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Intracytoplasmic Sperm Injection Indications:


How Rigorous?

Article in Seminars in Reproductive Medicine July 2014


DOI: 10.1055/s-0034-1375180 Source: PubMed

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283

Intracytoplasmic Sperm Injection Indications:


How Rigorous?
Samir N. Babayev, MD1 Chan Woo Park, MD1,2 Orhan Bukulmez, MD1

1 Division of Reproductive Endocrinology and Infertility, Department Address for correspondence Orhan Bukulmez, MD, Division of
of Obstetrics and Gynecology, University of Texas Southwestern Reproductive Endocrinology and Infertility, Department of Obstetrics
Medical Center, Dallas, Texas and Gynecology, University of Texas Southwestern Medical Center,
2 Division of Reproductive Endocrinology and Infertility, Department 5323 Harry Hines Blvd., Dallas, TX 75390-9032
of Obstetrics and Gynecology, Cheil General Hospital & Womens (e-mail: Orhan.Bukulmez@UTSouthwestern.edu).

Downloaded by: IP-Proxy University of Texas Southwestern, UT Southwestern Medical Center. Copyrighted material.
Healthcare Center, Kwandong University College of Medicine,
Seoul, Korea

Semin Reprod Med 2014;32:283290

Abstract Up to 15% of all couples of reproductive age are diagnosed with subfertility and about
one-third of those will have male factor infertility as a contributing factor. Intra-
cytoplasmic sperm injection (ICSI) has proven to be invaluable for couples with severely
compromised semen parameters. Since its introduction into the clinical practice in
1992, the indications for ICSI were dramatically expanded to include various patient
populations with normal or mildly abnormal semen parameters. Moreover, some
fertility programs choose to perform ICSI for all of their patients needing assisted
reproductive technologies. By all means, the male factor indications for ICSI are not well
Keywords dened, apart from its absolute utility with surgically obtained spermatozoa in the
intracytoplasmic presence of low motility, or in cases of severe defects with sperm concentration and
sperm injection motility. Based on current evidence, ICSI is not indicated for routine use. Its adoption for
ICSI previous history of total fertilization failure, in vitro oocyte maturation, cryopreserved
in vitro fertilization oocytes, polyploidy prevention, poor-quality oocytes, diminished ovarian reserve, and
IVF advanced reproductive age are not supported by current evidence, albeit further
conventional IVF research with well-designed studies is warranted. Finally, from a biological standpoint
assisted reproductive ICSI is considered to be more invasive, more energy consuming for the oocyte itself and
technology its adverse genetic and epigenetic effects cannot be ruled out. Although more studies
ART are needed to clarify denitive indications for ICSI, many of its current applications can
indications be deemed empiric at this time.

Intracytoplasmic sperm injection (ICSI) was introduced in more spermatozoa to achieve fertilization. We intend to review
1992 by Palermo et al for the treatment of infertile couples the widely proposed indications of ICSI to assess if in fact they
with severe male factor and unexplained total fertilization are well supported by the published literature or not.
failure (TFF).1,2 Soon after its introduction to human assisted
reproductive technologies (ARTs), ICSI received wide accep-
Male Factor Indications for Intracytoplasmic
tance even before any reassuring human data were available.
Sperm Injection
Since ICSI requires only one good spermatozoon, it has been
perceived to be much more efcient than in vitro fertilization ICSI involves manual selection of the spermatozoa and its
(IVF) with conventional insemination which requires many subsequent injection into the oocyte, following the stripping

Issue Theme Common Practices in Copyright 2014 by Thieme Medical DOI http://dx.doi.org/
Reproductive Endocrinology and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0034-1375180.
Infertility Supported by Weak or No New York, NY 10001, USA. ISSN 1526-8004.
Evidence; Guest Editor, Orhan Tel: +1(212) 584-4662.
Bukulmez, MD
284 Intracytoplasmic Sperm Injection Indications Babayev et al.

