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. 2018 Dec 18;2018(12):CD013233. doi: 10.1002/14651858.CD013233

Day 5 versus day 3 embryo biopsy for preimplantation genetic testing for monogenic/single gene defects

Alex Y Wang 1,✉, Elizabeth A Sullivan 1, Zhuoyang Li 1, Cindy Farquhar 2
PMCID: PMC6517237

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of day 5 embryo biopsy, in comparison to day 3 biopsy, in preimplantation genetic testing for monogenic/single gene defects (PGT‐M).

Background

Assisted reproductive technology (ART) has enabled the possibility of allowing couples with a family history of a genetic disease, or a disease‐carrying gene, to have preimplantation genetic diagnosis (PGD) to reduce the chance of them having a child with the genetic disorder (Handyside 1989; Cimadomo 2016). The PGD is a type of preimplantation genetic testing (PGT) where DNA from oocytes (polar bodies) or embryos (cleavage stage or blastocyst) are analysed for human leukocyte antigen typing or for determining genetic abnormalities (Zegers‐Hochschild 2017). With the updated International Glossary on Infertility and Fertility Care, PGD was renamed preimplantation genetic testing (PGT) for monogenic/single gene defects (PGT‐M) (Zegers‐Hochschild 2017). Along with PGT‐M, PGT is also used to test for aneuploidies (PGT‐A) and for chromosomal structural rearrangements (Zegers‐Hochschild 2017). The PGT‐M and PGT‐A are used for different purposes; PGT‐M is used for patients with genetic disease or a disease‐carrying gene, and PGT‐A is used for patients with repeated implantation failure, recurrent miscarriage, or advanced maternal age (Jing 2016). The review is related to PGT‐M only.

Description of the condition

In 1990, Handyside and colleagues reported the first pregnancies using PGT‐M in two couples known to be at risk of transmitting adrenoleukodystrophy and X‐linked intellectual disability (Handyside 1990). In 1992, after PGT‐M testing for cystic fibrosis, the first birth following PGT‐M was reported (Handyside 1992). Since then, PGT‐M has been used for a range of single gene disorders including cystic fibrosis, Tay‐Sachs disease, haemophilia A, sickle cell disease, spinal muscular atrophy, Duchenne muscular dystrophy, thalassaemia, reciprocal or Robertsonian translocations, Down syndrome (trisomy 21) and Edwards syndrome (trisomy 13) (Demko 2010; De Rycke 2017; Lee 2017), and more recently inherited eye disease and ocular cancer (Yahalom 2018). The Human Fertilisation and Embryology Authority (HFEA) publishes a list of conditions for which PGT‐M is currently approved or awaiting consideration (HFEA 2018).

Description of the intervention

Embryo biopsy is a key procedure in PGT‐M. In a biopsy procedure, one or more embryo cells are removed and analysed for genetic or chromosomal anomalies before transferring the embryos to the endometrial cavity. Biopsy for PGT‐M is usually performed at day 3 of cleavage‐stage embryo development, when the embryo is at the six‐ to eight‐cell stage (Harper 2010). The zona pellucida is opened with a near infra‐red laser, or by mechanical or chemical means, and either one or two blastomeres are removed for analysis (Braude 2002). From 1996 onwards, with transition to blastocyst culture occurring within ART, embryo biopsy at day 5 (the blastocyst stage) was introduced. In day 5 biopsy, generally five to six trophectoderm cells are removed from a typically 80‐ to 100‐cell blastocyst through micromanipulation (Henman 2005; McArthur 2005). In this systematic review, we plan to compare day 3 biopsy (cleavage‐stage biopsy) and day 5 biopsy (blastocyst‐stage biopsy).

Following day 5 or day 3 biopsy, the removed blastomere or trophectoderm cells are analysed using several different genetic tests. Two common PGT‐M tests are polymerase chain reaction and fluorescent in situ hybridisation (Demko 2010; De Rycke 2017), which represented 51.5% and 46.4% of PGT‐M tests in Europe in 2011 and 2012 (De Rycke 2017). Single nucleotide polymorphism microarrays and whole genome amplification are used in small percentage of PGT‐M tests (De Rycke 2017).

