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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
of Obstetrics and Gynecology, University of Texas Southwestern
Medical Center, Dallas, Texas
2 Division of Reproductive Endocrinology and Infertility, Department
of Obstetrics and Gynecology, Cheil General Hospital & Womens
Address for correspondence Orhan Bukulmez, MD, Division of
Reproductive Endocrinology and Infertility, Department of Obstetrics
and Gynecology, University of Texas Southwestern Medical Center,
5323 Harry Hines Blvd., Dallas, TX 75390-9032
(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
1992 by Palermo et al for the treatment of infertile couples
with severe male factor and unexplained total fertilization
failure (TFF).1,2 Soon after its introduction to human assisted
reproductive technologies (ARTs), ICSI received wide accep-
tance even before any reassuring human data were available.
Since ICSI requires only one good spermatozoon, it has been
perceived to be much more efcient than in vitro fertilization
(IVF) with conventional insemination which requires many
more spermatozoa to achieve fertilization. We intend to review
the widely proposed indications of ICSI to assess if in fact they
are well supported by the published literature or not.
Male Factor Indications for Intracytoplasmic
Sperm Injection
ICSI involves manual selection of the spermatozoa and its
subsequent injection into the oocyte, following the stripping

Issue Theme Common Practices in
Reproductive Endocrinology and
Infertility Supported by Weak or No
Evidence; Guest Editor, Orhan
Bukulmez, MD
Copyright 2014 by Thieme Medical DOI http://dx.doi.org/
Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0034-1375180.
New York, NY 10001, USA. ISSN 1526-8004.
Tel: +1(212) 584-4662.
284 Intracytoplasmic Sperm Injection Indications Babayev et al.
of the cumulus cells, using micromanipulation techniques.
Therefore, ICSI quickly became the treatment of choice when
only surgically obtained testicular or epididymal sperm is
available, in cases of acrosomal aplasia and for patients with
immotile, but viable spermatozoa.3
It has been challenging to establish a strict denition for
male factor infertility requiring treatment with ICSI, whereas
subfertile men may also benet from less costly and less
invasive method of intrauterine insemination (IUI). Over the
past 25 years, the World Health Organization revised its
criteria aimed at dening reference values for semen charac-
teristics three consecutive times after its rst introduction in
1987.4 Over time, normal values for quantitative and qualita-
tive parameters of sperm had been decreased down to the
semen volume of 1.5 mL; sperm count of 15 million per mL;
total motility of 40%; and morphologically normal forms of
4.0%.4 These values represent semen characteristics associat-
ed with achieving pregnancy within 12 months of unprotect-
ed sexual intercourse. Unfortunately, these cutoff values
cannot be used for accurate identication of fertile and
infertile men, but the trend toward decreasing lower refer-
ence limits demonstrates evolution of our understanding of
how much and what quality spermatozoa are necessary for
natural conception.
There are no randomized clinical trials comparing ICSI
with conventional IVF in couples with moderate to severe
abnormalities in semen parameters. It is generally accepted
that ICSI is the only treatment of choice for those cases.
However, it is important to note that certain types of male
factor can be successfully treated with IUI, which is less
invasive and less costly than either conventional IVF or
ICSI.3 For instance, a meta-analysis, which included 17 pro-
spectively designed studies showed increased pregnancy
rates with IUI compared with timed intercourse in couples
with male factor infertility.5 One prior study also indicates
that inseminating motile count of 1 million spermatozoa may
be enough for successful treatment with IUI and even lower
counts may lead to pregnancy with IUI if a 4% strict morphol-
ogy criterion has been met.6 Proceeding directly with ICSI in
men with only one abnormal semen parameter or resorting to
IVF/ICSI, early in the process of evaluation of male subfertility
may be questionable in terms of its cost-effectiveness.7
The decision for choosing ICSI over conventional IVF in
male factor infertility is generally arbitrary with some au-
thors proposing the use of total inseminating motile count
cutoff values of below 0.5 to 1 million to recommend that the
couple should be offered ICSI over conventional IVF.8,9
Kruger et al in 1986 proposed their strict sperm morphology
criteria and correlated these with probability of fertilization by
conventional IVF.10 Later other investigators adopted and rened
the system concluding that at least 5% morphologically normal
sperm is necessary to optimize the fertilization rate.11,12 Initially
high insemination concentration and then, ICSI was recom-
mended for treatment of teratozoospermia (< 5% morphologi-
cally normal sperm).1315 Yet, other studies questioned whether
teratozoospermia has any negative effects on fertilization, preg-
nancy, and live birth rates.1619 Therefore, well-designed studies
are still needed to make a denitive conclusion on the impact of
Seminars in Reproductive Medicine Vol. 32 No. 4/2014
strict sperm morphology on pregnancy outcomes, as well as the
utility of different techniques used to overcome the suggested
adverse effects of teratozoospermia.
