ORIGINAL ARTICLE: GENETICS

Comprehensive chromosome
screening improves embryo
selection: a meta-analysis
Elias M. Dahdouh, M.D., M.Sc.,a,b,c Jacques Balayla, M.D.,c and Juan Antonio García-Velasco, M.D., Ph.D.d
a
Assisted Reproduction Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada; b PROCREA Clinics,
Montreal, Canada; c Department of Obstetrics and Gynecology, University of Montreal, Montreal, Canada; and d Instituto
Valenciano de Infertilidad (IVI) Madrid and Rey Juan Carlos University, Madrid, Spain

Objective: To study whether preimplantation genetic screening with comprehensive chromosome screening (PGS-CCS) improves clin-
ical implantation rates (IR) and sustained IR (beyond 20 weeks) compared with routine care for embryo selection in IVF cycles.
Design: Meta-analysis of randomized controlled trials (RCTs) and observational studies (OSs).
Setting: University-affiliated teaching hospital.
Patient(s): Infertile couples undergoing IVF.
Intervention(s): PGS-CCS with the use of different genetic platforms performed on polar body (PB), cleavage embryo, or blastocyst
following embryo biopsy.
Main Outcomes Measure(s): Clinical IR and sustained IR in RCTs as well as OSs comparing PGS-CCS and routine care were determined
after a complete review of the literature. Pooled estimates of risk ratios (RRs) with their 95% confidence intervals (CIs) according to a
fixed-effects model with the use of the Mantel-Haenszel method were calculated after the meta-analysis. Forest plots are provided for
comparative purposes.
Result(s): Out of 763 citations identified, 29 articles met initial eligibility criteria and were further analyzed. Of these, only three RCTs
and eight OSs met full inclusion criteria, allowing direct comparison of PGS-CCS and routine IVF care based on embryo morphology
selection. In the RCTs, all embryo biopsies were performed on day 5–6 of embryo development. In the OSs, biopsies were performed on
different stages of embryo development, including PB, day 3, or day 5–6. Meta-analysis of the RCTs (3 studies; n ¼ 659) showed that
PGS-CCS was associated with a significantly higher clinical IR, with a pooled RR of 1.29 (95% CI 1.15–1.45), as well as a significantly
higher sustained IR, with a pooled RR of 1.39 (95% CI 1.21–1.60). Similar findings were shown in the OSs, where the pooled RR for
clinical IR was 1.78 (95% CI 1.60–1.99; 7 studies; n ¼ 2,993) and for sustained IR was 1.75 (95% CI 1.48–2.07; 4 studies; n ¼
1,124). Statistical heterogeneity (I2) was minimal for RCTs and substantial among OSs.
Conclusion(s): PGS with the use of CCS technology increases clinical and sustained IRs, thus improving embryo selection, particularly
in patients with normal ovarian reserve. Results from ongoing RCTs conducted on different patient populations (e.g., decreased ovarian
reserve) and different embryo stage biopsy (e.g., PB, day 3) may further clarify the role of this
technology. (Fertil SterilÒ 2015;104:1503–12. Ó2015 by American Society for Reproductive
Medicine.) Use your smartphone
Key Words: Preimplantation genetic screening, comprehensive chromosome screening, to scan this QR code
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I
n vitro fertilization (IVF) is a well es- different steps: ovarian stimulation, complement), endometrial receptivity,
tablished reproductive technique egg retrieval, embryo culture, and and an adequate embryo transfer
used in couples for the treatment of finally embryo transfer (2–5). Its technique (6–8). Unfortunately, a high
infertility (1). IVF is a complex proce- success depends on multiple factors, proportion of embryos may be
dure, which includes a number of namely, embryo status (genetic aneuploid, and the transfer of these is
associated with decreased implantation
Received July 9, 2015; revised and accepted August 26, 2015; published online September 16, 2015.
E.M.D. has nothing to disclose. J.B. has nothing to disclose. J.A.G.-V. has nothing to disclose.
rates (IRs), high miscarriage rates, and
Reprint requests: Elias M. Dahdouh, M.D., M.Sc., Assisted Reproduction Center, Department decreased live birth rates (9–13). To
of Obstetrics and Gynecology, CHU Sainte-Justine, University of Montreal, 3175 Chemin bypass the high embryo aneuploidy
de la Co^ te-Sainte-Catherine, Montreal, Quebec H3T1C5, Canada (E-mail: elias.dahdouh@
umontreal.ca). rate, reproductive endocrinologists
have traditionally transferred multiple
Fertility and Sterility® Vol. 104, No. 6, December 2015 0015-0282/$36.00
Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc.
embryos with the aim of achieving at
http://dx.doi.org/10.1016/j.fertnstert.2015.08.038 least one single live birth (14). This

