Hindawi Publishing Corporation
Obstetrics and Gynecology International
Volume 2010, Article ID 120130, 6 pages
doi:10.1155/2010/120130
Review Article
Preimplantation Genetic Screening: An Effective Testing for
Infertile and Repeated Miscarriage Patients?
Ning Wang, Ying-Ming Zheng, Lei Li, and Fan Jin
Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
Correspondence should be addressed to Fan Jin, jinfan@zju.edu.cn
Received 30 November 2009; Accepted 15 May 2010
Academic Editor: Shi-Wen Jiang
Copyright © 2010 Ning Wang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Aneuploidy in pregnancy is known to increase with advanced maternal age (AMA) and associate with repeated implantation
failure (RIF), and repeated miscarriage (RM). Preimplantation genetic screening (PGS) has been introduced into clinical practice,
screening, and eliminating aneuploidy embryos, which can improve the chance of conceptions for infertility cases with poor
prognosis. These patients are a good target group to assess the possible benefit of aneuploidy screening. Although practiced widely
throughout the world, there still exist some doubts about the efficacy of this technique. Recent randomized trials were not as
desirable as we expected, suggesting that PGS needs to be reconsidered. The aim of this review is to discuss the efficacy of PGS.
1. Introduction
Preimplantation genetic screening (PGS) has been used more
than 10 years for selecting genetically normal embryos giving
the highest potential for preimplantation genetic diagnosis
(PGD). PGS usually involves the aspiration of the first polar
body from oocyte before fertilization or one or two cells
from a 5- to 8-cell embryo 3 days after insemination. Fluorescence in situ hybridization (FISH), is often performed,
using probes for a specific number of chromosomes most
commonly involved in aneuploidy. The presence or absence
of a normal pair of chromosomes can be identified visually
by color, so we can eliminate the abnormal embryos and
select normal embryos for transfer [1]. Thus, choosing
embryos selected by PGS with normal chromosomes should
increase implantation rate and live-birth rate and reduce
miscarriages. The indications of PGS include advanced
maternal age (AMA), repeated implantation failure (RIF),
repeated miscarriage (RM), and severe male-factor infertility
[2].
Currently, there have been a great many studies into in
vitro fertilization (IVF) or intracytoplasmic sperm injection
(ICSI) with and without PGS. Several of them found
that selecting embryos with normal chromosomes had a
significant impact on the implantation rate compared with
the controls [3–6]. PGS has been advocated as a valuable
tool for embryo screening. In recent years, its trends become
controversial after the report published by Mastenbroek et al.
[7]. They found that PGS reduced the rates of pregnancies
and live births after IVF in women of AMA [7]. Actually
Mastenbroek was not the only one who claimed that PGS
might not be as beneficial as expected. Conclusions drawn
from other studies in AMA patients after PGS showed that
PGS did not significantly improve implantation rate and
pregnancy rate, on the contrary it worsened the outcome
[8, 9].
In this paper, we will acknowledge the importance of
aneuploidy screening and review the findings of currently
published studies of PGS, in order to discuss the efficacy of
this technique.
2. Indications of PGS in AMA, RM, RIF
and Severe Male-Factor Infertility
Aneuploidies, that is, deviations from the regular number
of chromosomes, are predominantly the result of maldistributions of chromosomes during meiosis. Aneuploidy
rates in oocytes and embryos are known to increase with
maternal age [10]. In a 40-year-old woman, an estimated
50% to 70% of the mature oocytes are affected by a
chromosomal abnormality [11, 12]. In a series of 6733
2
oocytes obtained during 1297 IVF cycles from patients of
AMA (mean 38.5 years) [13], 3509 (52%) were aneuploidy,
on the basis of FISH analysis using specific probes for
chromosomes 13, 16, 18, 21, and 22. It is well known that
the age-related increase in aneuploidy rate is correlated with
a reduced implantation and a higher abortion rate. Most
evidence collected so far suggests that failed implantation
due to embryo aneuploidy rather than failed conception
is the primary cause responsible for low human fertility
[14]. To date, these patients revealed an aneuploidy rate
of over 50%, suggesting the practical relevance of PGS
to women of advanced reproductive age. Screening for
aneuploidy in preimplantation embryos may help select
the best embryo to transfer and may open the way to
significant improvements in live-birth rates from IVF/ICSI,
especially relevant for more effective single embryo transfer
[15]. AMA patients, here defined as 35 years, are a good
target group to assess the possible benefit of aneuploidy
screening.