Recently introduced technique of intracytoplasmic mor-
phologically selected sperm injection (IMSI), using ultrahigh
magnication of
6,000 to 10,000 (compared with regular
ICSI with
200400) has been proposed as a method enabling
selection of motile spermatozoa free of any structural defects
to optimize ICSI outcome for couples with male factor infer-
tility.20 Reports of success of IMSI are conicting with some
studies showing advantage over ICSI and others failed to show
clinically signicant difference.21 Again denitive criteria to
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resort to IMSI do not exist.
It has been suggested that there is a relationship between
direct antisperm antibody (ASA) levels in semen and preg-
nancy rate after ART but reports in the literature have been
conicting. A meta-analysis that included 16 studies (10 IVF
and 6 ICSI) indicates that the presence of ASA does not
inuence pregnancy rates after IVF or ICSI.22 Hence, the
presence of ASA should not drive the decision of using ICSI
versus IVF.
In summary, male factor indications for ICSI are not
scrupulous apart from its use with surgically obtained sper-
matozoa, certain sperm abnormalities, and severe male factor
dened as inseminating motile count of < 0.5 million.
Intracytoplasmic Sperm Injection for All
According to 2011 Society for Assisted Reproductive Tech-
nology registry, ICSI was used in two-thirds of all ART cycles
in the United States.23 It would be nave to think that ICSI is
being used only when male factor infertility is present. The
same database shows that in only 35% of the patients male
component was a factor.
The routine use of ICSI regardless of cause of infertility has
been proposed by different authors.24 Probably the best study
evaluating this issue is a multicenter trial from the United
Kingdom which randomized 415 couples with nonmale
factor infertility to ICSI versus conventional IVF.25 Primary
outcome of implantation rate was actually higher with con-
ventional IVF than that was achieved with ICSI (30 vs. 22%
with p < 0.05). Of note, fertilization rates per oocyte re-
trieved and the pregnancy rate were also higher in IVF group,
although the difference in the pregnancy rates did not reach
statistical signicance (58 vs. 47% with p < 0.0001 and 33 vs.
26% with p 0.11, respectively). ICSI resulted in a higher
fertilization rate per oocyte injected, whereas this could be
due to a better detection of the oocyte maturational status
after cumulus cells were removed. Authors concluded that
ICSI requires signicantly higher resource utilization without
offering any clinical advantage over conventional IVF for
couples with nonmale factor infertility.
Intracytoplasmic Sperm Injection for Failed
Fertilization with IVF
An outcome of TFF following conventional IVF is a frustrating
experience for patients as well as clinicians. In normospermic
 Intracytoplasmic Sperm Injection Indications
patients undergoing conventional IVF, the rates of TFF and low
fertilization (dened as < 25% fertilization rate) were re-
ported as 5 to 15 and 20%, respectively.26,27 When TFF occurs
during conventional IVF, most clinicians would proceed di-
rectly with ICSI in subsequent cycles. Some authors have
proposed splitting the sibling oocytes into ICSI and conven-
tional IVF in subsequent cycles.28
The chance of recurrence of TFF in a subsequent conven-
tional IVF cycle is reported to be between 30 and 50% rather
than an expected rate of 100%. Therefore, it is suspected that
some factors other than the insemination method used may
be responsible for TFF and the condition may not be repeti-
tive. Hence, it may be reasonable to undertake additional
conventional IVF attempts before reverting to ICSI. One
retrospective analysis of 555 couples showed that 87% of
the patients (mean age with standard deviation [SD]
36.9  4.6) were able to achieve fertilization in subsequent
cycles using conventional IVF with delivery rates being 44%
per patient, 25% per embryo transfer (ET), which was compa-
rable to the delivery rates observed in ICSI group (23% per
patient and 23% per ET).29 Another interesting retrospective
report compared the fertilization, implantation, and preg-
nancy rates after ICSI, among 65 nonmale factor patients
with history of failed/low fertilization with conventional IVF,
and in 219 patients with primary male factor. Despite the
comparable fertilization and cleavage rates and similar num-
ber and quality of embryos transferred, patients with previ-
ous failed/low fertilization with conventional IVF had
signicantly lower clinical pregnancy rate following subse-
quent ICSI than those with primary male factor (19.6 vs.