VOL. 104 NO. 6 / DECEMBER 2015 1503

ORIGINAL ARTICLE: GENETICS
practice has been associated with a high rate of multiple
pregnancies, which carries a number of risks to the health of
both mother and fetus (15–18). Because of this major
drawback, techniques of embryo selection (ES) have been
developed to select the best available one or two embryos to
transfer into the uterus (19–21). Ideally, the best single
embryo carrying the highest implantation potential (euploid
embryo) should be selected for transfer, and this would lead
to a lower multiple pregnancy rate, making IVF with elective
single-embryo transfer (eSET) a more attractive procedure for
many assisted reproductive technology (ART) clinics (22–24).
Morphologic evaluation remains the gold standard and
most commonly used method for ES. This type of selection
carries many limits and has been associated with conflicting
reproductive results, despite adopting standard criteria for
oocyte and embryo morphology assessment (25, 26). Other
methods of ES aiming to improve the clinical outcomes and
to bypass the technical limitations encountered by the
morphologic embryo assessment have been developed in the
past decades (6, 27). These techniques have been introduced
into clinical practice and show promise, but they still need
to be proven as effective and to be available at affordable
cost before their widespread use (28). These include
embryonic morphokinetic evaluation with the use of time-
lapse imaging by new microscopy systems and embryo
assessment based on the analysis of embryo metabolism,
among others (20, 21, 29, 30).
The most biologically plausible and promising means of
ES remains the assessment of the genetic component of the
embryo following embryo biopsy, a process known as preim-
plantation genetic screening (PGS) (6, 31, 32). The first
reported pregnancies after PGS with the use of fluorescence
in situ hybridization (FISH) technique occurred in 1995, and
its clinical use has dramatically increased since then (9).
PGS has been applied in IVF for different indications where
the risk of embryo aneuploidy is high, notably advanced
maternal age (AMA) (9, 33–41), repeated implantation
failure (RIF) (35, 42, 43), recurrent miscarriage (44, 45), and
severe male factor infertility (46, 47). Recently, PGS has
been used to improve embryo selection in eSET cycles (24, 48).
However, most of the randomized controlled trials (RCTs)
on PGS using FISH technology after cleavage-embryo biopsy
showed no increase in live birth rates, and even a deleterious
effect on IVF outcomes (49). Therefore, many centers and rec-
ommendations have discouraged its use (49, 50). The reasons
for the latter results might be attributed to the FISH
technology itself, or to the stage of the embryo biopsy,
which may have adverse effects on embryo development
(51–53). It is now evident that the combination of FISH
with day-3 embryo biopsy does not confer any advantage
to infertile couples and that it may even lower their chance
of conceiving. A new genetic technique known as compre-
hensive chromosome screening (CCS), which analyzes the
whole chromosome complement, has been developed and
used recently in PGS cycles (46, 54–56). This technique has
been applied on different stages of embryo biopsies,
including polar body (PB), cleavage-stage, and blastocyst-
stage embryos (32, 55, 57). In addition, CCS can be achieved
with the use of different genetic platforms, including
1504
metaphase comparative genomic hybridization (mCGH),
array comparative genomic hybridization (aCGH), single-
nucleotide polymorphism (SNP) microarray, quantitative
polymerase chain reaction (qPCR), and most recently, and
next-generation sequencing (NGS) (32, 58–62). These have
been extensively tested and validated in PGS cycles and
show promising early clinical results. However, whether
PGS-CCS improves embryo selection in IVF remains unclear
and a matter of debate. As such, the aim of the present study
was to perform a meta-analysis on all published studies on
PGS-CCS compared with routine care in ES, and to perform
an in-depth evaluation of the available evidence of this new
form of PGS.
MATERIALS AND METHODS
Search Strategy
We performed an English-language Medline, Embase, Google
Scholar and Cochrane database search, as well as Pubmed and
RCT registry (www.clinicaltrials.gov) searches, up to the end
of May 2015 with no date limitations and the use of the
following boolean search criteria: ‘‘((Preimplantation Genetic
Screening OR PGS) AND (Comprehensive Chromosome
Screening OR CCS) OR (PGS AND embryo selection) OR (em-
bryo selection) OR (elective single embryo transfer).’’ No
limiting categoric terms were used other than restricting the
search to human studies. The reference lists and bibliogra-
phies of included studies were then searched for other salient
and pertinent manuscripts. Finally, manual searches of
studies belonging to research teams having previous publica-
tions on PGS were undertaken and pertinent studies retrieved.
This review was modeled on the Preferred Reporting Items for
Systematic Reviews and Meta-analyses statement, and the
flow chart depicting the search strategy is illustrated in
Figure 1.
Study Selection
The three authors independently examined the electronic
search results for reports of possibly relevant trials, which
were retrieved and analyzed in further detail. Published
observational studies (OSs) and RCTs were eligible for inclu-
sion if they compared women undergoing IVF with the use
of PGS-CCS and women undergoing IVF with standard care
and no PGS. All studies were assessed according to predeter-
mined quality criteria. Validity of RCTs was assessed in terms
of method of randomization, presence of a power calculation,
unit of analysis used, use of an intention-to-treat analysis,
and presence or absence of blinding. We did not find the
need to contact any authors in an attempt to retrieve missing
data, given that data to carry out the present meta-analysis
were complete. We made no distinction between fresh or
frozen cycle transfer; oocyte, blastomere, or blastocyst bi-
opsy; and type of CCS technology used.
Statistical Analysis
The effect of CCS technology was assessed for two main indi-
cations separately. Our first outcome of interest was clinical
IR, defined as the number of gestational sacs with or without
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 Fertility and Sterility®

FIGURE 1

PRISMA flowchart for the systematic review of PGS studies using CCS.
Dahdouh. CCS and embryo selection. Fertil Steril 2015.

fetal heart beats divided by the number of embryos trans- RESULTS

ferred. The second outcome of interest was sustained IR, Literature Search
defined as the number of embryos that progressed beyond
After our initial search, which retrieved 763 studies after
20 weeks of gestation divided by the number of embryos
duplication removal, 29 studies dealing with PGS performed
transferred. Pooled estimates of risk ratios (RRs) with their
with the use of CCS were potentially eligible. Following a
95% confidence intervals (CIs) according to a fixed-effects
closer evaluation, 18 were excluded. Of these, eight were re-
model with the use of the Mantel-Haenszel method were
view or opinion articles (6, 48, 63–68), eight had no control
calculated after the meta-analysis. Forest plots are provided
group or other control group than standard care (13, 32, 47,
for comparative purposes (Figs. 2 and 3). OSs and RCTs
60, 69–72), one dealt with cost-effectiveness of PGS-CCS
were analyzed separately to ensure the best critical analysis
(73), and one was concerned with obstetric and neonatal out-
of available data and to reduce selection bias. Statistical
comes following PGS-CCS (74). At the end, we were left with
heterogeneity among results of the studies was examined by
three RCTs (22, 24, 75) and eight OSs addressing the practice
inspecting the scatter in the data points on the graphs and
of PGS with CCS compared with standard care based on ES
the overlap of CIs and by checking the I2 statistic. Review
according to morphology (23, 43, 55, 58, 76–79) (Fig. 1).
Manager 5.3.5 software (version 5.3; Nordic Cochrane
In the three RCTs, embryo biopsy was performed on day
Center) was used to combine data for the meta-analysis.
5–6 of embryo development. In the OSs, embryo biopsy was
This meta-analysis was exempt from Institutional Review
performed either on PBs or on day 3 or day 5–6 of embryo
Board approval because of the nature of the research design
development (Tables 1). In one RCT, CCS was performed
(review article and meta-analysis) as well as the lack of use
with the use of aCGH (24), and in the two others with the
of identified patient data.

