819 cycles. Reprod Biomed Online 2012;25: 635-41.  Back to cited text no. 9
    
10.
Luna M, Bigelow C, Duke M, Ruman J, Sandler B, Grunfeld L, et al. Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved? J Assist Reprod Genet 2011;28:911-5.  Back to cited text no. 10
    
11.
Ou YC, Lan KC, Huang FJ, Kung FT, Lan TH, Chang SY. Comparison of in vitro fertilization versus intracytoplasmic sperm injection in extremely low oocyte retrieval cycles. Fertil Steril 2010;93:96-100.  Back to cited text no. 11
    
12.
Practice Committees of the American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Intracytoplasmic sperm injection (ICSI) for non-male factor infertility: A committee opinion. Fertil Steril 2012;98:1395-9.  Back to cited text no. 12
    
13.
Walls M, Junk S, Ryan JP, Hart R. IVF versus ICSI for the fertilization of in-vitro matured human oocytes. Reprod Biomed Online 2012;25:603-7.  Back to cited text no. 13
    
14.
Luna D, Hilario R, Dueñas-Chacón J, Romero R, Zavala P, Villegas L, et al. The IMSI procedure improves laboratory and clinical outcomes without compromising the aneuploidy rate when compared to the classical ICSI procedure. Clin Med Insights Reprod Health 2015;9:29-37.  Back to cited text no. 14
    
15.
Worrilow KC, Eid S, Woodhouse D, Perloe M, Smith S, Witmyer J, et al. Use of hyaluronan in the selection of sperm for intracytoplasmic sperm injection (ICSI): Significant improvement in clinical outcomes - multicenter, double-blinded and randomized controlled trial. Hum Reprod 2013;28:306-14.  Back to cited text no. 15
    
16.
Bouwmans CA, Lintsen BM, Eijkemans MJ, Habbema JD, Braat DD, Hakkaart L. A detailed cost analysis of in vitro fertilization and intracytoplasmic sperm injection treatment. Fertil Steril 2008;89:331-41.  Back to cited text no. 16
    
17.
Wen J, Jiang J, Ding C, Dai J, Liu Y, Xia Y, et al. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: A meta-analysis. Fertil Steril 2012;97:1331-7.e1-4.  Back to cited text no. 17
    



 
 
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