Pitfalls of PGTa

Pitfalls of
PGTa

1. Pitfalls of
PGTa
Dr KaberiBanerjee

2. WHAT IS PGSWHAT IS PGTAPROBLEMS
WITH PGTA
VARIOUS
STUDIES

3. The Earlier
names of
Genetic Tests
on Embryos

4. Current names of Genetic Tests on the
Embryo

5. PGTa claims to reduce
implantation failure in IVF and
reduce the risk of miscarriages.
It is a very expensive test!
Is it true?

7. Some Facts of
PGTa
•All cells in any embryo doesn’t
demonstrate aneuploidies i.echromosomal abnormalities.
There are only small number of
cells which shows abnormalities.
If embryo biopsy shows abnormal
DNA, it is not the whole cell will
be abnormal.

8. Some Facts of
PGTa
•It is also observed that abnormal cells
often self-destruct and some cells self-
correct by themselves. This self-correction
happens more in cells which makes baby
than the cells which makes placenta
(trophectoderm). For PGT-a, embryo
biopsy is taken from trophectoderm. This
shows that there is no benefit of doing
blastocyst stage embryo biopsy as cells
which are tested are of outer layer not the
inner layer which forms the baby.

9. The STAR Study
•A total of 661 women (average age 33.7 ±3.6
years) were randomized to PGT-A (n = 330) or
morphology alone (n = 331).
•PGT-A did not improve overall pregnancy
outcomes in all women, as analyzed per embryo
transfer or per ITT. There was a significant
increase in OPR per embryo transfer with the
use of PGT-A in the subgroup of women aged
35-40 years who had two or more embryos that
could be biopsied, but this was not significant
when analyzed by ITT.

10. SHORT COMMUNICATION Open Access
Preimplantation genetic screening- the
required RCT that has not yet been carried
out
Raoul Orvieto
1,2
Abstract
The utilization of trophectoderm biopsy combined with comprehensive chromosome screening (CCS) tests for
embryonic aneuploidy was recently suggested to improve IVF outcome, however, not without criticisms. The
ongoing discussion on the unrestricted clinical adoption of preimplantation genetic screening (PGS) has called for a
proper randomized controlled trial (RCT), aiming to further evaluate the cumulative live birth rates (LBRs) following
a single oocyte retrieval, utilizing all fresh and frozen embryos. Since this study seems not to appear for various
reasons, we present herewith, the hypothetical required RCT based on the hitherto published literature.
After implementing data from the hitherto published literature on blastulation and aneuploidy rates, the rate of
mosaicism and technical errors and implantation rates/LBRs of non-PGS day-3 and blastocyst and PGS blastocyst,
we could clearly demonstrate the superiority of non-PGS embryo (day-3 and blastocyst) transfer over PGS blastocyst
transfer, in terms of cumulative LBR (18.2–50 % vs 7.6–12.6 %, respectively).
We therefore believe that until the proper, non-hypothetical RCT on the efficacy of this procedure will appear, PGS
should be offered only under study conditions, and with appropriate informed consents.
Keywords:PGS, NGS, Trophectoderm biopsy, Mosaicism, Aneuploidy
Introduction
Preimplantation genetic screening (PGS) by blastomere
aspiration of day 3 embryos, followed by ploidy analysis
of these cells using fluorescence in situ hybridization
(FISH), was clearly shown to be ineffective in improving
in vitro fertilization (IVF) pregnancy rates and in reducing
miscarriage rates [1–4]. Recently, the utilization of troph-
ectoderm biopsy (day 5–6 embryos) combined with com-
prehensive chromosome screening (CCS) tests for
embryonic aneuploidy, was suggested to improve IVF out-
come [5], however, not without criticisms [6, 7].
The reintroduction of PGS, utilizing of trophectoderm bi-
opsy combined with CCS tests for embryonic aneuploidy,
was based on apparently improved ability to accurately
diagnose embryonic aneuploidies without compromising its
implantation potential. On the other hand, opponents have
claimed that the reported improved efficacy and outcome
are related to various factors [6, 7], including the favorably
selected patients, whose embryos have reached the blasto-
cyst stage, thus, excluding elderly and those with decrease
ovarian reserve and the definition of pregnancy outcomes
per embryo transfer, rather than by intention to treat.
Moreover, while all studies in favor of PGS have
reported on LBR following the first embryo transfer after
a fresh IVF cycle, a clinically more relevant is the cumu-
lative LBR following a single ovarian stimulation and
utilization of all fresh and frozen-thawed embryos after
one oocyte retrieval. We therefore believe, that the on-
going discussion on the unrestricted clinical adoption of
PGS should call for a proper randomized controlled trial
(RCT), aiming to further evaluate the cumulative live
birth rates (LBRs) following a single oocyte retrieval,
utilizing all fresh and frozen embryos. Prompted by the
aforementioned arguments, we will present the required
hypothetical RCT based on the hitherto published
literature.
Correspondence:[email protected]
1
Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim
Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel
2
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
© 2016 The Author(s).Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
OrvietoReproductive Biology and Endocrinology (2016) 14:35
DOI 10.1186/s12958-016-0171-z
•The utilization of trophectoderm biopsy combined
with comprehensive chromosome screening (CCS) tests
for embryonic aneuploidy was recently suggested to
improve IVF outcome, however, not without criticisms.
The ongoing discussion on the unrestricted clinical adoption of preimplantation genetic screening (PGS) has
called for a proper randomized controlled trial (RCT),
aiming to further evaluate the cumulative live birth rates
(LBRs) following a single oocyte retrieval, utilizing all
fresh and frozen embryos. Since this study seems not to
appear for various reasons, we present herewith, the
hypothetical required RCT based on the hitherto
published literature.
•After implementing data from the hitherto published
literature on blastulationand aneuploidy rates, the rate
of mosaicism and technical errors and implantation
rates/LBRs of non-PGS day-3 and blastocyst and PGS
blastocyst, we could clearly demonstrate the superiority
of non-PGS embryo (day-3 and blastocyst) transfer over
PGS blastocyst transfer, in terms of cumulative LBR
(18.2–50% vs 7.6–12.6%, respectively).
•We therefore believe that until the proper, non-
hypothetical RCT on the efficacy of this procedure will
appear, PGS should be offered only under study
conditions, and with appropriate informed consents.

