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... The first report of blastocyst rebiopsy was published in 2017 [21], and to date, most small-sample observational studies on the association between blastocyst rebiopsy and pregnancy outcomes have reported an increased risk compared to single biopsy [6,12,17,19]. In a study designed to isolate the effect of repeated TE biopsies, by controlling embryo exposure to double vitrification-warming, Sekhon and colleagues observed a 15% decrease in implantation rate in the double TE biopsy group [22]. Similarly, Zhuo and colleagues found that rebiopsied euploid embryos exhibit significantly lower odds of implantation and pregnancy compared to single-biopsied euploid embryos [16]. ...
... Since trophectoderm subsequently forms the placenta, it is proposed that multicellular TE biopsy is associated with adverse obstetrical or neonatal outcomes after a single frozen-warmed blastocyst transfer [1,[23][24][25][26][27][28]. Regarding repeated biopsies, obstetrical and neonatal outcomes have been underreported to date and vary between studies [12,19,20,22,29,30]. This lack of evidence creates uncertainty and limits the guidance clinicians can provide to patients considering PGT testing for their previously biopsied embryos [17]. ...
Background
The number of re-biopsied blastocysts is widely increasing in IVF cycles and concerns regarding retesting, which involves double biopsy and vitrification-warming, have been raised. The re-biopsy intervention seems to significantly reduce the pregnancy potential of a blastocyst but the evidence is still restricted to retrospective observational studies reporting a low number of cycles with re-biopsied embryos. Additionally, the neonatal outcomes after the transfer of re-biopsied and re-vitrified embryos are poorly documented to date.
Methods
A systematic review will be conducted, using PubMed/Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and Google Scholar to identify all relevant randomized control trials (RCTs), cohort and case–control studies published until December 2024. The participants will include women undergoing preimplantation genetic testing and single euploid frozen embryo transfer (FET) cycles. The primary outcomes are live birth rate (LBR) and singleton birthweight, whereas secondary outcomes are post-warming embryo survival rate, clinical pregnancy (fetal heart pregnancies at 4.5 weeks), miscarriage rate (loss of pregnancy before the 20th week, and stillbirth), preterm birth (PB) rate, small-for-gestational age (SGA, < − 1.28 SDS (standard deviation score)), large-for-gestational age (LGA, > + 1.28 SDS), low birthweight (LBW; birthweight < 2500 g), preterm birth (gestation < 37 weeks), macrosomia (birthweight > 4000 g), pre-eclampsia, eclampsia, perinatal death, and major congenital malformations. Eligible studies will be selected according to pre-specified inclusion and exclusion criteria. Additionally, manual search will target other unpublished reports and supplementary data. At least two independent reviewers will be responsible for article screening, data extraction and bias assessment of eligible studies. A third reviewer will resolve any disagreements. The Newcastle–Ottawa scale (NOS) will be used to assess the quality of the included studies. Studies that receive a score of 7 or higher on the NOS will be considered to have high methodological quality. The extracted data will be pooled and a meta-analysis will be performed. To carry out the data synthesis, a random effects meta-analysis will be conducted using the RevMan software. Heterogeneity will be evaluated by Cochran’s Q test and the I² statistics and the strength of evidence will be rated with reference to GRADE. The review and meta-analysis will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
Discussion
The findings of this systematic review will be important to clinicians, embryologists, patients, and assisted reproductive service providers regarding the decision-making on retesting embryos for PGT in FET cycles.
Systematic review registration
PROSPERO CRD42024498955.
... The number of blastocysts rebiopsied is widely increasing and concerns regarding rebiopsy and retesting (double biopsy and double vitri cation-warming) have been raised [2,4,[15][16][17][18][19]. In a study designed to isolate the effect of repeated TE biopsy, by controlling for embryo exposure to double vitri cation-warming, Sekhon and colleagues observed a 15% decrease in implantation rate in the double TE biopsy group [20]. Similarly, Zhuo and colleagues found that rebiopsied euploid embryos exhibit signi cantly lower odds of implantation and pregnancy compared to single-biopsied euploid embryos [16]. ...
