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Intrauterine fetal growth chart. The black dots represent the estimated fetal birthweight calculations of the fetus in the corresponding week of gestation.
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Mosaic embryos have the potential to implant and develop into healthy babies. The transfer of mosaic embryos is now considered to be a possible option for women undergoing ART with preimplantation genetic testing for aneuploidies and in the absence of euploid embryos, particularly those with diminished ovarian reserve and/or advanced maternal age....
Context in source publication
Context 1
... (IUGR). There were no pathological findings in detailed ultrasonography at Week 20 of pregnancy. There was no sign of limb, genitourinary, craniofacial, cardiac, spinal or renal abnormalities or hydronephrosis. The fetus showed normal growth around the 50th percentile in the ultrasonographic follow-up with no signs of fetal growth retardation (Fig. 4). After early rupture of the membranes, a healthy 2880-g, female baby 48 cm in length and with a 34.5-cm head circumference with no phenotypic abnormalities was born at Week 37 of ...
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Citations
... Embryos with uniform aneuploidies are deselected for transfer since they lead to implantation failure, miscarriage, and congenital anomalies (Capalbo et al., 2022). Conversely, embryos with mosaic aneuploidies rarely result in aneuploid pregnancies (Kahraman et al., 2020;Schlade-Bartusiak et al., 2022;Greco et al., 2023) but are rather associated with normal development and the birth of healthy babies (Abhari and Kawwass, 2021;Capalbo et al., 2021;Mourad et al., 2021;Treff and Marin, 2021;Viotti et al., 2021;Ma et al., 2022;Viotti et al., 2023). However, the reasons for the reproductive potential of mosaic embryos require further investigation. ...
STUDY QUESTION
Are there cell lineage-related differences in the apoptotic rates and differentiation capacity of human blastocysts diagnosed as euploid, mosaic, and aneuploid after preimplantation genetic testing for aneuploidy (PGT-A) based on concurrent copy number and genotyping analysis?
SUMMARY ANSWER
Trophectoderm (TE) cells of mosaic and aneuploid blastocysts exhibit significantly higher levels of apoptosis and significantly reduced differentiation capacity compared to those of euploid blastocysts.
WHAT IS KNOWN ALREADY
Embryos diagnosed as mosaic after PGT-A can develop into healthy infants, yet understanding the reasons behind their reproductive potential requires further research. One hypothesis suggests that mosaicism can be normalized through selective apoptosis and reduced proliferation of aneuploid cells, but direct evidence of these mechanisms in human embryos is lacking. Additionally, data interpretation from studies involving mosaic embryos has been hampered by retrospective analysis methods and the high incidence of false-positive mosaic diagnoses stemming from the use of poorly specific PGT-A platforms.
STUDY DESIGN, SIZE, DURATION
Prospective cohort study performing colocalization of cell-lineage and apoptotic markers by immunofluorescence (IF). We included a total of 64 human blastocysts donated to research on Day 5 or 6 post-fertilization (dpf) by 43 couples who underwent in vitro fertilization treatment with PGT-A at IVI-RMA Valencia between September 2019 and October 2022. A total of 27 mosaic blastocysts were analyzed.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The study consisted of two phases: Phase I (caspase-3, n = 53 blastocysts): n = 13 euploid, n = 22 mosaic, n = 18 aneuploid. Phase II (terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), n = 11 blastocysts): n = 2 euploid, n = 5 mosaic, n = 4 aneuploid. Following donation for research, vitrified blastocysts were warmed, cultured until re-expansion, fixed, processed for IF, and imaged using confocal microscopy. For each blastocyst, the following cell counts were conducted: total cells (DAPI+), TE cells (GATA3+), inner cell mass (ICM) cells (GATA3−/NANOG+), and apoptotic cells (caspase-3+ or TUNEL+). The incidence of apoptosis was calculated for each blastocyst by dividing the number of caspase-3+ cells (Phase I) or TUNEL+ cells (Phase II) by the number of TE or ICM cells. Statistical analysis was performed according to data type and distribution (P < 0.05 was considered statistically significant).