According to the test results, the unaffected embryos are then selected for transfers. In 2011 and 2012, the European Society of Human Reproduction and Embryology (ESHRE) reported that day 3 biopsy accounted for 90% of all embryo biopsy (De Rycke 2017). The ESHRE PGT‐M Consortium reported overall clinical pregnancy rates of 23% per oocyte retrieval, and an implantation rate of 22% per embryo transferred, following day 3 biopsy (Harper 2010).

How the intervention might work

It has been suggested that the removal of multiple cells on day 5 of embryo development, rather than a single cell on day 3, could potentially lead to improved sensitivity of genetic diagnosis, less biomass depletion of embryos, and better outcomes (de Boer 2004; Kokkali 2007). The removal of one to two blastomeres for testing on day 3 decreases the mass of a human embryo by 12.5% to 25% (Cohen 2007). Whilst there is evidence of a capacity within a human embryo to both tolerate and overcome the possible resultant damage, it is likely that embryos that would otherwise progress to implantation (and result in the birth of a live, healthy infant) will be lost as a consequence of the impact of biopsy conducted at this stage of embryo development (Scott 2013). Artley and colleagues reported a high rate of spontaneous cleavage arrest at the four‐ to eight‐cell stage of human embryo development, and noted that the timing was attuned to the activation of the embryonic genome (Artley 1992). It may therefore be suggested that biopsy of human embryos via removal of blastomeres on day 3 of development refocuses resources that would otherwise be used by an embryo, in suitable in vivo or in vitro environments, for progress to the blastocyst stage and beyond.

In contrast, because day 5 biopsy generally involves the removal of five to six trophectoderm cells from an embryo that has typically reached cell numbers of 80 to 100 (McArthur 2005), a smaller proportion of embryo cell mass is removed and it yields a sample of cells that does not comprise the inner cell mass. Since the embryo had already reached the blastocyst stage for possible implantation, it needs only to recover to the point of hatching or, if compromised, the regaining of implantation potential (McArthur 2005).

Along with embryo biopsy, other procedures in ART — such as in‐vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), and transfer of fresh or frozen embryos — are also associated with implantation, pregnancy and live births (Wang 2010; Glujovsky 2016). ICSI is the method most often used for fertilisation; it accounted for 88% of PGT‐M fertilisations in Europe in 2011 and 2012 (De Rycke 2017). In general, fresh embryos are transferred in day 3 biopsy, and frozen embryos are transferred in day 5 biopsy (Jing 2016).

Why it is important to do this review

Having a baby with a serious genetic disease can be a great source of distress for many families. Through PGT‐M, couples are empowered to select embryos with a high likelihood of developing into a healthy baby, by deselecting embryos afflicted with genetic disease variants (Demko 2010; Haude 2017). PGT‐M can help couples avoid later difficult decisions, including whether to terminate or continue with an affected pregnancy (Haude 2017; Klitzman 2018). However, regarding the biopsy procedure itself, concerns have been raised that the removal of cells in both day 3 and day 5 biopsy may result in a detrimental effect on the embryo by arresting its development. Firstly, there is the possibility that biopsy may negatively impact on pregnancy rates and perinatal outcomes. Secondly, the diagnostic error rates are high following day 3 biopsy since a single cell with amplified DNA is examined (Wells 2000; Cimadomo 2016). As a result, sometimes euploid or non‐affected embryos are not transferred.

Not every embryo would reach the blastocyst stage of development; waiting for day 5 biopsy may result in no PGT‐M test or no transfer (Papanikolaou 2008; Dahdouh 2015). Following day 5 biopsy, embryos typically need to be cryopreserved and then thawed (Demko 2010), which precludes the transfer of a fresh embryo (De Rycke 2017). Furthermore, not all embryos can survive the freezing and thawing process (Taylor 2014). The two different biopsies of PGT‐M (day 3 biopsy versus day 5 biopsy) might have quite different likelihood of a successful outcome. The removal of multiple cells by day 5 biopsy, rather than a single cell by day 3 biopsy, could potentially lead to improved sensitivity of genetic diagnosis and less biomass depletion of embryos, and therefore better treatment outcomes (de Boer 2004; Kokkali 2007).