RM is defined when two or more consecutive spontaneous abortions occur, which affects 1% of couples trying
to conceive [16]. The number of miscarriages stands out as
a predictor of the chromosome abnormality rate,which is
directly proportional to the number of miscarriages. A study
of 108 couples with history of repeated abortions found
that chromosome abnormalities were found in 5% of the
couples with two abortions, in 10.3% with three abortions,
and in 14.3% with four or more abortions [17]. The most
common anomaly observed in abortus is aneuploidy, and
reported aneuploidy rate could reach to 34–66% [18, 19].
This result suggested that aneuploidy was a common cause
of RM, and led to the proposal that PGS may be beneficial in
these patients.
RIF can be defined as the failure of a couple to conceive
after the transfer of 10 or more good-quality embryos, or
after three IVF cycles [20]. Although multiple aetiologies,
such as disturbed endometrial receptivity, uterine pathology,
and an inadequate transfer technique, have been proposed,
increased incidence of numerical chromosomal abnormalities is obviously the most common cause [21]. It has been
reported that the rate of chromosome abnormalities in the
embryos from RIF patients is almost twice as much as that
in the controls (67.4% versus 36.3%) [22]. Significantly
higher incidence of complex chromosome abnormalities
(which involves three or more chromosomes) was also found
in RIF [23]. The generation of aneuploidy embryos was
considered as a possible causative factor in RIF [24], and
it is suggested that PGS may improve the outcome in these
patients.
Infertile couples due to severe male factor can be treated
with ICSI. In order to generate normally fertilized oocytes
after ICSI, a spermatozoon containing a functional genome
and centriole is required [25]. Current study in cases
of macrocephalic spermatozoa demonstrated an increased
incidence of chromosomal abnormalities, and the majority
of the abnormalities were aneuploidy [26, 27]. Due to the
high incidence of aneuploidy these patients might benefit
from PGS owing to its effect of eliminating chromosomally
abnormal embryos.
Obstetrics and Gynecology International
3. Studies with Beneficial Outcome of PGS
3.1. PGS in AMA. An early study published by Gianaroli
et al. [3] on 157 cycles (73 for PGS group and 84 controls)
with AMA using FISH in analysis of chromosomes X, Y, 13,
14, 15, 16, 18, 21, and 22 in a blastomere biopsied from
day 3 embryos showed that 64% of embryos presented with
chromosomal abnormalities. 22 cycles in the study group had
clinical pregnancies versus 25 cycles in the control group,
whereas in the study group, the mean number of embryos
transferred per patient was significantly lower (2.2 ± 0.9
versus 3.2 ± 0.9), and the implantation rate was higher in
comparison with the control group (25.8% versus 14.3%;
P < .01). Concomitantly, the implantation rate per pregnant
patient was superior in the study group compared with the
controls (57.9% versus 38.5%; P < .05). More interestingly,
these patients were arbitrarily divided into three classes of
age: 36–37 years, 38–39 years, and 40 years; the pregnancy
and implantation rates characterized in the control group
revealed a significant decrease when patients aged 38
years. Conversely, in the study group, the percentages of
pregnancy and implantation did not differ among the three
classes of age, and the implantation rate observed in the
oldest categories (38 years) was significantly higher after
aneuploidy screening than the controls.
Verlinsky et al. [28] performed a study of polar body
diagnosis (PBD) with IVF cycles from patients of AMA. 5590
oocytes were obtained from 917 cycles and tested by polar
body sampling and FISH analysis using specific probes for
chromosomes 13, 16, 18, 21, and 22, this resulted in 22.2%
clinical pregnancies and 140 healthy children born. It seems
that polar body testing provides an approach for improving
pregnancy rate in IVF patients of AMA. But no control
group was presented in this report. Another study of women
ageing 35 to 39 years with two or more previous IVF/ICSI
treatment trials showed that a higher implantation rate was
achieved in the PBD group (17.5% versus 11.8%) [29]. These
results suggested that an indication-based use of PBD could
certainly provide benefits in older patients.
Some articles showed that aneuploidy screening in
preimplantation embryos can also reduce embryo loss,
increasing ongoing pregnancies and delivery rates. Munné et
al. [5] designed a multicentre IVF study to compare controls
and a test group that underwent aneuploidy screening,
obtaining a significant improvement in the number of
spontaneous abortions and ongoing pregnancies. Similar
beneficial effects have been reported by other studies.
