Keywords
intracytoplasmic sperm injection - unexplained infertility - assisted reproductive
technology - conventional in vitro fertilization - infertility
Injection of a single sperm cell directly into the ooplasm, known as intracytoplasmic
sperm injection (ICSI), is considered as one of the most dramatic technological breakthroughs
in assisted reproductive technology (ART). It enabled many couples worldwide with
compromised semen parameters or even azoospermia to have their own biological child.
Also, the technique opened a wide door to several studies and interventions performed
on the oocyte.
The first series of pregnancies and live births from ICSI was reported in 1992.[1] Interestingly enough, this technique was developed as early as the 1960s in nonmammalian
gametes, not for the purpose of assisted fertilization but to prove that sperm nuclear
decondensation and male pronuclear formation did not require prior interaction between
the spermatozoon and the oocyte membrane.[2] These results were replicated in humans in 1988, using surplus immature oocytes
and discarded sperm.[3] However, early attempts in applying this novel technique in clinical settings resulted
in inconsistent fertilization rates, and they did not achieve any pregnancy.[4]
[5] In the meantime, Palermo and his colleagues experienced random success when human
eggs were fully pierced during subzonal injection attempts. They pursued and refined
the technique, which later became known as ICSI.[6] It is worth noting that the most important stipulation was the necessity for injection
of the entire corpus of the spermatozoon, not solely the nucleus as it was in experimental
animals.[7] The amazing attribute of ICSI is that no restriction to the source of the sperm
used for fertilization exists. Soon after the first four live born babies from couples
with severely impaired sperm, the world's first pregnancies obtained by using sperm
aspirated from the epididymis of patients with obstructive azoospermia,[8] testicular sperm in obstructive azoospermia after failed epididymal aspiration,[9] and testicular sperm for nonobstructive azoospermia couples[10] were reported.
ICSI was first introduced to overcome the low and unpredictable fertilization rates
encountered with conventional in vitro fertilization (c-IVF). However, the last two
decades witnessed a rapid increase in the rate of use of ICSI, despite the fact that
the rate of male infertility remains unchanged.[11] Since 2011, ICSI has been shown to be the predominant method of ART-assisted conception
in many countries, resulting in over 2 million live births worldwide.[12] However, the real numbers are likely to be even higher, due to incomplete reporting
of the initiated cycles and the incomplete follow-up data until delivery. Ongoing
concerns exist about the extensive use of this technique both on the effectiveness
and long-term outcomes of the children born from it. The purpose of this review is
to draw readers' attentions to the widespread use of ICSI worldwide, its effectiveness
in the different indications of infertility (especially in those with unexplained
infertility), and the cost-effectiveness of the ICSI-for-all strategy. Also, we covered
current evidence on the short- and long-term safety of children born from ICSI.
Current Practice of Intracytoplasmic Sperm Injection
Current Practice of Intracytoplasmic Sperm Injection
When it was first introduced, ICSI was used in cases with severe male infertility
to overcome the poor fertilization rate. However, this novel technique soon gained
worldwide popularity, due to the broadening of its initial indications for several
reasons. The world report on ART by the International Committee for Monitoring Assisted
Reproductive Technology for the year 2012 showed that ICSI was used in approximately
two-thirds of the aspiration cycles. However, major disparities existed in the use
of ICSI worldwide, with nearly 97% in the Middle East against 55% in Asia and 69%
in Europe.[13] The predominance of ICSI over c-IVF in European countries still continues to be
more pronounced. The 19th annual report of the European IVF-Monitoring Consortium
of ESHRE in 2015 showed that a rise of 6.5% in the use of ICSI occurred compared with
the year 2014, with the proportion of ICSI being as high as 71.2% of the 541,632 cycles.[14] This figure also differs from country to country, with over 80% in Greece and Italy
or up to 100% in the Czech Republic. In the United States, a steady increase from
34 to 76% also occurred, in the proportion of ART cycles involving ICSI performed
from 1996 through 2012.[11] Interestingly, the greatest increase, from 15.4 to 66.9%, occurred in cycles without
male factor infertility. The use of ICSI also differs by region, with the highest
rates of ICSI occurring in Front Range (93.5%) and Gulf Coast (83.1%) megaregions.
The lowest rates occurred in the Northeast (63.4%) and Florida (64.8%) megaregions.[15] The report from Australia and New Zealand showed that the rate of use of ICSI increased
from 57.8% in 2005 to 67.5% in 2014 and then to 69.4% in 2016, whereas the proportion
of male factor infertility was relatively stable over the same period.[16]
[17]
[18] It is worth noting that this figure was even higher, exceeding 80% in cycles using
oocyte donors.[16] These data suggest that many clinics worldwide were using ICSI for non–male factor
indications, often at their own discretion. In Vietnam, IVF was started in 1997, with
the first baby being born from ICSI in 1999. Soon after that, legislations/regulations
on ART were issued by the government. No official national data exist yet, but the
proportion of ICSI use throughout the country is estimated to range from 70 to 80%.