11. Overall same , but can show as 50% and 100%
Depends which data you want to show!
Non PGS-50%?
10
8
6
4
2+2
-ve/+ve
PGS-100%?
10
8
6
4
2
+ve
Extra Cost
Freezing
Transfer Time
Extra Cost
PGS
Personnel
Laboratory
WaitingTime

12. Assumptions
•BlastulationRate-47%
•Aneuploidy Rate-59%
•IR-D3 21-50%, Non PGS D5
38-47%, PGS D5 39-65%
•Mosaicism and Technical
Errors reduce LBR
SHORT COMMUNICATION Open Access
Preimplantation genetic screening- the
required RCT that has not yet been carried
out
Raoul Orvieto
1,2
Abstract
The utilization of trophectoderm biopsy combined with comprehensive chromosome screening (CCS) tests for
embryonic aneuploidy was recently suggested to improve IVF outcome, however, not without criticisms. The
ongoing discussion on the unrestricted clinical adoption of preimplantation genetic screening (PGS) has called for a
proper randomized controlled trial (RCT), aiming to further evaluate the cumulative live birth rates (LBRs) following
a single oocyte retrieval, utilizing all fresh and frozen embryos. Since this study seems not to appear for various
reasons, we present herewith, the hypothetical required RCT based on the hitherto published literature.
After implementing data from the hitherto published literature on blastulation and aneuploidy rates, the rate of
mosaicism and technical errors and implantation rates/LBRs of non-PGS day-3 and blastocyst and PGS blastocyst,
we could clearly demonstrate the superiority of non-PGS embryo (day-3 and blastocyst) transfer over PGS blastocyst
transfer, in terms of cumulative LBR (18.2–50 % vs 7.6–12.6 %, respectively).
We therefore believe that until the proper, non-hypothetical RCT on the efficacy of this procedure will appear, PGS
should be offered only under study conditions, and with appropriate informed consents.
Keywords:PGS, NGS, Trophectoderm biopsy, Mosaicism, Aneuploidy
Introduction
Preimplantation genetic screening (PGS) by blastomere
aspiration of day 3 embryos, followed by ploidy analysis
of these cells using fluorescence in situ hybridization
(FISH), was clearly shown to be ineffective in improving
in vitro fertilization (IVF) pregnancy rates and in reducing
miscarriage rates [1–4]. Recently, the utilization of troph-
ectoderm biopsy (day 5–6 embryos) combined with com-
prehensive chromosome screening (CCS) tests for
embryonic aneuploidy, was suggested to improve IVF out-
come [5], however, not without criticisms [6, 7].
The reintroduction of PGS, utilizing of trophectoderm bi-
opsy combined with CCS tests for embryonic aneuploidy,
was based on apparently improved ability to accurately
diagnose embryonic aneuploidies without compromising its
implantation potential. On the other hand, opponents have
claimed that the reported improved efficacy and outcome
are related to various factors [6, 7], including the favorably
selected patients, whose embryos have reached the blasto-
cyst stage, thus, excluding elderly and those with decrease
ovarian reserve and the definition of pregnancy outcomes
per embryo transfer, rather than by intention to treat.
Moreover, while all studies in favor of PGS have
reported on LBR following the first embryo transfer after
a fresh IVF cycle, a clinically more relevant is the cumu-
lative LBR following a single ovarian stimulation and
utilization of all fresh and frozen-thawed embryos after
one oocyte retrieval. We therefore believe, that the on-
going discussion on the unrestricted clinical adoption of
PGS should call for a proper randomized controlled trial
(RCT), aiming to further evaluate the cumulative live
birth rates (LBRs) following a single oocyte retrieval,
utilizing all fresh and frozen embryos. Prompted by the
aforementioned arguments, we will present the required
hypothetical RCT based on the hitherto published
literature.
Correspondence:[email protected]
1
Infertility and IVF Unit, Department of Obstetrics and Gynecology, Chaim
Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel
2
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
© 2016 The Author(s).Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
OrvietoReproductive Biology and Endocrinology (2016) 14:35
DOI 10.1186/s12958-016-0171-z