of the cumulus cells, using micromanipulation techniques. strict sperm morphology on pregnancy outcomes, as well as the
Therefore, ICSI quickly became the treatment of choice when utility of different techniques used to overcome the suggested
only surgically obtained testicular or epididymal sperm is adverse effects of teratozoospermia.
available, in cases of acrosomal aplasia and for patients with Recently introduced technique of intracytoplasmic mor-
immotile, but viable spermatozoa.3 phologically selected sperm injection (IMSI), using ultrahigh
It has been challenging to establish a strict denition for magnication of 6,000 to 10,000 (compared with regular
male factor infertility requiring treatment with ICSI, whereas ICSI with 200400) has been proposed as a method enabling
subfertile men may also benet from less costly and less selection of motile spermatozoa free of any structural defects
invasive method of intrauterine insemination (IUI). Over the to optimize ICSI outcome for couples with male factor infer-
past 25 years, the World Health Organization revised its tility.20 Reports of success of IMSI are conicting with some
criteria aimed at dening reference values for semen charac- studies showing advantage over ICSI and others failed to show
teristics three consecutive times after its rst introduction in clinically signicant difference.21 Again denitive criteria to

Downloaded by: IP-Proxy University of Texas Southwestern, UT Southwestern Medical Center. Copyrighted material.
1987.4 Over time, normal values for quantitative and qualita- resort to IMSI do not exist.
tive parameters of sperm had been decreased down to the It has been suggested that there is a relationship between
semen volume of 1.5 mL; sperm count of 15 million per mL; direct antisperm antibody (ASA) levels in semen and preg-
total motility of 40%; and morphologically normal forms of nancy rate after ART but reports in the literature have been
4.0%.4 These values represent semen characteristics associat- conicting. A meta-analysis that included 16 studies (10 IVF
ed with achieving pregnancy within 12 months of unprotect- and 6 ICSI) indicates that the presence of ASA does not
ed sexual intercourse. Unfortunately, these cutoff values inuence pregnancy rates after IVF or ICSI.22 Hence, the
cannot be used for accurate identication of fertile and presence of ASA should not drive the decision of using ICSI
infertile men, but the trend toward decreasing lower refer- versus IVF.
ence limits demonstrates evolution of our understanding of In summary, male factor indications for ICSI are not
how much and what quality spermatozoa are necessary for scrupulous apart from its use with surgically obtained sper-
natural conception. matozoa, certain sperm abnormalities, and severe male factor
There are no randomized clinical trials comparing ICSI dened as inseminating motile count of < 0.5 million.
with conventional IVF in couples with moderate to severe
abnormalities in semen parameters. It is generally accepted
Intracytoplasmic Sperm Injection for All
that ICSI is the only treatment of choice for those cases.
However, it is important to note that certain types of male According to 2011 Society for Assisted Reproductive Tech-
factor can be successfully treated with IUI, which is less nology registry, ICSI was used in two-thirds of all ART cycles
invasive and less costly than either conventional IVF or in the United States.23 It would be nave to think that ICSI is
ICSI.3 For instance, a meta-analysis, which included 17 pro- being used only when male factor infertility is present. The
spectively designed studies showed increased pregnancy same database shows that in only 35% of the patients male
rates with IUI compared with timed intercourse in couples component was a factor.
with male factor infertility.5 One prior study also indicates The routine use of ICSI regardless of cause of infertility has
that inseminating motile count of 1 million spermatozoa may been proposed by different authors.24 Probably the best study
be enough for successful treatment with IUI and even lower evaluating this issue is a multicenter trial from the United
counts may lead to pregnancy with IUI if a 4% strict morphol- Kingdom which randomized 415 couples with nonmale
ogy criterion has been met.6 Proceeding directly with ICSI in factor infertility to ICSI versus conventional IVF.25 Primary
men with only one abnormal semen parameter or resorting to outcome of implantation rate was actually higher with con-
IVF/ICSI, early in the process of evaluation of male subfertility ventional IVF than that was achieved with ICSI (30 vs. 22%
may be questionable in terms of its cost-effectiveness.7 with p < 0.05). Of note, fertilization rates per oocyte re-
The decision for choosing ICSI over conventional IVF in trieved and the pregnancy rate were also higher in IVF group,
male factor infertility is generally arbitrary with some au- although the difference in the pregnancy rates did not reach
thors proposing the use of total inseminating motile count statistical signicance (58 vs. 47% with p < 0.0001 and 33 vs.
cutoff values of below 0.5 to 1 million to recommend that the 26% with p 0.11, respectively). ICSI resulted in a higher
couple should be offered ICSI over conventional IVF.8,9 fertilization rate per oocyte injected, whereas this could be
Kruger et al in 1986 proposed their strict sperm morphology due to a better detection of the oocyte maturational status
criteria and correlated these with probability of fertilization by after cumulus cells were removed. Authors concluded that
conventional IVF.10 Later other investigators adopted and rened ICSI requires signicantly higher resource utilization without
the system concluding that at least 5% morphologically normal offering any clinical advantage over conventional IVF for
sperm is necessary to optimize the fertilization rate.11,12 Initially couples with nonmale factor infertility.
high insemination concentration and then, ICSI was recom-
mended for treatment of teratozoospermia (< 5% morphologi-
Intracytoplasmic Sperm Injection for Failed
cally normal sperm).1315 Yet, other studies questioned whether
Fertilization with IVF
teratozoospermia has any negative effects on fertilization, preg-
nancy, and live birth rates.1619 Therefore, well-designed studies An outcome of TFF following conventional IVF is a frustrating
are still needed to make a denitive conclusion on the impact of experience for patients as well as clinicians. In normospermic