Staessen et al. [8] observed a trend toward a subsequent
higher ongoing implantation per transferred embryo rate
in tested group (16.5% versus 10.4%; P = .06). In the
recent study published in 2009 by Schoolcraft et al. [30], 62
infertile AMA couples undergoing fertility treatment were
assigned to the PGS and control group. Results showed
that the implantation rates, the number of oocytes, oocyte
maturity, and fertilization rate were similar between the two
groups. Nevertheless, the authors noted that the spontaneous
abortion rate was lower for the test group (25.9% versus
32.26% in the control group), resulting in an observed
increase in delivery rate for the test group (78% versus
Obstetrics and Gynecology International
67.74%). In addition, Hardarson et al. [9] found significantly
more good morphological quality embryos (GQEs) in the
PGS group on day 3 compared with those found in the
control group.
3.2. PGS in RM, RIF, and Severe Male-Factor Infertility.
The randomized, prospective study including 19 couples
with recurrent pregnancy loss (11 for PGS and 8 controls)
by Werlin et al. suggested an improved outcome after
performing PGS [31]. Pregnancy rate was 63.6% in study
group and 37.5% in controls. In another study performed
by Munné et al. [18], the rate of spontaneous abortions in
RM subjects undergoing PGS was compared with their own a
priori expectations. After PGS, miscarriage rate was reduced
from previous 90% (expected 29%) to 23% in the women at
age <35 years, and from 86% (expected 44.5%) to 12% in the
women at age 35 years. Similar results were also reported
by a multicenter retrospective controlled study [32], which
showed that the spontaneous abortion rate in the PGS group
was 14.1% for women ages 35–40 and 22.2% for over 40,
compared to 19.4% (P < .03) and 40.6% in the non-PGS
group (P < .001).
Improved outcomes in RIF were achieved with the
selection of chromosomally normal embryos. In a study
with 57 RIF cycles by Pehlivan et al. [22], a pregnancy rate
of 34.0% and an implantation rate of 19.8% was observed
in the PGS group. Recent data reported that, in women
with unexplained RIF [33], two consecutive PGS cycles
showing euploidy embryo(s) were strongly associated with
high ongoing pregnancy (40%) and implantation (18%)
rates. Conversely, the patients with no euploid embryos in
a PGS cycle were highly unlikely to achieve an ongoing
pregnancy in subsequent cycles.
Kahraman et al. compared the implantation and
ongoing-pregnancy rates of PGS cycles with non-PGS cycles
in cases with predominantly macrocephalic spermatozoa
and absolute teratozoospermia [34]. A statistically higher
implantation rate as well as a significantly reduced missed
abortion rate were found in PGS group (25.0% and 14.3%)
compared with non-PGS group (12.3% and 46.7%)
4. Studies without Beneficial Outcome of PGS
4.1. PGS in AMA. In the study by Staessen et al. [8]
used FISH for the chromosomes X, Y, 13, 16, 18, 21, and
22 in AMA couples with a control group without PGS.
In the 400 (200 for PGS and 200 controls) couples were
allocated to the trial, ICSI was used to fertilize the oocytes,
and two blastomeres per embryo were removed on day 3
after injection and transferred on day 5. In this study, the
implantation rates were not significantly different between
the two groups (17.1% in the test group versus 11.5%
in the control group). But the cycles that had embryos
transferred were significantly lower in test group (81 cycles
versus 121; P < .001), and 38 couples in the test group
had no genetically normal embryos to transfer. Less than
expected success of PGS was attributed to a higher number
of embryos transferred in the control group (2.8 versus
2.0) and the possible adverse effect of double-blastomere
3
biopsy [35]. The same group, comparing single-cell versus
two-cell biopsy, demonstrated a detrimental effect of twocell biopsy; they suggested that, if one-cell biopsy had
been used in their study, implantation rates may have
improved.