13. Current PGS clinical data
Several retrospective and prospective trials have reported
improved clinical outcomes following PGS, utilizing of
trophectoderm biopsy combined with CCS tests for em-
bryonic aneuploidy. These RCTs and observational stud-
ies have been recently evaluated by Dahdouh et al. [8] in
their meta-analysis, aiming to study whether PGS-CCS
improves clinical implantation rates (IR) and sustained
IR (beyond 20 weeks) compared with routine care for
embryo selection in IVF cycles. Of the 29 eligible arti-
cles, only three RCTs and eight observational studies
met full inclusion criteria, revealing significantly higher
clinical and sustained IRs with the use of PGS-CCS in
patients with normal ovarian reserve.
On the contrary, a recent analysis of national U.S. PGS
data for 2011–2012 have yielded different results [9].
While more PGS than non-PGS cycles reached ET
(64.2 % vs. 62.3 %), suggesting favorable patient selection
bias for patients using PGS, LBRs per cycle start (25.2 %
vs. 28.8 %) and per ET (39.3 % vs. 46.2 %) were signifi-
cantly better in non-PGS cycles, whereas miscarriage
rates were similar (13.7 % vs. 13.9 %).
The hypothetical RCT (Fig. 1)
The required hypothetical RCT should include 3 groups
of patients with comparable clinical characteristics: those
undergoing unscreened (non-PGS) day-3 transfer; those
undergoing non-PGS blastocyst transfer; and those under-
going screened (PGS) blastocyst transfer.
For the propose of the analysis, we will assume that
each group yielded 100 day-3 embryos and that all
embryos underwent vitrification with optimal results
(100 % survival post thawing).
Moreover, in order to procceed with the analysis, we need
precise estimation of the following data from the hitherto
published literature: blastulation rate, aneuploidy rate, the
rate of mosaicism and technical errors and IRs/LBRs of
non PGS day-3 and blastocyst and PGS blastocyst.
Blastulation rate
According to a comprehensive cochrane review that
analyzed cleavage stage versus blastocyst stage embryo
transfer in assisted reproductive technology [10], the range
of blastocyst formation rates across studies varied between
28 and 97 %. With a mean blastulation rate of47 %.
Aneuploidy rate
Franasiak et al. [11] have presented their clinical experi-
ence while reviewing 15,169 consecutive trophectoderm
biopsies evaluated with CCS. As expected, the preva-
lence of aneuploidy rose steadily with age. The preva-
lence of aneuploidy was 20 to 27 % in women 26 to
30 years of age, rose steadily from age 31 through age
43, and then plateaued at approximately 85 %. Among
the biopsies with aneuploidy, 64 % involved a single
chromosome, 20 % two chromosomes, and 16 % three
chromosomes, with the proportion of more complex an-
euploidy increasing with age. The calculated overall an-
euploidy risk across all screened blastocysts was59 %.
Mosaicism and technical errors
In a recent study [12] evaluating the accuracy of troph-
ectoderm multiple biopsies using next-generation
Fig. 1The required hypothetical RCT
OrvietoReproductive Biology and Endocrinology (2016) 14:35 Page 2 of 4