33.5%, respectively).30 These studies suggest that convention-
al IVF may be reattempted in subsequent cycles considering
the encouraging fertilization and pregnancy rates with this
more conservative approach.
To our knowledge, there is only one published prospective
study reporting that ICSI may be better than conventional
IVF.28 In this study, sibling oocytes were subjected to ICSI and
IVF after the rst IVF attempt resulted in TFF and low
fertilization. In TFF group, fertilization rate per oocyte re-
trieved was 48% for ICSI and 11% for conventional IVF. The
same rates for ICSI and conventional IVF in prior low fertili-
zation group were 60 and 22%, respectively, favoring ICSI. It is
noteworthy that this study included only 38 couples and the
pregnancy rates were difcult to assess since some patients
received both ICSI and IVF fertilized embryos. Thus, reaching
a denitive conclusion on this matter is somewhat difcult.
Even American Society for Reproductive Medicine (ASRM)
concluded that although subsequent total failed fertilization
may be related to the IVF stimulation, utilizing IVF/ICSI may
decrease the risk of subsequent fertilization failure, without
mentioning about any potential improvement in pregnancy
rates.31
Rescue Intracytoplasmic Sperm Injection
Rescue ICSI has been proposed as a method for overcoming
fertilization failure of oocytes the next day following conven-
tional IVF.32 To rescue the IVF cycle, reinsemination of the
Babayev et al. 285
unfertilized oocytes 15 to 18 hours after the initial insemina-
tion has been performed with ICSI.33 However, the reports
indicated that normal fertilization rates after rescue ICSI
remained relatively low and the generated embryos achieved
low pregnancy rates.33,34 It is thought that oocyte quality
diminishes 24 hours after retrieval, and although some
oocytes still may be fertilized, the embryos derived from
rescue ICSI procedures often arrest in early stages of devel-
opment. Furthermore, high rates of polyploidy were reported
in embryos fertilized by rescue ICSI.33
Considering the very low pregnancy rates in addition to
the potential genetic risks associated with the aging oocytes
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in culture, some authors suggest that rescue ICSI should not
be attempted.33
Intracytoplasmic Sperm Injection for
Unexplained Infertility
Up to 30% of couples seeking fertility treatment are ultimately
diagnosed with unexplained infertility.35 Although the un-
derlying cause of infertility is unknown, it is has been
hypothesized that the mechanisms may include fertilization
defects even when the semen parameters are normal.
In general, IVF has been shown to be an effective therapy
for couples with unexplained infertility. However, in 5 to 25%
of these couples, TFF may occur with the use of conventional
IVF.14,36 Since it is difcult to predict which couples with
unexplained infertility may experience TFF, some physicians
resort to the practice of split ICSI and IVF, to minimize the risk
of TFF.
A recent meta-analysis examined the fertilization rates
per retrieved oocyte of couples with unexplained infertility
in 11 randomized controlled studies.37 In ve of these
studies, sibling oocytes were specically stated to be as-
signed to ICSI or conventional IVF before assessment of
maturity while no relevant information was presented in
others. To avoid signicant heterogeneity one of these ve
trials were not included in relative risk (RR) calculation. The
likelihood of fertilization per allocated oocyte was signi-
cantly higher for ICSI when compared with conventional
IVF. The pooled RR of fertilization per oocyte before ran-
domization was higher with ICSI than with conventional
IVF (RR, 1.43; 95% condence interval [CI], 1.381.48). The
pooled RR of TFF for all 11 trials included in the meta-
analysis was signicantly higher with conventional IVF
than with ICSI (RR, 8.22; 95% CI, 4.4415.23). Importantly,
the number of ICSI procedures needed to prevent one case
of TFF was ve. In these trials, each patient served as her
own control, thereby reducing the impact of potentially
important confounders, such as maternal age, ovarian
stimulation, oocyte and sperm quality, and laboratory
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
bias may contribute to a higher fertilization rate per oocyte
compared with unselected oocytes undergoing conven-
tional IVF at least in some of these trials. Above all, 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
reported pregnancy-related outcomes with widely differ-
ent embryo selection criteria. Furthermore, the pooling of
embryos obtained from ICSI and conventional IVF for ET
and relatively few numbers of transfers rendered pregnan-
cy outcome assessment impossible.