Mastenbroek et al. [7] designed a multicenter, randomized, double-blind, controlled trial. 408 women of
AMA underwent 836 cycles of IVF, of which 206 women
with 434 cycles were assigned to PGS and 202 women
with 402 cycles to the control group. The ongoingpregnancy rate was significantly lower in the women assigned
to PGS (52 of 206 women, 25%) than in those not
assigned to PGS (74 of 202 women, 37%). The women
assigned to PGS also had a significantly lower live-birth
rate (24% versus 35%) and reduced implantation rate of
(11.7% versus 14.7%) compared with those in the control
group. The study was criticized mainly for inappropriate patient selection, inadequate probe selection, possible
biopsy-induced embryo damage, a low average number of
embryos biopsied, and a high rate of undiagnosed embryos
[36, 37].
In the Hardarson et al. study [9], 56 and 53 patients
with age 38 years were randomly assigned to the PGS
and control groups, respectively. Fertilization was performed
by IVF or ICSI following standard techniques and FISH
analyzed by probes chromosomes X, Y, 13, 16, 18, 21, and
22 in PGS group. Of the analyzed embryos (302 embryos),
only 32.4% (98 of 302) had normal chromosome content
and 70 of 98 normal embryos were transferred. The number
of patients who had embryos transferred was 45 (80.3%)
in PGS group and 53 (100%) in control group (P =
.001). The clinical pregnancy rate/randomized patient in
the PGS group was 8.9% compared with 24.5% in the
control group (P = .039). No significant differences were
found in the implantation rates (11.4% versus 18.9%) or
live-birth rate (5.4% versus 18.9%) per randomized patient
between the PGS group and the control group. As shown
in these randomized trials, no improvement in efficacy was
observed.
4.2. PGS in RM, RIF, and Severe Male-Factor Infertility.
Platteau et al. designed prospective cohort PGS study in
women with recurrent idiopathic miscarriages [19]. The
pregnancy results in the older group (37 years) were
disappointing, with an implantation rate of 2.77% and an
ongoing-pregnancy rate of 2.94%. The probable cause for
this poor result was that these older women had significantly
more chromosomally abnormal embryos than patients <37
years (66.95% versus 43.85%).
As to the RIF, a prospectively randomized controlled trial
of PGS in IVF/ICSI patients with recurrent failed implantation compared with conventional assisted reproduction
treatment procedures was carried out by Blockeel et al.
[38]. A total of 139 patients underwent ovarian stimulation,
and PGS was performed in 72 patients. No benefit to their
implantation and clinical pregnancy rates was found. The
implantation rate was 21.4% in the study group and 25.3%
in the control group. Moreover, the clinical pregnancy rate
was much lower in the study group (25.0% versus 40.3%).
4
Although severe male-factor infertility is one of the PGS
indications that have been put forward, current reports of
PGS in severe male-factor infertility are rare. There is a lack
of scientific evidence to prove whether PGS is effective in
these patients.
5. Reasons for Lack of Benefit in PGS
Technical reasons for lack of benefit in PGS include both
biopsy damage to the remaining embryo that reduces its
developmental potential and limitations of current FISH
technology that allows only a few chromosomes to be seen.
As a result, it is inevitable that some other abnormal chromosomes will escape from detection [39]. Moreover, FISH
could be misdiagnosed by the probability of hybridization
failure and the possibility that the fluorescent signals of two
chromosomes overlap each other. The testing of all chromosomes would probably further increase observed aneuploidy
rates [40]. Mosaicism, a difference of the chromosomal
constitution among individual cells in an embryo, is another
possible reason for confusion. A single blastomere that had
been biopsied might thus be classified as abnormal, whereas
the remaining blastomeres in the embryo are normal. Thus,
the test results from the biopsied cell may not be an accurate
indication of the embryo’s genetic status [41]. Besides
technical limitations and mosaicism, contamination and
laboratory mistakes can also result in inaccurate diagnoses.
For example, DNA from sources other than the biopsied
cell may be read as part of the genetic analysis, mixup, or
mislabeling of a sample or embryo from clinic or laboratory
mistakes in handling samples or embryos. All of these can
lead to inaccurate results.
6. Possible Future Trends in PGS
6.1. Comparative Genomic Hybridization (CGH). Performed
on a single cell basis, CGH enables the assessment of all
the chromosomes by comparing the studied DNA with a
normal sample. In brief, normal DNA samples are labelled
with red and test DNA with green fluorochromes, and then
applied to a slide where hybridization occurs for 48–72 h
[42]. The advantage of CGH over the conventional FISH is
that the copy number of all chromosomes can be determined.
CGH can provide a genome-wide profile without any prior
information of the chromosomal aberration [40].