This figure could be more than 90% in centers serving as referral centers. In mainland
China, the first national report on ART status showed that out of 530,718 oocyte retrieval
cycles performed in 2016, 154,948 (29.2%) cycles used ICSI. This low proportion of
use of ICSI could be due to female infertility, accounting for the majority of cycles
and the technique being mainly indicated for only male factor infertility, as documented
in ART guidelines in China.[19]
Despite the fact that in 2012 the use of ICSI for unexplained infertility, low oocyte
yield, and advanced maternal age has been shown not to improve clinical outcomes,[20] this technique is still being described as the “Santa Claus” of a fertility clinic.[21] Some possible explanations for this trend exist. An ICSI-for-all approach was implemented
by some clinics to avoid failed fertilization and increase the number of available
embryos.[22]
[23]
[24] The postulated high success rate of ICSI from previous data resulted in its increased
rate of use in other populations, for whom c-IVF might have been a viable option,
particularly in couples with non–male factor infertility,[25]
[26] unexplained infertility,[27] poor responders,[28] and women of advanced age.[29] Moreover, ICSI might exhibit a role in IVF cycles using preimplantation genetic
testing,[30] in vitro maturation,[31]
[32] or previously cryopreserved oocytes.[20] The increased use of ICSI in the absence of any indication is also likely being
encouraged by the availability of insurance coverage, laboratory efficiencies, and/or
perceived competition among clinics within the country. In the United States, researchers
showed that the rate of use of ICSI was higher in states without an IVF insurance
mandate than in states with an insurance mandate for nearly all of the non–male factor
infertility indications, especially low oocyte yield and unexplained infertility.[33] These findings suggest that insurance coverage for infertility treatment could demonstrate
certain impacts on clinical practice. Hence, both physicians and infertile couples
want to optimize the outcome of ART cycles, since treatments are often paid out-of-pocket
by patients.
Effectiveness of ICSI versus c-IVF
Effectiveness of ICSI versus c-IVF
Non–Male Factor Infertility
Since high fertilization rates and low rates of fertilization failure are associated
with ICSI to some extent, ICSI is considered as another choice for patients who could
be suited for c-IVF, particularly non–male factor infertility. Debates on the preferred
option (ICSI or c-IVF) in non–male factor infertility (as well as the different indications
within the diagnosis) have been ongoing for approximately 20 years. However, studies
comparing ICSI and c-IVF showed inconsistent results. Early in 2001, a multicenter
randomized controlled trial (RCT) compared clinical outcomes after ICSI or c-IVF in
415 couples with non–male factor infertility.[34] Among these patients, the implantation rate (30 vs. 22%) and pregnancy rate (33
vs. 26%) were both higher in the c-IVF group than in the ICSI group. The mean related
laboratory time was also lower in the c-IVF group than in the ICSI group. In a nutshell,
one of the major advantages of this study was randomizing patients rather than sibling
oocytes, which were able to evaluate clinically relevant outcomes, as well as just
excluding those who were obliged to receive ICSI due to severe male factor infertility
for larger indicated populations. It can be deduced from this study that ICSI offers
no advantages over c-IVF with regard to clinical outcomes for non–male factor infertility.
An evaluation was performed retrospectively on a population-based cohort made up of
14,693 women who experienced their first stimulated cycle. They presented with one
oocyte at least through either ICSI or c-IVF between 2009 and 2014 in Australia.[35] Altogether, 13,092 and 7,980 embryo transfers among 8,470 women who underwent ICSI
and 4,993 women who underwent c-IVF occurred, respectively. Compared with the ICSI
group, the c-IVF group exhibited a higher fertilization rate in terms of oocyte retrieval.
The ICSI group exhibited a general cumulative live birth rate of 36% as against 37%
for the c-IVF group with no significant difference. Compared with c-IVF, ICSI led
to a similar cumulative live birth rate for couples with non–male factor infertility.
A retrospective multicenter analysis was performed in 15 European tertiary referral
hospitals based on the individual patient data. This study aimed to determine if ICSI
provides any benefits over c-IVF under different ovarian response categories in couples
with non–male factor infertility.[36] The insemination method did not show any significant difference between the various
ovarian response categories. Thirty Arab couples were present exhibiting normal semen
concentrations and participating in the latest study.[37] An equal distribution existed between ICSI and c-IVF of the number of normal fertilizations
per cycle, and c-IVF significantly increased the incidence of abnormal fertilization.
On day 3, no difference was found between all fertilized oocytes in terms of the number
of good-quality embryos. No difference occurred in the basculation rate on day 5.
However, Kim et al from South Korea retrospectively reviewed 296 c-IVF/ICSI cycles
performed in patients with non–male factor infertility and found no significant difference
in the total fertilization failure (TFF) rate between these two groups (4 vs. 1%).
On the contrary, they found that the ICSI group presented a significantly higher rate
of normal fertilization (84 vs. 79%) and lower rate of abnormal PN formation (4 vs.