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ORIGINAL ARTICLE: GENETICS
FIGURE 2
Meta-analysis of RCTs on PGS-CCS vs. routine care.
Dahdouh. CCS and embryo selection. Fertil Steril 2015.
use of qPCR (22, 75). The CCS technologies used in the OSs
were mCGH, aCGH, or qPCR.
Trial Characteristics and Indications for PGS-CCS
Main characteristics and description of the three RCTs and
eight OSs are outlined in Table 1. For each study, the design,
the indication, the embryo stage biopsy, the CCS platform,
and the main outcomes are presented. In the two studies
where two control groups were present, we chose the one
related to standard care and the same indication as the CCS
group (43, 77).
Meta-analysis
Randomized trials. For the main outcomes of clinical IR and
sustained IR, we combined the results of the three RCTs,
comparing a total of 276 blastocyst-stage embryos undergo-
ing PGS-CCS versus a total of 383 blastocysts selected ac-
cording to basic morphology criteria (Fig. 2). Clinical IR was
significantly higher after PGS-CCS, with an RR of 1.29
(95% CI 1.15–1.45). This suggests that for the group of women
undergoing PGS-CCS, there is a 15%–45% chance of
improving clinical IR when using this technique. In addition,
sustained IR beyond 20 weeks gestation was significantly
higher after PGS-CCS, with an RR of 1.39 (95% CI 1.21–
1.60). This suggests that for the group of women undergoing
PGS-CCS, there is a 21%–60% chance of improving sustained
IR when using this technique. There was no heterogeneity re-
1506
ported in the meta-analysis for both clinical outcomes (I2 ¼ 0;
P¼ .51 and P¼ .53, respectively).
Observational studies. For the main outcome of clinical IR,
we combined the results of seven OSs, comparing a total of
589 embryos undergoing PGS-CCS versus a total of 2,404 em-
bryos selected according to basic morphology criteria (Fig. 3).
Clinical IR was significantly higher after PGS-CCS, with a risk
ratio (RR) of 1.78 (95% CI 1.60–1.99). In addition, we com-
bined the results of four OS where sustained IR was retrieved
or calculated, comparing a total of 399 embryos undergoing
PGS-CCS versus a total of 959 embryos selected according
to basic morphology criteria. Sustained IR was also signifi-
cantly higher after PGS-CCS, with an RR of 1.75 (95% CI
1.48–2.07). Heterogeneity reported in the meta-analysis was
marked, with I2 of 88% and 77% for clinical IR and sustained
IR, respectively (P< .00001 and P¼ .004, respectively).
DISCUSSION
Summary and Interpretation of Results
The present meta-analysis shows that PGS-CCS improves
both clinical IR and sustained IR, leading to enhancement
in ES. To the best of our knowledge, this is the first meta-
analysis on the new form of PGS since the one published by
Mastenbroek et al. (49) combining all RCTs performed on
PGS with the use of FISH applied on blastomere cell(s)
following day-3 embryo biopsy (22, 24, 75). A number of
indications and patient populations undergoing PGS were
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FIGURE 3
Meta-analysis of observational studies on PGS-CCS vs. routine care.
Dahdouh. CCS and embryo selection. Fertil Steril 2015.
evaluated in the studies included in that meta-analysis, such
as AMA (10, 40, 80–82), good-prognosis patients (83–85), and
RIF (42). They showed no improvement in live birth rates for
good-prognosis patients, and an even lower live birth rate for
other indications, notably AMA and RIF, where the risk of em-
bryo aneuploidy is theoretically higher. The encouraging pre-
liminary results from OSs on PGS-FISH were later
overshadowed by the adverse effects that RCTs pointed out,
especially by the multicenter RCT published by Mastenbroek
et al. (80). Therefore, many experts are calling again for
caution against the fast introduction of PGS-CCS to avoid
the same contradictions shown by the early studies with
PGS-FISH (66).
The lack of benefit of PGS-FISH may be explained by a
number of factors. First, the use of FISH technology may be
a culprit, given that up to a maximum of 12 chromosomes
can be evaluated, which may miss up to 20%–30% of aneu-
ploidies (51, 52, 86). Second, the deleterious effect of
embryo biopsy and extended culture on embryo
development may be contributory to the results (53, 87, 88).
It is possible that the combination of both FISH and day-3 bi-
opsy is the underlying cause. The latter may have conferred
adverse effects on embryo implantation potential under
certain circumstances, such as retrieving two blastomeres,
biopsying poor-quality embryos, or having a little experience
with embryo biopsy and extended embryo culture (49, 87, 88).
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Fertility and Sterility®
FISH Versus CCS
FISH is operator dependent and can be associated with hy-
bridization failure, signal overlap, and splitting. In contrast,
CCS is automated and can be applied to blastomeres and mul-
tiple trophectoderm cells, with the results available in less
than 24 hours with the use of either aCGH and qPCR (89).
Fresh ET is therefore still possible after day-5 embryo biopsy.
For example, aCGH can be performed on day 5, with subse-
quent transfer on day 6 of embryo development (24), or
even the same day after qPCR, where genetic results can be
available in 4 hours (61, 75). CCS has the advantages of
performing a complete 24-chromosome analysis by means
of different genetic platforms that have been extensively
evaluated and validated (54, 61, 90, 91).
In our opinion, prerequisites for the successful applica-
tion of PGS-CCS in today's practice should, at least, include
experience in extended embryo culture and biopsy (whether
day 3 or day 5), validated and tested CCS platforms, and an
established and effective cryopreservation program (6).
These platforms should have low false detection rates so as
not to discard normal embryos which may have been mis-
diagnosed as aneuploid or abnormal. Failing to do so will
lead to the opposite of the intended outcome: leading to a
decrease in cumulative live birth rates resulting from having
fewer available euploid embryos to transfer. Both aCGH and
qPCR can accurately test for aneuploidy and have been
1507
ORIGINAL ARTICLE: GENETICS

TABLE 1

Characteristics of included randomized and observational studies.

Embryo Genetic
Study Design Indication biopsy platform Main outcomes
Randomized studies
Yang et al., 2012 (24) Pilot RCT Good-prognosis patients, Blastocyst aCGH Clinical PR, ongoing PR
1st IVF cycle (>20 wk)
Forman et al. 2013 (22) Noninferiority Normal ovarian reserve, Blastocyst qPCR Ongoing PR (>24 wk),
trial (RCT) %1 previous IVF failure multiple PR
Scott et al., 2013 (75) RCT Normal ovarian reserve, Blastocyst qPCR Sustained IR, delivery rate
%1 previous IVF failure
Observational studies
Sher et al., 2009 (58) PCS AMA þ RIF þ RPL Cleavage mCGH IR, Live birth rate
Schoolcraft et al., 2010 (55) PCS Previous IVF failure Blastocyst aCGH IR
Fishel et al., 2011 (79) PCS RIF Polar Body aCGH IR
Forman et al., 2012 (23) RCS 1st SET cycle Blastocyst qPCR Ongoing PR (>12 wk)
Keltz et al., 2013 (76) RCC AMA þ RIF þ RPL Cleavage aCGH IR
Greco et al., 2014 (43) PCS RIF Blastocyst aCGH IR
Lee et al., 2015 (77) RCS AMA Blastocyst aCGH IR, Live birth rate
Feichtinger et al., 2015 (78) RCS RIF þ AMA Polar Body aCGH Live birth rate
Note: aCGH ¼ array comparative genomic hybridization; AMA ¼ advanced maternal age; IR ¼ implantation rate; mCGH ¼ metaphase comparative genomic hybridization; qPCR ¼ quantitative
polymerase chain reaction; PCS ¼ prospective cohort study; PR ¼ pregnancy rate; RCC ¼ retrospective case-control; RCS ¼ retrospective cohort study; RCT ¼ randomized controlled trial; RIF
¼ repeated implantation failure; RPL ¼ recurrent pregnancy loss; SET ¼ single-embryo transfer.
Dahdouh. CCS and embryo selection. Fertil Steril 2015.