Biopsy is an invasive process, and whether it is carried out at day 3 or day 5 of embryo development may have different impact on further development, implantation, pregnancy, live birth and perinatal outcomes. Cohen and colleagues suggested the removal of blastomeres at day 3 biopsy results in loss of cells during an embryo thawing process, and likely reduces the potential of the embryo development (Cohen 2007). In contrast, Magli and colleagues reported that for the purpose of PGT‐M, removing blastomeres on day 3 of embryo development does not affect the ongoing viability of an embryo (Magli 2004). Less than 30% of tested embryos that are likely to be euploid or unaffected from genetic disease will proceed to embryo transfer (De Rycke 2017); this results in only a small proportion of embryos being cryopreserved for future use. It is important to eliminate the possibility of affecting the outcome through the biopsy stage (Wells 2000; Demko 2010; Munne 2017). However, there is a lack of summarised evidence from randomised controlled trials that evaluates the difference in treatment outcomes between day 3 and day 5 biopsy. This review will compare the rates of embryo transfer, pregnancy and live birth between day 3 and day 5 biopsy.

Objectives

To assess the benefits and harms of day 5 embryo biopsy, in comparison to day 3 biopsy, in preimplantation genetic testing for monogenic/single gene defects (PGT‐M).

Methods

Criteria for considering studies for this review

Types of studies

Published and unpublished randomised controlled trials (RCTs) will be eligible for inclusion, irrespective of publication status, language or location. We will fully describe the methods used to translate any non‐English studies.

Types of participants

We will include women/couples undergoing embryo biopsy following assisted reproductive technology (ART).

We will exclude women/couples undergoing oocytes or zygotes biopsy (or both), mixed polar body and embryo biopsy, and embryo biopsy for PGT‐A and preimplantation genetic testing for structural rearrangements.

Types of interventions

Day 5 embryo biopsy versus day 3 embryo biopsy in preimplantation genetic testing for monogenic/single gene defects (PGT‐M).

Types of outcome measures

The primary and secondary outcomes will be calculated per woman randomised.

Primary outcomes

Live birth, defined as delivery of a live fetus.

Miscarriage, defined as the spontaneous loss of a clinical intra‐uterine pregnancy prior to 22 completed weeks of gestational age.

Secondary outcomes

Ongoing pregnancy, defined as evidence of a gestational sac with fetal heart motion at 12 weeks, confirmed with ultrasound.

Clinical pregnancy, defined as evidence of a gestational sac with or without fetal heart motion, confirmed by ultrasound, at six to eight weeks of gestation.

Multiple births: the complete expulsion or extraction of two or more fetuses from their mother, after 22 completed weeks of gestational age, irrespective of whether they are live births or stillbirths.

Number of transferable embryos: embryos transferred or frozen for future transfer.

Stillbirth: these events will be subgrouped according to the type of adverse event reported. Stillbirth is defined as the death of a fetus prior to the complete expulsion or extraction from its mother after 22 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. It includes deaths occurring during labour.

Congenital anomalies: structural or functional disorders that occur during intra‐uterine life and can be identified prenatally, at birth or later in life.

Search methods for identification of studies

We will search for all published and unpublished RCTs of embryo biopsy for PGT‐M, without language restrictions and in consultation with the Cochrane Gynaecology and Fertility Group (CGFG) Information Specialist.

Electronic searches

We will search the following electronic databases, trial registers and websites from their inception to present.

  1. The GGFC Specialised Register of Controlled Trials, PROCITE platform (Appendix 1)

  2. CENTRAL via The Cochrane Central Register of Studies Online (CRSO), web platform (Appendix 2)

  3. MEDLINE, OVID platform (Appendix 3)

  4. Embase, OVID platform (Appendix 4)

  5. PsycINFO, OVID platform (Appendix 5)

  6. CINAHL, EBSCO platform (Appendix 6)

The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in Chapter 6 of the Cochrane Handbook of Systematic Reviews of Interventions (Lefebvre 2011). The Embase, PsycINFO and CINAHL searches will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (Scottish Intercollegiate Network).

Other electronic sources of trials will include the following.

