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Current value of preimplantation genetic screening
Twisk, M.
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Twisk, M. (2011). Current value of preimplantation genetic screening
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Download date: 15 Jun 2017
Preimplantation genetic screening for abnormal number of
chromosomes (aneuploidies) in in vitro fertilisation or
intracytoplasmic sperm injection (Review)
Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 2
http://www.thecochranelibrary.com
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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Figure 7.
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Figure 8.
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Figure 9.
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Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Advanced maternal age, Outcome 1 Live birth rate per woman randomised. . . . .
Analysis 1.2. Comparison 1 Advanced maternal age, Outcome 2 Ongoing pregnancy rate per woman randomised.
Analysis 1.3. Comparison 1 Advanced maternal age, Outcome 3 Proportion of women reaching embryo transfer. .
Analysis 1.4. Comparison 1 Advanced maternal age, Outcome 4 Mean number of embryos transferred per transfer.
Analysis 1.5. Comparison 1 Advanced maternal age, Outcome 5 Clinical pregnancy rate per woman randomised.
Analysis 1.6. Comparison 1 Advanced maternal age, Outcome 6 Multiple pregnancy rate per live birth. . . . .
Analysis 1.7. Comparison 1 Advanced maternal age, Outcome 7 Miscarriage rate per woman randomised. . . .
Analysis 2.1. Comparison 2 Repeated IVF failure, Outcome 1 Live birth rate per woman randomised. . . . .
Analysis 2.2. Comparison 2 Repeated IVF failure, Outcome 2 Ongoing pregnancy rate per woman randomised. .
Analysis 2.3. Comparison 2 Repeated IVF failure, Outcome 3 Proportion of women reaching embryo transfer. .
Analysis 2.4. Comparison 2 Repeated IVF failure, Outcome 4 Mean number of embryos transferred per transfer. .
Analysis 2.5. Comparison 2 Repeated IVF failure, Outcome 5 Clinical pregnancy rate per woman randomised. .
Analysis 2.6. Comparison 2 Repeated IVF failure, Outcome 6 Multiple pregnancy rate per live birth. . . . . .
Analysis 2.7. Comparison 2 Repeated IVF failure, Outcome 7 miscarriage rate per woman randomised. . . . .
Analysis 3.1. Comparison 3 Good prognosis patients, Outcome 1 Live birth rate per woman randomised. . . .
Analysis 3.2. Comparison 3 Good prognosis patients, Outcome 2 Ongoing pregnancy rate per woman randomised.
Analysis 3.3. Comparison 3 Good prognosis patients, Outcome 3 Proportion of women reaching embryo transfer.
Analysis 3.4. Comparison 3 Good prognosis patients, Outcome 4 Mean number of embryos for transfer. . . .
Analysis 3.5. Comparison 3 Good prognosis patients, Outcome 5 Clinical pregnancy rate per woman randomised.
Analysis 3.6. Comparison 3 Good prognosis patients, Outcome 6 Multiple pregnancy rate per live birth. . . .
Analysis 3.7. Comparison 3 Good prognosis patients, Outcome 7 Miscarriage rate per woman randomised. . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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DECLARATIONS OF INTEREST . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
INDEX TERMS
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Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Preimplantation genetic screening for abnormal number of
chromosomes (aneuploidies) in in vitro fertilisation or
intracytoplasmic sperm injection
Moniek Twisk1 , Sebastiaan Mastenbroek2 , Madelon van Wely3 , Maas Jan Heineman4 , Fulco Van der Veen5 , Sjoerd Repping2
1 Center
for Reproductive Medicine, Academic Medical Center, Amsterdam, Netherlands. 2 Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. 3 Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, University of Amsterdam, Academic Medical Centre, Amsterdam, Netherlands. 4 Department of Obstetrics
& Gynaecology Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. 5 Center for Reproductive Medicine H4-205, Department of Obstetrics & Gynaecology, Academic Medical Center, Amsterdam, Netherlands
Contact address: Moniek Twisk, Center for Reproductive Medicine, Academic Medical Center, Meibergdreef 9 (H4-205), Amsterdam,
1105 AZ, Netherlands. [email protected].
Editorial group: Cochrane Menstrual Disorders and Subfertility Group.
Publication status and date: Edited (no change to conclusions), published in Issue 2, 2011.
Review content assessed as up-to-date: 14 July 2010.
Citation: Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for
abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of
Systematic Reviews 2006, Issue 1. Art. No.: CD005291. DOI: 10.1002/14651858.CD005291.pub2.
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
In both IVF and ICSI, selection of the most competent embryos for transfer is based on morphological criteria. However, many women
fail to achieve a pregnancy even after ’good quality’ embryo transfer. One of the presumed causes is that such embryos show an abnormal
number of chromosomes (aneuploidies). In preimplantation genetic screening (PGS), only euploid embryos are transferred, with the
goal of increasing live birth rates.
Objectives
To assess the effectiveness of PGS in terms of live birth in women undergoing an IVF or ICSI treatment.
Search strategy
In this updated review, the Cochrane Menstrual Disorders and Subfertility Group Trials Register, CENTRAL, MEDLINE and EMBASE
were searched to July 2010. This was supported by checking reference lists of included studies and conference abstract books. Authors
were contacted for additional data when necessary.
Selection criteria
Only randomised controlled trials were selected. They were eligible for inclusion if they compared IVF/ICSI with PGS versus IVF/
ICSI without PGS.
Data collection and analysis
Relevant data were extracted independently by two reviewers. Trials were screened and analysed according to predetermined quality
criteria and disagreements were resolved by a third reviewer. The primary outcome measure was live birth rate per woman. Secondary
outcomes were the proportion of women reaching embryo transfer, mean number of embryos transferred, clinical pregnancy rate,
multiple pregnancy rate, miscarriage rate, ongoing pregnancy rate, and proportion of women whose child has a congenital malformation.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
Main results
Nine trials met the inclusion criteria. Live birth rate per woman was significantly lower after IVF/ICSI with PGS compared to IVF/
ICSI without PGS in women of advanced maternal age and in women with repeated IVF failure (OR 0.59; 95% CI 0.44 to 0.81 and
OR 0.41, 95% CI 0.20 to 0.88 respectively). In good prognosis patients a similar trend was seen, albeit not significant (OR 0.50, 95%
CI 0.20 to 1.26, random effects model).
Authors’ conclusions
PGS as currently performed significantly decreases live birth rates in women of advanced maternal age and those with repeated IVF
failure. Trials in which PGS was offered to women with a good prognosis suggested similar outcomes. PGS technique development
is still ongoing in an effort to increase its efficacy. This involves biopsy at other stages of development (polar body or trophectoderm
biopsy) and other methods of analysis (comparative genome hybridisation (CGH) or array-based technologies) than used by the trials
included in this review. These new developments should be properly evaluated before their routine clinical application. Until such trials
have been performed, PGS should not be offered as routine patient care in any form.
PLAIN LANGUAGE SUMMARY
Preimplantation genetic screening (PGS) for abnormal number of chromosomes in assisted reproduction.
In IVF and ICSI embryos are selected for transfer on the basis of morphological criteria. Unfortunately, many women fail to become
pregnant after an IVF or ICSI treatment. A reason for this could be that the number of chromosomes present in the embryos selected
for transfer is abnormal, even though they are ’of good quality’. Preimplantation genetic screening (PGS) is a technique used to identify
the number of chromosomes present in embryos created through IVF or ICSI. After PGS, only embryos with a normal number of
chromosomes for the chromosomes tested are transferred. PGS has been suggested to improve live birth rates. This review shows that
PGS in fact decreases live birth rates in women of advanced maternal age and in women with repeated IVF failure. PGS should not be
applied in routine patient care. New forms of PGS that perform the procedure at other stages of development and/or use a different
method of analysis should first be evaluated in clinical trials before being introduced into clinical practice.
BACKGROUND
netic screening for aneuploidies (PGS) was introduced to improve
pregnancy rates.
Description of the condition
In both in vitro fertilisation (IVF) and intracytoplasmic sperm
injection (ICSI) selection of the most competent embryo(s) for
transfer is based on morphological criteria, such as the number
of pronuclei, the number and regularity of blastomeres and the
percentage of fragmentation. Even so, many women fail to achieve
a pregnancy after transfer of embryos which are morphologically
of good quality.
One of the presumed causes is that such morphologically normal
embryos contain an abnormal number of chromosomes (aneuploidies). Since the early 1980s many reports have been published
showing numerical chromosome abnormalities in morphologically normal human cleavage stage embryos (Angell 1983; Munne
1993; Benadiva 1996; Delhanty 1997). Since most aneuploid embryos are expected to not develop to term, preimplantation ge-
Description of the intervention
In PGS, embryos created in vitro are analysed for aneuploidies and
only those that show a normal number of chromosomes, i.e. those
that are euploid for the chromosomes tested are transferred into
the uterine cavity. There are three approaches to obtain nuclear
material for this genetic analysis. One approach is aspiration of
the first and second polar body from fertilized oocytes (Verlinsky
1995). Another approach is removal of one or two blastomeres
from embryos at the early cleavage stage (Handyside 1989). A
third approach is removal of trophectoderm cells at the blastocyst
stage (Dokras 1990). The method of analysis can be limited to a
certain number of chromosomes (usually using fluorescence in situ
hybridisation (FISH)) or it can encompass all chromosomes (using
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
comparative genomic hybridisation or array based technologies).
PGS has thus far been conducted mostly at the cleavage stage using
FISH (Goossens 2009).
PGS has often been called preimplantation genetic diagnosis
(PGD) for infertility or PGD for aneuploidies (PGD-AS). Although the technology used in PGS and PGD is nearly identical,
PGS and PGD have completely different indications. PGS aims
to improve treatment outcome in subfertile couples undergoing
IVF/ICSI treatment, while PGD aims to prevent the birth of affected children in fertile couples with a high risk of transmitting
genetic disorders.
At first PGS was recommended and carried out for the following
indications: (i) advanced maternal age (Gianaroli 1999; Munne
1999; Kahraman 2000; Obasaju 2001;Munne 2003; Montag
2004; Platteau 2005) (ii) repeated IVF failure (Gianaroli 1999;
Kahraman 2000; Pehlivan 2003; Munne 2003; Wilding 2004) (iii)
repeated miscarriage (Pellicer 1999; ; Rubio 2003; Rubio 2005;
Munne 2005) (iv) severe male factor (Silber 2003; Platteau 2004).
More recently PGS has been offered to younger women with a
good prognosis for a pregnancy too, as high aneuploidy rates were
found in their embryos as well (Baart 2006; Goossens 2009).
Types of studies
Randomised controlled trials.
Types of participants
Women undergoing IVF or ICSI with and without PGS for all
suggested indications, i.e. (i) advanced maternal age, (ii) repeated
IVF failure, (iii) repeated miscarriage, (iv) TESE-ICSI and (v)
good prognosis patients. We assessed the effect of PGS for each
indication separately. In addition, whenever possible, studies were
subgrouped based on the timing of biopsy as well as on the type
of genetic analysis.
Types of interventions
IVF/ICSI with PGS was compared to IVF/ICSI without PGS.
Types of outcome measures
Primary outcomes
• live birth rate per woman randomised.
How the intervention might work
Only embryos that are euploid for the chromosomes tested are
transferred into the uterine cavity. It is presumed that this is likely
to increase the live birth rate by excluding embryos that would
most likely not implant or not develop to term.
Why it is important to do this review
Although IVF/ICSI with PGS has been increasingly used over
the past decade (Goossens 2009) and indeed in some centres has
become a standard treatment for some indications, its effectiveness
is still unclear. Therefore this systematic review was undertaken
and updated to investigate whether there is a difference in live
birth rate. This involved comparing IVF/ICSI with PGS to IVF/
ICSI without PGS.
Secondary outcomes
• proportion of women reaching embryo transfer
• mean number of embryos transferred per transfer
• clinical pregnancy rate per woman randomised (defined by
the presence of an intrauterine gestational sac)
• multiple pregnancy rate per woman randomised
• miscarriage rate per woman randomised
• ongoing pregnancy rate per woman randomised
• women whose child has a congential malformation
Search methods for identification of studies
Electronic searches
OBJECTIVES
To review the effect of PGS on treatment outcome in women
undergoing IVF or ICSI treatment.