14. •Presented reanalysis here of the recently
published STAR study [8], which already has
been affecting IVF practice worldwide,
reveals significant shortcomings in the study’s
statistical analyses. Those, however, do not
change the principal conclusion of the STAR
study that PGT-A doesnotfavorably affect IVF
outcomes by increasing pregnancy chances or
reducing miscarriage risks.
•The STAR study thus reveals that PGT-A
does not beneficially affect IVF outcomes in
confirmation of another relatively recent
study in women 37years and older by Kang
et al. Like the STAR study, Kang et al. reported
seemingly improved live birth rates following
PGT-A but this outcome advantage, actually,
reverseditself after correct intent-to-treat
analysis of outcomes with reference cycle
start: Pregnancy as well as live birth rates,
indeed, ended up to be significantly higher in
control non-PGT-A patients (49.5 vs 21.5%
and 39.8 vs 19.9%).
•Considering all presented evidence here, it
is difficult to understand what further
argument can be made for the continuous
routine clinical utilization of PGT-A to improve
IVF outcomes.
•
COMMENTARY
Preimplantation genetic testing for aneuploidy (PGT-A)
—finally revealed
Raoul Orvieto
1,2
&Norbert Gleicher
3,4,5,6
Received: 10 December 2019 / Accepted: 27 January 2020 / Published online: 2 February 2020
#Springer Science+Business Media, LLC, part of Springer Nature 2020
KeywordsPGT-A.PGS.Live-birth rate.Intention to treat.RCT
Introduction
Natural fecundity of women decreases gradually and more
rapidly after age 37 years. This decrease is accompanied by
rising aneuploidy rates of pregnancies and can also be ob-
served in products of conception of spontaneous abortions
[1]. These observations lead to the hypothesis that transferring
only euploid embryos in association with in vitro fertilization
(IVF) might decrease miscarriages and increase live birth rates
(LBRs), attesting-procedure now called preimplantation ge-
netic testing (of embryos) for aneuploidy (PGT-A), until re-
cently generally referred to as preimplantation genetic screen-
ing (PGS).
Verlinsky and Kuliev further proposed that the removal of
all aneuploid embryos prior to transfer would improve implan-
tation rates and live birth rates and suggested that the diagno-
sis be made via biopsy of both polar bodies [2]. Polar body
biopsy, however, proved technically too difficult for general
IVF practice and would have revealed only meiotic
aneuploidies. The procedure was, therefore, initially per-
formed biopsying 1–2 blastomeres of day-3 cleavage-stage
embryos, often given the acronym PGS 1.0.
This form of embryo testing has, since, been replaced by
PGS 2.0, with the embryo biopsy being moved from day-3
cleavage stage to trophectoderm biopsy of blastocyst-stage
embryos on days 5–6 after fertilization. In July 2016, another
major change in PGT-A was announced, for the first time
introducing the concept pf“mosaic”embryos (also called
PGS 3.) (Preimplantation Genetic Diagnosis Society
(PGDIS) position statement on chromosome mosaicism and
preimplantation aneuploidy testing at the blastocyst stage,
Chicago, IL; July 19, 2016http://pgdis.org/docs/newsletter_
071816.html).
After almost two decades of PGS 1.0 through PGS 3.0, the
procedure has, however, still been unable to demonstrate the
promised improvements in live births and anticipated declines
in miscarriage rates [3–5]. Several studies, even summarized
in a meta-analysis [6], have claimed improved clinical IVF
outcomes following PGT-A. They, however, reported IVF
outcomes with reference point embryo transfer rather than
cycle start (intent-to-treat) and, therefore, by excluding poorer
prognosis patients, were severely biased [7].
The STAR study
This is why the recently published STAR study [8] attracted
special attention: It avoided at least some patient selection
biases of earlier fresh-cycle studies by being prospectively
randomized and reporting on IVF outcomes from transfers
of only single frozen-thawed embryos at blastocyst stage.
That qualifying patients required having at least two frozen
embryos from a prior fresh cycle, however, still demonstrates
a favorable patient selection bias. Importantly, however, the
study at least analyzed outcomes for study and control groups
with reference point initial first cycle start [7].
*Raoul Orvieto
[email protected]
1
Department of Obstetrics and Gynecology, Chaim Sheba Medical
Center, Tel-Hashomer, Ramat Gan, Israel
2
The Tarnesby-Tarnowski Chair for Family Planning and Fertility
Regulation, Sackler Faculty of Medicine, Tel-Aviv University, Tel
Aviv-Yafo, Israel
3
The Center for Human Reproduction, New York, NY 10021, USA
4
Foundation for Reproductive Medicine, New York, NY 10021, USA
5
Stem Cell Biology and Molecular Embryology Laboratory, The
Rockefeller University, New York, NY 10016, USA
6
Department of Obstetrics and Gynecology, Vienna University of
Medicine, 1090 Vienna, Austria
Journal of Assisted Reproduction and Genetics(2020) 37:669–672
https://doi.org/10.1007/s10815-020-01705-w