  1. Trial registers (for ongoing and registered trials)

    1. ClinicalTrials.gov (www.clinicaltrials.gov) (a service of the US National Institutes of Health)

    2. the World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.aspx)

  2. LILACS and other Spanish/Portuguese databases, via the Virtual Health Library Regional Portal (VHL) (http://bvsalud.org/en/)

  3. PubMed and Google Scholar (for recent trials not yet indexed in the major databases)

  4. OpenGrey (www.opengrey.eu) (for unpublished literature)

  5. The Web of Science (www.wokinfo.com) (another source of trials and conference abstracts)

Searching other resources

We will handsearch reference lists of articles retrieved by the search, and will contact experts in the field to obtain additional studies. We will use EndNote bibliographic management software to manage the search output.

Data collection and analysis

Selection of studies

We will use Covidence software for selection of studies, data extraction and assessment of risk of bias of included studies (Covidence). Two review authors (AYW and ZL) will conduct an initial screen of titles and abstracts retrieved by the search, then we will retrieve the full texts of all potentially eligible studies. Independently, two review authors (AYW and ZL) will examine these full‐text articles for compliance with the inclusion criteria, and will select studies eligible for inclusion in the review. We will record the reason(s) for excluding any study following a review of the full text. We will correspond with study investigators as required, to clarify study eligibility. Disagreements regarding study eligibility will be resolved by discussion or by a third review author (CF). We will document the selection process in a PRISMA flow chart.

Data extraction and management

Independently, two review authors (AYW and ZL) will extract data from eligible studies using a data extraction form in Covidence (Covidence). Any disagreements will be resolved by discussion or by a third review author (EAS). Data extracted will include study characteristics and outcome data. We will collate multiple reports of the same study, so that each study — rather than each report — is the unit of interest in the review, and these studies will have a single 'study ID' with multiple references. We will correspond with study investigators for further information about methods and results, as required.

Assessment of risk of bias in included studies

Independently, two review authors (AYW and ZL) will use the Cochrane tool to assess the risk of bias in each study, for the following domains (Higgins 2011): selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other bias. We will resolve disagreements by discussion or by involving a third review author (CF). We will describe all judgements fully and present the conclusions in the 'Risk of bias' table. We will incorporate our 'Risk of bias' assessments into the interpretation of review findings by means of sensitivity analyses (see Sensitivity analysis). We will take care to search for evidence of within‐trial selective reporting, such as trials failing to report obvious outcomes, or reporting them in insufficient detail. We will seek published protocols and compare the outcomes specified in the protocol and reported in the final published study.

Measures of treatment effect

We expect all outcomes to be dichotomous. We will calculate Mantel‐Haenszel odds ratio (OR) with 95% confidence intervals (CIs), using the numbers of events in the day 5 biopsy and day 3 biopsy groups of each study. Where data to calculate ORs are not available, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (for example, test statistics, P values). For outcomes with event rates below 1% we will use the Peto one‐step OR method to calculate the combined outcome with a 95% CI.

Unit of analysis issues

The primary analysis will be by woman/couple randomised. For miscarriage data, we will perform an additional secondary analysis by clinical pregnancy in order to give the full picture of effects. If outcomes are reported in post‐randomisation subgroups, such as per transfer cycles and per live births, they will be briefly summarised in an additional table and will not be meta‐analysed. However 'per initiated cycle’ data will be analysed, when the trial provides data for only one cycle per woman. We will count multiple live births (twins or triplets) as one live‐birth event. We will include only first‐phase data from cross‐over trials.

Dealing with missing data

We will contact study authors to obtain missing data in order to perform analyses on an intention‐to‐treat basis. In the case of unobtainable data on live birth, we will conduct imputation using ongoing pregnancy data, if available. We will assume that live births have not occurred in women without a reported live birth or ongoing pregnancy outcome. We will assume no miscarriage occurred in women lost to follow‐up. For secondary outcomes, we will analyse only the available data.

We will conduct sensitivity analyses for primary outcome, with and without imputation.

Assessment of heterogeneity

We will consider whether the clinical and methodological characteristics of the included studies are sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We will assess statistical heterogeneity using the I2 statistic, and will interpret a value greater than 50% as indicative of substantial heterogeneity (Higgins 2011).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we will aim to minimise their potential impact by ensuring we perform a comprehensive search for eligible studies, and by being alert for duplication of data. If there are ten or more studies in an analysis, we will use a funnel plot to explore the possibility of small‐study effects (the tendency for estimates of the intervention effect to be more beneficial in smaller studies) (Higgins 2011).