Seminars in Reproductive Medicine Vol. 32 No. 4/2014


Intracytoplasmic Sperm Injection Indications Babayev et al. 285

patients undergoing conventional IVF, the rates of TFF and low unfertilized oocytes 15 to 18 hours after the initial insemina-
fertilization (dened as < 25% fertilization rate) were re- tion has been performed with ICSI.33 However, the reports
ported as 5 to 15 and 20%, respectively.26,27 When TFF occurs indicated that normal fertilization rates after rescue ICSI
during conventional IVF, most clinicians would proceed di- remained relatively low and the generated embryos achieved
rectly with ICSI in subsequent cycles. Some authors have low pregnancy rates.33,34 It is thought that oocyte quality
proposed splitting the sibling oocytes into ICSI and conven- diminishes 24 hours after retrieval, and although some
tional IVF in subsequent cycles.28 oocytes still may be fertilized, the embryos derived from
The chance of recurrence of TFF in a subsequent conven- rescue ICSI procedures often arrest in early stages of devel-
tional IVF cycle is reported to be between 30 and 50% rather opment. Furthermore, high rates of polyploidy were reported
than an expected rate of 100%. Therefore, it is suspected that in embryos fertilized by rescue ICSI.33
some factors other than the insemination method used may Considering the very low pregnancy rates in addition to
be responsible for TFF and the condition may not be repeti- the potential genetic risks associated with the aging oocytes