15. 4/5/2021 Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation - Cornelisse, S - 2020 | Cochrane Library
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005291.pub3/full 4/6
Authors' conclusions
There is insuwicient good‐quality evidence of a diwerence in cumulative live birth rate, live birth rate axer the first embryo transfer, or miscarriage rate
between IVF with and IVF without PGT‐A as currently performed. No data were available on ongoing pregnancy rates. The ewect of PGT‐A on clinical
pregnancy rate is uncertain.
Women need to be aware that it is uncertain whether PGT‐A with the use of genome‐wide analyses is an ewective addition to IVF, especially in view of the
invasiveness and costs involved in PGT‐A. PGT‐A using FISH for the genetic analysis is probably harmful.
The currently available evidence is insuwicient to support PGT‐A in routine clinical practice.
Plain language summary ?
Available inEnglish Español ?ر?I Français 한국어 Bahasa Malaysia
Preimplantation genetic testing for abnormal chromosome numbers for couples
undergoing in vitro fertilisation
Review question
Does preimplantation genetic testing for abnormal chromosome numbers improve the chances of a pregnancy followed by a live‐born baby?
Background
In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), the selection of the best embryo(s) for transfer is mainly based on
morphological assessment of the embryos, which includes the number of cells, the regularity of cells, and the presence of cell fragments. Unfortunately,
almost two‐thirds of couples do not get pregnant even axer transfer of ‘good quality’ embryos. One of the presumed causes is that such embryos have an
abnormal number of chromosomes (aneuploidy). Preimplantation genetic testing for aneuploidy (PGT‐A) is a technique used to analyse the number of
chromosomes present in IVF embryos. In PGT‐A, a polar body (a waste product of maternal meiosis),or one or a few cells of the embryo are obtained by
biopsy and tested. Only polar bodies or embryos with a normal number of chromosomes in each cell, so‐called 'euploid embryos', are transferred into the
4/5/2021 Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation - Cornelisse, S - 2020 | Cochrane Library
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005291.pub3/full 1/6
.
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Cochrane Database of Systematic Reviews Review - Intervention
New search
Abstract ?
Available inEnglish Español ?ر?I Français 한국어
Background
In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is based on
morphological criteria. However, many women do not achieve a pregnancy even axer 'good quality' embryo transfer. One of the presumed causes is that
such morphologically normal embryos have an abnormal number of chromosomes (aneuploidies). Preimplantation genetic testing for aneuploidies (PGT‐
Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro
fertilisation
, Simone Cornelisse , Miriam Zagers , Elena Kostova , Kathrin Fleischer , Madelon Wely?Sebastiaan MastenbroekAuthors' declarations of interest
Version published: 08 September 2020 Version history
https://doi.org/10.1002/14651858.CD005291.pub3

16. Preimplantation genetic
screening: what is the
clinical ef!ciency?
In the current practice of in vitro fertilization (IVF), preim-
plantation genetic screening (PGS) is increasingly used to
select embryos for transfer. This strategy is designed to maxi-
mize the probability of embryo implantation by eliminating
embryos with low implantation potential from the cohort.
However, PGS is inherently imperfect. Errors may occur dur-
ing the genetic analysis of the small amount of DNA collected.
More importantly, mitotic mosaicism, whose precise inci-
dence in the preimplantation embryo is not known, may
lead to sampling errors due to the intentionally limited collec-
tion of cells in the trophectoderm biopsy. In this manner,
abnormal cells may be collected in an otherwise euploid em-
bryo and vice versa. Therefore, it is inevitable that some
normal embryos will be discarded, leading to an overall
decrease in the cumulative pregnancy rate achievable by the
eventual transfer of all embryos in the cohort.