13%). In addition, the cleavage-stage embryo quality was better in the ICSI group.[38] Data from an RCT comparing ICSI and c-IVF in 1,064 couples with non–male factor
infertility were recently reported at the 36th Annual Meeting of ESHRE by the team
from My Duc Hospital in Vietnam.[39] The results showed that there is no advantage of ICSI over c-IVF, especially as
far as clinical outcomes are concerned. The protocol of this trial has been published.[40]
Polycystic Ovarian Syndrome
During ART cycles for patients with polycystic ovarian syndrome (PCOS), the fertilization
rate has been reported to be significantly lower and the fertilization failure rate
higher in numerous studies.[41]
[42]
[43] As a technique originally intended to overcome the issues mentioned earlier for
patients with severe male factor infertility, will ICSI be beneficial for patients
with PCOS during their IVF cycles? A prospective study randomizing 1,089 sibling oocytes
compared the fertilization rate and embryonic development between c-IVF and ICSI in
patients with PCOS for the sole indication of infertility. Results showed that fertilization
rate was significantly higher (73 vs. 45%), and no TFF occurred in the ICSI group.[25] However, this study did not compare the pregnancy outcomes, which was limited as
randomizing sibling oocytes. Further RCTs on individual patients or cycles instead
of sibling oocytes need to be considered to compare the pregnancy outcomes of ICSI
to those of c-IVF in PCOS patients.
Tubal Ligation
The necessity also exists to explore what the outcomes are for couples with history
of tubal ligation between c-IVF and ICSI. A total of 8,102 first autologous fresh
ART cycles collected from women with a history of tubal ligation were present, and
these women underwent the surgery in the United States between 2004 and 2012. A longitudinal
cohort study was performed and found that no significant difference was found in the
adjusted fertilization rate between these two groups (58 vs. 49%). The live birth
rate and clinical intrauterine gestation rate were both lower in the ICSI group than
in the c-IVF group. To conclude, the fertilization rate was not improved by the use
of ICSI. Meanwhile, women who received tubal ligation exhibited lower live birth and
pregnancy rates due to the use of ICSI.[44]
Endometriosis
Approximately 10% of women are affected by endometriosis in their reproductive ages.
Currently, up to 50% of females exhibit infertility issues impacted by endometriosis.[45] To explore the preferred approach for endometriosis, a randomized study was performed
on sibling oocytes only among people who present with endometriosis and received ART.[46] Researchers found that the ICSI group exhibited a significantly higher fertilization
rate than the c-IVF group (74 vs. 55%), leading to a higher mean number of day 2 embryos
(5.2 vs. 3.6). Meanwhile, the c-IVF group exhibited a significantly higher triploid
fertilization rate than the ICSI group (3.9 vs. 0.9%). To conclude, ICSI seemed to
demonstrate a better effect than c-IVF on endometriosis-associated infertility. Its
main advantages were lower triploid fertilization and total fertilization rates, a
higher mean number of embryos, and a fertilization rate.
Poor Ovarian Response
Due to the high rate of cycle cancellation, patients with poor ovarian response always
exhibit lower pregnancy and fertilization rates than normal couples. To maximize the
success rate of pregnancy for these patients, choosing the most suitable fertilization
approach is of great importance.[47]
[48] The outcomes of 194 patients were compared, and these patients were the ones retrieving
only one or two oocytes. Researchers showed from the results that the fertilization
rate was higher for patients who underwent ICSI than for those who underwent c-IVF
(83 vs. 67%). No significant difference was found in terms of the rates of pregnancy
and good-quality embryos.[49]
Advanced Maternal Age
One of the least explored groups is that of women taking infertility treatments at
an advanced age. An increase in the number of women seeking infertility treatment
occurs after the age of 35. Many of them need c-IVF because of their age-related infertility
issues.[50] Thus, ICSI was identified as the preferred approach for clinicians. A total of 745
women aged 40 to 43 years participated in the retrospective study. These women underwent
either c-IVF or ICSI because of the non–male factor infertility. Researchers showed
from the results that c-IVF was better in terms of available transferred blastocysts
and embryos and oocyte maturity. The two groups exhibited similar live birth and fertilization
rates.[51] Data on patients aged over 35 years, with non–male factor infertility and experiencing
their first ART cycle, were collected in another retrospective cohort study.[52] The rate of fertilization after ICSI was 71% compared with the rate of 50% after
c-IVF. ICSI produced a top-quality embryo rate of 63%, as against 46% for c-IVF. However,
the difference was nonsignificant among women between 40 and 45 years old. The effectiveness
of ICSI was evaluated in the latest meta-analysis, which is also a systematic review,
in terms of how it enhances the fertilization rate as compared with c-IVF for those
females who were older than 38 years and exhibited non–male factor infertility.[53] No significant difference was found between ICSI and c-IVF among the 8,796 oocytes
being retrieved. The mean age of these women was above 38 years. It was indicated
by the author that more studies are required for the evaluation of ICSI in this group.