METHODS
Criteria for considering studies for this review
We searched the following electronic databases up to July 2010 in
this update of the review:
Cochrane Menstrual Disorders and Subfertility Group Trials Register (Appendix 1),
the Cochrane Central Register of Controlled Trials (CENTRAL)
(Appendix 2) , MEDLINE (1966 to present) (Appendix 3),
EMBASE (1980 to present) (Appendix 4) and
PsycInfo (Appendix 5)
The MEDLINE search was combined with the Cochrane highly
sensitive search strategy for identifying randomised trials which
appears in the Cochrane Handbook of Systematic Reviews of Interventions (Version 5.0.1 chapter 6, 6.4.11)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3
The EMBASE search was combined with trial filters developed
by the Scottish Intercollegiate Guidelines Network (SIGN) http:
//www.sign.ac.uk/methodology/filters.html#random
were retrieved in full. Both reviewers applied the selection criteria
independently to the trial reports rechecking trial eligibility and
resolving disagreements by discussion with the other reviewers
(MH, SR, FV, MVW).
Searching other resources
The reference lists of included studies were searched for relevant studies, reviews and background papers. Conference abstract
books of the American Society of Reproductive Medicine (ASRM)
and the European Society of Human Reproduction and Embryology (ESHRE) were consulted for unpublished trials. The trial register of controlled trials was checked (www.controlled-trials.com,
www.clinicaltrials.gov). There was no language restriction. When
important information was lacking from the original publications
the authors were contacted.
Data extraction and management
All assessment of the quality of trials and the data extraction were
performed independently (SM, MT) using forms designed according to Cochrane guidelines. If required disagreements were
resolved by discussion with the other reviewers (MH, SR, FV,
MvW). Where studies had multiple publications the main trial
was used as the reference and additional papers provided supplementary data. Preliminary results were presented when the full
report had not been published; this will be superceded when the
full paper is available. Data extracted from the trials were analysed
on an intention-to-treat basis when possible.
Data collection and analysis
Assessment of risk of bias in included studies
Selection of studies
Two reviewers (SM, MT) independently examined the electronic
search results for reports of possibly relevant trials and these reports
Two reviewers (SMA, MT) independently evaluated the risk of
bias. The information is provided in the Characteristics of included
studies tables and Figure 1 and Figure 2. These provide a context
for discussing the reliability of the results:
Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4
Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5
Sequence generation (e.g. low risk: investigators using random
number tables, computer generated random number generator,
shuffling cards. High risk: sequence generated from date of birth,
hospital or clinic record number)
Allocation concealment (e.g. Low risk: central allocation. sequentially numbered sealed opaque envelopes. High risk: open number
allocation schedule, alternation or rotation)
Blinding (e.g. Low risk: blinding of participants and or key study
personnel, use of placebo. High risk: incomplete or no blinding)
Attrition bias (e.g. Low risk: no missing outcome data. High risk:
attrition greater or equal to 20%)
Selective outcome reporting and other potential sources of bias.
(e.g. Low risk: study protocol available. High risk: not all primary
outcomes reported, outcomes reported that were no prespecified)
Additional information was sought from primary authors if required.
Measures of treatment effect
Statistical analysis was performed in accordance with the statistical guidelines developed by the Cochrane MDSG (Higgins and
Green, 2009) .
For dichotomous data, results were expressed as odds ratios (OR)
with 95% confidence intervals (CI) for each individual trial. The
fixed-effect model was used to combine data as a standard.
For continuous data, mean differences (MD) with 95% CI were
calculated. The Review Manager software (RevMan 5, Cochrane
Collaboration, Oxford, UK) was used for statistical analysis.
Unit of analysis issues
Data were presented as rates per woman randomised. Unit of analysis issues may occur where individual study data is presented as
per embryo or per cycle and not per woman. In this scenario outcomes were recalculated per woman or when this was not possible
the original authors were contacted for data.
Dealing with missing data
The data were analysed on an intention to treat basis where possible
and attempts were made to obtain missing data from the primary
authors. If missing data became available they were included in
the analysis. When clarification was not available methodological
issues were reported as unclear.
Assessment of heterogeneity
Heterogeneity was assessed using the I2 (Higgins 2008). An I2
statistic greater than 50% was considered indicative of substantive
heterogeneity. Where heterogeneity was detected subgroup and or
sensitivity analysis was conducted in an attempt to explain this.
Where heterogeneity is within acceptable limits meta-analysis can
be conducted.
Assessment of reporting biases
If more than ten studies are identified a funnel plot will be produced to evaluate the risk of publication bias. In view of the difficulty in detecting and correcting for publication bias and other
reporting biases, we aimed to minimise the potential for such errors by searching multiple databases and other literature.
Data synthesis
The data from the primary studies were combined and presented
for the following comparisons where data was available:
• Advanced maternal age
◦ Live birth rate per woman randomised
◦ Ongoing pregnancy rate per woman randomised
◦ Proportion of women reaching embryo transfer per
woman randomised
◦ Number of embryos transferred per woman
randomised
◦ Clinical pregnancy rate per woman randomised
◦ Multiple pregnancy rate per woman randomised
◦ Miscarriage rate per woman randomised
• Repeated IVF failure
◦ Live birth rate per woman randomised
◦ Ongoing pregnancy rate per woman randomised
◦ Proportion of women reaching embryo transfer per
woman randomised
◦ Number of embryos transferred per woman
randomised
◦ Clinical pregnancy rate per woman randomised
◦ Multiple pregnancy rate per woman randomised
◦ Miscarriage rate per woman randomised
• Good prognosis patients
◦ Live birth rate per woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
◦ Ongoing pregnancy rate per woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
◦ Proportion of women reaching embryo transfer per
woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6
◦ Number of embryos transferred per woman
randomised
◦ Clinical pregnancy rate per woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
◦ Multiple pregnancy rate per woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
◦ Miscarriage rate per woman randomised
⋄ Biopsy at cleavage stage
⋄ Biopsy at blastocyst stage
Subgroup analysis and investigation of heterogeneity
When heterogeneity was high the random effects model was used.
Whenever possible, studies were subgrouped based on the timing
of biopsy as well as on the type of genetic analysis.
Sensitivity analysis
Where heterogeneity was high, sensitivity analysis was conducted
in order to explain the data by examining the differences in
methodological quality of included trials.
Updating of the review
This Cochrane review will be updated every two years.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Results of the search
Fourteen potentially eligible studies were identified by the search
strategy, all prospective in design (Gianaroli 1997; Gianaroli
1999;Werlin 2003; Staessen 2004; Stevens 2004; Debrock 2010;
Mastenbroek 2007; Blockeel 2008; Hardarson 2008; Jansen 2008;
Mersereau 2008; Meyer 2009; Schoolcraft 2009; Staessen 2008).
In addition three upcoming randomised controlled trials were
identified, Two of these trials are currently recruiting patients
(www.controlled-trials.com, www.clinicaltrials.gov). One trial,
performed in women of advanced maternal age defined as an age
between 37 and 42 is suspended because of lack of funding. In
one trial the indication is repeated IVF failure, defined as ≥ 2 previous IVF failures with the transfer of at least two quality embryos
per transfer. The last trial performed PGS in women of advanced
maternal age, defined an age between 38-44. All trials use FISH
for a limited number of chromosome and biopsy will take place
at cleavage stage.
Included studies
Included studies
Nine studies were included (Staessen 2004; Mastenbroek 2007;
Blockeel 2008; Hardarson 2008; Jansen 2008; Staessen 2008;
Meyer 2009; Schoolcraft 2009; Debrock 2010).
Types of participants
In five studies PGS was performed for the indication advanced
maternal age (Staessen 2004; Debrock 2010; Mastenbroek 2007;
Hardarson 2008; Schoolcraft 2009), in three studies PGS was performed in good prognosis patients (Jansen 2008; Meyer 2009;
Staessen 2008) and in one study PGS was performed for the indication repeated IVF failure (Blockeel 2008).
Five studies for the indication advanced maternal age were included. Advanced maternal age was defined as 37 years or higher
(Staessen 2004),35 years or higher (Schoolcraft 2009; Debrock
2010), 35 till 41 years (Mastenbroek 20077), or 38 years or higher
(Hardarson 2008). Other inclusion criteria in these studies were:
normal karyotype of both partners (Staessen 2004), need for ICSI
with motile sperm (Staessen 2004), at least two fertilised oocytes
one day after oocyte retrieval (Debrock 2010), at least two 6-cell
stage embryos on day three (Debrock 2010), at least five 6-cell
stage embryos with no more than 15% fragmentation on day three
(Schoolcraft 2009), no previous failed IVF cycles (Mastenbroek
2007), no objection to double embryo transfer (Mastenbroek
2007), and at least three embryos of good morphological quality
if double embryo transfer was performed or at least two embryos
of good morphological quality if single embryo transfer was performed (Hardarson 2008).
Three studies for the indication good prognosis patients were included. Good prognosis patients were in one trial defined as patients below 39 years, with normal ovarian reserve, body mass index below 30 kg/m, presence of ejaculated sperm, a normal uterus,
no more than two previous failed IVF cycles, and at least four embryos containing at least 5-cells with less than 40% fragmentation
(Meyer 2009). In another trial good prognosis patients were defined as women below 36 years with the need for ICSI with motile
sperm and a normal karyotype of both partners (Staessen 2008).
In the third trial good prognosis patients were defined as patients
below 38 years, with no objection to single embryo transfer, in
their first or second IVF attempt with no cycles cancelled because
of poor response. Additional criteria were: no less than eight ovarian follicles over 1 cm in diameter at day 8-10 of stimulation, at
least four embryos with seven or more cells on day three of culture
and at least two blastocysts for biopsy on day 5 or 6 (Jansen 2008).
One study for the indication repeated IVF failure was included.
Repeated IVF failure was defined as three or more failed IVF
or ICSI attempts with embryos of good morphological quality.
Other inclusion criteria in this study were subfertility with need
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for assisted reproduction with motile spermatozoa, maternal age <
37 years and a normal karyotype in both partners (Blockeel 2008).
Types of intervention
The assisted reproduction technology (ART) method used was
ICSI exclusively in four trials (Staessen 2004; Blockeel 2008;
Meyer 2009; Staessen 2008) both IVF and ICSI in three trials
(Mastenbroek 2007; Hardarson 2008; Schoolcraft 2009), IVF,
ICSI and TESE in one trial (Debrock 2010) and in one trial it was
not mentioned whether IVF and/or ICSI was used (Jansen 2008).
A couple was offered one treatment cycle in six trials (Staessen
2004; Blockeel 2008; Hardarson 2008; Jansen 2008; Meyer 2009;
Schoolcraft 2009; Staessen 2008) and a maximum of three cycles
in one study (Mastenbroek 2007). In one trial a couple could participate in the study several times with independent randomisation for each cycle (Debrock 2010). Dr. Debrock kindly provided
us data in which each patient was only included in one treatment
group.
No trials performed biopsy at the polar body stage, eight trials performed biopsy at the cleavage stage (Staessen 2004; Mastenbroek
2007; Blockeel 2008; Hardarson 2008; Meyer 2009; Schoolcraft
2009; Staessen 2008; Debrock 2010), and one trials performed
biopsy at the blastocyst stage (Jansen 2008).
In seven trials zona drilling was performed by laser (Staessen 2004;
Debrock 2010; Mastenbroek 2007; Hardarson 2008; Jansen 2008;
Staessen 2008; Blockeel 2008 personal communication), in one
trials acidic tyrode’s was used (Meyer 2009) and in one trial both
laser and acidic tyrode’s were used (Schoolcraft 2009). In most
trials preferably one blastomere was removed from the embryo and
in two trials mostly two blastomeres were removed (Staessen 2004;
Debrock 2010). In one trial between March 2001 and October
2005 two blastomeres were removed from those embryos with at
least six blastomeres, and between November 2005 and December
2007 one blastomere was removed from the embryo (Blockeel
2008). In the trial that performed PGS at the blastocyst stage two
to nine trophectoderm cells were removed (Jansen 2008).
Biopsy was performed on all embryos with at least four blastomeres
with a maximum of 50% fragmentation (Mastenbroek 2007), on
all embryos with at least five blastomeres with a maximum of 50%
fragmentation (Staessen 2004; Staessen 2008), on all embryos with
at least six blastomeres (Debrock 2010), on all blastocysts (Jansen
2008), on embryos with a minimum of five cells of good morphological quality (Blockeel 2008), and on embryos with more
than five cells with a maximum of 20% fragmentation (Hardarson
2008). In two trials it was not specified which embryos were biopsied (Meyer 2009; Schoolcraft 2009).