tested and validated extensively, showing low false positive
and false negative rates. In a recent trial, Werner et al.
demonstrated that the clinically recognizable error rate
with qPCR-based CCS is real but quite low: 0.13% per
ongoing pregnancy rate (95% CI 0.03–0.37) (92). This error
rate appears to result from embryo mosaicism rather than
misdiagnoses. On the other hand, Capalbo et al. (71) per-
formed a comparison of aCGH- and qPCR-based aneuploidy
screening of blastocyst biopsies. Although a high reliability
of diagnosis of aneuploidy can be achieved by both plat-
forms, the discordant aneuploidy call rate per chromosome
was significantly higher for aCGH (5.7%) compared with
qPCR (0.6%; P< .01).
Stage of Embryo Biopsy
Polar body. The improvement of ES with PGS-CCS may be
explained by a paradigm shift in embryo biopsy stage.
Nowadays, PB biopsy is the least used technique, given ev-
idence from several studies that it is less predictive of repro-
ductive potential than other approaches (57, 72, 93). In the
only two reported OSs in our meta-analysis dealing with
PB biopsy, clinical IR was as low as 27.7% and sustained
IR was 26.3% (78, 79). These low IRs make the PB
approach less attractive for introduction into clinical
practice, considering its high relative cost, because more
samples have to be tested from PB biopsies than with
other embryo stages (94, 95). Furthermore, in the only
ongoing European RCT of PB biopsy with CCS (ESTEEM;
ClinicalTrials.gov NCT01532284), investigators from seven
centers are having difficulty with patient recruitment, and
as such the trial's future is in question. Besides legal
constraints in some countries where other embryo stage
biopsies are impossible, it seems that PB biopsy does not
confer any advantage regarding cost, convenience,
predictive value, or clinical outcomes.
Cleavage stage (day 3). Regarding cleavage-stage embryo
biopsies, a number of considerations need to be taken into ac-
count. Day-3 biopsy can be associated with mosaicism and
decreased implantation potential (95, 96). These drawbacks
must be taken into account when dealing with PGS. It is
worthwhile to note, however, that a recent RCT by Rubio
et al. using PGS-FISH on day-3 embryo biopsy did show clin-
ical improvements for both AMA and RIF indications (35). It is
therefore fairly evident that ideal laboratory and media cul-
ture conditions, combined with extensive experience in em-
bryo biopsy, are key aspects to consider for the success of
any PGS program. The same researchers recently released
their preliminary data from a current trial of PGS-CCS and
cleavage-stage biopsy. Favorable reproductive outcomes
were reported for the following two indications, AMA and
male factor infertility, at recent meetings (American Society
for Reproductive Medicine and European Society for Human
Reproduction and Embryology, 2014; ClinicalTrials.gov
NCT01571076).
Blastocyst (day 5–6). As evidenced by our study, where
three RCTs and four OSs used the technology, trophectoderm
biopsy is commonly used in modern PGS practice (23, 55). It
appears that this type of biopsy confers no adverse effects of
embryo development and implantation potential. In the only
available level I evidence, by Scott et al., a cleavage-stage bi-
opsy was shown to decrease IR by 39% compared with non-
biopsied day 3 embryos, whereas no similar effect was
reported after blastocyst biopsy (75). Interestingly, IRs
were equivalent between day 3 and day 5 embryos in this
study (53). In addition, by retrieving 3–10 trophectoderm
cells, more DNA material is available for CCS analysis,
thus improving the accuracy of genetic analysis. Schoolcraft
et al. reported the first successful application of aCGH on
trophectoderm cells, showing improvement in both clinical
IR and ongoing IR in the PGS group compared with routine