MAIN RESULTS AND THE ROLE OF CHANCE
Phase I: Mosaic blastocysts displayed a similar number of total cells (49.6 ± 15 cells at 5 dpf; 58.8 ± 16.9 cells at 6 dpf), TE cells (38.8 ± 13.7 cells at 5 dpf; 49.2 ± 16.2 cells at 6 dpf), and ICM cells (10.9 ± 4.2 cells at 5 dpf; 9.7 ± 7.1 cells at 6 dpf) compared to euploid and aneuploid blastocysts (P > 0.05). The proportion of TE cells retaining NANOG expression increased gradually from euploid blastocysts (9.7% = 63/651 cells at 5 dpf; 0% = 0/157 cells at 6 dpf) to mosaic blastocysts (13.1% = 104/794 cells at 5 dpf; 3.4% = 12/353 cells at 6 dpf) and aneuploid blastocysts (27.9% = 149/534 cells at 5 dpf; 4.6% = 19/417 cells at 6 dpf) (P < 0.05). At the TE level, caspase-3+ cells were frequently observed (39% = 901/2310 cells). The proportion of caspase-3+ TE cells was significantly higher in mosaic blastocysts (44.1% ± 19.6 at 5 dpf; 43% ± 16.8 at 6 dpf) and aneuploid blastocysts (45.9% ± 16.1 at 5 dpf; 49% ± 15.1 at 6 dpf) compared to euploid blastocysts (26.6% ± 16.6 at 5 dpf; 17.5% ± 14.8 at 6 dpf) (P < 0.05). In contrast, at the ICM level, caspase-3+ cells were rarely observed (1.9% = 11/596 cells), and only detected in mosaic blastocysts (2.6% = 6/232 cells) and aneuploid blastocysts (2.5% = 5/197 cells) (P > 0.05). Phase II: Consistently, TUNEL+ cells were only observed in TE cells (32.4% = 124/383 cells). An increasing trend was identified toward a higher proportion of TUNEL+ cells in the TE of mosaic blastocysts (37.2% ± 21.9) and aneuploid blastocysts (39% ± 41.7), compared to euploid blastocysts (23% ± 32.5), although these differences did not reach statistical significance (P > 0.05).
LIMITATIONS, REASONS FOR CAUTION
The observed effects on apoptosis and differentiation may not be exclusive to aneuploid cells. Additionally, variations in aneuploidies and unexplored factors related to blastocyst development and karyotype concordance may introduce potential biases and uncertainties in the results.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings demonstrate a cell lineage-specific effect of aneuploidy on the apoptotic levels and differentiation capacity of human blastocysts. This contributes to unravelling the biological characteristics of mosaic blastocysts and supports the concept of clonal depletion of aneuploid cells in explaining their reproductive potential.
STUDY FUNDING/COMPETING INTEREST(S)
This work was funded by grants from Centro para el Desarrollo Tecnológico Industrial (CDTI) (20190022) and Generalitat Valenciana (APOTIP/2019/009). None of the authors has any conflict of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.
... In addition, our research supports the notion that mosaic embryos can, especially for patients without any available euploid embryos, be considered for transfer, albeit with caution regarding potential risks and undesired negative effects. Similar to previous reports, the results indicate that types of embryonic mosaicism may affect clinical outcomes in mosaic ET cycles [22], but most LB babies are healthy and have a low risk of abnormal ploidy [21,[27][28][29]. Moreover, advanced embryo analysis software accompanied by TL annotations can be used to effectively rank euploid blastocysts by their implantation potential [20,30]. ...
... The dataset also exhibited a skewed distribution of embryo data, with a concentration of AI scores ≥ 8.0 (75.3%, 363/482), which may have led to an underestimation of the predictive ability of iDAScore. Although this study, along with our previous study [21], confirmed that healthy live births could be delivered from mosaic embryo transfers, these results should be interpreted with caution because several studies have revealed that embryonic mosaicism can persist during pregnancy, leading to the development of mosaic fetuses [29] and even babies with mosaicism [28]. Therefore, patients should receive adequate and comprehensive genetic counseling before ET on the possible outcomes of transferring mosaic embryos. ...