Downloaded by: IP-Proxy University of Texas Southwestern, UT Southwestern Medical Center. Copyrighted material.
tive. Hence, it may be reasonable to undertake additional in culture, some authors suggest that rescue ICSI should not
conventional IVF attempts before reverting to ICSI. One be attempted.33
retrospective analysis of 555 couples showed that 87% of
the patients (mean age with standard deviation [SD]
Intracytoplasmic Sperm Injection for
36.9  4.6) were able to achieve fertilization in subsequent
Unexplained Infertility
cycles using conventional IVF with delivery rates being 44%
per patient, 25% per embryo transfer (ET), which was compa- Up to 30% of couples seeking fertility treatment are ultimately
rable to the delivery rates observed in ICSI group (23% per diagnosed with unexplained infertility.35 Although the un-
patient and 23% per ET).29 Another interesting retrospective derlying cause of infertility is unknown, it is has been
report compared the fertilization, implantation, and preg- hypothesized that the mechanisms may include fertilization
nancy rates after ICSI, among 65 nonmale factor patients defects even when the semen parameters are normal.
with history of failed/low fertilization with conventional IVF, In general, IVF has been shown to be an effective therapy
and in 219 patients with primary male factor. Despite the for couples with unexplained infertility. However, in 5 to 25%
comparable fertilization and cleavage rates and similar num- of these couples, TFF may occur with the use of conventional
ber and quality of embryos transferred, patients with previ- IVF.14,36 Since it is difcult to predict which couples with
ous failed/low fertilization with conventional IVF had unexplained infertility may experience TFF, some physicians
signicantly lower clinical pregnancy rate following subse- resort to the practice of split ICSI and IVF, to minimize the risk
quent ICSI than those with primary male factor (19.6 vs. of TFF.
33.5%, respectively).30 These studies suggest that convention- A recent meta-analysis examined the fertilization rates
al IVF may be reattempted in subsequent cycles considering per retrieved oocyte of couples with unexplained infertility
the encouraging fertilization and pregnancy rates with this in 11 randomized controlled studies.37 In ve of these
more conservative approach. studies, sibling oocytes were specically stated to be as-
To our knowledge, there is only one published prospective signed to ICSI or conventional IVF before assessment of
study reporting that ICSI may be better than conventional maturity while no relevant information was presented in
IVF.28 In this study, sibling oocytes were subjected to ICSI and others. To avoid signicant heterogeneity one of these ve
IVF after the rst IVF attempt resulted in TFF and low trials were not included in relative risk (RR) calculation. The
fertilization. In TFF group, fertilization rate per oocyte re- likelihood of fertilization per allocated oocyte was signi-
trieved was 48% for ICSI and 11% for conventional IVF. The cantly higher for ICSI when compared with conventional
same rates for ICSI and conventional IVF in prior low fertili- IVF. The pooled RR of fertilization per oocyte before ran-
zation group were 60 and 22%, respectively, favoring ICSI. It is domization was higher with ICSI than with conventional
noteworthy that this study included only 38 couples and the IVF (RR, 1.43; 95% condence interval [CI], 1.381.48). The
pregnancy rates were difcult to assess since some patients pooled RR of TFF for all 11 trials included in the meta-
received both ICSI and IVF fertilized embryos. Thus, reaching analysis was signicantly higher with conventional IVF
a denitive conclusion on this matter is somewhat difcult. than with ICSI (RR, 8.22; 95% CI, 4.4415.23). Importantly,
Even American Society for Reproductive Medicine (ASRM) the number of ICSI procedures needed to prevent one case
concluded that although subsequent total failed fertilization of TFF was ve. In these trials, each patient served as her
may be related to the IVF stimulation, utilizing IVF/ICSI may own control, thereby reducing the impact of potentially
decrease the risk of subsequent fertilization failure, without important confounders, such as maternal age, ovarian
mentioning about any potential improvement in pregnancy stimulation, oocyte and sperm quality, and laboratory
rates.31 conditions. It is important to note that the oocytes allocated
to ICSI are routinely assessed for nuclear maturity, while
those fertilized by conventional IVF are not. This selection
Rescue Intracytoplasmic Sperm Injection
bias may contribute to a higher fertilization rate per oocyte
Rescue ICSI has been proposed as a method for overcoming compared with unselected oocytes undergoing conven-
fertilization failure of oocytes the next day following conven- tional IVF at least in some of these trials. Above all, the
tional IVF.32 To rescue the IVF cycle, reinsemination of the comparison of pregnancy and live birth rates between the

Seminars in Reproductive Medicine Vol. 32 No. 4/2014


286 Intracytoplasmic Sperm Injection Indications Babayev et al.

two groups could not be made, since only few studies embryo quality between ICSI and conventional IVF in this
reported pregnancy-related outcomes with widely differ- study.43 This study did not use any additional genetic meth-
ent embryo selection criteria. Furthermore, the pooling of ods to assess if the 3PN embryos observed were in fact triploid
embryos obtained from ICSI and conventional IVF for ET or not.
and relatively few numbers of transfers rendered pregnan- Surprisingly, one published report claimed that the per-
cy outcome assessment impossible. centage of multipronucleated zygote formation may in fact be
Although there are clues that ICSI may benet some a good prognostic sign for conception because signicantly
couples with unexplained infertility, more studies reporting higher 2PN fertilization and improved pregnancy rates were
pregnancy outcomes are needed. found in these cases.44 Of note, the embryos developed from
multinucleated zygotes were deemed to be untransferrable. A
possible explanation for this correlation could be that the
Intracytoplasmic Sperm Injection for Poor-
multipronucleated zygote formation was associated with