Aneuploidy screening was performed using FISH for the chromosomes X, Y, 13, 16, 18, 21 and 22 (Staessen 2004; Debrock
2010; Staessen 2008; Blockeel 2008) or X, Y, 13, 15, 16, 17, 18,
21 and 22 (Schoolcraft 2009), or X,Y, 1, 13, 16, 17, 18, and 21
(Mastenbroek 2007), or X, Y, 13, 18, 21 (Hardarson 2008; Jansen
2008), or X, Y, 13, 16, 17, 18, 21, 22 (Meyer 2009). There were
no trials that analysed all chromosomes or that used other tech-
niques than FISH.
In all studies, in the control group the morphologically best embryos were transferred, in the intervention group embryos that
were found to be chromosomally normal were transferred. In one
study undetermined embryos with good morphologic features
were transferred if no chromosomally normal embryos with good
morphologic features were available (Mastenbroek 2007), in the
other studies undetermined embryos were not transferred. Though
in one study, one embryo was transferred in which no result was
obtained for chromosomes 16 and 18 due to technical difficulties,
and one embryo was transferred in which the chromosomal pattern was only evaluated in one nucleus while this study normally
removed and investigated two embryos (Debrock 2010).
In two trials one embryo was transferred (Jansen 2008; Staessen
2008), in one trial two embryos were transferred if there were
two embryos available (Mastenbroek 2007), in one trial one or
two embryos were transferred according to the patients’ wishes
and the availability of normal embryos (Hardarson 2008), and in
one trial up to three embryos were transferred (Blockeel 2008). In
one trial the number of embryos transferred depended on the age
of the woman, namely up to three blastocysts when the patient
was between 37 and 39 years old and up to a maximum of six
blastocysts if the patient was 40 years or older (Staessen 2004).
In one trial a maximum of two to three embryos were transferred
before 1 July 2003, and only one embryo after 1 July 2003 in the
first IVF/ICSI attempt in patients younger than 36 years (Debrock
2010). In two trials transfer policy was not described (Meyer 2009;
Schoolcraft 2009).
Data on cryopreservation and pregnancies originating from
frozen/thawed embryos was only available in two trials (
Mastenbroek 2007; Debrock 2010). In one of these trials only one
embryo transfer was performed in the PGS group and two in the
control group, although many more embryos were cryopreserved
(Debrock 2010). In this study, one pregnancy was obtained in the
PGS group after a mixed transfer of both a non-biopsied embryo
(from a previous IVF cycle) and a biopsied embryo, so no conclusion concerning the origin of the embryo could be made. In
this study no pregnancies were obtained in the control group. In
the other trial four ongoing pregnancies were obtained in the control group, and no pregnancies were obtained in the PGS group
(Mastenbroek 2007). .
Types of outcomes
The included trials used embryo implantation rate (Staessen
2004; Blockeel 2008; Debrock 2010) (clinical) pregnancy rate
(Hardarson 2008) ongoing pregnancy rate (Mastenbroek 2007)
or live birth rate (Jansen 2008; Meyer 2009; Staessen 2008) as primary outcome measure. For one trial the primary outcome was not
specified (Schoolcraft 2009). Implantation rate was defined as the
ratio between the number of gestational sacs with a fetal heartbeat
and the total number of embryos transferred. However, this is an
inappropriate outcome measure since the denominator (number
of embryos transferred) depends on the strategy, not on the design
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and since it is not a randomised outcome measure (Mastenbroek
2005). It is also an inappropriate outcome since it introduces a
unit of analysis error and analysis fails to account for non-independence in outcomes between separate embryos transferred to
the same woman (Mastenbroek 2005).
The primary outcome measure of this review, live birth rate per
woman was reported in six trials (Mastenbroek 2007; Blockeel
2008; Hardarson 2008; Staessen 2008; Meyer 2009; Jansen 2008).
In one trial live birth rate was incomplete since one pregnancy was
still ongoing at the time of writing (Blockeel 2008), but the author
kindly provided us the outcome of this pregnancy. In one trial
live birth rate was not reported but it was possible to calculate the
numbers from the data provided (Schoolcraft 2009). Drs. Staessen
and Dr. Debrock kindly provided live birth rates from their trials
upon request (Staessen 2004;Debrock 2010), so live birth rate was
available for all trials.
As for secondary outcome measures, the proportion of women
reaching embryo transfer and the mean number of embryos
per transfer were available for all nine trials (Staessen 2004;
Debrock 2010; Mastenbroek 2007; Blockeel 2008; Hardarson
2008; Jansen 2008; Meyer 2009; Schoolcraft 2009 ;Staessen
2008), clinical pregnancy rate was available for eight trials
(Staessen 2004; Debrock 2010;Mastenbroek 2007;Blockeel 2008;
Hardarson 2008; Jansen 2008;Meyer 2009; Staessen 2008) and
miscarriage rate was available for all trials, multiple pregnancy
rate was available in five trials (Staessen 2004; Debrock 2010;
Mastenbroek 2007; Blockeel 2008; Staessen 2008) ongoing pregnancy rate was available for five trials (Staessen 2004; Debrock
2010; Mastenbroek 2007; Staessen 2008; Blockeel 2008), and information on congenital malformation was only available from
two trials (Mastenbroek 2007; Staessen 2004 personal communication).
Excluded studies
Excluded studies
Two studies were excluded after retrieving and reading the full
text because couples were allocated to the treatment or control
group on the basis of their volunteer decision, instead of random
allocation (Gianaroli 1997; Gianaroli 1999). PGS in these trials
was performed for advanced maternal age and repeated IVF failure. One study was excluded (Stevens 2004) because the patients
included in this study were also included in an other larger study
(Schoolcraft 2009). Werlin 2003 was excluded as it only reported
on biochemical pregnancies.
Excluded study awaiting further assessment
One study was excluded because it was an ongoing trial and since
outcome measures were reported as percentages without mentioning the unit of analysis and it was not possible to calculate the
exact numbers (Mersereau 2008). PGS was offered in this trial
to women with a good prognosis. We tried to obtain additional
information from the authors but have not received any response
yet.
Risk of bias in included studies
Further reference to risk of bias can be made in Characteristics of
included studies, Figure 1 and Figure 2.
Allocation
All included studies were randomised controlled trials. One trial
reported adequate allocation concealment using ’sealed’, ’opaque’
envelopes (Meyer 2009). Two studies reported ’sealed’ envelopes
but no details as to whether these were opaque (Debrock 2010;
Jansen 2008). Five studies used a computer for randomisation
(Mastenbroek 2007; Blockeel 2008; Hardarson 2008; Schoolcraft
2009; Staessen 2008), in one of them there was concealment of allocation (Mastenbroek 2007), in the other four nothing was mentioned on concealment of allocation. There was no concealment
of allocation by Blockeel 2008.
Blinding
Only one trial was double blind (Mastenbroek 2007), six trials
were not blind (Staessen 2004; Debrock 2010; Blockeel 2008;
Hardarson 2008; Meyer 2009; Staessen 2008). In two trials it
was not mentioned whether patients and treatment providers were
blind to assignment status (Jansen 2008; Schoolcraft 2009).
Incomplete outcome data
There were drop-outs in both the intervention and the control
group (respectively 52/200 and 77/206 and 13/120 and 14/95
and 15/52 in the intervention group and 59/200 and 71/202 and
13/120 and 28/105 and 28/52 in the control group) in five trials
(Staessen 2004; Mastenbroek 2007; Staessen 2008; Blockeel 2008;
Debrock 2010). Reasons for cancelling the intended treatment cycle were insufficient ovarian response (Staessen 2004; Mastenbroek
2007; Blockeel 2008), no oocytes at oocyte retrieval (Debrock
2010), no fertilisation (Debrock 2010), less than two fertilised
oocytes available (Debrock 2010), less than two embryos with at
least six cells available on day three (Debrock 2010), no embryo
available for biopsy (Debrock 2010), cancer cyst detected (Staessen
2004), no technical support for genetic analysis (Debrock 2010),
other medical reasons (Mastenbroek 2007), inability to manage
the treatment burden (Staessen 2004; Mastenbroek 2007; Staessen
2008), stop further fertility treatment (Blockeel 2008), spontaneous pregnancy (Staessen 2004; Blockeel 2008;Staessen 2008),
not finished at the end of follow-up (Mastenbroek 2007), request
of the patient (Debrock 2010), and other reasons (Mastenbroek
2007). Drop-outs were included in an intention to treat analysis
in one trial (Mastenbroek 2007), but they were not included in
an intention to treat analysis in the other trials (Staessen 2004;
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Blockeel 2008; Staessen 2008; Debrock 2010). In the rest of the
studies nothing was mentioned about drop-outs. In one study four
women declined embryo transfer for reasons not related to the
study, two women in the PGS treatment group and two women
in the control group, they were not included in an intention to
treat analysis (Meyer 2009). Dr. Debrock kindly provided information about the drop-out cycles, so we could include these in an
intention-to-treat analysis.
Selective reporting
There was no evidence of selective reporting. Although not all
studies reported all outcomes, these were available after correspondence with the trial authors.
Other potential sources of bias
The sample size was based on a power calculation in eight trials (Staessen 2004; Mastenbroek 2007; Blockeel 2008; Hardarson
2008; Jansen 2008; Meyer 2009; Staessen 2008; Debrock 2010).
In four trials the calculated number of inclusions was not reached.
In one trial the study was ended prematurely because an interim
analysis showed such a lower implantation rate for the PGS group
it was considered unethical to continue (Meyer 2009), in one
trial the study was ended prematurely because an interim analysis
showed futility (Staessen 2008), and one trial was ended prematurely because the trend was opposite to that required to disprove
the null hypothesis and because in the control group many more
cryo stored blastocysts were accumulating (Jansen 2008). In one
trial the study was ended prematurely because an interim analysis
showed a very low conditional power of superiority for the primary
outcome (Hardarson 2008). In three studies the power calculation
was based on embryos instead of women (Staessen 2004; Blockeel
2008; Debrock 2010).
In one trial there was a difference in embryo transfer policy between the PGS group and the control group. In the PGS group
embryo transfer was performed on day five while in the control
group transfer was performed on day three (Hardarson 2008). In
one study in three women in the control group embryo transfer
was erroneously planned at day three instead of day five (Blockeel
2008), in an other study four embryo transfers in the control group
were erroneously planned at day three instead of day five (Staessen
2008).
In the study of Staessen et al. published in 2004 400 women were
randomised, 200 were assigned to the PGS group and 200 to the
control group. In the PGS group one woman did not fulfil the
inclusion criteria, in the control group 10 women did not fulfil the
inclusion criteria. Therefore, a total of 199 versus 190 women were
correctly assigned to the treatment and control group respectively.
In 51 women in the treatment group and 49 women in the control
group ovum pick-up was not performed. In the original article
these women were excluded from the analysis, but we included
these women in an intention-to-treat analysis. Therefore from this
article, we included a total of 199 women in the PGS group and
190 women in the control group.
In the study of Blockeel 2008, 95 women were randomised to
the PGS group and 105 women were randomised to the control
group. In the PGS group eight women did not fulfil the inclusion
criteria, in the control group 10 women did not fulfil the inclusion criteria and we excluded those from the meta-analysis. The
authors excluded nine women in the PGS group and 11 women in
the control group because of wrong allocation and a spontaneous
pregnancy . Therefore, a total of 87 versus 95 women were correctly assigned to the treatment and the control group respectively.
Nine women in the PGS group and 10 women in the control
group were wrongly allocated, these women should be included in
an intention-to-treat-analysis. This was not possible because the
results of their treatment are unknown to us. The authors further excluded six women in the PGS group and 18 women in the
control group because of insufficient ovarian response, stop further fertility treatment and spontaneous pregnancy. These women
should be included in an intention-to-treat analysis but this was
not possible for the same reason as mentioned above. Therefore
from this article, we included a total of 72 women in the PGS
group and 67 women in the control group.
In the study by Meyer 2009 four women were excluded from the
analysis because no embryo transfer was performed for personal
reasons. In the original article these women were excluded from
the analysis, but we included these women in an intention-to-treat
analysis. Therefore from this article, we included 23 women in the
PGS group and 24 women in the control group.
In the study by Debrock 2010 52 women were randomised to the
PGS group and 52 women were randomised to the control group.
However, women could be included several times with independent randomisation for each cycle, this introduces a bias since
these cycles are not independent. After excluding these cycles, i.e.
when each women could be included only once 44 women could
be included in the PGS group and 50 women could be included
in the control group (Debrock, personal communication). Fifteen
women in the PGS group and 28 women in the control group did
not receive the intended treatment, we included these women in
an intention-to-treat analysis. Therefore from this analysis, we included 44 women in the PGS group and 50 women in the control
group.