Background
Several studies have demonstrated that iDAScore is more accurate in predicting pregnancy outcomes in cycles without preimplantation genetic testing for aneuploidy (PGT-A) compared to KIDScore and the Gardner criteria. However, the effectiveness of iDAScore in cycles with PGT-A has not been thoroughly investigated. Therefore, this study aims to assess the association between artificial intelligence (AI)-based iDAScore (version 1.0) and pregnancy outcomes in single-embryo transfer (SET) cycles with PGT-A.
Methods
This retrospective study was approved by the Institutional Review Board of Chung Sun Medical University, Taichung, Taiwan. Patients undergoing SET cycles (n = 482) following PGT-A at a single reproductive center between January 2017 and June 2021. The blastocyst morphology and morphokinetics of all embryos were evaluated using a time-lapse system. The blastocysts were ranked based on the scores generated by iDAScore, which were defined as AI scores, or by KIDScore D5 (version 3.2) following the manufacturer’s protocols. A single blastocyst without aneuploidy was transferred after examining the embryonic ploidy status using a next-generation sequencing-based PGT-A platform. Logistic regression analysis with generalized estimating equations was conducted to assess whether AI scores are associated with the probability of live birth (LB) while considering confounding factors.
Results
Logistic regression analysis revealed that AI score was significantly associated with LB probability (adjusted odds ratio [OR] = 2.037, 95% confidence interval [CI]: 1.632–2.542) when pulsatility index (PI) level and types of chromosomal abnormalities were controlled. Blastocysts were divided into quartiles in accordance with their AI score (group 1: 3.0–7.8; group 2: 7.9–8.6; group 3: 8.7–8.9; and group 4: 9.0–9.5). Group 1 had a lower LB rate (34.6% vs. 59.8–72.3%) and a higher rate of pregnancy loss (26% vs. 4.7–8.9%) compared with the other groups (p < 0.05). The receiver operating characteristic curve analysis verified that the iDAScore had a significant but limited ability to predict LB (area under the curve [AUC] = 0.64); this ability was significantly weaker than that of the combination of iDAScore, type of chromosomal abnormalities, and PI level (AUC = 0.67). In the comparison of the LB groups with the non-LB groups, the AI scores were significantly lower in the non-LB groups, both for euploid (median: 8.6 vs. 8.8) and mosaic (median: 8.0 vs. 8.6) SETs.
Conclusions
Although its predictive ability can be further enhanced, the AI score was significantly associated with LB probability in SET cycles. Euploid or mosaic blastocysts with low AI scores (≤ 7.8) were associated with a lower LB rate, indicating the potential of this annotation-free AI system as a decision-support tool for deselecting embryos with poor pregnancy outcomes following PGT-A.
... The best-characterised types of mitotic errors resulting in mosaicism are sister chromatid malsegregations: anaphase lagging, mainly resulting in one normal and one monosomic daughter cell, and non-disjunction, leading to reciprocal trisomic and monosomic daughter cells [10]. The observation that monosomies are commonly found without reciprocal trisomies in mosaic embryos indicates that anaphase lagging might be more frequent than non-disjunction during mitotic errors [11,12,13]. The specific method by which mosaicism arises can result in distinctly different outcomes because the impact on fetal development depends on the percentage of mosaicism, specific chromosomes involved, monosomy versus trisomy and inclusion of complete or segmental chromosome mosaicism [11,12,13]. ...
... The observation that monosomies are commonly found without reciprocal trisomies in mosaic embryos indicates that anaphase lagging might be more frequent than non-disjunction during mitotic errors [11,12,13]. The specific method by which mosaicism arises can result in distinctly different outcomes because the impact on fetal development depends on the percentage of mosaicism, specific chromosomes involved, monosomy versus trisomy and inclusion of complete or segmental chromosome mosaicism [11,12,13]. ...