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Quality Oocytes
higher number of retrieved oocytes and better sperm motility
It has been hypothesized that ICSI might be a better method parameters after swim-up.
of fertilization than conventional IVF for patients with Although it might be possible to prevent polyploidy caused
poor-quality oocytes, which is assessed mainly by morpho- by dispermy utilizing ICSI, the development of multinucleat-
logical features. To our knowledge, there is no published ed zygotes can also be caused by oocyte-related factors such
study assessing whether the use of ICSI actually improves as the fertilization of a diploid oocyte by the haploid sperm,
the pregnancy outcome in morphologically abnormal suggesting that ICSI may not prevent all cases of polyploidy.
oocytes. Although it is possible to decrease the number of ART-
associated polyploidy cases utilizing ICSI, further studies
are needed to assess if it is actually benecial in terms of
Intracytoplasmic Sperm Injection for Poor
achieving more healthy live births.
Responders
ICSI is commonly used in poor responders to ovarian stimu-
Intracytoplasmic Sperm Injection for
lation with the idea of improving fertilization rates in the few
Prevention of Male-to-Female HIV and HCV
oocytes that are available for fertilization. One prospective
Transmission
trial randomized 96 nonmale infertility cases with six or
fewer retrieved oocytes to conventional IVF and ICSI.38 ICSI ICSI has been suggested to be instrumental for prevention of
and conventional IVF resulted in similar fertilization rates per human immunodeciency virus (HIV) and hepatitis C virus
retrieved oocyte (56.5 vs. 58.8%, respectively). Furthermore, (HCV) transmission from infected men in serodiscordant
comparable quantity and quality of embryos, implantation couples based on the idea that using single spermatozoon
rates, and pregnancy rates (17.3 vs. 21.1%, with ICSI and per inseminated oocyte would be safer.45,46 Contrary to this
conventional IVF, respectively) were obtained. Few retrospec- idea, the Dutch Society of Obstetrics and Gynecology recom-
tive reports also conrmed that ICSI did not improve out- mends against using ICSI in HIV serodiscordant couples,
comes in patients with poor response to stimulation when justifying it with the concern that the injection of a sperma-
semen parameters were normal.3941 As it was concluded in tozoon that might carry an HIV-1 particle, directly into the
recently published committee opinion of the ASRM, based oocyte may lead to incorporation of the viral genetic material
on current evidence, the use of ICSI for low oocyte yield does into the future embryo with unknown but potentially disas-
not signicantly improve fertilization rates, embryo number trous consequences.47 To our knowledge, there are no well-
and quality, or pregnancy rates.31 designed studies to address this issue. Since most serodis-
cordant couples are not infertile, ICSI may not be used
routinely. Although being much cheaper and less invasive
Intracytoplasmic Sperm Injection for
than ICSI, sperm gradient separations in combination with
Prevention of Triploidy
IUI have been used for prevention of male-to-female viral
The incidence of triploidy in human embryos after conven- transmission with more than 20 years of clinical experi-
tional IVF has been reported as anywhere from 2 to 10% with ence.48 The efcacy of gradient techniques to reduce viral
dispermy, that is, the fertilization of a haploid oocyte with loads in sperm preparations is well established, and it may be
two haploid sperm, being the most common cause.42 A improved by incorporation of polymerase chain reaction
retrospective analysis of 95 couples with 20% incidence of based techniques for viral detection.48,49 It is important to
tripronucleated (3PN) zygotes in their initial conventional IVF note that the decrease in viral load does not translate into
cycles followed by the use of ICSI in a subsequent attempt complete prevention of viral transmission. Nevertheless, in
showed that after ICSI, the rate of two pronucleated (2PN) the absence of strong supporting evidence, there is no
zygotes was higher (65 vs. 34.1%) and the rate of 3PN ones was consensus about the relative merits of ICSI to prevent a
lower (5.0 vs. 33.9%) than the prior conventional IVF proce- horizontal transmission of HIV and HCV from male-to-fe-
dures. Eventually, more 2PN embryos were obtained with ICSI male partner.50 Finding the right evidence is especially
as compared with conventional IVF (5.5  3.7 vs. 3.4  2.2 challenging in HCV transmission research, since it was
[mean  SD], respectively). There was no difference in shown to be a rare event.51

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Intracytoplasmic Sperm Injection Indications Babayev et al. 287

Intracytoplasmic Sperm Injection for Oocyte Cryopreservation and


Preimplantation Genetic Testing Intracytoplasmic Sperm Injection
Irrespective of what approach is taken for preimplantation ICSI has currently been adopted as a method for fertilization
genetic testing (PGT), accurate diagnosis is of utmost impor- of cryopreserved oocytes. It is thought that the removal of
tance. Although the testing errors can arise from many cumulus cells and the cryopreservation process itself might
different problems in a PGT procedure, the most common decrease the chances of conventional IVF to fertilize the
and worrisome ones have been quoted to be the issues related oocyte after it is thawed. Evidence examining this hypothesis
to sample contamination. Utilizing ICSI rather than the is conicting with some studies reporting comparable fertili-
conventional IVF in PGT cycles is recommended to prevent zation rates in cryopreserved oocytes between conventional
paternal contamination from excess sperm introduced into IVF and ICSI and yet others proclaiming ICSI as the superior
the zona pellucida, or maternal contamination from granu- method in that respect.5759 Again, there is lack of evidence