Male Factor Infertility
For male infertility, the choice of c-IVF versus ICSI is usually based on the count,
motility, and morphology of sperm, and their ability to penetrate the zona pellucida
of oocyte. Over time, different definitions of male subfertility and infertility were
used. Due to these different definitions that exist worldwide, estimating what proportion
of fertility treatments are associated with this indication or how it affects the
overall success rate is difficult. Also, no consensus exists on this selection in
many previous pieces of literature.[54]
[55]
[56] Therefore, treatment for patients with male infertility is always empirical, which
could lead to failure of c-IVF or to the unnecessary use of ICSI.[57] In most severe male infertility cases, including azoospermia, cryptozoospermia,
and necrospermia, because the effects of empirical drug therapy and surgery are limited,
ICSI might be the only viable option that enables a clear majority of infertile males
to become the biological fathers of their children. As early as the 1990s, several
specific studies all recommended ICSI as the first choice therapy for severe male
infertility with different indications and types.[58]
[59]
[60] Currently, it is clear that the severe male infertility can be treated successfully
only with ICSI.[61]
[62]
[63] However, whether or not ICSI comes with advantages regarding pregnancy outcomes
as the powerful indications for effectiveness in patients with nonsevere male factor
infertility remains controversial.
Sole Teratozoospermia
Till date, no widely accepted criteria exist for the treatment technique for isolated
teratozoospermia. Thus, several studies were also conducted to determine if any therapeutic
benefit for isolated teratozoospermia exists. In 1999, Pisarska et al[64] conducted a prospective experimental study to compare c-IVF with ICSI in males with
isolated severe teratozoospermia (defined as morphology of ≤ 4% normal forms according
to Kruger's strict criteria[65]
[66] along with normal count and motility) using randomized sibling oocytes. In these
patients, ICSI resulted in higher fertilization rates than c-IVF, without significantly
altering the embryo quality (66 vs. 48%). However, Fan et al[67] conducted a similar study which used the same eligibility criteria and recruited
a total of 183 patients diagnosed as isolated teratozoospermia undergoing their first
c-IVF/ICSI cycle in 2012. Data showed that no difference was found in the percentage
of eggs fertilized, implantation rate, pregnancy rate, and spontaneous abortion rate
between participants who underwent c-IVF and those who underwent ICSI regardless of
the percentage of normal morphology. However, the heterogeneity between studies might
be owing to different technology in laboratory as well as selection bias and the limitation
of randomizing sibling oocytes.
Nonsevere Male Infertility
Different from severe male infertility, less clarity is present regarding whether
or not a difference exists between ICSI and c-IVF among patients who suffer from nonsevere
male infertility. In 2002, a comparison between c-IVF and ICSI was performed in an
RCT for sibling oocytes based on the third edition of the WHO Laboratory Manual for
Human Semen.[65]
[68] Researchers reported that patients who underwent c-IVF exhibited a significantly
lower overall fertilization rate than those who underwent ICSI (37.4 vs. 64.3%), indicating
that ICSI is more effective in fertilization for nonsevere male infertility.[69] However, in 2002 as well, similar standards of semen were used for another study,
which showed that no significant differences were found between ICSI and c-IVF in
sibling oocytes for the variables being explored, including implantation, pregnancy,
embryo morphology, rates of development, and the fertilization rate.[70] In the same year, another prospective cohort study with more strict standards[56] was performed on randomizing sibling oocytes. No significant difference was found
between c-IVF (56.7%) and ICSI (58.1%), in terms of the fertilization rate.
In 2004, a study was performed by randomly classifying the sibling oocytes. Afterward,
an evaluation was made regarding the performance of ICSI and c-IVF among couples who
presented with mild oligoteratoasthenozoospermia.[65] According to the results of the study, compared with ICSI (64%), c-IVF exhibited
a much lower fertilization rate (52%). c-IVF was found to exhibit a higher total fertilization
rate (7%) than ICSI (0%).[71] van der Westerlaken et al[54] then performed a randomized research for sibling oocytes back in 2006 and found
that unnecessary fertilization could be prevented by ICSI among people with borderline
semen. Meanwhile, when compared with c-IVF, no significant difference was found.
From 2013 to 2015, Xie et al[57]
[72]
[73] performed several studies randomizing sibling oocytes among patients with the amount
of 5 to 20 × 106 sperm/mL. The corresponding progressive motility was 10 to 32%. The ICSI and c-IVF
groups did not differ from each other in terms of the pregnancy, implantation, and
fertilization rates. However, ICSI group exhibited significantly more good-quality
embryos than the c-IVF group. In terms of the nonsevere male factor infertility (both
moderate and mild oligospermia without or with asthenospermia included), ICSI exhibited
less clear pregnancy and fertilization outcomes.
To conclude, several inconsistent results were found by some prospective and retrospective
studies regarding randomized sibling oocytes. Lower fertilization failure rates and
higher fertilization rates among patients who underwent ICSI treatment are documented
in some studies. The benefit of ICSI was not supported by other data in terms of the
live birth rate, clinical pregnancy rate, implantation rate, embryo quality, and prevention
of TFF. All these studies demonstrate some inherent weakness, such as no evaluation
of live births, nonrandomized patients, and small sample size.