Introduction. Mosaic monosomy 20 is a rare chromosomal aberration, without characteristic clinical features. We present a case of a fetus with monosomy 20 mosaicism revealed after prenatal ultrasound detection of anhydramnios and multiple anomalies. Case outline. The second pregnancy of a 33 years old woman, was terminated at 23rd gestational week, because of the multiple fetal anomalies and anhydramnios, detected by ultrasound. The autopsy of a female fetus revealed multiple congenital anomalies: ventriculomegaly, bilateral choroid plexus cysts, perivascular gliosis in periventricular region of cerebri, hydropericardium, severe cardiomegaly, severe myocardial hypertrophy, hydrothorax, glandular/canalicular stage of fetal lung development, bilateral renal and ureter agenesis (Potter syndrome), bladder aplasia, agenesis of the uterus, fallopian tubes and proximal vagina and valgus deformity of left foot (pes valgus). Fetal growth was adequate for gestational age with no craniofacial dysmorphy or radiographically visible anomalies of the skeleton, without signs of infection. The umbilical cord was too much length for gestational age-48cm. Analysis of fetal karyotype from fetal blood sampling revealed monosomy of chromosome 20 in 10% of analyzed cells in metaphase. Conclusion. Revealing the genetic basis of fetal anomalies is at outmost importance not only for further evaluation of pregnancy, but also for proper genetic informing of patients.
... Only rarely, a fetal aneuploidy originating from a mosaic embryo (for the same chromosome) has been confirmed with advanced prenatal or postnatal stages. One case resulted in a non-syndromic, phenotypically healthy baby with 2% mosaicism in one tissue after the transfer of a "low level" (35%) mosaicism embryo [25]. The other has recently been reported as a liveborn with partial trisomy 15 and maternal uniparental disomy (UPD) 15 in a likely non-mosaic form as a result of a double embryo transfer involving a "highlevel" mosaic embryo for trisomy 15 and a deletion in the long arm of chromosome 20 [26]. ...
The implementation of next generation sequencing (NGS) in preimplantation genetic testing for aneuploidy (PGT-A) has led to a higher prevalence of mosaic diagnosis within the trophectoderm (TE) sample. Regardless, mosaicism could potentially increase the rate of live-born children with chromosomic syndromes, though available data from the transfer of embryos with putative PGT-A mosaicism are scarce but reassuring. Even with lower implantation and higher miscarriage rates, mosaic embryos can develop into healthy live births. Therefore, this urges an explanation for the disappearance of aneuploid cells throughout development, to provide guidance in the management of mosaicism in clinical practice. Technical overestimation of mosaicism, together with some sort of “self-correction” mechanisms during the early post-implantation stages, emerged as potential explanations. Unlike the animal model, in which the elimination of genetically abnormal cells from the future fetal lineage has been demonstrated, in human embryos this capability remains unverified even though the germ layer displays an aneuploidy-induced cell death lineage preference with higher rates of apoptosis in the inner cell mass (ICM) than in the TE cells. Moreover, the reported differential dynamics of cell proliferation and apoptosis between euploid, mosaic, and aneuploid embryos, together with pro-apoptosis gene products (cfDNA and mRNA) and extracellular vesicles identified in the blastocoel fluid, may support the hypothesis of apoptosis as a mechanism to purge the preimplantation embryo of aneuploid cells. Alternative hypotheses, like correction of aneuploidy by extrusion of a trisomy chromosome or by monosomic chromosome duplication, are even, though they represent an extremely rare phenomenon. On the other hand, the technical limitations of PGT-A analysis may lead to inaccuracy in embryo diagnoses, identifying as “mosaic” those embryos that are uniformly euploid or aneuploid. NGS assumption of “intermediate copy number profiles” as evidence of a mixture of euploid and aneuploid cells in a single biopsy has been reported to be poorly predictive in cases of mosaicism diagnosis. Additionally, the concordance found between the TE and the ICM in cases of TE biopsies displaying mosaicism is lower than expected, and it correlates differently depending on the type (whole chromosome versus segmental) and the level of mosaicism reported. Thus, in cases of low-/medium-level mosaicism (<50%), aneuploid cells would rarely involve the ICM and other regions. However, in high-level mosaics (≥50%), abnormal cells in the ICM should display higher prevalence, revealing more uniform aneuploidy in most embryos, representing a technical variation in the uniform aneuploidy range, and therefore might impair the live birth rate.