Data synthesis

We will combine the data from similar RCTs using a random‐effects model, which considers that the different studies are estimating different intervention effects (Higgins 2011). We will display an increase in the odds of an outcome to the right of the centre axis, and a decrease in the odds of an outcome to the left of the centre axis. In the event of problematic clinical, methodological or statistical heterogeneity (I2 value greater than 75%), we will not combine data in a meta‐analysis. Where data are incomplete and cannot be presented in the analyses, we will report available data in narrative form. We will organise the data on the basis of the main comparison (day 5 versus day 3 biopsy).

Subgroup analysis and investigation of heterogeneity

Where data are available, we will conduct subgroup analyses for primary and secondary outcomes to investigate the efficacy of day 5 biopsy, depending on the following factors.

  1. Transfer of fresh versus transfer of frozen‐thawed embryo

  2. Fertilisation procedure (in‐vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI))

  3. Time at randomisation (before oocyte pick‐up (OPU) versus after OPU and before biopsy)

  4. Ovarian stimulation protocol (agonist or antagonist)

In addition to visual inspection of the subgroup differences, we will use a significance test to determine the differences in effect estimates between two or more subgroups when the subgroups are independent (Higgins 2003; Higgins 2011). We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.

Sensitivity analysis

We will perform sensitivity analyses to examine the stability and robustness of the results for the primary outcomes (live birth and miscarriage) regarding the eligibility and analysis. These analyses will include consideration of whether the review conclusions would have differed when accounting for the following factors.

  1. Risk of bias (we will repeat the analysis, restricting it to RCTs without high risk of bias)

  2. Publication type (we will repeat the analysis, restricting it to full‐text RCTs)

  3. Imputation of outcomes (we will repeat the analysis, restricting it to RCTs where imputation strategies had been implemented)

Overall quality of the body of evidence: 'Summary of findings' table

We will prepare a 'Summary of findings' table according to Cochrane methods, using GRADEpro GDT (GRADEpro GDT). This table will evaluate the overall quality of the body of evidence for the main review outcomes (live birth, miscarriage, ongoing pregnancy, clinical pregnancy, multiple births, number of transferable embryos and adverse events), using GRADE criteria. Two independent review authors will be involved in the GRADE assessment, which is based on: study limitations (risk of bias), consistency of effect, imprecision, indirectness, and publication bias (Schünemann 2011). We will justify, document, and incorporate into the reporting of results our judgements about evidence quality (high, moderate, low or very low) for each outcome. The main comparison in the main 'Summary of findings' table will compare the use of the day 5 biopsy versus day 3 biopsy.

Acknowledgements

We thank the Cochrane Gynaecology and Fertility Group. We also thank the following peer reviewers for their time and comments: Demián Glujovsky, Karen Ma, Andy Vail, Jack Wilkinson, and Evi Vogiatzi.

Appendices

Appendix 1. Cochrane Gynaecology and Fertility specialised register search strategy

Searched from inception to present

PROCITE platform

Keywords CONTAINS "PGD" or "PGS" 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 techniques" or "chromosomal abnormalities" or "chromosomes" or "aneuploidy" or "aneuploidy screening" or "comparative genomic hybridization" or "CGH" or "aCGH" or "array comparative genomic hybridization" or "genotyping" or "embryo aneuploidy" or "blastocyst biopsy" or "FISH" or Title CONTAINS "PGD" or "PGS" 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 "chromosomes" or "aneuploidy" or "aneuploidy screening" or "comparative genomic hybridization" or "CGH" or "aCGH" or "array comparative genomic hybridization" or "genotyping" or "embryo aneuploidy" or "blastocyst biopsy" or "FISH"