Previous Fertilization Failure
Among the couples who undergo ART, 5 to 15% of them present with TFF despite an obviously
regular sperm quality.[22] To determine if ICSI should be performed for the couples with TFF in the prior IVF
attempt, a prospective study was being performed while 228 sibling oocytes were randomized.
The results showed that ICSI was significantly superior to an additional IVF attempt
with further enhanced insemination concentrations.[74] van der Westerlaken et al later performed a prospective study that involved 38 couples
who underwent c-IVF and ICSI on sibling oocytes after they made an attempt of IVF
with TFF first or demonstrated a low fertilization rate (< 25%).[22] Researchers showed from the results that during the second cycle, the sibling oocytes
with c-IVF treatment were significantly lower than those with ICSI in terms of the
fertilization rate. Besides, the c-IVF-treated oocytes exhibited a high occurrence
rate of TFF. c-IVF and ICSI still exhibit differences in pregnancy outcomes.
In a nutshell, current available data are mostly based on cohort studies, which are
prone to selection bias. However, an increasing body of literature exists showing
that pregnancy outcomes could be compromised after the use of ICSI in cases without
a firm indication. Therefore, well-designed, adequately powered RCTs are absolutely
needed. Two ongoing RCTs exist from Asia in this field. To determine whether ICSI
or c-IVF is more appropriate in couples with mild to moderate male factor infertility,
researchers from the Peking University Third Hospital proposed a multicenter, open-label
RCT in 10 Chinese hospitals.[75] This trial was designed to recruit 2,346 couples in total, of whom the male spouse
was defined as a sperm concentrate of 5 to 15 × 106/mL or progressive motility of 10 to 32% undergoing their first or second ICSI or
c-IVF cycle. The primary outcome to assess in this study was ongoing pregnancy leading
to live birth after the first cycle with embryo transfer.
Intracytoplasmic Sperm Injection in Unexplained Infertility
Intracytoplasmic Sperm Injection in Unexplained Infertility
Unexplained infertility is a diagnosis given to couples who demonstrate normal semen
analysis, tubal patency, and standard tests (like the midluteal progesterone, serum
luteinizing hormone surge, cervical mucus changes, and basal body temperature).[76] Due to the lack of a particular tests or misdiagnosis, the prevalence of unexplained
infertility still remains debatable, which has been diagnosed in up to 30 to 40% of
infertile couples.[77]
[78] Genetic and reproductive physiology, immunology, and hormonal balance were identified
as the possible causes of unexplained infertility.[79]
Several studies exist proposing that couples demonstrating unexplained infertility
issues might exhibit spontaneous conception.[80]
[81]
[82] Generally, each month, around 1 to 4% of the couples with explained infertility
issues could conceive. In addition, women who are younger and demonstrate shorter
infertility durations will exhibit a higher chance of conception through expectant
management. More aggressive initial therapy is required when the wife is above 35
years of age and the couple has been trying to conceive for more than 2 years.[83]
By default, no correctable abnormality exists, and unexplained infertility therapy
will be empiric. Treatment plans for this condition usually include ovarian stimulation
(OS) with intrauterine insemination (IUI).[76] Patients needed to take CC and similar oral agents. Afterward, they needed injectable
gonadotropins with IUI.[84] For the couples who still could not conceive after OS-IUI, IVF was performed.[85] Once the decision to perform IVF is made, one needs to decide the most beneficial
approach through which the fertilization can be realized, either ICSI or c-IVF. The
failure of fertilization happens in 5 to 10% of cases during IVF for unexplained infertility.[69]
[78] Reports of high live birth rates and high implantation rates expanded the spectrum
of indications for ICSI beyond conventional male factor diagnoses, making it possibly
beneficial for couples with this condition. However, researchers found that no benefit
was found in terms of adding ICSI to the treatment of non–male factor infertility
over adding c-IVF.[34] Meanwhile, some controversial outcomes exist regarding the comparison of the efficacies
of ICSI and c-IVF in unexplained infertility.
The TFF was reported to be 20% among 117 couples who failed to conceive over four
to six cycles of superovulation and IUI in a retrospective case–control study.[86] To deal with this issue, sibling oocytes of 22 patients who underwent ICSI and c-IVF
were recruited in a prospective study.[87] No significant difference was found between c-IVF (51%) and ICSI (63%) in terms
of the fertilization rate per oocyte. However, data showed that 23% of the unexplained
infertility patients would exhibit a total loss of their embryo transfer chance due
to TFF if c-IVF was performed. Later, in 1997, a prospective randomized study was
performed, in which the sibling oocytes of 63 patients were randomized into c-IVF
and ICSI. According to the results, c-IVF and ICSI did not show a significant difference
in the fertilization rate. No significant difference was found between the two groups
in terms of the embryo quality. However, none presenting with TFF in the ICSI group
were found, while 11% of those in the c-IVF presented with it.[24] It is demonstrated from the case–control study that a low fertilization rate and
a high rate of failed fertilization were found for the couples who failed to conceive
through the direct intraperitoneal insemination. However, through ICSI, they showed
a good pregnancy rate.[88]
To decide if fertilization failure can be prevented by ICSI in unexplained infertility,
a prospective cohort study was performed on the sibling oocyte cumulus complexes c-IVF
and ICSI allocation in 60 couples with such an issue.[56] ICSI patients exhibited much higher fertilization rates per oocyte cumulus complex
(65%) as against only 48% for c-IVF patients. Ten out of 60 couples with failed fertilization
after c-IVF were present, whereas none for ICSI were found.