Fragouli et al. [43] collected 270 oocytes from the 16
female patients (average age 38.4 years) and 168 embryos
were fertilized on day 3 (average 12 embryos per patient,
range 6–18). Of the 168 embryos, 78 (46.4%) were cultured
further to the blastocyst stage and underwent trophectoderm
biopsy with CGH screening. Their data displayed high
implantation and pregnancy rates for the patients with RIF
who have received blastocyst analysis [43]. CGH yielded
results for 73 of the 78 blastocysts, leading to a diagnostic
efficacy of 94%. Of these, 40 were classified as euploidy
and 24 were transferred in 13 patients, leading to nine
ongoing pregnancies from 13 completed cycles (69.2%)
and the implantation rate was 58.3% (14/24 ETs). The
limitations of CGH are that it is time-consuming and labour
Obstetrics and Gynecology International
intensive. The long period required for hybridization (5
days) has limited the widespread clinical implementation of
this technique, as it is necessary to freeze all the embryos
after the biopsy. In addition, the survival rate of the thawed
embryos was relatively poor (46% did not survive the
thawing process). More recently, the development of highly
efficient techniques has greatly reduced fears concerning
the impact of cryopreservation on embryo viability. Array
CGH is one of the newest technologies developed for the
detection of a chromosomal imbalance; it is able to analyze
the very limited amount of genetic material in a single cell
and takes less time [42]. Accuracy microarray platforms also
can offer the advantage of embryo fingerprinting and the
potential for combined aneuploidy and single-gene disorder
diagnosis [44]. The first report to show a pregnancy after
PGS using array CGH technology by Hellani et al. obtained
a high pregnancy rate; six out of a total eight patients had
embryos for transfer with five out of those six showing
positive pregnancy tests [45]. The result was encouraging
and further studies on array CGH with larger sample sizes
will be required before it is suitable for clinical application.
However, some disadvantages need to be addressed before
array-CGH is suitable for clinical services. First of all, the
accuracy needs further evaluation. Array sometimes gave
incorrect results for chromosomes 2, 4, 9, 11, 17 and 22 [46].
Partial aneuploidy and imbalance of chromosome segments
are not currently detected. Besides, the present array CGH
protocol is expensive and it doesn’t seem to fit easily into all
clinical PGS services. This requires us to find new ways to
reduce costs and bring the advantages to more patients.
6.2. Blastocyst Biopsy. Blastocyst biopsy or trophectoderm
biopsy is an emerging technique for performing PGS. It
shows several advantages over traditional day-3 biopsy [46].
One of them is more cells can be biopsied for genetic testing
without damaging the inner cell mass. Biopsy at this stage
has little, if any, impact on the further development of the
blastocysts. The data from McArthur et al. demonstrates high
blastocyst survival rates with excellent implantation rates and
low rates of twinning or miscarriage [47]. Recently, a study
involving 399 egg retrievals and 1879 embryo biopsies for
patients undergoing PGD to avoid a serious monogenic disease or an unbalanced chromosomal translocation has been
published. The implantation rates per embryo transferred
were 43.4% if biopsied at the blastocyst stage and 25.6%
if biopsied at the cleavage stage (P < .01), with ongoing
or live-birth pregnancy rates per egg retrieval at 34.2%
(average transfer number 1.1) for blastocyst biopsies and
25.5% (transfer number 1.6) for cleavage stage biopsies (P <
.05). The results mean that taking the biopsy later in embryo
development conferred considerable efficacy through not
testing embryos whose development was compromised [48].
Nevertheless, more data is still needed to confirm these
promising results.
7. Conclusions
In conclusion, the efficacy of PGS is still controversial.
According to the studies, there is still insufficient evidence to
Obstetrics and Gynecology International
support a beneficial effect of PGS in AMA women. The use
of PGS applied for RM, RIF and severe male factor infertility
needs more scientific data from clinical trials. The routine
use of PGS to avert the birth of an aneuploidy infant is still in
question. Application of micro-CGH and blastocyst biopsy
might be new approaches for improvement of the efficacy of
PGS. Furthermore, the cost-effectiveness of PGS for the IVF
patients should be considered.
Acknowledgments
Ning Wang and Ying-Ming Zheng are contributed equally
to this paper. The research was supported by National Basic
Research Program of China (2007CB948104) and Natural
Science Foundation Projects of Zhejiang (Z207021).
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