... No differences in neonatal outcomes between euploid or mosaic embryo transfers have been reported (Yakovlev et al., 2022). It should also be noted that a few cases of mosaicism or aneuploidy persistence have been reported (Greco et al., 2023;Kahraman et al., 2020;Schlade-Bartusiak et al., 2022); however, the incidence appears to be equal to that seen in unassisted conception. ...
... As noted, more than 2700 instances of mosaic embryo transfer have been documented to date. However, only a limited number of cases have officially been reported of live newborns exhibiting confirmed mosaicism after such transfers (Greco et al., 2023;Kahraman et al., 2020;Schlade-Bartusiak et al., 2022). The first case was the birth of a healthy child with mosaicism (2%, monosomy 2 by peripheral blood karyotyping and confirmation by fluorescence in-situ hybridization), previously detected by PGT-A (35%, monosomy 2). ...
... This case involved prenatal testing through amniocentesis, which detected mosaicism (2%, trisomy 2). With the absence of any pathological findings on detailed ultrasonography and normal fetal growth, the couple made the decision not to terminate the pregnancy (Kahraman et al., 2020). ...
... Prenatal testing data further confirm this notion. To date, true fetal mosaicism has only been confirmed in �0.03% of cases in over several thousand putatively mosaic embryos transferred to date (Kahraman et al., 2020;Schlade-Bartusiak et al., 2022;Greco et al., 2023). Mosaic pregnancies have also been reported following euploid embryo transfers (Haddad et al., 2013). ...
STUDY QUESTION
Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)?
SUMMARY ANSWER
Our analysis of 36 395 blastocyst biopsies across eight genetic testing laboratories revealed that euploidy rates were significantly higher in providers reporting low rates of mosaicism.
WHAT IS KNOWN ALREADY
Diagnoses consistent with chromosomal mosaicism have emerged as a third category of possible embryo ploidy outcomes following PGT-A. However, in the era of mosaicism, embryo selection has become increasingly complex. Biological, technical, analytical, and clinical complexities in interpreting such results have led to substantial variability in mosaicism rates across PGT-A providers and clinics. Critically, it remains unknown whether these differences impact the number of euploid embryos available for transfer. Ultimately, this may significantly affect clinical outcomes, with important implications for PGT-A patients.
STUDY DESIGN, SIZE, DURATION
In this international, multicenter cohort study, we reviewed 36 395 consecutive PGT-A results, obtained from 10 035 patients across 11 867 treatment cycles, conducted between October 2015 and October 2021. A total of 17 IVF centers, across eight PGT-A providers, five countries and three continents participated in the study. All blastocysts were tested using trophectoderm biopsy and next-generation sequencing. Both autologous and donation cycles were assessed. Cycles using preimplantation genetic testing for structural rearrangements were excluded from the analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The PGT-A providers were randomly categorized (A to H). Providers B, C, D, E, F, G, and H all reported mosaicism, whereas Provider A reported embryos as either euploid or aneuploid. Ploidy rates were analyzed using multilevel mixed linear regression. Analyses were adjusted for maternal age, paternal age, oocyte source, number of embryos biopsied, day of biopsy, and PGT-A provider, as appropriate. We compared associations between genetic testing providers and PGT-A outcomes, including the number of chromosomally normal (euploid) embryos determined to be suitable for transfer.