Later, c-IVF and ICSI were compared in a RCT performed on 60 patients.[89] They were randomized to either ICSI or c-IVF. No significant difference was found
in the fertilization rates between the patients of the ICSI and c-IVF groups (82 vs.
77%). The rates of implantation were 44 and 38%, while the clinical pregnancy rate
was 50% for each group. The live birth rates were then 50 and 47%. Afterwards a meta-analysis
and a systematic review was carried to decide if TFF is prevented and fertilization
is improved among the couples with unexplained infertility.[26] ICSI exhibited higher fertilization (relative risk [RR]: 1.49, 95% confidence interval
[CI]: 1.35–1.65), fertilization per allocated oocyte (RR: 1.27, 95% CI: 1.02–1.58),
and pooled RRs of a mature oocyte than c-IVF. Meanwhile, it exhibited lower pooled
RR of TFF (RR: 8.22, 95% CI: 4.44–15.23 for c-IVF compared with ICSI). A preference
of the results existed for ICSI in terms of the decrease in TFF and the increase in
fertilization rates. Additionally, authors also pointed out that the impact on the
live birth rate and clinical pregnancy rate requires further studies.
Based on the aforementioned literature review, ICSI serves as a preferred choice for
fertilization, which could minimize complete failure of fertilization while maximizing
the number of embryos. However, a paucity of studies exist exploring pregnancy after
ICSI taking into account other factors. For example, this process could not be confidently
used to treat unexplained infertility considering time-consuming and extra costs and
current knowledge of ICSI as an outcome procedure. Properly powered RCTs are still
required to explore the role of ICSI in the treatment.[90]
Safety Concerns of Intracytoplasmic Sperm Injection
Safety Concerns of Intracytoplasmic Sperm Injection
Surveillance of long-term outcomes of fertility treatments, including the health of
children born from ICSI, remains of interest both to professional healthcare providers
and infertile couples. This is of particular importance with children born from ICSI,
a procedure that is considered invasive and crosses all natural barriers. Two types
of risk associated with ICSI were suggested, namely, the procedure-dependent and procedure-independent
risks.[90]
[91] The main risks associated with the procedure itself are related to both the physical
and/or biochemical disturbance of the ooplasm or meiotic spindle, which might result
in aneuploidy. Moreover, the use of polyvinylpyrrolidone or injection of foreign,
sperm-associated exogenous DNA as well as the handling of oocytes outside the incubator
could also be potential risks associated with the procedure. For procedure-independent
risks, the causes of infertility and the use of sperm with structural defects should
be considered. To facilitate the discussion of long-term outcomes, we divide the current
section into six major areas: (1) perinatal outcomes, (2) aneuploidy and congenital
malformations, (3) physical developmental outcomes, (4) reproductive outcomes, (5)
psychological and neurodevelopmental outcomes, and (6) risk of cancers.
Perinatal Outcomes
ICSI is associated with a significantly higher risk of (very) preterm birth,[92] lower mean birth weight,[93] and an increased risk of rare imprinting disorders[94] compared with spontaneously conceived and non-IVF ART pregnancies. When ICSI is
compared with c-IVF, most large-scale studies found similar or lower risks of (very)
preterm birth and (very) low birth weight as well as peri/neonatal mortality in singletons.[95] These findings could be explained by the reproductively healthy status of women
in couples undergoing ICSI, which could give a more favorable perinatal outcome.[96]
Aneuploidy and Congenital Anomalies
An abnormal karyotype was found in 3% of ICSI fetuses, of which 1.6% were de novo and 1.4% inherited. The frequency of aberrations was significantly higher in the
de novo cohort compared with those in the general newborn population (1.6 vs. 0.45%) and
was mostly due to an increased incidence of sex-chromosomal aberrations.[91] Researchers showed that these de novo chromosome anomalies in the offspring are linked to sperm concentrations, with a
cut-off of 20 million sperm/mL.[91] Compared with c-IVF, the risk of presenting with chromosomal abnormalities, particularly
sexual chromosome aneuploidy, in children conceived through ICSI is higher.[97]
Some controversy exists regarding the risk of birth defects after ICSI. It has been
established that ICSI does not lead to major abnormalities in offspring,[98] which is in line with a meta-analysis that indicated no significant increase was
found in major birth defects in babies conceived through ICSI when compared with those
conceived through c-IVF.[99] However, a large Australian study of babies born from assisted conception reported
a significantly higher rate of congenital malformations in babies born from ICSI than
that from c-IVF.[100]
Physical Developmental Outcomes
A recent meta-analysis was conducted to compare 3,972 c-IVF/ICSI children with 11,012
spontaneously conceived children up to a mean follow-up time of 22 years. The results
showed that compared with spontaneously conceived controls, c-IVF singleton children
exhibited lower body weights, although the difference between theirs and the weights
of the children in the c-IVF/ICSI group was not statistically significant. Similarly,
the mean weight of children following ICSI treatment was comparable with that of the
controls. It is worth noting that the mean weight of c-IVF/ICSI children was significantly
lower than that of the controls, but only up to preschool age. These results indicate
that c-IVF/ICSI children exhibit an increased postnatal growth rate. However, these
results must be interpreted with caution, as very few studies included children beyond
preschool age.[101]
Reproductive Outcomes