One study reported only percentages and used transfers and pregnancies as units of analysis, therefore we recalculated the numbers
per patient for the various outcomes (Schoolcraft 2009). From this
article, we included 32 women in the PGS group and 30 women
in the control group.
All studies defined clear inclusion and exclusion criteria. In the
study of Schoolcraft 2009 only women with at least five good
quality embryo’s on day three were included, and Hardarson 2008
only included women with at least three embryos of good quality
when DET and with at least two embryos of good quality when
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SET were included. By doing this, poor responders were excluded.
Indeed in the study by Hardarson 2008 331 women were identified
and only 109 were included in the study. The main reason for a
patient not being included in the study was that she did not have
sufficient embryos of good quality.
Outcome measures were not defined the same in all studies. Live
birth was defined as a live born child after 20 weeks of gestation
(Staessen 2008; Blockeel 2008 personal communication) as a live
born child after 24 weeks of gestation (Mastenbroek 2007), as progression of pregnancy past the 24th week of gestation (Schoolcraft
2009), or it was not defined (Debrock 2010; Hardarson 2008;
Jansen 2008; Meyer 2009).
A clinical pregnancy was defined as the presence of at least one
intrauterine gestational sac on ultrasound exam (Mastenbroek
2007; Meyer 2009; Debrock 2010), or as fetal heart activity on
ultrasound exam (Staessen 2004: Blockeel 2008; Jansen 2008;
Hardarson 2008; Staessen 2008).
A miscarriage in some studies only included clinical miscarriage
(Meyer 2009), in other studies it included both preclinical and
clinical miscarriages (Staessen 2004; Mastenbroek 2007; Blockeel
2008; Hardarson 2008; Jansen 2008; Schoolcraft 2009; Staessen
2008; Debrock 2010).
Effects of interventions
(1) PGS for advance maternal age
Five trials were included that evaluated PGS in women of advanced
maternal age (Debrock 2010; Hardarson 2008;Mastenbroek
2007;Schoolcraft 2009;Staessen 2004). In total, 537 women were
analysed in the PGS group and 525 women were analysed in the
control group.
Primary outcomes
All five trials had data on live birth (see Figure 3). The combined
live birth rate per woman was significantly lower in the PGS group
(18%, 95 out of 537) than in the control group (26%, 136 out
of 525) resulting in an OR of 0.59 (95% CI 0.44 to 0.81; P =
0.0008). For a control group rate of 26%, these data suggest a
live birth rate after PGS of between 13% and 23%. There was
no indication for statistical heterogeneity. Visual inspection of the
forest plot showed that the OR and 95%CI of the individual trials
overlapped and the I2 was 0%.
Figure 3. Forest plot of comparison: 1 advanced maternal age, outcome: 1.1 live birth rate per woman
randomised.
Secondary outcomes
Three trials had data on ongoing pregnancy (Debrock 2010;
Mastenbroek 2007; Staessen 2004). The ongoing pregnancy rate
was significantly lower in the PGS group (18%, 80 out of 449)
than in the control group (26%, 113 out of 442) resulting in an
OR of 0.62 (95% CI 0.45 to 0.86; P = 0.004) and the I2 was 0%.
For a control group rate of 26%, these data suggest an ongoing
pregnancy rate after PGS of between 13% and 24% (see Figure
4).
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Figure 4. Forest plot of comparison: 1 advanced maternal age, outcome: 1.2 ongoing pregnancy rate per
woman randomised.
Two studies were not included in the analysis of women reaching
embryo transfer because in these studies only women with a minimal number of good quality embryos on day three were included,
thereby excluding women with poor or average ovarian response
and a higher risk for not reaching embryo transfer (Hardarson
2008; Schoolcraft 2009). Indeed in these studies respectively 80%
and 97% of the women in the PGS group reached embryo transfer
compared to 100% of the women in the control group. For the
other trials (Debrock 2010; Mastenbroek 2007; Staessen 2004)
the combined proportion of women reaching embryo transfer was
significantly lower in the PGS group (64%, 286 out of 449) than
in the control group (78%, 344 out of 442) resulting in an OR of
0.46 (95% CI 0.34 to 0.64; P < 0.00001). For a control group rate
of 78%, these data suggest a proportion of women reaching embryo transfer after PGS of between 59% and 70%. There was no
indication for statistical heterogeneity, the I2 was 0% (see Figure
5).
Figure 5. Forest plot of comparison: 1 advanced maternal age, outcome: 1.3 proportion of women reaching
embryo transfer.
Four trials had data on the mean number of embryos transferred
(Debrock 2010; Hardarson 2008; Mastenbroek 2007; Staessen
2004). The mean number of embryos transferred was significantly
different in favour of the control group (Mean difference -0.22;
95% CI -0.30 to -0.14; P < 0.00001). There was statistical heterogeneity, the I2 was 87% (see Figure 6). This could partly be
explained by the fact that the maximum embryos for transfer was
much higher in one study, namely up to six if a woman was 40
years or older (Staessen 2004) as compared tot the other studies,
where the maximum of embryos for transfer was two or three.
However, if this study was excluded from the analysis the I2 was
still high, namely 73%.
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Figure 6. Forest plot of comparison: 1 advanced maternal age, outcome: 1.4 mean number of embryos
transferred per transfer.
Four trials had data on clinical pregnancy (Debrock 2010;
Hardarson 2008; Mastenbroek 2007; Staessen 2004). The clinical
pregnancy rate was significantly lower in the PGS group (19%,
96 out of 505) than in the control group (29%, 144 out of 495)
resulting in an OR of 0.56 ( 95% CI 0.41 to 0.75; P = 0.0002)
and the I2 was 0%. For a control group rate of 29%, these data
suggest a clinical pregnancy rate using PGS of between 14% and
24%. (see Figure 7).
Figure 7. Forest plot of comparison: 1 advanced maternal age, outcome: 1.5 clinical pregnancy rate per
woman randomised.
The multiple pregnancy rate per live birth was not significantly
different between the PGS and the control group. A total of 15 twin
and one triplet pregnancies were reported in the PGS group, with
one twin pregnancy resulting from a vanishing triplet pregnancy,
versus 24 twin pregnancies and three triplet pregnancies in the
control group. Two triplet pregnancies were reduced to a singleton
pregnancy and one to a twin pregnancy, which ended in a singleton
pregnancy. This results in an OR of 1.04 (4 studies; 95% CI 0.51
to 2.13). The I2 was 0% (see Figure 8).
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Figure 8. Forest plot of comparison: 1 advanced maternal age, outcome: 1.6 multiple pregnancy rate per
live birth.
All five trials also reported on miscarriage rate per woman randomised. The miscarriage rate was not significantly different between the PGS (11%, 58 out of 537) and the control group (12%
,64 out of 525), with an OR of 0.87 ( 95% CI 0.59 to 1.27) and
the I2 was 0% (see Figure 9).
Figure 9. Forest plot of comparison: 1 advanced maternal age, outcome: 1.7 miscarriage rate per woman
randomised.
Two trials reported data on women reaching embryo transfer after
cryopreservation of embryos. In the PGS group significantly less
women reached embryo transfer after cryopreservation of embryos
(OR 0.52, 95% CI 0.30 to 0.90). However in both of these trials
many more embryos were cryopreserved than transferred at the
time of publication, suggesting many embryos were still available
to be transferred.
In the PGS group there was one trisomy 18 (after spontaneous conception), one intrauterine death (due to abruptio placentae) and
one premature delivery of twins at 24 weeks of gestation, resulting
in the postpartum death of both children (Mastenbroek 2007).
In the control group there was one Down syndrome (Staessen
2004, personal communication) one trisomy 18, one conception
with a cleft lip and palate and one intrauterine death of a fetus (Mastenbroek 2007). In one study there were no malformed
children (Hardarson 2008, personal communication). The other
studies did not report on pregnancy outcome.
(2) PGS for repeated IVF failure
Only one trial (Blockeel 2008) examined PGS for repeated IVF
failure. There were 72 women included in the PGS group and 67
women were included in the control group.
Primary outcomes
Live birth rate per woman was significantly lower in the PGS group
(21%, 15 out of 72) than in the control group (39%, 26 out of
67) with an OR of 0.41 (95% CI 0.20 to 0.88; P = 0.02). For
a control group rate of 39%, this suggests a live birth rate using
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PGS of between 6% and 36%.
Secondary outcomes
The ongoing pregnancy rate per woman was significantly lower
in the PGS group (21%, 15 out of 72) than in the control group
(39%, 26 out of 67) with an OR of 0.41 (95% CI 0.20 to 0.88;
P = 0.02).
The proportion of women reaching embryo transfer was significantly lower after PGS (76%, 55 out of 72) than in the control
group (94%, 63 out of 67) with an OR of 0.21 (95% CI 0.07 to
0.65; P= 0.007).
The mean number of embryos transferred per transfer was significantly different in favour of the control group (weighted mean
difference -0.70; 95% CI -1.06 to -0.34; P = 0.0001)).
The clinical pregnancy rate was not significantly different between
the PGS (25%, 18 out of 72) and the control group (40%, 27 out
of 67), with an OR of 0.49 (95% CI 0.24 to 1.02; NS). For a
control group rate of 40% this suggests a clinical pregnancy rate
using PGS of between 9% and 40%.
Multiple pregnancy rate was not significantly different between the
PGS and the control group. In the PGS group 3 twin pregnancies
were reported. In the control group 10 twin pregnancies were
reported (OR 0.40; 95% CI 0.09 to 1.78; NS).
The miscarriage rate was not significantly different between the
PGS (14%, 10 out of 72) and the control group (7%, 5 out of
67), with an OR of 2.00 (95% CI 0.65 to 6.19; NS).
All children in the PGS group as well as the control group were
born healthy.
(3) PGS for repeated miscarriage
No trials that met our inclusion criteria were found on this subject.
(4) PGS for TESE-ICSI
No randomised controlled trials on this subject were found.
(5) PGS for good prognosis patients
Three trials were included that evaluated PGS in primarily good
prognosis patients (Meyer 2009;Staessen 2008;Jansen 2008) In
total, 198 women were analysed in the PGS treatment group and
190 women were analysed in the control group. Two studies performed biopsy at the cleavage stage (Meyer 2009; Staessen 2008)
and one studies performed biopsy at the blastocyst stage (Jansen
2008). Odds ratios were calculated for all studies together and
performed subgroup analyses based on the moment of biopsy.
Primary outcomes
All four trials provided data on live birth. The combined live birth
rate per woman was significantly lower in the PGS group (32%,
63 out of 198) than in the control group (402%, 79 out of 190)
resulting in an OR of 0.64 ( 95% CI 0.42 to 0.97, P = 0.03).
However, there was substantial statistical heterogeneity as shown
by the inconsistency measure (I-squared = 71%). When pooling
the data using a random effects model no difference in live birth
rate could be proven (OR 0.50, 95% CI 0.20 to 1.26, P = 0.12).
In the subgroup analysis live birth rates were significantly lower
after PGS at the blastocyst stage (OR 0.40, 95% CI 0.18-0.90, P
= 0.03). When PGS was performed at the cleavage stage the live
birth rate was also lower after PGS, but this was not significant
(OR 0.77, 95% CI 0.47-1.25, P = 0.29) (see Figure 10)
Figure 10. Forest plot of comparison: 3 good prognosis patients, outcome: 3.1 live birth rate per woman
randomised.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
Secondary outcomes
Ongoing pregnancy rate per woman was only reported in one trial
(Staessen 2008), therefore no meta-analysis could be performed.
The ongoing pregnancy rate was not significantly different between the PGS (31%, 37 out of 120) and the control group (33%,
39 out of 120), with an OR of 0.93 (95% CI 0.54 to 1.60, P =
0.78).
Three trials provided data on the number of women reaching embryo transfer. The combined proportion of women reaching embryo transfer after PGS at the cleavage stage was not significantly
different between the PGS (81%, 160 out of 198) and the control
group (83%, 157 out of 190), with an OR of 0.83 (95% CI 0.49
to 1.42, P = 0.49) and the I-squared was 0% . For a control group
rate of 83%, these data suggest a proportion of women reaching
embryo transfer after PGS of between 73% and 88%. The proportion of women reaching embryo transfer in all three trials is high
in comparison to other trials in which PGS is performed for other
indications. This is most likely because only women with a minimum of good quality embryos were included, thereby excluding
women with poor or average ovarian response and a higher risk
for not reaching embryo transfer. (see Figure 11).