Although there are clues that ICSI may benet some
couples with unexplained infertility, more studies reporting
pregnancy outcomes are needed.
Intracytoplasmic Sperm Injection for Poor-
Quality Oocytes
It has been hypothesized that ICSI might be a better method
of fertilization than conventional IVF for patients with
poor-quality oocytes, which is assessed mainly by morpho-
logical features. To our knowledge, there is no published
study assessing whether the use of ICSI actually improves
the pregnancy outcome in morphologically abnormal
oocytes.
Intracytoplasmic Sperm Injection for Poor
Responders
ICSI is commonly used in poor responders to ovarian stimu-
lation with the idea of improving fertilization rates in the few
oocytes that are available for fertilization. One prospective
trial randomized 96 nonmale infertility cases with six or
fewer retrieved oocytes to conventional IVF and ICSI.38 ICSI
and conventional IVF resulted in similar fertilization rates per
retrieved oocyte (56.5 vs. 58.8%, respectively). Furthermore,
comparable quantity and quality of embryos, implantation
rates, and pregnancy rates (17.3 vs. 21.1%, with ICSI and
conventional IVF, respectively) were obtained. Few retrospec-
tive reports also conrmed that ICSI did not improve out-
comes in patients with poor response to stimulation when
semen parameters were normal.3941 As it was concluded in
recently published committee opinion of the ASRM, based
on current evidence, the use of ICSI for low oocyte yield does
not signicantly improve fertilization rates, embryo number
and quality, or pregnancy rates.31
Intracytoplasmic Sperm Injection for
Prevention of Triploidy
The incidence of triploidy in human embryos after conven-
tional IVF has been reported as anywhere from 2 to 10% with
dispermy, that is, the fertilization of a haploid oocyte with
two haploid sperm, being the most common cause.42 A
retrospective analysis of 95 couples with 20% incidence of
tripronucleated (3PN) zygotes in their initial conventional IVF
cycles followed by the use of ICSI in a subsequent attempt
showed that after ICSI, the rate of two pronucleated (2PN)
zygotes was higher (65 vs. 34.1%) and the rate of 3PN ones was
lower (5.0 vs. 33.9%) than the prior conventional IVF proce-
dures. Eventually, more 2PN embryos were obtained with ICSI
as compared with conventional IVF (5.5  3.7 vs. 3.4  2.2
[mean  SD], respectively). There was no difference in
Seminars in Reproductive Medicine Vol. 32 No. 4/2014
embryo quality between ICSI and conventional IVF in this
study.43 This study did not use any additional genetic meth-
ods to assess if the 3PN embryos observed were in fact triploid
or not.
Surprisingly, one published report claimed that the per-
centage of multipronucleated zygote formation may in fact be
a good prognostic sign for conception because signicantly
higher 2PN fertilization and improved pregnancy rates were
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
multipronucleated zygote formation was associated with
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higher number of retrieved oocytes and better sperm motility
parameters after swim-up.
Although it might be possible to prevent polyploidy caused
by dispermy utilizing ICSI, the development of multinucleat-
ed zygotes can also be caused by oocyte-related factors such
as the fertilization of a diploid oocyte by the haploid sperm,
suggesting that ICSI may not prevent all cases of polyploidy.
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
achieving more healthy live births.