To accurately counsel patients about the use of PGS, it is
important to understand its clinical ef!ciency: How reliable
are the results, and how many losses of potential implanta-
tions occur as a result of the procedure? In the only study
to date in which biopsied embryos were transferred and the
results of PGS were available only after the outcomes of the
transfers were known, 41% of the‘‘normal’’embryos and
4% of the‘‘abnormal’’embryos implanted, suggesting a
10% error rate(1), and a 96% negative predictive value of
an‘‘abnormal’’test result.
However, this study does not present a complete picture
of the clinical ef!ciency of PGS. The ef!ciency of PGS may
be further limited by the very real possibility of damage to
the blastocyst as result of the trophectoderm biopsy. Only
one study so far has directly addressed this issue(2), and no
deleterious effect of the trophectoderm biopsy on embryo im-
plantation was found. However, all of the patients in that
study were under the age of 35 years and transfers took place
within 3 hours after the biopsy. No studies have addressed the
impact of trophectoderm biopsy in embryos with less than
ideal morphologic characteristics, in older patients, or after
an intervening cryopreservation procedure.
If the ef!ciency of PGS were 100%, then all embryos
judged to be‘‘abnormal’’would have a 0% chance of implan-
tation and their exclusion from transfer would result in an
increased implantation rate of the remaining‘‘normal’’em-
bryos. This idealized embryo implantation rate, EI(idealized),
would be higher than the implantation rate of unscreened em-
bryos, EI(unscreened), by the proportion of embryos that were
normal:
EI!idealized"#
EI!unscreened"
%normal
This is an idealized model, and because testing is unlikely
to be perfect the actual embryo implantation rate of screened
embryos, EI(screened), will likely be lower than the calculated
EI(idealized). The ef!ciency of the screening process can then
be expressed as:
Efficiency#
EI!screened"
EI!idealized"
The percentage of embryos lost in the process can then be
calculated as:
%embryos lost#1$Efficiency
The depiction of this analysis is most easily demonstrated
in a graphic fashion. For this example, let us consider a hypo-
thetical cohort of embryos from‘‘good-prognosis’’patients
(2), under the age of 35 years, with multiple blastocysts in
the 4AA or 4BB category, an unscreened implantation rate
of 50%, and an‘‘aneuploidy’’rate of 40%. In the parlance
of this calculation:
EI!unscreened"#0:50
%normal#60%#0:60
Figure 1shows a hypothetical cohort of 100 embryos, 50
of which would implant if transferred. If these embryos are
screened with the use of PGS and 40% are found to be‘‘aneu-
ploid,’’the screening test would eliminate 40 presumably
low–implantation potential embryos from the cohort
(Fig. 2). In this idealized setting, only nonimplanting embryos
are eliminated, and of the remaining 60 embryos, all 50 of the
original implanting embryos would be expected to implant
(Fig. 3).
EI!idealized"#
EI!unscreened"
%normal
#
0:50
0:60
#0:833
Because implantation rates this high have not been re-
ported, let us consider a hypothetical implantation rate of
66.7%, which would clearly be a major improvement over
the baseline rate of 50%. In this theoretical example:
EI!screened"#0:677
Efficiency#
EI!screened"
EI!idealized"
#
0:667
0:833
#0:80
The embryo loss rate would be:
%embryos lost#1$0:80#0:20
This is depicted graphically inFigure 4. With a post-PGS
implantation rate of 66.7%, 40 of the remaining 60 embryos
would implant, representing a loss of 10 of the original 50
VOL.-NO.-/-2017 1
INKLINGS
•Errors may occur during the genetic analysis of the small amount of DNA collected.
•Mitotic mosaicism may lead to sampling errors
•Some normal embryos will be discarded, leading to an overall decrease in the cumulative pregnancy rate achievable by the eventual transfer of all embryos in the cohort.
•Real possibility of damage to the blastocyst as result of the trophectoderm biopsy.
•No studies have addressed the impact of trophectoderm biopsy in embryos with less than idealmorphologic characteristics, in older patients, or after an intervening cryopreservation procedure.