The first study attempting to assess semen quality in the oldest ICSI young adult
was recently reported. Compared with men born from spontaneous conception, those born
from ICSI aged between 18 and 22 years were nearly three times more likely to have
sperm concentrations below 15 million per milliliter of semen and four times more
likely to have total sperm counts below 39 million per millimeter of semen.[97] The significant difference between these findings remains even after adjusting for
relevant confounders. However, no clear correlation between semen parameters of the
young ICSI men and their fathers was found.[102] In another study with a limited sample size, the same group showed that reproductive
hormone levels in these ICSI young adults were comparable to those in young adults
conceived spontaneously.[103] For young adult women conceived by ICSI due to male factor infertility, antral follicle
count and circulating reproductive hormone levels were found to be similar to those
in their peers born after spontaneous conception.[104] It should be noted that patients in this cohort were conceived after the use of
ICSI with ejaculated sperm in couples with male infertility. Reassuring data on the
pubertal development of the ICSI offspring cohort with a mean age of 16.5 years at
the time of investigation were recently reported in the largest prospective controlled
trial.[105] The mean age at menarche was comparable between both groups and was also in line
with data from a nationwide survey. The pubertal development determined by Tanner
stages of both female and male ICSI offspring was similar to that of the spontaneously
conceived adolescents.[105] The aforementioned data suggest that male fertility might be compromised in ICSI
offspring, most likely owing to paternal inheritance. However, for female fertility,
the existing information is insufficient to draw any conclusions.
Psychological and Neurodevelopment Outcomes
The neurodevelopment of children born from ART (with 52.5% from c-IVF/ICSI) was assessed
in a prospective cohort study, involving 175 children in the ART group (62.9%) and
1,345 in the natural-conception group (64.4%) at 24 months of age.[106] After adjusting for relevant confounders, researchers found that the neurodevelopmental
outcomes in children born from ART were not significantly different from those of
naturally conceived children. Also, no significant difference was found between ICSI
versus c-IVF and other treatment techniques.[106] However, it should be noted that the study was not powered for this outcome. In
children ranging from toddlers to teenagers, a systematic review on 79 cohort or case–control
studies indicated that overall, the neurodevelopment of children born from ICSI and
c-IVF was comparable to that of children born from spontaneous conception.[107] Furthermore, the results of the first nationwide study in adolescents aged 15 to
16 years showed that ICSI and IVF adolescents exhibited similar academic performances
in both the crude and adjusted analyses for both singletons and twins.[108] These reassuring data were recently confirmed in a pragmatic study, where children
born after ICSI (n = 6,953) were compared with children born after c-IVF (n = 11,713) and with children born after spontaneous conception (n = 2,022,995). Of children born after ICSI, those born with nonejaculated sperm (n = 462) were compared with those born with ejaculated sperm (n = 6,491).[109] The authors concluded that children born after ICSI exhibited similar school performances
as those born after c-IVF. Although a small difference was found in favor of the spontaneously
conceived children in the national tests in third grade, no difference was found between
these groups in the ninth grade. Interestingly, children born from nonejaculated ICSI
achieved significantly lower scores in Swedish and English. They also exhibited a
significantly higher risk of poor performance than children born from ejaculated ICSI.[109]
Cancers
As with any new techniques in the field of reproduction, a general awareness of the
risks from the introduction of new tools and chemical substances should be present,
for example, the safety of using polyvinylpyrrolidone which has long been considered
as a carcinogen. A large nationwide historical cohort study recently showed that after
a median follow-up of 21.0 years, the overall cancer risk in ART-conceived children
is not significantly increased, neither when compared with the general population
nor when compared with the population of naturally conceived children born to subfertile
women. A nonsignificantly increased risk of cancer was found in children conceived
from ICSI compared with that in naturally conceived children (adjusted hazard ratio
[aHR] = 1.52, 95% CI: 0.81–2.85) or with c-IVF-conceived children (aHR = 1.60, 95%
CI: 0.87–2.93).[110]
Safety of Intracytoplasmic Sperm Injection in Non–Male Factor
Another important question is whether the ICSI procedure, in particular, poses any
risk for congenital malformations and long-term health of the offspring when used
for non-male indications. However, limited evidence exists regarding this issue, most
likely because the use of ICSI for non-male indications has been broadened only in
the past two decades. Data from the U.S. National ART Surveillance System from 1996
to 2012 reported that ICSI in non–male factor infertility was associated with lower
birth weight than with c-IVF.[11] In a population-based retrospective cohort study, after a 5-year observation period
of all live born ART-conceived children in California between 1997 and 2006 (n = 42,383), the authors reported that ICSI in non–male factor infertility was associated
with a higher risk of autism than c-IVF (adjusted HR: 1.57; 95% CI: 1.18–2.09).[111]
Limitations
All aforementioned data on the safety of ICSI should be interpreted with caution.