Intracytoplasmic Sperm Injection for
Prevention of Male-to-Female HIV and HCV
Transmission
ICSI has been suggested to be instrumental for prevention of
human immunodeciency virus (HIV) and hepatitis C virus
(HCV) transmission from infected men in serodiscordant
couples based on the idea that using single spermatozoon
per inseminated oocyte would be safer.45,46 Contrary to this
idea, the Dutch Society of Obstetrics and Gynecology recom-
mends against using ICSI in HIV serodiscordant couples,
justifying it with the concern that the injection of a sperma-
tozoon that might carry an HIV-1 particle, directly into the
oocyte may lead to incorporation of the viral genetic material
into the future embryo with unknown but potentially disas-
trous consequences.47 To our knowledge, there are no well-
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
than ICSI, sperm gradient separations in combination with
IUI have been used for prevention of male-to-female viral
transmission with more than 20 years of clinical experi-
ence.48 The efcacy of gradient techniques to reduce viral
loads in sperm preparations is well established, and it may be
improved by incorporation of polymerase chain reaction
based techniques for viral detection.48,49 It is important to
note that the decrease in viral load does not translate into
complete prevention of viral transmission. Nevertheless, in
the absence of strong supporting evidence, there is no
consensus about the relative merits of ICSI to prevent a
horizontal transmission of HIV and HCV from male-to-fe-
male partner.50 Finding the right evidence is especially
challenging in HCV transmission research, since it was
shown to be a rare event.51
 Intracytoplasmic Sperm Injection Indications
Intracytoplasmic Sperm Injection for
Preimplantation Genetic Testing
Irrespective of what approach is taken for preimplantation
genetic testing (PGT), accurate diagnosis is of utmost impor-
tance. Although the testing errors can arise from many
different problems in a PGT procedure, the most common
and worrisome ones have been quoted to be the issues related
to sample contamination. Utilizing ICSI rather than the
conventional IVF in PGT cycles is recommended to prevent
paternal contamination from excess sperm introduced into
the zona pellucida, or maternal contamination from granu-
losa cells especially with PGT performed for single gene
defects.52
Although literature is lacking well-designed trials, in
light of biological plausibility, ICSI was recommended for
PGT when DNA amplication techniques are used. But
again by using more advanced technologies in proper
identication of maternal and paternal DNA as well as
the embryonic DNA, these concerns can be relieved in
the near future.53,54
Intracytoplasmic Sperm Injection for
Oocytes Matured In Vitro
For in vitro maturation (IVM) cases, due to the potential
changes in the characteristics of the oocytes and zona
pellucida potentially caused by prolonged exposure of
immature oocytes to the culture media, ICSI has been
advocated as the preferred method of fertilization. The
outcomes from one randomized trial suggest that in the
presence of normal semen parameters, conventional IVF
would be a valid fertilization technique for oocytes re-
trieved from women with polycystic ovary syndrome and
matured in vitro.55 The lack of a signicant difference in
fertilization rates between the ICSI and conventional IVF
groups in this study indicates that IVF can be used to
achieve acceptable fertilization rates after IVM. The simi-
larity in cleavage and blastocyst development rates sug-
gests that the oocytes inseminated by conventional IVF are
just as capable of producing viable embryos as ICSI fertil-
ized oocytes.
Although in another retrospective analysis, fertilization
rates appear to be increased by utilizing ICSI after IVM, the
better fertilization rates did not translate into better out-
comes. In this study, the fertilization rates in oocytes sub-
jected to IVM were 37.7% (229/608) with conventional IVF as
compared with 69.3% (318/459) when ICSI was used. Despite
the lower fertilization rate, the implantation rate was signi-
cantly higher in embryos derived from oocytes fertilized with
conventional IVF as compared with ICSI (24.2 vs. 14.8%;
p < 0.05). Furthermore, the clinical pregnancy rate per ET
was signicantly higher with conventional IVF as well (34.5
vs. 20.0%; p < 0.05).56
With the improvements in IVM culture conditions, con-
ventional IVF can achieve viable embryos with improved
implantation and pregnancy rates while being a more cost-
effective and less invasive technique.