1508 VOL. 104 NO. 6 / DECEMBER 2015


care (55). Euploid blastocysts are expected to carry high im-
plantation rates, because they have been selected twice: once
after extended embryo culture and another time after CCS
analysis. In the present meta-analysis, all CCS studies per-
formed on trophectoderm cells reported high clinical IR
(>50%) and sustained IR (>45%), confirming once again
their favorable reproductive potential by transferring
euploid blastocyst(s). In our opinion, these figures should
encourage eSET.
Finally, the results of this meta-analysis concur with the
conclusions from two recent systematic reviews of PGS-
CCS, by Dahdouh et al. and Lee at al. Both agree that CCS
technology is favorable in improving IRs and ongoing preg-
nancies in patients with normal ovarian reserve; however,
they call for robust evidence before PGS-CCS is used as
routine practice in all patient populations (6, 64). In
addition, recent published guidelines from the Society of
Obstetricians and Gynaecologists of Canada (SOGC) on
PGD-PGS further approve the concept of CCS for ES. Those
guidelines establish the following recommendation ‘‘(#9):
Preimplantation genetic screening using comprehensive
chromosome screening technology on blastocyst biopsy in-
creases implantation rates and improves embryo selection in
IVF cycles in patients with a good prognosis’’; the level of
evidence for the latter statement was rated as I-B (68).
Robust evidence on the effectiveness of CCS on different pa-
tients' populations is still lacking, and caution must be taken
before its widespread application is undertaken as routine
practice. If applied on a routine basis, especially in poorly re-
sponding patients, where embryo banking for CCS is per-
formed by some practitioners, this will inevitably increase
the cost of ART treatments with no proven benefit (34) and
may even lead to an increase in IVF dropouts. Indeed,
ongoing trials should clarify the future role of PGS-CCS.
At the present time, investigation is ongoing for the
following indications: low responders (antim€ ullerian hor-
mone <1.1 or antral follicle count <8; Scott et al., Clinical-
Trials.gov NCT01977144), day-3 biopsy with CCS (Rubio
et al., 2014, ClinicalTrials.gov NCT01571076), CCS with
the use of NGS for fresh versus frozen embryos (Munne
et al., ClinicalTrials.gov NCT02000349), RIF or recurrent
pregnancy loss (RPL; ClinicalTrials.gov NCT02265614),
and others.
CCS Improves Embryo Selection for eSET
Aneuploidy is highly prevalent in embryos, increases with
AMA, and is inversely proportional to IRs. One large CCS
retrospective analysis, by Franasiak et al. on >15,000 blasto-
cyst biopsies, reported a progressive increase in aneuploidy
rates with AMA (70). In that study, the risk of having no
euploid embryos available for transfer was lowest in women
aged 26–37 years (2%–6%), 33% at age 42 years, and 53%
at age 44 years. These findings are of paramount importance
when counseling patients for the use and potential benefits of
PGS. Thus, by selecting euploid embryos, CCS should theoret-
ically improve IRs and live birth rates (97). Recent data from
Harton et al. demonstrated that the selective transfer of
euploid embryos after aCGH, applied to cleavage-stage em-
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Fertility and Sterility®
bryos or blastocysts, confers equal implantation and preg-
nancy rates between reproductively younger and older
patients up to the age of 42 years (13). That finding should
mandate eSET by transferring one single euploid embryo
even in older patients, where the risk of carrying multiples
is both higher and more troublesome (48, 98, 99). All
studies included in the present meta-analysis reported high
IRs after PGS-CCS. Therefore, PGS might overcome the
reduced live birth rates reported by eSET based on morpho-
logic ES alone (100–103). Implementation of CCS may
actually increase the risk of multiple gestations unless the
number of transferred embryos is reduced (104): Because
implantation rates increase after PGS-CCS, if there is no
decrease in transfer order then multiple gestation rates will
inevitably rise. For the first time, there are class I data demon-
strating eSET after CCS to be as effective as double-embryo
transfer of unscreened embryos (22). Equivalent ongoing
pregnancy rates beyond 24 weeks are maintained while
dramatically reducing the risk of twins (74). Based on these
data, eSET in any PGS program should be the standard of care.
Cost-effectiveness of CCS
An alternative to embryo selection (105) consists of cryopres-
ervation by vitrification and subsequent serial embryo trans-
fer(s) (106, 107). The cost-effectiveness of CCS can be resolved
only following cumulative live birth rates. NGS may represent
the next frontier of PGS (108) and has the potential to
decrease costs (62, 109, 110). Any future study evaluating
the cost-effectiveness of CCS versus standard care must
take into account all available procedures and related costs.
These should include, at minimum, the costs of the following
techniques: the IVF cycle, the CCS analysis, the first fresh em-
bryo transfer and all subsequent frozen transfers, the obstet-
rical care, and any additional prenatal care provided to
ongoing aneuploid gestations, from pregnancy time until
delivery (104). These aforementioned points need to be
considered, but until such data become available, the debate
continues on this crucial aspect of PGS.
Study Strengths and Limitations
The limitations of our study are several and worth
mentioning. First, although all of the studies included in
the meta-analysis used CCS technology, the indications,
genetic platforms, and embryo stages of biopsy were
different between studies. Second, although we separated
the analysis between OSs and RCTs, the patient populations
in both types of studies are vastly different. Most of the in-
dications in the OSs are for patients at high risk of produc-
ing aneuploid embryos (AMA, RIF, RPL), compared with the
three RCTs where the patient population was more homo-
geneous and of good prognosis. The heterogeneity between
both types of population may preclude a definite conclu-
sion about the generalizability of our results. Finally and
most importantly, there is a paucity of RCTs: Only one
small pilot study and two RCTs originating from the
same IVF clinic have been published and included in this
meta-analysis. Randomization was carried out on a
1509
ORIGINAL ARTICLE: GENETICS
per-embryo-available-to-biopsy basis and not on a per-
cycle-started basis. Ideally, the analysis of future RCTs
should be performed according to an intention-to-treat ba-
sis after per-cycle-started randomization to reduce bias.
Primary outcomes should include cumulative live birth
rates originating from both fresh and subsequent frozen
cycles (22, 75).
On the other hand, this study has a number of strengths.