Figure 11. Forest plot of comparison: 3 good prognosis patients, outcome: 3.3 proportion of women
reaching embryo transfer.
Three trials provided data on clinical pregnancy (Meyer 2009;
Staessen 2008; Jansen 2008). The clinical pregnancy rate was significantly lower in the PGS group (35%, 70 out of 198) than in
the control group (46%, 87 out of 190) resulting in an OR of 0.63
( 95% CI 0.42 to 0.95; P = 0.03), and the I2 was 0%. For a control
group rate of 46%, these data suggest a clinical pregnancy rate
using PGS of between 26% and 45%. In both subgroups (PGS
at the cleavage stage and PGS at the blastocyst stage) the clinical
pregnancy rate was lower after PGS, but this was not significant
(OR 0.70; 95% CI 0.43-1.15 and OR 0.47; 95% CI 0.21-1.04
respectively). (see Figure 12)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16
Figure 12. Forest plot of comparison: 3 good prognosis patients, outcome: 3.5 clinical pregnancy rate per
woman randomised.
In the study by Staessen et al. one multiple pregnancy occurred
in the PGS group versus two multiple pregnancies in the control
group (OR 0.49; 95% CI 0.04-5.61). All multiple pregnancies
occurred despite the fact that single embryo transfer was applied.
In the other studies multiple pregnancy rate was not mentioned
(Jansen 2008) or it was only provided as a percentage and it was
not possible to recalculate this into exact numbers (Meyer 2009).
Three trials provided data on miscarriage (Meyer 2009; Staessen
2008; Jansen 2008). The miscarriage rate was not significantly
different between the PGS and the control group. The combined
miscarriage rate per woman randomised was 10% (20 out of 198)
in the PGS group versus 9% (17 out of 190) in the control group,
resulting in an OR of 1.17 (95% CI 0.59 to 2.30). There was
substantial statistical heterogeneity as shown by the inconsistency
measure (I-squared = 65%). When pooling the data using a random effects model there was also no difference in miscarriage rate
(OR 2.02, 95% CI 0.38 to 10.76). For a control group rate of 9%,
these data suggest a miscarriage rate using PGS of between 3%
and 24%. In both subgroups (PGS at the cleavage stage and PGS
at the blastocyst stage) the miscarriage rate was not significantly
different between the PGS and the control group (OR 1.59; 95%
CI 0.17-14.82 (random effects model) and OR 4.50; 95% CI
0.51-39.99 respectively). (see Figure 13)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
Figure 13. Forest plot of comparison: 3 good prognosis patients, outcome: 3.7 miscarriage rate per woman
randomised.
One study reported that no major or minor congenital abnormalities were detected in any of the children and that there were no
chromosomal abnormalities (Meyer 2009). In the other two studies abnormalities in the live born children were not mentioned.
DISCUSSION
Summary of main results
In this review on the effectiveness of PGS nine trials for three
indications could be included. All trials used FISH for the analysis.
Live birth rate and ongoing pregnancy rate were significantly lower
after IVF/ICSI with PGS as compared to IVF/ICSI without PGS
in women of advanced maternal age and in women with repeated
IVF failure. Trials in which PGS was offered to good prognosis
patients suggested similar outcomes. Similar results were found in
the trial with blastocyst stage biopsy as in the trials with cleavage
stage biopsy.
Overall completeness and applicability of
evidence
The observation that significantly more women reached embryo
transfer and that significantly more embryos were transferred per
transfer in the control group in women of advanced maternal age
and in women with repeated IVF failure can be explained by the
fact that in the PGS group all chromosomal abnormal embryos
were excluded for transfer, while in the control group all embryos
are in principle available for transfer. Of the embryos tested 41.5%,
49.7%, 63%, 67.3% and 69.7% were found to be chromosomally abnormal, and therefore not suitable for embryo transfer in
the studies by Mastenbroek 2007; Blockeel 2008; Staessen 2008;
Hardarson 2008; Debrock 2010 respectively. In good prognosis patients there was no difference in the proportion of women
reaching embryo transfer. This is not surprising since only women
with a minimum number of good quality embryos were included,
thereby excluding women with a higher risk for not reaching embryo transfer.
The transfer of significantly more embryos in the control group
could explain the increased number of multiple pregnancies in this
group, though this difference was not statistically different.
There are several possible explanations for the lower number of
ongoing pregnancies and live births after PGS found in this review.
First, the technique itself, or more precisely the use of a laser or
acidic tyrode’s to create a hole in the zona pellucida and the removal
of one or more blastomeres could hamper the potential of the
embryo to successfully develop and implant (Tarin 1992; Cohen
2007).
Second, the use of FISH for the analysis could result in false-positive or false-negative diagnosis. Scoring errors of FISH signals may
arise from loss or damage of nuclear material, overlapping signals,
split signals, diffused signals, hybridisation failure and probe inefficiency. FISH analysis has in general a 92-99% accuracy per probe,
so when using a multi-probe panel on one blastomere, there is
always the risk of misdiagnosis (Michiels 2006; DeUgarte 2008),
thereby possibly incorrectly including or excluding embryos for
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
18
transfer. Furthermore, only a limited number of chromosomes can
be tested by FISH, thus embryos labelled as normal after PGS
could in fact be aneuploid for one or more chromosomes not
tested.
Third, the chromosomal constitution of the cell analysed does
not necessarily represent the embryo, as mosaicism is common in
human preimplantation embryos (Coonen 2005; Staessen 2004).
This could lead to the transfer of non-viable embryos and the
discarding of potentially viable embryos.
Because of the disappointing results of PGS thus far, the technique is continuously under development to improve the accuracy of PGS. This involves either a different timing of the embryo
biopsy or the use of more advanced genetic analysis to determine
the genetic content of a single cell. Some advocate that biopsy at
the blastocyst stage may allow sampling of representative genetic
material without compromising embryo viability (Munne 2009).
However, in the only randomised controlled trial that performed
PGS at the blastocyst stage live birth rates were lower after IVF/
ICSI with PGS (Jansen 2008), similar to the trials included in our
review where PGS was performed at the cleavage stage. Polar body
biopsy may offer another alternative to blastomere biopsy (Montag
2009; Geraedts 2010). This approach has the advantage that the
integrity of the embryo remains unaffected as polar bodies play
no major role in further embryonic development. A disadvantage
of PGS using polar bodies is its inability to detect chromosome
errors of paternal and/or post zygotic origin. However, the overall
paternal contribution to the aneuploidy risk of an embryo derived
from assisted reproduction has been suggested to be low with more
than 90% of all aneuploidies being of maternal origin (Montag
2009).
Alternatives for the use of FISH, such as methods based on comparative genomic hybridisation (CGH), or the analysis of single
nucleotide polymorphisms (SNPs) have also been proposed (Wells
2008). These techniques allow simultaneous screening of all chromosomes. Although this possibly improves the detection of abnormalities in a single cell, it still has to be weighted against possible harm by the biopsy procedure and the presence of mosaicism
(Mastenbroek 2008; Vanneste 2009).
Considering the outcomes of our review these new developments
should properly be evaluated before their routine clinical use by
method assessment studies, followed by pilot-studies showing a
potential benefit in terms of live birth per woman and subsequent
randomised controlled trials.
In conclusion, this analysis shows that PGS as currently performed
significantly decreases live birth rates in women of advanced maternal age and in women with repeated IVF failure. New trials
on PGS should be preceded by proper method assessment and
pilot-studies showing a potential benefit in terms of live birth per
woman. Until such trials have been performed, PGS should not
be offered as routine care in any form.
Quality of the evidence
Overall quality of the trials varied, for more detail see table ’characteristics of studies’. All but one trial performed a power calculation,
but the power was not reached in four trials and in three trials the
power calculation was based on embryos instead of women. Just
one trial was double blind. In two trials there was concealment of
allocation, in the other trials this was not mentioned. Drop-outs
were included in an intention-to-treat analysis in only one trial.
Outcome measures were not defined the same in all trials. These
factors can all cause bias.
Potential biases in the review process
All but one trial included in this analysis performed biopsy at the
blastocyst stage. All trials used FISH analysis. Whether PGS is
effective when biopsy is performed at a different stage of development or when CGH is used, is yet unknown.
Agreements and disagreements with other
studies or reviews
In line with the results of this review, in 2008 the American Society of Reproductive Medicine (ASRM 2008), the American College of Obstetricians and Gynaecologists (American Society of
Reproductive Medicine 2008) and the British Fertility Society
(Anderson 2008) have all issued statements that PGS should not
be performed for any indication. Recently the European Society
for Human Reproduction and Embryology also stated that there is
no evidence that routine PGS is beneficial for patients of advanced
maternal age (Harper 2010).
AUTHORS’ CONCLUSIONS
Implications for practice
This analysis shows that PGS significantly decreases live birth rates
in women of advanced maternal age and in women with repeated
IVF failure. Trials in good prognosis patients suggested similar
outcomes. PGS should not be used in routine clinical practice.
Implications for research
There are efforts to modify the PGS procedure to increase its efficacy. This involves biopsy at other stages of development (polar
body or blastocyst stage) and other methods of analysis (comparative genome hybridisation or array-based technologies) than used
by the trials included in our review. Considering the outcomes of
our review, these new developments should properly be evaluated
before their routine clinical application. This involves method assessment studies, pilot-studies showing a potential benefit in terms
of live birth per woman, followed by randomised controlled trials.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
ACKNOWLEDGEMENTS
The authors wish to acknowledge the support of the Menstrual
Disorders and Subfertility Group staff.
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∗
Indicates the major publication for the study
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
22
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Blockeel 2008
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women below 37 years of age, with three or more failed IVF or ICSI attempts with
embryos of good morphological quality. Patients with an abnormal karyotype or nonmotile sperm were excluded.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Ongoing pregnancy rate
clinical pregnancy rate
miscarriage rate
multiple pregnancy rate
proportion of women reaching embryo transfer
mean number of embryos per transfer
Notes
ICSI only. Maximum three embryos for transfer. Method for zona drilling not reported.
Between 2001 and October 2005, two blastomeres were removed from those embryos
with at least six blastomeres. From November 2005 onwards, only one blastomere was
removed from the embryo. Embryos for biopsy not reported. FISH analysis for chromosomes X,Y, 13,16,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Unclear risk
Computer generated list
Allocation concealment?
High risk
Not concealed from the physicians
Blinding?
All outcomes
Unclear risk
Blinding not reported
Incomplete outcome data addressed?
All outcomes
Low risk
Flow chart of attrition including reasons
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Yes, but based on embryos instead of on
women
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
23
Debrock 2010
Methods
Prospective randomised controlled trial. Randomisation by blinded envelopes.
Participants
Women of 35 years or older, with at least two fertilized oocytes available on day 1 after
oocyte retrieval, and with at least two embryos consisting of six or more cells at day 3
after oocyte retrieval.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Live birth rate
ongoing pregnancy rate
clinical pregnancy rate
miscarriage rate
multiple pregnancy rate
proportion of women reaching embryo transfer
mean number of embryos per transfer
Notes
IVF, ICSI and TESE used. Before juli 1, 2003 a maximum of two to three embryos were
transferred, after that only one embryo was transferred in the first trial in patients less than
age 36 years. Zona drilling by laser. Two blastomeres removed with biopsy. Biopsy on embryos with at least six blastomeres. FISH analysis for chromosomes X,Y,13,16,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Unclear risk
’randomized’
Allocation concealment?
Unclear risk
’sealed’ envelopes but not stated if opaque
Blinding?
All outcomes
High risk
No blinding
Incomplete outcome data addressed?
All outcomes
Low risk
Flow chart documents attrition through
out trial
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Yes, but based on embryos instead of on
women
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
24
Hardarson 2008
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women of 38 years or older with at lest three embryos of good morphological quality if
DET or at least two embryos of good morphological quality if SET.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Live birth rate
ongoing pregnancy rate
clinical pregnancy rate
miscarriage rate
proportion of women reaching embryo transfer
mean number of embryos per transfer
Notes
IVF and ICSI used. Maximum two embryos for transfer. Zona drilling by laser. Mostly
one blastomere removed. Biopsy on embryos with at least 6 cells and less than 20%
fragmentation. FISH analysis for chromosomes X,Y,13,18,21.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Low risk
computer randomisation
Allocation concealment?
Unclear risk
Concealment of allocation not reported
Blinding?
All outcomes
High risk
No blinding
Incomplete outcome data addressed?