Babayev et al. 287
Oocyte Cryopreservation and
Intracytoplasmic Sperm Injection
ICSI has currently been adopted as a method for fertilization
of cryopreserved oocytes. It is thought that the removal of
cumulus cells and the cryopreservation process itself might
decrease the chances of conventional IVF to fertilize the
oocyte after it is thawed. Evidence examining this hypothesis
is conicting with some studies reporting comparable fertili-
zation rates in cryopreserved oocytes between conventional
IVF and ICSI and yet others proclaiming ICSI as the superior
method in that respect.5759 Again, there is lack of evidence
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from prospective randomized studies to suggest that ICSI is
superior to conventional IVF, although ICSI has been the
method of choice in majority of the clinical studies on
cryopreserved oocytes.60
Risks of Intracytoplasmic Sperm Injection
One must be aware of the differences between the fertiliza-
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
introducing a genetically defective material. Moreover, ICSI
also involves the immobilization of spermatozoon before
injection, which is commonly achieved by crushing its tail
with subsequent exposure of its internals to potentially
damaging medium components. Another important differ-
ence between ICSI and conventional IVF is that during ICSI,
the entire spermatozoon is introduced into the ooplasm
including the acrosome with its hydrolyzing enzymes, sperm
plasma membrane, tail, and mitochondria, whereas these
components are largely avoided during conventional IVF and
the oocyte will not require extra energy and material for their
intracytoplasmic elimination.61 We may not rule out the
potentially harmful effects of acrosomal enzymes on embryo
development with injection of acrosome-intact spermatozoa
as well. It seems that ICSI is more energy consuming for the
oocyte itself than conventional IVF, which may have impli-
cations for its routine application for oocytes retrieved from
women with advanced reproductive age.61
Pregnancies achieved by ART are considered as high-risk
pregnancies with increased risks of hypertensive disorders,
preeclampsia, intrauterine growth restriction, premature
birth, and intrauterine fetal demise.62 These risks are as-
sumed to be the complications of multiple pregnancies
associated with ART and also associated with other specics
of infertile couples and not the methods used for their
treatment. Although, earlier reports did not show any signi-
cant increase in the congenital malformations after ICSI, the
quality of these studies has been questioned.6368 Even in
studies where ICSI has been shown to be associated with an
increased risk of adverse outcome, this risk was attributed to
the underlying male factors as the indications for the use of
ICSI. Recent studies are indicating slight increase in the
congenital malformation risk in children born after ICSI.
One prospective, multicenter study from Germany included
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
infertility and fertilization failure in prior IVF cycles. Com-
pared with 8,016 children and fetuses conceived naturally,
the RR for major malformation in ICSI cohort was 1.44 (95% CI,
1.251.6). After adjustment for confounding factors, ICSI
cohort still showed increased odds ratio (1.24; 95% CI,
1.021.50).69
With two-thirds of ART pregnancies in the United States
achieved by ICSI, clearly this technique is used not only for
male factor infertility. Unfortunately, there are no studies
evaluating safety of ICSI in nonmale factor infertility and
hence the literature still suggests that the perceived increase
in birth defect rates with ICSI as compared with conventional
IVF might be related to the genetic or epigenetic factors
associated with severe male factor.70
Conclusion
In the eld of ART, it is common to see widespread adoption of
new technology with ever expanding indications but without
sufcient evidence to support these uses unequivocally. The
application of the new technologies tends to be empirical, and
the available evidence may be largely ignored or dismissed in
favor of the new intervention. ICSI is used as a robust method
for achieving fertilization by many IVF centers around the
world, whereas the reproductive specialists may also consid-
er offering the most cost-effective and the least invasive
techniques while maximizing the likelihood of a healthy
live birth. The current scientic evidence does not support
the widespread use of ICSI without well-established indica-
tions. There is paucity of good-quality data from prospective
studies to further clarify the indications for ICSI. There is also
lack of comparative studies between ICSI and conventional
IVF reproducing the previously reported ndings. Therefore,
currently, the indications for ICSI are not rigorous and ICSI is
applied for any perceived reason that conventional IVF may
not work in a very subjective fashion, at times to convince the
couples that most advanced techniques have been used in
their particular case. ICSI indications need to be revisited by
designing more prospective studies investigating meaningful
clinical outcomes.
References
1 Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies
after intracytoplasmic injection of single spermatozoon into an
oocyte. Lancet 1992;340(8810):1718
2 Van Steirteghem AC, Nagy Z, Joris H, et al. High fertilization and
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