First, it is the largest and most up-to-date review on the sub-
ject of PGS with the use of CCS. Second, we provide both
qualitative and quantitative summaries of the data. Third,
by conducting a meta-analysis, which hints at the overall
benefit of this technology, we lead the way for future research
to build upon these findings.
CONCLUSION
There is evidence from this meta-analysis that PGS-CCS im-
proves methods of ES by increasing both clinical and sus-
tained IRs. All of the available data from RCTs of CCS
stem from patients with normal ovarian reserve producing
blastocysts available to biopsy, which might introduce selec-
tion bias and overestimate the success rate of PGS-CCS. Re-
sults from ongoing RCTs, including different patient
categories (e.g., AMA, poor responders), and different
embryo-stage biopsies (e.g., day 3) are urgently awaited,
and might clarify the role of PGS-CCS. If applied properly
and under ideal laboratory and technical conditions, it
might shorten time to pregnancy and decrease miscarriage
rates. In addition, cost-effectiveness of this new form of
PGS should be evaluated before its widespread use in clin-
ical practice. New CCS technology, such as NGS, is expected
to lower PGS cost and decrease the financial burden to pa-
tients. Ongoing RCTs will better define patient populations
who may or may not benefit from use of this technique. It
seems that PGS-CCS is still a viable procedure, but is not
suitable for every patient, and definitely not for every IVF
practice, at least for the time being.
REFERENCES
1. Pandian Z, Gibreel A, Bhattacharya S. In vitro fertilisation for unexplained
subfertility. Cochrane Database Syst Rev 2012:CD003357.
2. Tarlatzis BC, Fauser BC, Kolibianakis EM, Diedrich K, Rombauts L,
Devroey P. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod
Update 2006;12:333–40.
3. Abou-Setta AM, Al-Inany HG, Mansour RT, Serour GI, Aboulghar MA. Soft
versus firm embryo transfer catheters for assisted reproduction: a system-
atic review and meta-analysis. Hum Reprod 2005;20:3114–21.
4. Chronopoulou E, Harper JC. IVF culture media: past, present and future.
Hum Reprod Update 2015;21:39–55.
5. Nardo LG, Bosch E, Lambalk CB, Gelbaya TA. BFS Policy and Practice
Committee. Controlled ovarian hyperstimulation regimens: a review
of the available evidence for clinical practice. Hum Fertil 2013;16:
144–50.
6. Dahdouh EM, Balayla J, Garcia-Velasco JA. Impact of blastocyst biopsy and
comprehensive chromosome screening technology on preimplantation ge-
netic screening: a systematic review of randomized controlled trials. Reprod
Biomed Online 2015;30:281–9.
7. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S.
Evidence of impaired endometrial receptivity after ovarian stimulation for
in vitro fertilization: a prospective randomized trial comparing fresh and
1510
frozen-thawed embryo transfer in normal responders. Fertil Steril 2011;
96:344–8.
8. Mains L, van Voorhis BJ. Optimizing the technique of embryo transfer. Fertil
Steril 2010;94:785–90.
9. Munne S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology,
developmental rates, and maternal age are correlated with chromosome
abnormalities. Fertil Steril 1995;64:382–91.
10. Hardarson T, Hanson C, Lundin K, Hillensjo T, Nilsson L, Stevic J, et al. Pre-
implantation genetic screening in women of advanced maternal age
caused a decrease in clinical pregnancy rate: a randomized controlled trial.
Hum Reprod 2008;23:2806–12.
11. Munne S. Preimplantation genetic diagnosis for aneuploidy and transloca-
tions using array comparative genomic hybridization. Curr Genomics 2012;
13:463–70.
12. Kroon B, Harrison K, Martin N, Wong B, Yazdani A. Miscarriage karyotype
and its relationship with maternal body mass index, age, and mode of
conception. Fertil Steril 2011;95:1827–9.
13. Harton GL, Munne S, Surrey M, Grifo J, Kaplan B, McCulloh DH, et al.
Diminished effect of maternal age on implantation after preimplantation
genetic diagnosis with array comparative genomic hybridization. Fertil
Steril 2013;100:1695–703.
14. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of
embryos for transfer following in vitro fertilisation or intra-cytoplasmic
sperm injection. Cochrane Database Syst Rev 2013:CD003416.
15. Chambers GM, Ledger W. The economic implications of multiple preg-
nancy following ART. Semin Fetal Neonatal Med 2014;19:254–61.
16. Murray SR, Norman JE. Multiple pregnancies following assisted reproduc-
tive technologies—a happy consequence or double trouble? Semin Fetal
Neonatal Med 2014;19:222–7.
17. Gocmen A, Guven S, Bagci S, Cekmez Y, Sanlikan F. Comparison of
maternal and fetal outcomes of IVF and spontaneously conceived twin
pregnancies: three year experience of a tertiary hospital. Int J Clin Exp
Med 2015;8:6272–6.
18. Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result
from multiple pregnancies associated with assisted reproductive technolo-
gies in the USA: a cost analysis. Curr Opin Obstet Gynecol 2011;23:168–73.
19. Montag M, Toth B, Strowitzki T. New approaches to embryo selection.
Reprod Biomed Online 2013;27:539–46.
20. Basile N, Caiazzo M, Meseguer M. What does morphokinetics add to
embryo selection and in-vitro fertilization outcomes? Curr Opin Obstet
Gynecol 2015;27:193–200.
21. Sakkas D. Embryo selection using metabolomics. Methods Mol Biol 2014;
1154:533–40.
22. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, et al. In vitro fertil-
ization with single euploid blastocyst transfer: a randomized controlled
trial. Fertil Steril 2013;100:100–7.e1.
23. Forman EJ, Tao X, Ferry KM, Taylor D, Treff NR, Scott RT Jr. Single embryo
transfer with comprehensive chromosome screening results in improved
ongoing pregnancy rates and decreased miscarriage rates. Hum Reprod
2012;27:1217–22.
24. Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, et al. Selection of single
blastocysts for fresh transfer via standard morphology assessment alone
and with array CGH for good prognosis IVF patients: results from a ran-
domized pilot study. Mol Cytogenet 2012;5:24.
25. Alpha Scientists in Reproductive Medicine, ESHRE Special Interest Group of
Embryology Balaban B, Brison D, Caldero n G, Catt J, et al. The Istanbul
consensus workshop on embryo assessment: proceedings of an expert
meeting. Hum Reprod 2011;26:1270–83.
26. Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst
score affects implantation and pregnancy outcome: toward a single blas-
tocyst transfer. Fertil Steril 2000;73:1155–8.
27. Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic
testing. BMJ 2015;350:g7611.
28. Wong KM, Repping S, Mastenbroek S. Limitations of embryo selection
methods. Semin Reprod Med 2014;32:127–33.
29. Basile N, Vime P, Florensa M, Aparicio Ruiz B, Garcia Velasco JA, Remohi J,
et al. The use of morphokinetics as a predictor of implantation: a
VOL. 104 NO. 6 / DECEMBER 2015