17. Preimplantation genetic
screening: what is the
clinical ef!ciency?
In the current practice of in vitro fertilization (IVF), preim-
plantation genetic screening (PGS) is increasingly used to
select embryos for transfer. This strategy is designed to maxi-
mize the probability of embryo implantation by eliminating
embryos with low implantation potential from the cohort.
However, PGS is inherently imperfect. Errors may occur dur-
ing the genetic analysis of the small amount of DNA collected.
More importantly, mitotic mosaicism, whose precise inci-
dence in the preimplantation embryo is not known, may
lead to sampling errors due to the intentionally limited collec-
tion of cells in the trophectoderm biopsy. In this manner,
abnormal cells may be collected in an otherwise euploid em-
bryo and vice versa. Therefore, it is inevitable that some
normal embryos will be discarded, leading to an overall
decrease in the cumulative pregnancy rate achievable by the
eventual transfer of all embryos in the cohort.
To accurately counsel patients about the use of PGS, it is
important to understand its clinical ef!ciency: How reliable
are the results, and how many losses of potential implanta-
tions occur as a result of the procedure? In the only study
to date in which biopsied embryos were transferred and the
results of PGS were available only after the outcomes of the
transfers were known, 41% of the‘‘normal’’embryos and
4% of the‘‘abnormal’’embryos implanted, suggesting a
10% error rate(1), and a 96% negative predictive value of
an‘‘abnormal’’test result.
However, this study does not present a complete picture
of the clinical ef!ciency of PGS. The ef!ciency of PGS may
be further limited by the very real possibility of damage to
the blastocyst as result of the trophectoderm biopsy. Only
one study so far has directly addressed this issue(2), and no
deleterious effect of the trophectoderm biopsy on embryo im-
plantation was found. However, all of the patients in that
study were under the age of 35 years and transfers took place
within 3 hours after the biopsy. No studies have addressed the
impact of trophectoderm biopsy in embryos with less than
ideal morphologic characteristics, in older patients, or after
an intervening cryopreservation procedure.
If the ef!ciency of PGS were 100%, then all embryos
judged to be‘‘abnormal’’would have a 0% chance of implan-
tation and their exclusion from transfer would result in an
increased implantation rate of the remaining‘‘normal’’em-
bryos. This idealized embryo implantation rate, EI(idealized),
would be higher than the implantation rate of unscreened em-
bryos, EI(unscreened), by the proportion of embryos that were
normal:
EI!idealized"#
EI!unscreened"
%normal
This is an idealized model, and because testing is unlikely
to be perfect the actual embryo implantation rate of screened
embryos, EI(screened), will likely be lower than the calculated
EI(idealized). The ef!ciency of the screening process can then
be expressed as:
Efficiency#
EI!screened"
EI!idealized"
The percentage of embryos lost in the process can then be
calculated as:
%embryos lost#1$Efficiency
The depiction of this analysis is most easily demonstrated
in a graphic fashion. For this example, let us consider a hypo-
thetical cohort of embryos from‘‘good-prognosis’’patients
(2), under the age of 35 years, with multiple blastocysts in
the 4AA or 4BB category, an unscreened implantation rate
of 50%, and an‘‘aneuploidy’’rate of 40%. In the parlance
of this calculation:
EI!unscreened"#0:50
%normal#60%#0:60
Figure 1shows a hypothetical cohort of 100 embryos, 50
of which would implant if transferred. If these embryos are
screened with the use of PGS and 40% are found to be‘‘aneu-
ploid,’’the screening test would eliminate 40 presumably
low–implantation potential embryos from the cohort
(Fig. 2). In this idealized setting, only nonimplanting embryos
are eliminated, and of the remaining 60 embryos, all 50 of the
original implanting embryos would be expected to implant
(Fig. 3).
EI!idealized"#
EI!unscreened"
%normal
#
0:50
0:60
#0:833
Because implantation rates this high have not been re-
ported, let us consider a hypothetical implantation rate of
66.7%, which would clearly be a major improvement over
the baseline rate of 50%. In this theoretical example:
EI!screened"#0:677
Efficiency#
EI!screened"
EI!idealized"
#
0:667
0:833
#0:80
The embryo loss rate would be:
%embryos lost#1$0:80#0:20
This is depicted graphically inFigure 4. With a post-PGS
implantation rate of 66.7%, 40 of the remaining 60 embryos
would implant, representing a loss of 10 of the original 50
VOL.-NO.-/-2017 1
INKLINGS