Appendix 2. Cochrane CENTRAL Register of Studies Online (CRSO) search strategy

Searched from inception to present

Web platform

#1 MESH DESCRIPTOR Chromosome Aberrations EXPLODE ALL TREES

#2 MESH DESCRIPTOR Aneuploidy EXPLODE ALL TREES

#3 MESH DESCRIPTOR Preimplantation Diagnosis EXPLODE ALL TREES

#4 (Preimplant* adj3 gene*):TI,AB,KY

#5 Preimplant* adj2 Diagnos*:TI,AB,KY

#6 aneuploid*:TI,AB,KY

#7 (PGS or PGD or PGT):TI,AB,KY

#8 (NGS or CGH* or aCGH):TI,AB,KY

#9 ((embryo* or blasto* or Trophectoderm or cleavage) adj3 biops*):TI,AB,KY

#10 chromosome*:TI,AB,KY

#11 "generation sequenc*":TI,AB,KY

#12 MESH DESCRIPTOR In Situ Hybridization EXPLODE ALL TREES

#13 (In Situ Hybridization):TI,AB,KY

#14 (In Situ Hybridisation):TI,AB,KY

#15 (Preimplant* adj2 screen*):TI,AB,KY

#16 (gene* adj2 screen*):TI,AB,KY

#17 MESH DESCRIPTOR Comparative Genomic Hybridization EXPLODE ALL TREES

#18 (genom* adj2 hybridi?ation):TI,AB,KY

#19 (Preimplant* adj2 Diagnos*):TI,AB,KY

#20 #1 OR #2 OR #3 OR #4 OR #6 OR #7 OR #10 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

#21 MESH DESCRIPTOR Blastocyst EXPLODE ALL TREES

#22 Blastocyst*:TI,AB,KY

#23 (day 5 or day 6):TI,AB,KY

#24 (day5 or day6):TI,AB,KY

#25 (day five or day six):TI,AB,KY

#26 #21 OR #22 OR #23 OR #24 OR #25

#27 #20 AND #26

Appendix 3. MEDLINE search strategy

Searched from 1946 to present

OVID platform

1 exp chromosome aberrations/ or exp aneuploidy/ 2 exp Preimplantation Diagnosis/ 3 (Preimplant$ adj3 gene$).tw. 4 aneuploid$.tw. 5 ((embryo$ or blasto$ or Trophectoderm or cleavage) adj3 biops$).tw. 6 (PGS or PGD or PGT).tw. 7 chromosome$.tw. 8 exp in situ hybridization/ or exp in situ hybridization, fluorescence/ 9 In Situ Hybridi?ation.tw. 10 FISH.tw. 11 (Preimplant$ adj2 Diagnos$).tw. 12 (Preimplant$ adj2 screen$).tw. 13 (gene$ adj2 screen$).tw. 14 exp Comparative Genomic Hybridization/ 15 (genom$ adj2 hybridi?ation).tw. 16 NGS.tw. 17 next generation sequenc*.tw. 18 CGH.tw. 19 aCGH.tw. 20 or/1‐19 21 exp Blastocyst/ 22 (Blastocyst$ or blastomere$).tw. 23 (day 5 or day 6).tw. 24 (day5 or day6).tw. 25 (day five or day six).tw. 26 or/21‐25 27 randomized controlled trial.pt. 28 controlled clinical trial.pt. 29 randomized.ab. 30 randomised.ab. 31 placebo.tw. 32 clinical trials as topic.sh. 33 randomly.ab. 34 trial.ti. 35 (crossover or cross‐over or cross over).tw. 36 or/27‐35 37 exp animals/ not humans.sh. 38 36 not 37 39 20 and 26 and 38

Appendix 4. Embase search strategy

Searched from 1980 to present

OVID platform

1 exp prenatal diagnosis/ 2 (prenatal adj3 diagnos$).tw. 3 exp chromosome aberration/ 4 (Preimplant$ adj3 gene$).tw. 5 ((embryo$ or blasto$ or Trophectoderm or cleavage) adj3 biops$).tw. 6 aneuploid$.tw. 7 (PGS or PGD or PGT).tw. 8 chromosome$.tw. 9 exp in situ hybridization/ or exp hybridization/ 10 In Situ Hybridi?ation.tw. 11 (Preimplant$ adj2 Diagnos$).tw. 12 (Preimplant$ adj2 screen$).tw. 13 (gene$ adj2 screen$).tw. 14 exp comparative genomic hybridization/ 15 next generation sequenc$*.tw. 16 (genom$ adj2 hybridi?ation).tw. 17 (CGH$ or NGS).tw. 18 aCGH.tw. 19 or/1‐18 20 exp BLASTOCYST/ 21 (Blastocyst$ or blastomere$).tw. 22 (day 5 or day 6).tw. 23 (day5 or day6).tw. 24 (day five or day six).tw. 25 or/20‐24 26 19 and 25 27 Clinical Trial/ 28 Randomized Controlled Trial/ 29 exp randomization/ 30 Single Blind Procedure/ 31 Double Blind Procedure/ 32 Crossover Procedure/ 33 Placebo/ 34 Randomi?ed controlled trial$.tw. 35 Rct.tw. 36 random allocation.tw. 37 randomly.tw. 38 randomly allocated.tw. 39 allocated randomly.tw. 40 (allocated adj2 random).tw. 41 Single blind$.tw. 42 Double blind$.tw. 43 ((treble or triple) adj blind$).tw. 44 placebo$.tw. 45 prospective study/ 46 or/27‐45 47 case study/ 48 case report.tw. 49 abstract report/ or letter/ 50 or/47‐49 51 46 not 50 52 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 53 51 not 52 54 26 and 53