multicentric study to define and validate an algorithm for embryo selection.
Hum Reprod 2015;30:276–83.
30. Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The
use of morphokinetics as a predictor of embryo implantation. Hum Reprod
2011;26:2658–71.
31. Munne S, Cohen J, Sable D. Preimplantation genetic diagnosis for
advanced maternal age and other indications. Fertil Steril 2002;78:234–6.
32. Rubio C, Rodrigo L, Mir P, Mateu E, Peinado V, Milan M, et al. Use of array
comparative genomic hybridization (array-CGH) for embryo assessment:
clinical results. Fertil Steril 2013;99:1044–8.
33. Hanson C, Hardarson T, Lundin K, Bergh C, Hillensjo T, Stevic J, et al. Re-
analysis of 166 embryos not transferred after PGS with advanced reproduc-
tive maternal age as indication. Hum Reprod 2009;24:2960–4.
34. Orris JJ, Taylor TH, Gilchrist JW, Hallowell SV, Glassner MJ, Wininger JD.
The utility of embryo banking in order to increase the number of embryos
available for preimplantation genetic screening in advanced maternal age
patients. J Assist Reprod Genet 2010;27:729–33.
35. Rubio C, Bellver J, Rodrigo L, Bosch E, Mercader A, Vidal C, et al. Preimplan-
tation genetic screening using fluorescence in situ hybridization in patients
with repetitive implantation failure and advanced maternal age: two ran-
domized trials. Fertil Steril 2013;99:1400–7.
36. Milan M, Cobo AC, Rodrigo L, Mateu E, Mercader A, Buendia P, et al. Re-
defining advanced maternal age as an indication for preimplantation ge-
netic screening. Reprod Biomed Online 2010;21:649–57.
37. Platteau P, Staessen C, Michiels A, van Steirteghem A, Liebaers I,
Devroey P. Preimplantation genetic diagnosis for aneuploidy screening in
women older than 37 years. Fertil Steril 2005;84:319–24.
38. Gianaroli L, Magli MC, Ferraretti AP, Munne S. Preimplantation diagnosis
for aneuploidies in patients undergoing in vitro fertilization with a poor
prognosis: identification of the categories for which it should be proposed.
Fertil Steril 1999;72:837–44.
39. Kuliev A, Verlinsky Y. The role of preimplantation genetic diagnosis in
women of advanced reproductive age. Curr Opin Obstet Gynecol 2003;
15:233–8.
40. Schoolcraft WB, Katz-Jaffe MG, Stevens J, Rawlins M, Munne S. Preimplan-
tation aneuploidy testing for infertile patients of advanced maternal age: a
randomized prospective trial. Fertil Steril 2009;92:157–62.
41. Munne S, Magli C, Bahce M, Fung J, Legator M, Morrison L, et al. Preim-
plantation diagnosis of the aneuploidies most commonly found in sponta-
neous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenat
Diagn 1998;18:1459–66.
42. Blockeel C, Schutyser V, de Vos A, Verpoest W, de Vos M, Staessen C, et al.
Prospectively randomized controlled trial of PGS in IVF/ICSI patients with
poor implantation. Reprod Biomed Online 2008;17:848–54.
43. Greco E, Bono S, Ruberti A, Lobascio AM, Greco P, Biricik A, et al. Compar-
ative genomic hybridization selection of blastocysts for repeated implanta-
tion failure treatment: a pilot study. Biomed Res Int 2014;2014:457913.
44. Munne S, Chen S, Fischer J, Colls P, Zheng X, Stevens J, et al. Preimplanta-
tion genetic diagnosis reduces pregnancy loss in women aged 35 years and
older with a history of recurrent miscarriages. Fertil Steril 2005;84:331–5.
45. Shahine LK, Lathi RB. Embryo selection with preimplantation chromosomal
screening in patients with recurrent pregnancy loss. Semin Reprod Med
2014;32:93–9.
46. Harper JC, Sengupta SB. Preimplantation genetic diagnosis: state of the art
2011. Hum Genet 2012;131:175–86.
47. Rodrigo L, Mateu E, Mercader A, Cobo AC, Peinado V, Milan M, et al. New
tools for embryo selection: comprehensive chromosome screening by array
comparative genomic hybridization. Biomed Res Int 2014;2014:517125.
48. Schoolcraft WB, Katz-Jaffe MG. Comprehensive chromosome screening of
trophectoderm with vitrification facilitates elective single-embryo transfer
for infertile women with advanced maternal age. Fertil Steril 2013;100:
615–9.
49. Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation
genetic screening: a systematic review and meta-analysis of RCTs. Hum
Reprod Update 2011;17:454–66.
50. Ginsburg ES, Baker VL, Racowsky C, Wantman E, Goldfarb J, Stern JE. Use
of preimplantation genetic diagnosis and preimplantation genetic
VOL. 104 NO. 6 / DECEMBER 2015
Fertility and Sterility®
screening in the United States: a Society for Assisted Reproductive Technol-
ogy Writing Group paper. Fertil Steril 2011;96:865–8.
51. Mir P, Rodrigo L, Mateu E, Peinado V, Milan M, Mercader A, et al.
Improving FISH diagnosis for preimplantation genetic aneuploidy
screening. Hum Reprod 2010;25:1812–7.
52. Munne S, Fragouli E, Colls P, Katz-Jaffe M, Schoolcraft W, Wells D.
Improved detection of aneuploid blastocysts using a new 12-
chromosome FISH test. Reprod Biomed Online 2010;20:92–7.
53. Scott RT Jr, Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage bi-
opsy significantly impairs human embryonic implantation potential while
blastocyst biopsy does not: a randomized and paired clinical trial. Fertil
Steril 2013;100:624–30.
54. Gutierrez-Mateo C, Colls P, Sanchez-Garcia J, Escudero T, Prates R,
Ketterson K, et al. Validation of microarray comparative genomic hybridi-
zation for comprehensive chromosome analysis of embryos. Fertil Steril
2011;95:953–8.
55. Schoolcraft WB, Fragouli E, Stevens J, Munne S, Katz-Jaffe MG, Wells D.
Clinical application of comprehensive chromosomal screening at the blas-
tocyst stage. Fertil Steril 2010;94:1700–6.
56. Harper JC, Harton G. The use of arrays in preimplantation genetic diagnosis
and screening. Fertil Steril 2010;94:1173–7.
57. Capalbo A, Bono S, Spizzichino L, Biricik A, Baldi M, Colamaria S, et al.
Sequential comprehensive chromosome analysis on polar bodies, blasto-
meres and trophoblast: insights into female meiotic errors and chromosomal
segregation in the preimplantation window of embryo development. Hum
Reprod 2013;28:509–18.
58. Sher G, Keskintepe L, Keskintepe M, Maassarani G, Tortoriello D, Brody S.
Genetic analysis of human embryos by metaphase comparative genomic
hybridization (mCGH) improves efficiency of IVF by increasing embryo
implantation rate and reducing multiple pregnancies and spontaneous
miscarriages. Fertil Steril 2009;92:1886–94.
59. Fiorentino F, Spizzichino L, Bono S, Biricik A, Kokkali G, Rienzi L, et al. PGD
for reciprocal and robertsonian translocations using array comparative
genomic hybridization. Hum Reprod 2011;26:1925–35.
60. Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-Jaffe M, Scott RT Jr. Live
birth outcome with trophectoderm biopsy, blastocyst vitrification, and
single-nucleotide polymorphism microarray–based comprehensive chro-
mosome screening in infertile patients. Fertil Steril 2011;96:638–40.
61. Treff NR, Scott RT Jr. Four-hour quantitative real-time polymerase chain re-
action–based comprehensive chromosome screening and accumulating
evidence of accuracy, safety, predictive value, and clinical efficacy. Fertil
Steril 2013;99:1049–53.
62. Wells D. Next-generation sequencing: the dawn of a new era for preim-
plantation genetic diagnostics. Fertil Steril 2014;101:1250–1.
63. Dahdouh EM, Balayla J, Garcia-Velasco JA. Preimplantation genetic
screening using comprehensive chromosome screening: evidence and re-
maining challenges. Hum Reprod 2015;30:1515–6.
64. Lee E, Illingworth P, Wilton L, Chambers GM. The clinical effectiveness of
preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes
(PGD-A): systematic review. Hum Reprod 2015;30:473–83.
65. Lee E, Illingworth P, Wilton L, Chambers GM. Reply: Preimplantation ge-
netic screening using comprehensive chromosome screening: evidence
and remaining challenges. Hum Reprod 2015;30:1516.
66. Mastenbroek S, Repping S. Preimplantation genetic screening: back to the
future. Hum Reprod 2014;29:1846–50.
67. Gleicher N, Kushnir VA, Barad DH. Preimplantation genetic screening (PGS)
still in search of a clinical application: a systematic review. Reprod Biol En-
docrinol 2014;12:22.
68. Dahdouh EM, Balayla J, Audibert F. The SOGC Genetics Committee. Tech-
nical Update: preimplantation genetic diagnosis and screening. J Obstet
Gynaecol Can 2015;37:451–63.
69. Fragouli E, Katz-Jaffe M, Alfarawati S, Stevens J, Colls P, Goodall NN, et al.
Comprehensive chromosome screening of polar bodies and blastocysts
from couples experiencing repeated implantation failure. Fertil Steril