Downloaded by: IP-Proxy University of Texas Southwestern, UT Southwestern Medical Center. Copyrighted material.
losa cells especially with PGT performed for single gene from prospective randomized studies to suggest that ICSI is
defects.52 superior to conventional IVF, although ICSI has been the
Although literature is lacking well-designed trials, in method of choice in majority of the clinical studies on
light of biological plausibility, ICSI was recommended for cryopreserved oocytes.60
PGT when DNA amplication techniques are used. But
again by using more advanced technologies in proper
Risks of Intracytoplasmic Sperm Injection
identication of maternal and paternal DNA as well as
the embryonic DNA, these concerns can be relieved in One must be aware of the differences between the fertiliza-
the near future.53,54 tion processes with conventional IVF and ICSI. In biological
terms, ICSI is quite an invasive procedure. ICSI bypasses the
natural selection barriers of the oocyte with a potential of
Intracytoplasmic Sperm Injection for
introducing a genetically defective material. Moreover, ICSI
Oocytes Matured In Vitro
also involves the immobilization of spermatozoon before
For in vitro maturation (IVM) cases, due to the potential injection, which is commonly achieved by crushing its tail
changes in the characteristics of the oocytes and zona with subsequent exposure of its internals to potentially
pellucida potentially caused by prolonged exposure of damaging medium components. Another important differ-
immature oocytes to the culture media, ICSI has been ence between ICSI and conventional IVF is that during ICSI,
advocated as the preferred method of fertilization. The the entire spermatozoon is introduced into the ooplasm
outcomes from one randomized trial suggest that in the including the acrosome with its hydrolyzing enzymes, sperm
presence of normal semen parameters, conventional IVF plasma membrane, tail, and mitochondria, whereas these
would be a valid fertilization technique for oocytes re- components are largely avoided during conventional IVF and
trieved from women with polycystic ovary syndrome and the oocyte will not require extra energy and material for their
matured in vitro.55 The lack of a signicant difference in intracytoplasmic elimination.61 We may not rule out the
fertilization rates between the ICSI and conventional IVF potentially harmful effects of acrosomal enzymes on embryo
groups in this study indicates that IVF can be used to development with injection of acrosome-intact spermatozoa
achieve acceptable fertilization rates after IVM. The simi- as well. It seems that ICSI is more energy consuming for the
larity in cleavage and blastocyst development rates sug- oocyte itself than conventional IVF, which may have impli-
gests that the oocytes inseminated by conventional IVF are cations for its routine application for oocytes retrieved from
just as capable of producing viable embryos as ICSI fertil- women with advanced reproductive age.61
ized oocytes. Pregnancies achieved by ART are considered as high-risk
Although in another retrospective analysis, fertilization pregnancies with increased risks of hypertensive disorders,
rates appear to be increased by utilizing ICSI after IVM, the preeclampsia, intrauterine growth restriction, premature
better fertilization rates did not translate into better out- birth, and intrauterine fetal demise.62 These risks are as-
comes. In this study, the fertilization rates in oocytes sub- sumed to be the complications of multiple pregnancies
jected to IVM were 37.7% (229/608) with conventional IVF as associated with ART and also associated with other specics
compared with 69.3% (318/459) when ICSI was used. Despite of infertile couples and not the methods used for their
the lower fertilization rate, the implantation rate was signi- treatment. Although, earlier reports did not show any signi-
cantly higher in embryos derived from oocytes fertilized with cant increase in the congenital malformations after ICSI, the
conventional IVF as compared with ICSI (24.2 vs. 14.8%; quality of these studies has been questioned.6368 Even in
p < 0.05). Furthermore, the clinical pregnancy rate per ET studies where ICSI has been shown to be associated with an
was signicantly higher with conventional IVF as well (34.5 increased risk of adverse outcome, this risk was attributed to
vs. 20.0%; p < 0.05).56 the underlying male factors as the indications for the use of
With the improvements in IVM culture conditions, con- ICSI. Recent studies are indicating slight increase in the
ventional IVF can achieve viable embryos with improved congenital malformation risk in children born after ICSI.
implantation and pregnancy rates while being a more cost- One prospective, multicenter study from Germany included
effective and less invasive technique. 3,372 children and fetuses beyond 16 weeks of gestation

