Recent data suggest that male factors are the commonest single defined cause of infertility.1 For couples with such types of infertility there are therapeutic options, such as urological interventions and assisted reproductive techniques (ARTs), that are extremely successful in aiding conception. Among the ARTs, intracytoplasmic sperm injection (ICSI)² has revolutionised the approach to cases presenting with moderate to severe oligoastheno-teratozoospermia and other sperm dysfunctions^.3,4 In the USA during 1998, ICSI was used in about 40% of 53154 ART cycles to overcome potential fertilisation failure due to sperm deficiencies. Such cycles resulted in a livebirth rate per transfer cycle of over 30%, similar to that obtained with non-ICSI ART cycles done during the same period.⁵ The technique has also made it possible to treat patients with azoospermia (either of obstructive or non-obstructive origin) by the use of surgically retrieved testicular or epididymal spermatozoa.

ICSI is commonly done in the absence of a defined aetiological or pathophysiological diagnosis. Unfortunately, male infertility is still considered “idiopathic” in a large proportion of cases. The need to establish the causes (and thus the means of prevention) of male infertility⁶ is reinforced by the fact that, by assisting fertilisation through oocyte micromanipulation, ICSI bypasses natural sperm-selection barriers. This point has raised serious concerns, including that of the risk of transmission of chromosomal or genetic disease. It is well established that some cases of male infertility, particularly those associated with severe oligozoospermia or azoospermia of testicular origin, are associated with an increased incidence of peripheral karyotype abnormalities, microdeletions of the Y chromosome, and sperm aneuploidy.”^7–10

There is evidence of possible paternal contributions to abnormal embryogenesis. The use of “functionally immature” or “structurally abnormal” spermatozoa for ICSI could theoretically be associated with gamete genomic imprinting anomalies and even transmission of damaged DNA.¹¹ At a testicular level, induction of germ-line genomic instability or the suppression of germ-cell apoptosis may be the result of male-mediated teratogenicity and could result in malformation, cancer, and susceptibility to cancer in the offspring.¹² DNA damage could also result from oxidative stress induced by free radicals or be the consequence of apoptosis.^13,14 The short-term and long-term effects of ICSI remain of concern, so the results of the technique must still be closely monitored.

It has been suggested that the incidence of sex chromosomal abnormalities among children born as a result of ICSI is slightly, but significantly, increased.¹⁵ Moreover, limited reports of children conceived through ICSI also suggest developmental problems. In this issue of The Lancet A G Sutcliffe and colleagues report the results of a well-designed, case-control study of neurodevelopmental delay among children in their second year of life who had been conceived through ICSI. There was no difference in the primary outcome measure, neurodevelopmental scores, between the two groups. Additionally, perinatal outcome was similar except for a higher rate of caesarean section and a lower mean birthweight in the study group. Congenital abnormality rates were also similar overall, although there was a trend to more congenital anomalies, especially anomalies of the genitourinary tract, in children born to fathers with oligozoospermia. This new evidence is reassuring in that the majority of children conceived after ICSI were healthy and developmentally normal. However, larger studies with longer follow-up periods, and stratified according to the various spermatozoal defects, are desirable.

On a purely pragmatic level, some ART centres consider that ICSI rather than conventional in-vitro fertilisation (IVF) should be offered as the treatment of choice to all cases requiring assisted reproduction. If generalised without further study, such policy could have a serious impact on medical resources and perhaps even, on overall safety (because of bypassing natural gamete selection and because of the invasiveness of the technique itself).

ICSI has been compared with traditional IVF in a multicentre randomised controlled trial by Siladitya Bhattacharya and colleagues in couples with non-malefactor infertility due to a variety of abnormalities. They report in today's Lancet that implantation rates—the primary outcome reflective of the implantation potential of each transferred embryo—were fairly similar for both techniques. The slightly but significantly higher rate with IVF than with ICSI was possibly due to the method of analysis, which seemed to exaggerate the benefit of IVF because it was not adjusted for the correlated outcomes resulting from clustering of embryos transferred to each woman. In addition, the overall fertilisation rates (per oocyte retrieved) and clinical pregnancy rates were not different. ICSI provided a higher fertilisation rate per oocyte injected (possibly because of better diagnosis of oocyte maturational status at time of injection than is the case with insemination) but was associated with a longer laboratory time.

Notwithstanding limitations such as unmasking of treatment allocation and lack of information on reasons for exclusion from the study, these results strongly support the concept that ICSI offers no advantage in terms of clinical outcomes over standard IVF in cases of non-male-factor infertility and unexplained infertility. The study did not address the impact of the future use of cryopreserved embryos derived from the ICSI and IVF cycles. This issue needs to be clarified, since the “total reproductive potential” probably represents the best estimate of the overall efficacy of ART procedures.¹⁶ Whether ICSI is beneficial in some cases of poor ovarian response or oocyte quality also remains to be further investigated.

On the basis of current evidence, the use of ICSI should be restricted to male-factor infertility, for which it seems to be cost-effective⁶ and relatively safe. However, as in other areas of the ever expanding subspecialty of ART, vigilance is required to identify any potential negative impact on the long-term health of children conceived after ICSI.




References

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