2010;94:875–87.
70. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR,
et al. The nature of aneuploidy with increasing age of the female partner:
1511
ORIGINAL ARTICLE: GENETICS
a review of 15,169 consecutive trophectoderm biopsies evaluated with
comprehensive chromosomal screening. Fertil Steril 2014;101:656–63.e1.
71. Capalbo A, Treff NR, Cimadomo D, Tao X, Upham K, Ubaldi FM, et al.
Comparison of array comparative genomic hybridization and quantitative
real-time PCR-based aneuploidy screening of blastocyst biopsies. Eur J
Hum Genet 2015;23:901–6.
72. Salvaggio CN, Forman EJ, Garnsey HM, Treff NR, Scott RT Jr. Polar body
based aneuploidy screening is poorly predictive of embryo ploidy and
reproductive potential. J Assist Reprod Genet 2014;31:1221–6.
73. Murugappan G, Ohno MS, Lathi RB. Cost-effectiveness analysis of preim-
plantation genetic screening and in vitro fertilization versus expectant man-
agement in patients with unexplained recurrent pregnancy loss. Fertil Steril
2015;103:1215–20.
74. Forman EJ, Hong KH, Franasiak JM, Scott RT Jr. Obstetrical and neonatal
outcomes from the BEST Trial: single embryo transfer with aneuploidy
screening improves outcomes after in vitro fertilization without compro-
mising delivery rates. Am J Obstet Gynecol 2014;210:157.e1–6.
75. Scott RT Jr, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, et al. Blas-
tocyst biopsy with comprehensive chromosome screening and fresh embryo
transfer significantly increases in vitro fertilization implantation and delivery
rates: a randomized controlled trial. Fertil Steril 2013;100:697–703.
76. Keltz MD, Vega M, Sirota I, Lederman M, Moshier EL, Gonzales E, et al. Pre-
implantation genetic screening (PGS) with comparative genomic hybridiza-
tion (CGH) following day 3 single cell blastomere biopsy markedly improves
IVF outcomes while lowering multiple pregnancies and miscarriages.
J Assist Reprod Genet 2013;30:1333–9.
77. Lee HL, McCulloh DH, Hodes-Wertz B, Adler A, McCaffrey C, Grifo JA.
In vitro fertilization with preimplantation genetic screening improves im-
plantation and live birth in women age 40 through 43. J Assist Reprod
Genet 2015;32:435–44.
78. Feichtinger M, Stopp T, Gobl C, Feichtinger E, Vaccari E, Madel U, et al.
Increasing live birth rate by preimplantation genetic screening of pooled
polar bodies using array comparative genomic hybridization. PLoS One
2015;10:e0128317.
79. Fishel S, Craig A, Lynch C, Dowell K, Ndukwe G, Jenner L, et al. Assessment
of 19,803 paired chromosomes and clinical outcome from first 150 cycles
using array CGH of the first polar body for embryo selection and transfer. J
In Vitro Fert Embryo Transf 2011;1:1–8.
80. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B,
Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation
genetic screening. N Engl J Med 2007;357:9–17.
81. Staessen C, Platteau P, van Assche E, Michiels A, Tournaye H, Camus M,
et al. Comparison of blastocyst transfer with or without preimplantation
genetic diagnosis for aneuploidy screening in couples with advanced
maternal age: a prospective randomized controlled trial. Hum Reprod
2004;19:2849–58.
82. Debrock S, Melotte C, Spiessens C, Peeraer K, Vanneste E, Meeuwis L, et al.
Preimplantation genetic screening for aneuploidy of embryos after in vitro
fertilization in women aged at least 35 years: a prospective randomized
trial. Fertil Steril 2010;93:364–73.
83. Jansen RP, Bowman MC, de Boer KA, Leigh DA, Lieberman DB,
McArthur SJ. What next for preimplantation genetic screening (PGS)?
Experience with blastocyst biopsy and testing for aneuploidy. Hum Reprod
2008;23:1476–8.
84. Staessen C, Verpoest W, Donoso P, Haentjens P, van der Elst J, Liebaers I,
et al. Preimplantation genetic screening does not improve delivery rate in
women under the age of 36 following single-embryo transfer. Hum Reprod
2008;23:2818–25.
85. Meyer LR, Klipstein S, Hazlett WD, Nasta T, Mangan P, Karande VC. A pro-
spective randomized controlled trial of preimplantation genetic screening
in the ‘‘good prognosis’’ patient. Fertil Steril 2009;91:1731–8.
86. Ly KD, Agarwal A, Nagy ZP. Preimplantation genetic screening: does it help
or hinder IVF treatment and what is the role of the embryo? J Assist Reprod
Genet 2011;28:833–49.
87. Munne S, Wells D, Cohen J. Technology requirements for preimplantation
genetic diagnosis to improve assisted reproduction outcomes. Fertil Steril
2010;94:408–30.
1512
88. Rubio C. Update on preimplantation genetic diagnosis for chromosomal
abnormalities. Expert Rev Mol Diagn 2010;10:973–6.
89. Handyside AH. 24-chromosome copy number analysis: a comparison of
available technologies. Fertil Steril 2013;100:595–602.
90. Werner MD, Scott RT Jr, Treff NR. 24-chromosome PCR for aneuploidy
screening. Curr Opin Obstet Gynecol 2015;27:201–5.
91. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR,
et al. Aneuploidy across individual chromosomes at the embryonic level
in trophectoderm biopsies: changes with patient age and chromosome
structure. J Assist Reprod Genet 2014;31:1501–9.
92. Werner MD, Leondires MP, Schoolcraft WB, Miller BT, Copperman AB,
Robins ED, et al. Clinically recognizable error rate after the transfer of
comprehensive chromosomal screened euploid embryos is low. Fertil Steril
2014;102:1613–8.
93. Forman EJ, Treff NR, Stevens JM, Garnsey HM, Katz-Jaffe MG, Scott RT Jr,
et al. Embryos whose polar bodies contain isolated reciprocal chromosome
aneuploidy are almost always euploid. Hum Reprod 2013;28:502–8.
94. Montag M, Koster M, Strowitzki T, Toth B. Polar body biopsy. Fertil Steril
2013;100:603–7.
95. Xu K, Montag M. New perspectives on embryo biopsy: not how, but when
and why? Semin Reprod Med 2012;30:259–66.
96. Scott KL, Hong KH, Scott RT Jr. Selecting the optimal time to perform
biopsy for preimplantation genetic testing. Fertil Steril 2013;100:
608–14.
97. Ubaldi FM, Capalbo A, Colamaria S, Ferrero S, Maggiulli R, Vajta G, et al.
Reduction of multiple pregnancies in the advanced maternal age popula-
tion after implementation of an elective single embryo transfer policy
coupled with enhanced embryo selection: pre- and post-intervention
study. Hum Reprod 2015;30:2097–106.
98. Jauniaux E, Ben-Ami I, Maymon R. Do assisted-reproduction twin pregnan-
cies require additional antenatal care? Reprod Biomed Online 2013;26:
107–19.
99. Zollner U, Dietl J. Perinatal risks after IVF and ICSI. J Perinat Med 2013;41:
17–22.
100. McLernon DJ, Harrild K, Bergh C, Davies MJ, de Neubourg D, Dumoulin JC,
et al. Clinical effectiveness of elective single versus double embryo transfer:
meta-analysis of individual patient data from randomised trials. BMJ 2010;
341:c6945.
101. Gerris J. Single-embryo transfer versus multiple-embryo transfer. Reprod
Biomed Online 2009;18 Suppl 2:63–70.
102. Grady R, Alavi N, Vale R, Khandwala M, McDonald SD. Elective single em-
bryo transfer and perinatal outcomes: a systematic review and meta-
analysis. Fertil Steril 2012;97:324–31.
103. Practice Committee of American Society for Reproductive Medicine, Prac-
tice Committee of Society for Assisted Reproductive Technology. Criteria
for number of embryos to transfer: a committee opinion. Fertil Steril
2013;99:44–6.
104. Scott RT Jr, Franasiak JM, Forman EJ. Comprehensive chromosome
screening with synchronous blastocyst transfer: time for a paradigm shift.
Fertil Steril 2014;102:660–1.
105. Gleicher N, Kushnir VA, Barad DH. Is it time for a paradigm shift in under-
standing embryo selection? Reprod Biol Endocrinol 2015;13:3.
106. Wong KM, Mastenbroek S, Repping S. Cryopreservation of human em-
bryos and its contribution to in vitro fertilization success rates. Fertil Steril
2014;102:19–26.
107. Moragianni VA, Penzias AS. Cumulative live-birth rates after assisted repro-
ductive technology. Curr Opin Obstet Gynecol 2010;22:189–92.
108. Rubio C. Next-generation sequencing: challenges in reproductive genetics.
Fertil Steril 2014;101:1252–3.
109. Yang Z, Lin J, Zhang J, Fong WI, Li P, Zhao R, et al. Randomized comparison
of next-generation sequencing and array comparative genomic hybridiza-
tion for preimplantation genetic screening: a pilot study. BMC Med Geno-
mics 2015;8:30.
110. Fiorentino F, Biricik A, Bono S, Spizzichino L, Cotroneo E, Cottone G, et al.
Development and validation of a next-generation sequencing-based pro-
tocol for 24-chromosome aneuploidy screening of embryos. Fertil Steril
2014;101:1375–82.
VOL. 104 NO. 6 / DECEMBER 2015