All outcomes
Low risk
Number of randomised patients is the
number of analysed patients
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Unclear risk
No suggestion of other bias
power calculation
Low risk
Yes, but not reached since the study was
ended prematurely because an interim analysis showed a very low conditional power
of superiority for the primary outcome
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
Jansen 2008
Methods
Prospective randomised controlled trial. Allocation by sealed envelopes.
Participants
Women below 38 years of age in their first or second IVF with no cancelled cycles because
of poor response, agreement to elective single embryo transfer, with at least 8 follicles of
one centimetre of more on day 8-10 of stimulation. Women with less than four embryos
with eat least seven cells on day three, and women with less than two blastocysts for
biopsy were excluded.
Interventions
IVF and ICSI with PGS versus IVF and ICSI without PGS. FISH analysis. Trophectoderm biopsy.
Outcomes
Live birth rate
clinical pregnancy rate
miscarriage rate
proportion of women reaching embryo transfer
Notes
Method for fertilisation not reported. Single embryo transfer. Zona drilling by laser. 2-9
trophectoderm cells removed. Biopsy only on blastocysts. FISH analysis for chromosomes
X,Y,13,18,21.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Unclear risk
randomised but no further details
Allocation concealment?
Unclear risk
used ’sealed envelopes’ no details as to
whether these were opaque
Blinding?
All outcomes
High risk
No blinding.
Incomplete outcome data addressed?
All outcomes
Low risk
All randomised patients analysed. Also data
on women who were withdrawn from the
study before randomisation because of suboptimal responses to stimulation, and data
on women who were eligible but elected
not to take part in the study.
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Yes, but not reached. Trial stopped prematurely because at interim analysis the trend
was opposite to that required to disprove
the null hypothesis.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
Mastenbroek 2007
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women between 35 and 41 years with no previous failed IVF cycles. Women who
objected to DET were excluded.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Live birth rate
Ongoing pregnancy rate
Clinical pregnancy rate
Miscarriage rate
Multiple pregnancy rate
Proportion of women reaching embryo transfer
Mean number of embryos per transfer
Proportion of women reaching embryo transfer after cryopreservation.
Notes
IVF and ICSI. Maximum two embryos for transfer. Zona drilling by laser. Mostly one
blastomere removed. Biopsy on embryos with at least four blastomeres and with a maximum of 50% fragmentation. FISH analysis for chromosomes X,Y, 1,13,16,17,18,21.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Low risk
Randomisation by computer.
Allocation concealment?
Low risk
used computer randomisation with concealment of allocation
Blinding?
All outcomes
Low risk
Double blinded trial. Physicians and
women were blinded
Incomplete outcome data addressed?
All outcomes
Low risk
Number of randomised patients is the
number of analysed patients
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Power calculation performed
Meyer 2009
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women below 39 years of age with a normal ovarian reserve, a body mass index below
30 kg/m2 , a normal uterus, no more than two previous failed IVF cycles, with at least
four embryos containing at least five cells with less than 40% fragmentation. Absence of
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27
Meyer 2009
(Continued)
severe male factor infertility. No smoking history, no hydrosalpinx. At least four embryos
with at least five blastomeres with a fragmentation rate of under 40%.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Live birth rate
clinical pregnancy rate
miscarriage rate
proportion of women reaching embryo transfer
mean number of embryos per transfer
Notes
ICSI only. Maximum embryos for transfer not reported. Zona drilling with acid Tyrode’s
solution. Mostly one blastomere removed. Embryos for biopsy not reported. FISH analysis for chromosomes X,Y,13,16,17,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Low risk
Randomisation by computer
Allocation concealment?
Low risk
Sealed opaque randomisation
Blinding?
All outcomes
High risk
No blinding.
Incomplete outcome data addressed?
All outcomes
Low risk
Four patients declined transfers for reasons
not related to the study, all other patients
randomised are analysed.
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Power calculation performed but not
reached because an interim analysis found
a dramatically lower implantation rate for
the PGS group.
Schoolcraft 2009
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women of 35 years or older with at least five embryos consisting of at least six cells and
less than 15% fragmentation on day three.
Interventions
IVF and ICSI with PGS versus IVF and ICSI without PGS.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Schoolcraft 2009
(Continued)
Outcomes
Live birth rate
Proportion of women reaching embryo transfer
Miscarriage rate
Notes
IVF and ICSI. Maximum number of embryos transferred not reported. Zona drilling
using acid Tyrode’s solution or laser. One blastomere removed. Embryos for biopsy not
reported. FISH analysis for chromosomes X,Y,13,15,16,17,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Low risk
’computer generated random number table’
Allocation concealment?
Unclear risk
Concealment of allocation not reported.
Blinding?
All outcomes
Unclear risk
Blinding not reported
Incomplete outcome data addressed?
All outcomes
Low risk
All women randomised were analysed
Free of selective reporting?
Low risk
A priori outcomes reported
Free of other bias?
Low risk
No suggestion of other bias
power calculation
High risk
No power calculation reported.
Staessen 2004
Methods
Prospective randomised controlled trial. Method of randomisation not described.
400 patients were randomised, 1 woman in the intervention group and 10 women in
the control group did not fulfil the inclusion criteria.
Participants
Women of 37 years or older receiving ICSI as infertility treatment.
Patients with an abnormal karyotype or non-motile sperm were excluded.
The study was performed March 2000-December 2003 in the University Hospital,
Dutch-speaking Brussels Free University.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Percentage of ongoing implantations (per transferred embryo)
Positive serum HCG (per transfer and per cycle)
Percentage of implantations with fetal heartbeat (per transferred embryo)
Rates of abortion (per positive serum HCG)
Women reaching embryo transfer (per cycle)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29
Staessen 2004
(Continued)
Number of embryos per transfer
Notes
CSI only. A maximum of three blastocysts were transferred when the patients were
between 37 and 39 years ols, and up to a maximum of six blastocysts were transferred in
patients of 40 years or older. Zona drilling using laser. Mostly two blastomeres removed.
Embryos with at least five blastomeres with a maximum of 50% fragmentation for biopsy.
FISH analysis for chromosomes X,Y, 13,16,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Unclear risk
’Randomized’
Allocation concealment?
Unclear risk
Concealment of allocation not reported.
Blinding?
All outcomes
High risk
No blinding.
Incomplete outcome data addressed?
All outcomes
High risk
Data on drop-outs not reported.
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Power calculation performed but based on
embryos instead of on women.
Staessen 2008
Methods
Prospective randomised controlled trial. Randomisation by computer.
Participants
Women below 36 years. Patients with an abnormal karyotype or non-motile sperm were
excluded.
Interventions
ICSI with PGS versus ICSI without PGS. FISH analysis. Blastomere biopsy.
Outcomes
Live birth rate
Ongoing pregnancy rate
Clinical pregnancy rate
Miscarriage rate
Multiple pregnancy rate
Proportion of women reaching embryo transfer
mean number of embryos per transfer
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
Staessen 2008
(Continued)
Notes
ICSI only. Single embryo transfer. Zona drilling using laser. Mostly one blastomere
removed. Embryos with at least five blastomeres with a maximum of 50% fragmentation
for biopsy. FISH analysis for chromosomes X,Y,13,16,18,21,22.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Adequate sequence generation?
Unclear risk
Randomised - no details
Allocation concealment?
Unclear risk
Concealment of allocation not reported.
Blinding?
All outcomes
High risk
Not blinded.
Incomplete outcome data addressed?
All outcomes
High risk
Data on drop-outs not reported.
Free of selective reporting?
Low risk
No suggestion of selective reporting
Free of other bias?
Low risk
No suggestion of other bias
power calculation
Low risk
Power calculation performed but not
reached because an interim analysis showed
futility.
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Gianaroli 1997
Allocation to intervention or control group based on volunteer decision.
Gianaroli 1999
Allocation to intervention or control group based on volunteer decision.
Mersereau 2008
Ongoing trial. Outcome measures reported as percentages without mentioning the unit of analysis, not possible
to calculate the exact numbers
Stevens 2004
The patients included in this study were also included in an other larger study
Werlin 2003
No data beyond biochemical pregnancy
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
DATA AND ANALYSES
Comparison 1. Advanced maternal age
Outcome or subgroup title
1 Live birth rate per woman
randomised
2 Ongoing pregnancy rate per
woman randomised
3 Proportion of women reaching
embryo transfer
4 Mean number of embryos
transferred per transfer
5 Clinical pregnancy rate per
woman randomised
6 Multiple pregnancy rate per live
birth
7 Miscarriage rate per woman
randomised
No. of
studies
No. of
participants
5
1062
Odds Ratio (M-H, Fixed, 95% CI)
0.59 [0.44, 0.81]
3
891
Odds Ratio (M-H, Fixed, 95% CI)
0.62 [0.45, 0.86]
3
891
Odds Ratio (M-H, Fixed, 95% CI)
0.46 [0.34, 0.64]
4
1131
Mean Difference (IV, Fixed, 95% CI)
-0.22 [-0.30, -0.14]
4
1000
Odds Ratio (M-H, Fixed, 95% CI)
0.56 [0.41, 0.75]
4
199
Odds Ratio (M-H, Fixed, 95% CI)
1.04 [0.51, 2.13]
5
1062
Odds Ratio (M-H, Fixed, 95% CI)
0.87 [0.59, 1.27]
Statistical method
Effect size
Comparison 2. Repeated IVF failure
Outcome or subgroup title
1 Live birth rate per woman
randomised
2 Ongoing pregnancy rate per
woman randomised
3 Proportion of women reaching
embryo transfer
4 Mean number of embryos
transferred per transfer
5 Clinical pregnancy rate per
woman randomised
6 Multiple pregnancy rate per live
birth
7 miscarriage rate per woman
randomised
No. of
studies
No. of
participants
Statistical method
Effect size
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
1
Mean Difference (IV, Fixed, 95% CI)
Subtotals only
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
1
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
32
Comparison 3. Good prognosis patients
Outcome or subgroup title
1 Live birth rate per woman
randomised
1.1 biopsy at cleavage stage
1.2 biopsy at blastocyst stage
2 Ongoing pregnancy rate per
woman randomised
2.1 biopsy at cleavage stage
3 Proportion of women reaching
embryo transfer
3.1 biopsy at cleavage stage
3.2 biopsy at blastocyst stage
4 Mean number of embryos for
transfer
5 Clinical pregnancy rate per
woman randomised
5.1 biopsy at cleavage stage
5.2 biopsy at blastocyst stage
6 Multiple pregnancy rate per live
birth
6.1 biopsy at cleavage stage
7 Miscarriage rate per woman
randomised
7.1 biopsy at cleavage stage
7.2 biopsy at blastocyst stage
No. of
studies
No. of
participants
3
388
Odds Ratio (M-H, Random, 95% CI)
0.50 [0.21, 1.20]
2
1
1
287
101
Odds Ratio (M-H, Random, 95% CI)
Odds Ratio (M-H, Random, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
0.51 [0.11, 2.31]
0.40 [0.18, 0.90]
Totals not selected
Odds Ratio (M-H, Fixed, 95% CI)
Risk Difference (M-H, Fixed, 95% CI)
Not estimable
-0.03 [-0.10, 0.05]
1
3
388
Statistical method
Effect size
2
1
1
287
101
Risk Difference (M-H, Fixed, 95% CI)
Risk Difference (M-H, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
-0.03 [-0.13, 0.07]
-0.02 [-0.07, 0.03]
Totals not selected
3
388
Odds Ratio (M-H, Fixed, 95% CI)
0.63 [0.42, 0.95]
2
1
1
287
101
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
0.70 [0.43, 1.15]
0.47 [0.21, 1.04]
Totals not selected
1
3
388
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Not estimable
1.17 [0.59, 2.30]
2
1
287
101
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
0.94 [0.45, 1.97]
4.50 [0.51, 39.99]
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
33