Background The number of re-biopsied blastocysts is widely increasing in PGT cycles and concerns regarding retesting, which involve double biopsy and vitrification-warming, have been raised. The re-biopsy intervention seems to significantly reduce the pregnancy potential of a blastocyst but the evidence is still restricted to retrospective observational studies reporting a low number of cycles with re-biopsied embryos. Additionally, the neonatal outcomes after the transfer of re-biopsied and re-vitrified embryos are poorly documented to date. Methods A systematic review, using PubMed/Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science and Google Scholar to identify all relevant RCTs, cohort and case-control studies published until December 2024. The participants will include women undergoing preimplantation genetic testing and single euploid FET cycles. The primary outcomes are live birth rate (LBR) and singleton birthweight, whereas secondary outcomes are post-warming embryo survival rate, clinical pregnancy (fetal heart pregnancies at 4.5 weeks), miscarriage rate (loss of pregnancy before the 20th week, and stillbirth), preterm birth (PB) rate, small-for-gestational age (SGA, <-1.28 SDS), large-for-gestational age (LGA, >+1.28 SDS), low birthweight (LBW; birthweight < 2500g), preterm birth (gestation < 37 weeks), macrosomia (birthweight > 4000g), pre-eclampsia, eclampsia, perinatal death and major congenital malformations. Eligible studies will be selected according to pre-specified inclusion and exclusion criteria. Additionally, manual search will target other unpublished reports and supplementary data. At least two independent reviewers will be responsible for article screening, data extraction and bias assessment of eligible studies. A third reviewer will resolve any disagreements. The Newcastle-Ottawa scale and will be used to assess the quality of the included studies. Studies that receive a score equal to or greater than 7 on the NOS will be considered high quality. The extracted data will be pooled and a meta-analysis will be performed. To carry out the data synthesis, a random effects meta-analysis will be conducted using the RevMan software. Heterogeneity will be evaluated by Cochran’s Q test and the I 2 statistics and the strength of evidence will be rated with reference to GRADE. The review and meta-analysis will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Discussion The findings of this systematic review will be important to clinicians, embryologists, patients, and assisted reproductive service providers regarding the decision-making on retesting embryos for PGT in FET cycles. Systematic review registration: PROSPERO CRD42024498955
STUDY QUESTION
Compared to the ‘single biopsy + single vitrification’ approach, do ‘double biopsy + double vitrification’ or ‘single biopsy + double vitrification’ arrangements compromise subsequent clinical outcomes following euploidy blastocyst transfer?
SUMMARY ANSWER
Both ‘double biopsy + double vitrification’ and ‘single biopsy + double vitrification’ led to reduced live birth/ongoing pregnancy rates and clinical pregnancy rates.
WHAT IS KNOWN ALREADY?
It is not uncommon to receive inconclusive results following blastocyst biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Often these blastocysts are warmed for re-test after a second biopsy, experiencing ‘double biopsy + double vitrification’. Furthermore, to achieve better workflow, IVF laboratories may choose to routinely vitrify all blastocysts and schedule biopsy at a preferred timing, involving ‘single biopsy + double vitrification’. However, in the current literature, there is a lack of systematic evaluation of both arrangements regarding their potential clinical risks in reference to the most common ‘single biopsy + single vitrification’ approach.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis were performed, with the protocol registered in PROSPERO (CRD42023469143). A search in PUBMED, EMBASE, and the Cochrane Library for relevant studies was carried out on 30 August 2023, using the keywords ‘biopsy’ and ‘vitrification’ and associated variations respectively. Only studies involving frozen transfers of PGT-A tested euploid blastocysts were included, with those involving PGT-M or PGT-SR excluded.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Study groups included blastocysts having undergone ‘double biopsy + double vitrification’ or ‘single biopsy + double vitrification’, with a ‘single biopsy + single vitrification’ group used as control. The primary outcome was clinical pregnancy, while secondary outcomes included live birth/ongoing pregnancy, miscarriage, and post-warming survival rates. Random effects meta-analysis was performed with risk ratios (RR) and 95% CIs were used to present outcome comparisons.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 607 records were identified through the initial search and nine studies (six full articles and three abstracts) were eventually included. Compared to ‘single biopsy + single vitrification’, ‘double biopsy + double vitrification’ was associated with reduced clinical pregnancy rates (six studies, n = 18 754; RR = 0.80, 95% CI = 0.71–0.89; I2 = 0%) and live birth/ongoing pregnancy rates (seven studies, n = 20 964; RR = 0.72, 95% CI = 0.63–0.82; I2 = 0%). However, no significant changes were seen in miscarriage rates (seven studies, n = 22 332; RR = 1.40, 95% CI = 0.92–2.11; I2 = 53%) and post-warming survival rates (three studies, n = 13 562; RR = 1.00, 95% CI = 0.99–1.01; I2 = 0%) following ‘double biopsy + double vitrification’. Furthermore, ‘single biopsy + double vitrification’ was also linked with decreased clinical pregnancy rates (six studies, n = 13 284; RR = 0.84, 95% CI = 0.76–0.92; I2 = 39%) and live birth/ongoing pregnancy rates (seven studies, n = 16 800; RR = 0.79, 95% CI = 0.69–0.91; I2 = 70%), and increased miscarriage rates (five studies, n = 15 781; RR = 1.48, 95% CI = 1.31–1.67; I2 = 0%), but post-warming survival rates were not affected (three studies, n = 12 452; RR = 0.99, 95% CI = 0.97–1.01; I2 = 71%) by ‘single biopsy + double vitrification’.
LIMITATIONS, REASONS FOR CAUTION
All studies included in this meta-analysis were retrospective with varying levels of heterogeneity for different outcomes. Not all studies had accounted for potential confounding factors. Only one study reported neonatal outcomes.
WIDER IMPLICATIONS OF THE FINDINGS
Our data indicated adverse impacts of ‘double biopsy + double vitrification’ and ‘single biopsy + double vitrification’ on clinical outcomes following euploid blastocyst transfers. Patients should be carefully consulted about the risks when offered such approaches. The biopsy process should be carried out as carefully and competently as possible to minimize an inconclusive diagnosis.
STUDY FUNDING/COMPETING INTEREST(S)
R.W. is supported by a National Health and Medical Research Council Emerging Leadership Investigator Grant (2009767). There is no other external funding to report. All authors report no conflict of interest.
REGISTRATION NUMBER
CRD42023469143.