Seminars in Reproductive Medicine Vol. 32 No. 4/2014


288 Intracytoplasmic Sperm Injection Indications Babayev et al.

conceived via ICSI, mainly indicated for severe male factor 6 Ombelet W, Vandeput H, Van de Putte G, et al. Intrauterine
infertility and fertilization failure in prior IVF cycles. Com- insemination after ovarian stimulation with clomiphene citrate:
pared with 8,016 children and fetuses conceived naturally, predictive potential of inseminating motile count and sperm
morphology. Hum Reprod 1997;12(7):14581463
the RR for major malformation in ICSI cohort was 1.44 (95% CI,
7 Goverde AJ, McDonnell J, Vermeiden JP, Schats R, Rutten FF,
1.251.6). After adjustment for confounding factors, ICSI Schoemaker J. Intrauterine insemination or in-vitro fertilisation
cohort still showed increased odds ratio (1.24; 95% CI, in idiopathic subfertility and male subfertility: a randomised
1.021.50).69 trial and cost-effectiveness analysis. Lancet 2000;355(9197):
With two-thirds of ART pregnancies in the United States 1318
8 Kastrop PM, Weima SM, Van Kooij RJ, Te Velde ER. Comparison
achieved by ICSI, clearly this technique is used not only for
between intracytoplasmic sperm injection and in-vitro fertiliza-
male factor infertility. Unfortunately, there are no studies
tion (IVF) with high insemination concentration after total fertili-
evaluating safety of ICSI in nonmale factor infertility and zation failure in a previous IVF attempt. Hum Reprod 1999;14(1):
hence the literature still suggests that the perceived increase

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6569
in birth defect rates with ICSI as compared with conventional 9 Verheyen G, Tournaye H, Staessen C, De Vos A, Vandervorst M,
IVF might be related to the genetic or epigenetic factors Van Steirteghem A. Controlled comparison of conventional in-
vitro fertilization and intracytoplasmic sperm injection in pa-
associated with severe male factor.70
tients with asthenozoospermia. Hum Reprod 1999;14(9):
23132319
10 Kruger TF, Menkveld R, Stander FS, et al. Sperm morphologic
Conclusion
features as a prognostic factor in in vitro fertilization. Fertil Steril
In the eld of ART, it is common to see widespread adoption of 1986;46(6):11181123
new technology with ever expanding indications but without 11 Gunalp S, Onculoglu C, Gurgan T, Kruger TF, Lombard CJ. A study of
semen parameters with emphasis on sperm morphology in a
sufcient evidence to support these uses unequivocally. The
fertile population: an attempt to develop clinical thresholds.
application of the new technologies tends to be empirical, and Hum Reprod 2001;16(1):110114
the available evidence may be largely ignored or dismissed in 12 Menkveld R, Wong WY, Lombard CJ, et al. Semen parameters,
favor of the new intervention. ICSI is used as a robust method including WHO and strict criteria morphology, in a fertile and
for achieving fertilization by many IVF centers around the subfertile population: an effort towards standardization of in-vivo
thresholds. Hum Reprod 2001;16(6):11651171
world, whereas the reproductive specialists may also consid-
13 Plachot M, Belaisch-Allart J, Mayenga JM, Chouraqui A, Tesquier L,
er offering the most cost-effective and the least invasive
Serkine AM. Outcome of conventional IVF and ICSI on sibling
techniques while maximizing the likelihood of a healthy oocytes in mild male factor infertility. Hum Reprod 2002;17(2):
live birth. The current scientic evidence does not support 362369
the widespread use of ICSI without well-established indica- 14 Tournaye H, Verheyen G, Albano C, et al. Intracytoplasmic sperm
tions. There is paucity of good-quality data from prospective injection versus in vitro fertilization: a randomized controlled trial
and a meta-analysis of the literature. Fertil Steril 2002;78(5):
studies to further clarify the indications for ICSI. There is also
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