Analysis 1.1. Comparison 1 Advanced maternal age, Outcome 1 Live birth rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 1 Live birth rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Debrock 2010
6/44
10/50
7.5 %
0.63 [ 0.21, 1.91 ]
Hardarson 2008
3/56
10/53
9.1 %
0.24 [ 0.06, 0.94 ]
49/206
71/202
50.9 %
0.58 [ 0.37, 0.89 ]
16/32
16/30
7.7 %
0.88 [ 0.32, 2.37 ]
21/199
29/190
24.7 %
0.65 [ 0.36, 1.19 ]
537
525
100.0 %
0.59 [ 0.44, 0.81 ]
Mastenbroek 2007
Schoolcraft 2009
Staessen 2004
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 95 (PGS group), 136 (Control group)
Heterogeneity: Chi2 = 2.39, df = 4 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 3.35 (P = 0.00082)
0.1 0.2
0.5
1
Favours control
2
5
10
Favours PGS
Analysis 1.2. Comparison 1 Advanced maternal age, Outcome 2 Ongoing pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 2 Ongoing pregnancy rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
6/44
10/50
8.9 %
0.63 [ 0.21, 1.91 ]
Mastenbroek 2007
52/206
74/202
61.8 %
0.58 [ 0.38, 0.89 ]
Staessen 2004
22/199
29/190
29.2 %
0.69 [ 0.38, 1.25 ]
449
442
100.0 %
0.62 [ 0.45, 0.86 ]
Debrock 2010
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 80 (PGS group), 113 (Control group)
Heterogeneity: Chi2 = 0.20, df = 2 (P = 0.90); I2 =0.0%
Test for overall effect: Z = 2.85 (P = 0.0044)
0.1 0.2
0.5
Favours control
1
2
5
10
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
Analysis 1.3. Comparison 1 Advanced maternal age, Outcome 3 Proportion of women reaching embryo
transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 3 Proportion of women reaching embryo transfer
Study or subgroup
Debrock 2010
Mastenbroek 2007
Staessen 2004
Total (95% CI)
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
39/44
47/50
4.4 %
0.50 [ 0.11, 2.22 ]
166/206
176/202
30.6 %
0.61 [ 0.36, 1.05 ]
81/199
121/190
65.0 %
0.39 [ 0.26, 0.59 ]
449
442
100.0 %
0.46 [ 0.34, 0.64 ]
M-H,Fixed,95% CI
Total events: 286 (PGS group), 344 (Control group)
Heterogeneity: Chi2 = 1.70, df = 2 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 4.74 (P < 0.00001)
0.2
0.5
Favours control
1
2
5
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
35
Analysis 1.4. Comparison 1 Advanced maternal age, Outcome 4 Mean number of embryos transferred per
transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 4 Mean number of embryos transferred per transfer
Study or subgroup
PGS group
Control group
Mean Difference
Weight
Mean(SD)
N
Mean(SD)
Debrock 2010
53
1.6 (0.6)
47
2 (0.6)
11.2 %
-0.40 [ -0.64, -0.16 ]
Hardarson 2008
45
1.5 (0.5)
53
1.8 (0.4)
18.9 %
-0.30 [ -0.48, -0.12 ]
367
1.8 (0.75)
364
1.9 (0.62)
62.5 %
-0.10 [ -0.20, 0.00 ]
81
2 (0.9)
121
2.8 (1.2)
7.4 %
-0.80 [ -1.09, -0.51 ]
Mastenbroek 2007
Staessen 2004
Total (95% CI)
546
IV,Fixed,95% CI
Mean Difference
N
IV,Fixed,95% CI
585
100.0 % -0.22 [ -0.30, -0.14 ]
Heterogeneity: Chi2 = 23.91, df = 3 (P = 0.00003); I2 =87%
Test for overall effect: Z = 5.55 (P < 0.00001)
-1
-0.5
0
0.5
Favours control
1
Favours PGS
Analysis 1.5. Comparison 1 Advanced maternal age, Outcome 5 Clinical pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 5 Clinical pregnancy rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Debrock 2010
8/44
13/50
8.9 %
0.63 [ 0.23, 1.71 ]
Hardarson 2008
5/56
13/53
10.9 %
0.30 [ 0.10, 0.92 ]
Mastenbroek 2007
61/206
88/202
55.9 %
0.54 [ 0.36, 0.82 ]
Staessen 2004
22/199
30/190
24.4 %
0.66 [ 0.37, 1.20 ]
505
495
100.0 %
0.56 [ 0.41, 0.75 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 96 (PGS group), 144 (Control group)
Heterogeneity: Chi2 = 1.58, df = 3 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 3.78 (P = 0.00015)
0.01
0.1
Favours control
1
10
100
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
Analysis 1.6. Comparison 1 Advanced maternal age, Outcome 6 Multiple pregnancy rate per live birth.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 6 Multiple pregnancy rate per live birth
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Debrock 2010
1/6
1/10
4.2 %
1.80 [ 0.09, 35.42 ]
Hardarson 2008
1/3
3/10
6.3 %
1.17 [ 0.07, 18.35 ]
10/49
14/71
61.8 %
1.04 [ 0.42, 2.59 ]
Staessen 2004
4/21
6/29
27.7 %
0.90 [ 0.22, 3.70 ]
Total (95% CI)
79
120
100.0 %
1.04 [ 0.51, 2.13 ]
Mastenbroek 2007
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 16 (PGS group), 24 (Control group)
Heterogeneity: Chi2 = 0.18, df = 3 (P = 0.98); I2 =0.0%
Test for overall effect: Z = 0.12 (P = 0.91)
0.05
0.2
1
5
20
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
Analysis 1.7. Comparison 1 Advanced maternal age, Outcome 7 Miscarriage rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 1 Advanced maternal age
Outcome: 7 Miscarriage rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Debrock 2010
2/44
5/50
8.0 %
0.43 [ 0.08, 2.33 ]
Hardarson 2008
7/56
6/53
9.7 %
1.12 [ 0.35, 3.58 ]
37/206
36/202
53.6 %
1.01 [ 0.61, 1.68 ]
5/32
7/30
11.0 %
0.61 [ 0.17, 2.18 ]
Staessen 2004
7/199
10/190
17.7 %
0.66 [ 0.24, 1.76 ]
Total (95% CI)
537
525
100.0 %
0.87 [ 0.59, 1.27 ]
Mastenbroek 2007
Schoolcraft 2009
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 58 (PGS group), 64 (Control group)
Heterogeneity: Chi2 = 1.80, df = 4 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 0.73 (P = 0.47)
0.01
0.1
Favours PGS
1
10
100
Favours control
Analysis 2.1. Comparison 2 Repeated IVF failure, Outcome 1 Live birth rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 1 Live birth rate per woman randomised
Study or subgroup
Blockeel 2008
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
15/72
26/67
0.41 [ 0.20, 0.88 ]
0.01
0.1
Favours control
1
10
100
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
Analysis 2.2. Comparison 2 Repeated IVF failure, Outcome 2 Ongoing pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 2 Ongoing pregnancy rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
15/72
26/67
Blockeel 2008
0.41 [ 0.20, 0.88 ]
0.01
0.1
1
Favours control
10
100
Favours PGS
Analysis 2.3. Comparison 2 Repeated IVF failure, Outcome 3 Proportion of women reaching embryo
transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 3 Proportion of women reaching embryo transfer
Study or subgroup
Blockeel 2008
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
55/72
63/67
0.21 [ 0.07, 0.65 ]
0.01
0.1
Favours control
1
10
100
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
Analysis 2.4. Comparison 2 Repeated IVF failure, Outcome 4 Mean number of embryos transferred per
transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 4 Mean number of embryos transferred per transfer
Study or subgroup
Blockeel 2008
PGS group
Control group
Mean Difference
N
Mean(SD)
N
Mean(SD)
55
1.4 (1)
63
2.1 (1)
Mean Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
-0.70 [ -1.06, -0.34 ]
-4
-2
0
Favours control
2
4
Favours PGS
Analysis 2.5. Comparison 2 Repeated IVF failure, Outcome 5 Clinical pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 5 Clinical pregnancy rate per woman randomised
Study or subgroup
Blockeel 2008
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
18/72
27/67
0.49 [ 0.24, 1.02 ]
0.01
0.1
Favours control
1
10
100
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Analysis 2.6. Comparison 2 Repeated IVF failure, Outcome 6 Multiple pregnancy rate per live birth.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 6 Multiple pregnancy rate per live birth
Study or subgroup
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
3/15
10/26
Blockeel 2008
0.40 [ 0.09, 1.78 ]
0.01
0.1
1
10
100
Analysis 2.7. Comparison 2 Repeated IVF failure, Outcome 7 miscarriage rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 2 Repeated IVF failure
Outcome: 7 miscarriage rate per woman randomised
Study or subgroup
Blockeel 2008
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
10/72
5/67
2.00 [ 0.65, 6.19 ]
0.01
0.1
Favours PGS
1
10
100
Favours control
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
41
Analysis 3.1. Comparison 3 Good prognosis patients, Outcome 1 Live birth rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 1 Live birth rate per woman randomised
Study or subgroup
PGS group
Control group
n/N
n/N
Odds Ratio
Weight
6/23
15/24
24.7 %
0.21 [ 0.06, 0.74 ]
37/120
37/120
40.8 %
1.00 [ 0.58, 1.73 ]
143
144
65.5 %
0.51 [ 0.11, 2.31 ]
M-H,Random,95% CI
Odds Ratio
M-H,Random,95% CI
1 biopsy at cleavage stage
Meyer 2009
Staessen 2008
Subtotal (95% CI)
Total events: 43 (PGS group), 52 (Control group)
Heterogeneity: Tau2 = 0.96; Chi2 = 5.01, df = 1 (P = 0.03); I2 =80%
Test for overall effect: Z = 0.87 (P = 0.38)
2 biopsy at blastocyst stage
Jansen 2008
Subtotal (95% CI)
20/55
27/46
34.5 %
0.40 [ 0.18, 0.90 ]
55
46
34.5 %
0.40 [ 0.18, 0.90 ]
190
100.0 %
0.50 [ 0.21, 1.20 ]
Total events: 20 (PGS group), 27 (Control group)
Heterogeneity: not applicable
Test for overall effect: Z = 2.22 (P = 0.026)
Total (95% CI)
198
Total events: 63 (PGS group), 79 (Control group)
Heterogeneity: Tau2 = 0.42; Chi2 = 6.86, df = 2 (P = 0.03); I2 =71%
Test for overall effect: Z = 1.55 (P = 0.12)
0.01
0.1
Favours control
1
10
100
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Analysis 3.2. Comparison 3 Good prognosis patients, Outcome 2 Ongoing pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 2 Ongoing pregnancy rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
37/120
39/120
1 biopsy at cleavage stage
Staessen 2008
0.93 [ 0.54, 1.60 ]
0.01
0.1
1
Favours control
10
100
Favours PGS
Analysis 3.3. Comparison 3 Good prognosis patients, Outcome 3 Proportion of women reaching embryo
transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 3 Proportion of women reaching embryo transfer
Study or subgroup
PGS group
Control group
n/N
n/N
Risk Difference
Weight
21/23
22/24
12.1 %
0.00 [ -0.16, 0.16 ]
85/120
89/120
62.0 %
-0.03 [ -0.15, 0.08 ]
143
144
74.1 %
-0.03 [ -0.13, 0.07 ]
54/55
46/46
25.9 %
-0.02 [ -0.07, 0.03 ]
55
46
25.9 %
-0.02 [ -0.07, 0.03 ]
M-H,Fixed,95% CI
Risk Difference
M-H,Fixed,95% CI
1 biopsy at cleavage stage
Meyer 2009
Staessen 2008
Subtotal (95% CI)
Total events: 106 (PGS group), 111 (Control group)
Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 0.57 (P = 0.57)
2 biopsy at blastocyst stage
Jansen 2008
Subtotal (95% CI)
Total events: 54 (PGS group), 46 (Control group)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
-0.2
-0.1
Favours control
0
0.1
0.2
Favours PGS
(Continued . . . )
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
Study or subgroup
PGS group
Total (95% CI)
Control group
n/N
n/N
198
190
Risk Difference
(. . . Continued)
Risk Difference
Weight
M-H,Fixed,95% CI
M-H,Fixed,95% CI
100.0 %
-0.03 [ -0.10, 0.05 ]
Total events: 160 (PGS group), 157 (Control group)
Heterogeneity: Chi2 = 0.18, df = 2 (P = 0.92); I2 =0.0%
Test for overall effect: Z = 0.68 (P = 0.49)
-0.2
-0.1
0
Favours control
0.1
0.2
Favours PGS
Analysis 3.4. Comparison 3 Good prognosis patients, Outcome 4 Mean number of embryos for transfer.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 4 Mean number of embryos for transfer
Study or subgroup
Meyer 2009
PGS group
Control group
Mean Difference
N
Mean(SD)
N
Mean(SD)
21
1.78 (0.6)
22
1.79 (0.6)
Mean Difference
IV,Fixed,95% CI
IV,Fixed,95% CI
-0.01 [ -0.37, 0.35 ]
-0.5
-0.25
Favours control
0
0.25
0.5
Favours PGS
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
Analysis 3.5. Comparison 3 Good prognosis patients, Outcome 5 Clinical pregnancy rate per woman
randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 5 Clinical pregnancy rate per woman randomised
Study or subgroup
PGS group
Control group
n/N
n/N
Odds Ratio
Weight
11/23
16/24
14.5 %
0.46 [ 0.14, 1.49 ]
37/120
44/120
54.1 %
0.77 [ 0.45, 1.32 ]
143
144
68.6 %
0.70 [ 0.43, 1.15 ]
22/55
27/46
31.4 %
0.47 [ 0.21, 1.04 ]
55
46
31.4 %
0.47 [ 0.21, 1.04 ]
190
100.0 %
0.63 [ 0.42, 0.95 ]
M-H,Fixed,95% CI
Odds Ratio
M-H,Fixed,95% CI
1 biopsy at cleavage stage
Meyer 2009
Staessen 2008
Subtotal (95% CI)
Total events: 48 (PGS group), 60 (Control group)
Heterogeneity: Chi2 = 0.62, df = 1 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 1.41 (P = 0.16)
2 biopsy at blastocyst stage
Jansen 2008
Subtotal (95% CI)
Total events: 22 (PGS group), 27 (Control group)
Heterogeneity: not applicable
Test for overall effect: Z = 1.86 (P = 0.063)
Total (95% CI)
198
Total events: 70 (PGS group), 87 (Control group)
Heterogeneity: Chi2 = 1.34, df = 2 (P = 0.51); I2 =0.0%
Test for overall effect: Z = 2.18 (P = 0.029)
0.01
0.1
Favours control
1
10
100
Favours PGS
Analysis 3.6. Comparison 3 Good prognosis patients, Outcome 6 Multiple pregnancy rate per live birth.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 6 Multiple pregnancy rate per live birth
Study or subgroup
PGS group
Control group
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1/37
2/37
1 biopsy at cleavage stage
Staessen 2008
0.49 [ 0.04, 5.61 ]
0.01
0.1
1
10
100
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
Analysis 3.7. Comparison 3 Good prognosis patients, Outcome 7 Miscarriage rate per woman randomised.