Appendix 5. PsycINFO search strategy

Searched from 1806 to present

OVID platform

1 exp Prenatal Diagnosis/ 2 (Preimplant$ adj3 gene$).tw. 3 exp Chromosome Disorders/ 4 aneuploid$.tw. 5 (PGS or PGD or PGT).tw. 6 chromosome$.tw. 7 Preimplant$ Diagnos$.tw. 8 (genom$ adj2 hybridi?ation).tw. 9 (Preimplant$ adj2 screen$).tw. 10 next generation sequenc*.tw. 11 NGS.tw. 12 In Situ Hybridi?ation.tw. 13 (CGH or aCGH).tw. 14 ((embryo$ or blasto$ or Trophectoderm or cleavage) adj3 biops$).tw. 15 (gene$ adj2 screen$).tw. 16 or/1‐15 17 exp Embryo/ 18 exp Infertility/ or exp Reproductive Technology/ 19 Blastocyst*.tw. 20 (day 5 or day 6).tw. 21 (day5 or day6).tw. 22 (day five or day six).tw. 23 or/17‐22 24 16 and 23 25 random.tw. 26 control.tw. 27 double‐blind.tw. 28 clinical trials/ 29 placebo/ 30 exp Treatment/ 31 or/25‐30 32 24 and 31

Appendix 6. CINAHL search strategy

Searched from 1961 to present

EBSCO platform

# Query
S39 S26 AND S38
S38 S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37
S37 TX allocat* random*
S36 (MH "Quantitative Studies")
S35 (MH "Placebos")
S34 TX placebo*
S33 TX random* allocat*
S32 (MH "Random Assignment")
S31 TX randomi* control* trial*
S30 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )
S29 TX clinic* n1 trial*
S28 PT Clinical trial
S27 (MH "Clinical Trials+")
S26 S14 AND S25
S25 S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24
S24 TX(day five or day six)
S23 TX day5 or TX day6
S22 TX day 5 or TX day 6
S21 (MM "Blastocyst")
S20 TX blastocyst*
S19 TX embryo*
S18 TX IVF or TX ICSI
S17 (MM "Fertilization in Vitro")
S16 TX vitro fertilization
S15 TX vitro fertilisation
S14 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13
S13 TX aCGH
S12 TX (CGH or NGS)
S11 TX (genom* N2 hybridi?ation)
S10 (MM "Nucleic Acid Hybridization")
S9 TX (gene* N2 screen*)
S8 TX (Preimplant* N2 screen*)
S7 TX Preimplant* Diagnos*
S6 (MM "In Situ Hybridization+") OR (MM "In Situ Hybridization, Fluorescence+")
S5 TX (PGS or PGD or PGT)
S4 TX aneuploid*
S3 TX (Preimplant* N3 gene*)
S2 (MM "Aneuploidy")
S1 (MM "Preimplantation Diagnosis")
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Contributions of authors

AYW drafted the protocol.

EAS commented on the protocol.

ZL revised the protocol.

CF gave clinical advice commented on the protocol.

Sources of support

Internal sources

  • The Cochrane Gynaecology and Fertlity editorial team, Other.

External sources

  • No sources of support supplied

Declarations of interest

AYW has no conflicts of interest to declare.

EAS has no conflicts of interest to declare.

ZL has no conflicts of interest to declare.

CF has no conflicts of interest to declare.

New

References

Additional references

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