18. Clinical application of PGT!A: is the price too high?
T El!Toukhy
Guys and St. Thomas Hospital NHS Trust, London, UK
Linked article: This is a mini commentary on K Neumann et al., pp. 710–718 in this issue. To view this article visit
https://doi.org/10.1111/1471-0528.16089
Published Online 8 March 2020.
Pre!implantation genetic testing for
aneuploidy (PGT!A) continues to pro-
voke interest, discussion and debate in
the field of reproductive medicine.
The two touted benefits of compre-
hensive screening of pre!implantation
embryos for chromosomal aneuploidies
in in vitro fertilisation (IVF) treat-
ment are improvement in the live
birth rate per cycle and reduction in
miscarriage risk.
Two recent large randomised trials
employing two different techniques
for PGT!A (ESTEEM Trial–Verpoest
et al.Hum Reprod2018;33:1767–76
and STAR Study–Munne et al.Fertil
Steril2019;112:1071–9) have shown
no improvement in the live birth rate
per IVF cycle started in screened
cycles compared with no screening.
The ESTEEM trial did not show a
shorter time to pregnancy and the
STAR study did not show a reduc-
tion in the miscarriage rate associated
with PGT!A (pregnancy loss rate in
women aged 35–40 years was 21.3%
in the PGT!A group versus 22% in
the control group,P=0.88). A
pregnancy loss rate of 24.7% was
also reported recently after PGT!A
and single cryopreserved embryo
transfer in the first IVF cycle (Wang
et al.,Reprod Biomed Online2019;
39:617–23).
In this issue of our journal, the
study of Neumann et al. (BJOG
2020;127:710–8) focused on the
cost!effectiveness of PGT!A, using
data from the ESTEEM trial. The
study demonstrated the high cost
of preventing one miscarriage
through the application of PGT!A,
in both high!cost and low!cost
healthcare settings. This result is con-
sistent with the conclusion of a ‘theo-
retical’ cost!effectiveness study in a UK
setting (Scriven,Reprod Biol Endocrinol
2017;15:49). Both studies highlighted
the financial burden of PGT!A and
emphasised that applying PGT!A to all
IVF cycles in women below the age of
40 years would be a very expensive
approach to reduce the risk of
miscarriage.
Although it is important not to
underestimate the emotional and
medical cost of a miscarriage, it is
unlikely that healthcare providers or
patients themselves would be willing
to pay such a high price to poten-
tially prevent one miscarriage while
not increasing the likelihood of
attaining a live birth. Given the fre-
quent need to undergo multiple IVF
cycles to achieve a live birth, it
would seem more reasonable to use
the limited resources for funding
more standard IVF cycles to achieve
more live births rather than chasing
the possibility of fewer miscarriages
and end up with fewer babies.
Although the initial PGT!A results
involving day!3 embryo biopsy and
fluorescence in situ hybridisation
were disappointing, it was expected
that improvement in blastocyst cul-
ture, embryo cryopreservation and
molecular genetic testing technolo-
gies would enable PGT!A to achieve
its potential benefits in improving
IVF outcome (Fiorentino et al.Hum
Reprod2014;29:2802–13). However,
recent publications of studies using
those improved technologies, including
the study of Neumann et al. (BIOG
2020;127:710–8), serve as a stark
reminder of the importance of unbi-
ased objective assessment, including
cost!effectiveness, of novel technolo-
gies before they are introduced into
clinical practice.
Disclosure of interests
A completed disclosure of interests
form is available to view online as
supporting information.&
719ª2020 Royal College of Obstetricians and Gynaecologists
Economic analysis of preimplantation genetic testing for aneuploidy
Clinical application of PGT!A: is the price too high?
T El!Toukhy
Guys and St. Thomas Hospital NHS Trust, London, UK
Linked article: This is a mini commentary on K Neumann et al., pp. 710–718 in this issue. To view this article visit
https://doi.org/10.1111/1471-0528.16089
Published Online 8 March 2020.
Pre!implantation genetic testing for
aneuploidy (PGT!A) continues to pro-
voke interest, discussion and debate in
the field of reproductive medicine.
The two touted benefits of compre-
hensive screening of pre!implantation
embryos for chromosomal aneuploidies
in in vitro fertilisation (IVF) treat-
ment are improvement in the live
birth rate per cycle and reduction in
miscarriage risk.
Two recent large randomised trials
employing two different techniques
for PGT!A (ESTEEM Trial–Verpoest
et al.Hum Reprod2018;33:1767–76
and STAR Study–Munne et al.Fertil
Steril2019;112:1071–9) have shown
no improvement in the live birth rate
per IVF cycle started in screened
cycles compared with no screening.
The ESTEEM trial did not show a
shorter time to pregnancy and the
STAR study did not show a reduc-
tion in the miscarriage rate associated
with PGT!A (pregnancy loss rate in
women aged 35–40 years was 21.3%
in the PGT!A group versus 22% in
the control group,P=0.88). A
pregnancy loss rate of 24.7% was
also reported recently after PGT!A
and single cryopreserved embryo
transfer in the first IVF cycle (Wang
et al.,Reprod Biomed Online2019;
39:617–23).
In this issue of our journal, the
study of Neumann et al. (BJOG
2020;127:710–8) focused on the
cost!effectiveness of PGT!A, using
data from the ESTEEM trial. The
study demonstrated the high cost
of preventing one miscarriage
through the application of PGT!A,
in both high!cost and low!cost
healthcare settings. This result is con-
sistent with the conclusion of a ‘theo-
retical’ cost!effectiveness study in a UK
setting (Scriven,Reprod Biol Endocrinol
2017;15:49). Both studies highlighted
the financial burden of PGT!A and
emphasised that applying PGT!A to all
IVF cycles in women below the age of
40 years would be a very expensive
approach to reduce the risk of
miscarriage.
Although it is important not to
underestimate the emotional and
medical cost of a miscarriage, it is
unlikely that healthcare providers or
patients themselves would be willing
to pay such a high price to poten-
tially prevent one miscarriage while
not increasing the likelihood of
attaining a live birth. Given the fre-
quent need to undergo multiple IVF
cycles to achieve a live birth, it
would seem more reasonable to use
the limited resources for funding
more standard IVF cycles to achieve
more live births rather than chasing
the possibility of fewer miscarriages
and end up with fewer babies.
Although the initial PGT!A results
involving day!3 embryo biopsy and
fluorescence in situ hybridisation
were disappointing, it was expected
that improvement in blastocyst cul-
ture, embryo cryopreservation and
molecular genetic testing technolo-
gies would enable PGT!A to achieve
its potential benefits in improving
IVF outcome (Fiorentino et al.Hum
Reprod2014;29:2802–13). However,
recent publications of studies using
those improved technologies, including
the study of Neumann et al. (BIOG
2020;127:710–8), serve as a stark
reminder of the importance of unbi-
ased objective assessment, including
cost!effectiveness, of novel technolo-
gies before they are introduced into
clinical practice.
Disclosure of interests
A completed disclosure of interests
form is available to view online as
supporting information.&
719ª2020 Royal College of Obstetricians and Gynaecologists
Economic analysis of preimplantation genetic testing for aneuploidy

19. •Any Intervention that claims to
increase the pregnancy rate in IVF must stand the test of time…till
then must be clearly offered as an
experimental test and at least
should not financially drain the
patient.