Review:
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection
Comparison: 3 Good prognosis patients
Outcome: 7 Miscarriage rate per woman randomised
Study or subgroup
PGS group
Control group
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
5/23
1/24
4.9 %
6.39 [ 0.68, 59.65 ]
10/120
15/120
88.7 %
0.64 [ 0.27, 1.48 ]
143
144
93.6 %
0.94 [ 0.45, 1.97 ]
5/55
1/46
6.4 %
4.50 [ 0.51, 39.99 ]
55
46
6.4 %
4.50 [ 0.51, 39.99 ]
190
100.0 %
1.17 [ 0.59, 2.30 ]
M-H,Fixed,95% CI
1 biopsy at cleavage stage
Meyer 2009
Staessen 2008
Subtotal (95% CI)
Total events: 15 (PGS group), 16 (Control group)
Heterogeneity: Chi2 = 3.65, df = 1 (P = 0.06); I2 =73%
Test for overall effect: Z = 0.16 (P = 0.87)
2 biopsy at blastocyst stage
Jansen 2008
Subtotal (95% CI)
Total events: 5 (PGS group), 1 (Control group)
Heterogeneity: not applicable
Test for overall effect: Z = 1.35 (P = 0.18)
Total (95% CI)
198
Total events: 20 (PGS group), 17 (Control group)
Heterogeneity: Chi2 = 5.68, df = 2 (P = 0.06); I2 =65%
Test for overall effect: Z = 0.45 (P = 0.65)
0.01
0.1
Favours PGS
1
10
100
Favours control
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
APPENDICES
Appendix 1. MDSG search string
Menstrual disorders and subfertility group search string 20.07.10
Keywords CONTAINS “perimplantation genetic diagnosis” or “pre-implantation genetic diagnosis” or “pre-implantation genetic
screening” or “preimplantation genetic analysis” or “preimplantation genetic diagnosis” or “preimplantation genetic screening” or “genetic analysis” or “genetic screening” or “genetic testing” or “genetic techniques” or “chromosomal abnormalities” or “chromosomes”
or “aneuploidy screening” or “PGS” or “PGD” or Title CONTAINS“perimplantation genetic diagnosis” or “pre-implantation genetic
diagnosis” or “pre-implantation genetic screening” or “preimplantation genetic analysis” or “preimplantation genetic diagnosis” or
“preimplantation genetic screening” or “genetic analysis” or “genetic screening” or “genetic testing” or “genetic techniques” or “chromosomal abnormalities” or “chromosomes” or “aneuploidy screening” or “PGS” or “PGD”
Appendix 2. CENTRAL Search strategy
Database: EBM Reviews - Cochrane Central Register of Controlled Trials <2nd Quarter 2010>
Search Strategy:
-------------------------------------------------------------------------------1 exp chromosome aberrations/ or exp aneuploidy/ (327)
2 exp Preimplantation Diagnosis/ (22)
3 (Preimplant$ adj3 gene$).tw. (32)
4 aneuploid$.tw. (123)
5 (PGS or PGD-AS).tw. (115)
6 chromosome$.tw. (379)
7 exp in situ hybridization/ or exp in situ hybridization, fluorescence/ (188)
8 In Situ Hybridization.tw. (243)
9 FISH.tw. (1441)
10 Preimplant$ Diagnos$.tw. (5)
11 (Preimplant$ adj2 screen$).tw. (13)
12 (gene$ adj2 screen$).tw. (210)
13 or/1-12 (2558)
14 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ (1428)
15 embryo transfer$.tw. (804)
16 in vitro fertili?ation.tw. (1222)
17 ivf-et.tw. (234)
18 (ivf or et).tw. (5457)
19 icsi.tw. (587)
20 intracytoplasmic sperm injection$.tw. (359)
21 (blastocyst adj2 transfer$).tw. (59)
22 poor implantation.tw. (2)
23 pregnancy fail$.tw. (47)
24 or/14-23 (6600)
25 13 and 24 (66)
Appendix 3. MEDLINE search strategy
Database: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process
Search Strategy:
-------------------------------------------------------------------------------1 exp chromosome aberrations/ or exp aneuploidy/ (115490)
2 exp Preimplantation Diagnosis/ (1666)
3 (Preimplant$ adj3 gene$).tw. (1649)
4 aneuploid$.tw. (13573)
5 (PGS or PGD-AS).tw. (7646)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
chromosome$.tw. (197455)
exp in situ hybridization/ or exp in situ hybridization, fluorescence/ (71849)
In Situ Hybridization.tw. (67547)
FISH.tw. (79856)
Preimplant$ Diagnos$.tw. (376)
(Preimplant$ adj2 screen$).tw. (140)
(gene$ adj2 screen$).tw. (11324)
or/1-12 (414866)
exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ (27389)
embryo transfer$.tw. (6606)
in vitro fertili?ation.tw. (13944)
ivf-et.tw. (1565)
(ivf or et).tw. (139696)
icsi.tw. (4009)
intracytoplasmic sperm injection$.tw. (3730)
(blastocyst adj2 transfer$).tw. (366)
poor implantation.tw. (26)
pregnancy fail$.tw. (625)
or/14-23 (161204)
13 and 24 (8763)
randomized controlled trial.pt. (295430)
controlled clinical trial.pt. (82003)
randomized.ab. (209882)
placebo.tw. (127328)
clinical trials as topic.sh. (149702)
randomly.ab. (155208)
trial.ti. (90308)
(crossover or cross-over or cross over).tw. (48734)
or/26-33 (718183)
exp animals/ not humans.sh. (3507916)
34 not 35 (664462)
25 and 36 (172)
Appendix 4. EMBASE search strategy
Database: EMBASE <1980 to 2010 Week 28>
1 exp prenatal diagnosis/ (47716)
2 exp chromosome aberration/ (87710)
3 (Preimplant$ adj3 gene$).tw. (1568)
4 aneuploid$.tw. (11557)
5 (PGS or PGD-AS).tw. (6036)
6 chromosome$.tw. (152212)
7 exp in situ hybridization/ or exp hybridization/ (179338)
8 In Situ Hybridi?ation.tw. (62952)
9 Preimplant$ Diagnos$.tw. (368)
10 (Preimplant$ adj2 screen$).tw. (136)
11 (gene$ adj2 screen$).tw. (9473)
12 or/1-11 (406654)
13 exp embryo transfer/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/ (28397)
14 embryo$ transfer$.tw. (6096)
15 in vitro fertili?ation.tw. (12327)
16 ivf-et.tw. (1527)
17 icsi.tw. (4203)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
intracytoplasmic sperm injection$.tw. (3614)
(blastocyst adj2 transfer$).tw. (358)
(ivf or et).tw. (181525)
poor implantation.tw. (27)
pregnancy fail$.tw. (532)
or/13-22 (200790)
12 and 23 (13755)
Clinical Trial/ (606353)
Randomized Controlled Trial/ (191699)
exp randomization/ (28515)
Single Blind Procedure/ (9640)
Double Blind Procedure/ (78647)
Crossover Procedure/ (23267)
Placebo/ (144613)
Randomi?ed controlled trial$.tw. (41186)
Rct.tw. (3654)
random allocation.tw. (701)
randomly allocated.tw. (11299)
allocated randomly.tw. (1422)
(allocated adj2 random).tw. (575)
Single blind$.tw. (8240)
Double blind$.tw. (91103)
((treble or triple) adj blind$).tw. (153)
placebo$.tw. (120294)
prospective study/ (97264)
or/25-42 (796248)
case study/ (7303)
case report.tw. (133903)
abstract report/ or letter/ (544293)
or/44-46 (682715)
43 not 47 (768896)
24 and 48 (373)
(2009$ or 2010$).em. (1194879)
49 and 50 (75)
Appendix 5. PsycInfo search strategy
Database: PsycINFO <1806 to July Week 2 2010>
1 exp Chromosome Disorders/ (6174)
2 aneuploid$.tw. (80)
3 Preimplant$ Diagnos$.tw. (3)
4 (Preimplant$ adj3 gene$).tw. (57)
5 (PGS or PGD-AS).tw. (245)
6 Preimplant$ Diagnos$.tw. (3)
7 (Preimplant$ adj2 screen$).tw. (0)
8 (gene$ adj2 screen$).tw. (666)
9 exp reproductive technology/ (984)
10 embryo transfer$.tw. (72)
11 in vitro fertili?ation.tw. (391)
12 icsi.tw. (33)
13 intracytoplasmic sperm injection$.tw. (23)
14 (blastocyst adj2 transfer$).tw. (2)
15 poor implantation.tw. (1)
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49
16
17
18
19
20
pregnancy fail$.tw. (22)
ivf.tw. (275)
or/1-8 (7130)
or/9-17 (1165)
18 and 19 (48)
WHAT’S NEW
Last assessed as up-to-date: 14 July 2010.
Date
Event
Description
16 July 2010
Amended
New studies added. All fields opened and format amended.
HISTORY
Protocol first published: Issue 2, 2005
Review first published: Issue 1, 2006
Date
Event
Description
13 June 2008
Amended
New RCT’s included. Results and discussion updated.
11 November 2005
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
Twisk and Mastenbroek developed and wrote the protocol, developed the intended methods of review, entered the protocol into
RevMan and responded to peer reviewers’ comments. Any differences of opinion, during the extraction of information or while writing
the review, were registered and resolved by consensus with Heineman, Repping and van der Veen. Repping and van der Veen were
consultants on clinical issues. Van Wely provided statistical expertise.
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50
DECLARATIONS OF INTEREST
Mastenbroek, Twisk, van der Veen, Repping and Heineman have performed a randomised controlled trial on the effect of PGS in IVF/
ICSI in women aged 35 and over. This was an independent trial funded by the Netherlands Organisation for Health Research and
Development.
SOURCES OF SUPPORT
Internal sources
• There were no internal sources of support, Not specified.
External sources
• There were no external sources of support, Not specified.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
none.
INDEX TERMS
Medical Subject Headings (MeSH)
∗ Aneuploidy; ∗ Fertilization
in Vitro; ∗ Preimplantation Diagnosis; ∗ Sperm Injections, Intracytoplasmic; Birth Rate; Genetic Testing
[ methods]; Maternal Age; Randomized Controlled Trials as Topic
∗
MeSH check words
Female; Humans; Pregnancy
Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic
sperm injection (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
51