A key limitation of the existing literature is the overall small sample size of the
ICSI group. Given the low incidence of specific congenital anomalies, a large number
of children are obviously required to detect a true increase in incidence, if any.
Another major challenge is the difficulty in separating the contribution of infertility
per se from the technique itself, the so-called the chicken or the egg.[95] Furthermore, selecting appropriate comparison groups for children born through ART
is vital and challenging. In most studies, children conceived spontaneously are used
as the control group, but whether this is the correct group is debatable, since parental
factors such as infertility per se might influence the health of the offsprings.[112] It is worth noting that the long-term developmental outcomes of children, especially
intelligence and cognitive function, are closely associated with parents' level of
education and socioeconomic status.[113] Last, existing studies are also subject to bias as a result of incomplete follow-up
arising from attrition.
Cost-Effectiveness
ICSI is considered as being extensive given that public funding usually would not
subsidize it. Therefore, the increased costs exhibit a substantial scope throughout
the society. Meanwhile, ICSI is time- and resource- consuming but actually increases
success rate among specific patients. Introducing these services comes with costs
and also effects, which are also assessed thoroughly. Hollingsworth et al[114] once assessed the incremental costs of the ICSI and also the available practice
comparators for every patient group in Australia and made an assessment of this service
economically. According to the estimation based on the results, authors pointed out
that the additional cost of ICSI over the relevant target populations in Australia
gives potential total financial implications of over A$31 million per annum. Moolenaar
et al[115] from the Netherlands made an assessment of the TMSC (total mobile sperm count) and
used it to assess the cost-effectiveness of interventions for male subfertility. A
study was performed targeting subfertile women who were 30 years old and their partners
presented with a pre-wash TMSC, which was between 0 and 10 million. An evaluation
was made regarding the expected live birth rate among IUI, c-IVF, and ICSI. Significant
differences were found in the cost per live birth, the range of which could be between
€14,986 for a 0.1 million pre-wash TMSC and €11,811 for a 10 million one. There was
a cost of €12,783 per live birth of the ICSI cycle irrespective of pre-wash TMSC.
When the pre-wash TMSC was lower than 3 million, ICSI could generate less cost than
c-IVF, which started to exhibit a lower cost than 3 million. The incremental cost-effectiveness
ratio (ICER) varies greatly, which could be between €4,598 for a 0.1 million pre-wash
TMSC of 0.1 million and €4,873,646 for a 10 million one. In light of this, it can
be seen that ICSI could generate more costs and be more effective.
An abundant amount of cost analyses exists regarding infertility treatment, even though
very few of them explored unexplained infertility. Besides, the cost-effectiveness
is analyzed by few cost analyses, such as the incremental cost per live birth when
there is an alternative treatment. To measure the cost-effectiveness of split c-IVF-ICSI,
Vitek et al adopted an adaptive decision model for the prediction of the costs among
the cohort in which women were younger than 35 years and underwent c-IVF and also
among 154 couples presenting with a split c-IVF/ICSI cycle.[116] c-IVF, split c-IVF/ICSI, or all ICSI, and adapting treatment are used as the modeling
insemination method in the first IVF cycle according to fertilization outcomes. All
c-IVF is preferred in a single cycle, given that the increased live birth rate (3%)
cannot be justified by ICER of split c-IVF/ICSI or all ICSI ($58,766). Split c-IVF/ICSI
is preferred under the circumstances where two cycles are required given that the
increased cumulative live birth rate (3.3%) is obtained at an ICER of $29,666. With
regard to the single cycle, due to which the increased cost per live birth did not
justify all ICSI and the enhanced live birth rate with split c-IVF/ICSI, a preference
on all c-IVF was found. However, a preference over the split c-IVF/ICSI approach was
found when it requires two IVF cycles due to the comparison of the lesser cost per
live birth with all ICSI and also the higher cumulative live birth rate with all IVF.
According to the results of the study, the increased cost of 50:50 could not be justified
by the minimal growth of the live birth rate (3%) as c-IVF:ICSI, though this was a
statistical modeling study.
Conclusion
In conclusion, a paucity of evidence of a clear benefit of ICSI use over c-IVF exists,
except for severe male infertility. However, its use continues to increase, particularly
among couples without male factor infertility. Also, ICSI might bring additional costs
and potential health risks, although current results are to be interpreted with caution.
Further evidence-based studies should be undertaken to determine whether ICSI is more
beneficial for different indications of infertility than c-IVF regarding effectiveness,
safety, and cost-effectiveness. With such certain results, it will bring new knowledge
to offer future guidance to clinicians treating infertile patients.