MAIN RESULTS AND THE ROLE OF CHANCE
The mean maternal age (±SD) across all providers was 36.2 (±5.2). Our findings reveal a strong association between PGT-A provider and the diagnosis of euploidy and mosaicism. Amongst the seven providers that reported mosaicism, the rates varied from 3.1% to 25.0%. After adjusting for confounders, we observed a significant difference in the likelihood of diagnosing mosaicism across providers (P < 0.001), ranging from 6.5% (95% CI: 5.2–7.4%) for Provider B to 35.6% (95% CI: 32.6–38.7%) for Provider E. Notably, adjusted euploidy rates were highest for providers that reported the lowest rates of mosaicism (Provider B: euploidy, 55.7% (95% CI: 54.1–57.4%), mosaicism, 6.5% (95% CI: 5.2–7.4%); Provider H: euploidy, 44.5% (95% CI: 43.6–45.4%), mosaicism, 9.9% (95% CI: 9.2–10.6%)); and Provider D: euploidy, 43.8% (95% CI: 39.2–48.4%), mosaicism, 11.0% (95% CI: 7.5–14.5%)). Moreover, the overall chance of having at least one euploid blastocyst available for transfer was significantly higher when mosaicism was not reported, when we compared Provider A to all other providers (OR = 1.30, 95% CI: 1.13–1.50). Differences in diagnosing and interpreting mosaic results across PGT-A laboratories raise further concerns regarding the accuracy and relevance of mosaicism predictions. While we confirmed equivalent clinical outcomes following the transfer of mosaic and euploid blastocysts, we found that a significant proportion of mosaic embryos are not used for IVF treatment.
LIMITATIONS, REASONS FOR CAUTION
Due to the retrospective nature of the study, associations can be ascertained, however, causality cannot be established. Certain parameters such as blastocyst grade were not available in the dataset. Furthermore, certain platform-related and clinic-specific factors may not be readily quantifiable or explicitly captured in our dataset. As such, a full elucidation of all potential confounders accounting for variability may not be possible.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings highlight the strong need for standardization and quality assurance in the industry. The decision not to transfer mosaic embryos may ultimately reduce the chance of success of a PGT-A cycle by limiting the pool of available embryos. Until we can be certain that mosaic diagnoses accurately reflect biological variability, reporting mosaicism warrants utmost caution. A prudent approach is imperative, as it may determine the difference between success or failure for some patients.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the Torres Quevedo Grant, awarded to M.P. (PTQ2019-010494) by the Spanish State Research Agency, Ministry of Science and Innovation, Spain. M.P., L.B., A.R.L., A.L.R.d.C.L., N.P.P., M.P., D.S., F.A., A.P., B.M., L.D., F.V.M., D.S., M.R., E.P.d.l.B., A.R., and R.V. have no competing interests to declare. B.L., R.M., and J.A.O. are full time employees of IB Biotech, the genetics company of the Instituto Bernabeu group, which performs preimplantation genetic testing. M.G. is a full time employee of Novagen, the genetics company of Cegyr, which performs preimplantation genetic testing.
TRIAL REGISTRATION NUMBER
N/A.
... The main concern with mosaicism is elucidating whether mosaic embryo transfer would lead to a higher frequency of congenital abnormalities in newborns. Except for two cases where mosaicism was confirmed in advanced prenatal stages, the rate of mosaicism verified in pregnancies is exceedingly low [33,34], and the results to date appear encouraging until further investigations are released. Indeed, there is no evidence that mosaicism is more prevalent in pregnancies resulting from IVF than in natural conceptions, even when IVF embryos from no PGT-A cycles, which include euploids, aneuploids, and mosaics, are "blindly" transferred [35]. ...
Mosaicism represents a genuine real phenomenon, but its high prevalence and undisclosed clinical significance, stress the burden on genetic counseling and the management of PGT-A results. Even though the assumption of mosaicism from NGS intermediate chromosome copy number profiles may represent a reasonable interpretation, other potential technical reasons, including amplification bias, contamination, biopsy technique, or the analysis algorithms, may constitute alternative explanations. Thresholds confining mosaicism ranges are established according to models employing mixtures of normal and abnormal cells with steady conditions of quantity and quality which are unable to reflect the full extent of variability present in a trophectoderm (TE) biopsy specimen. When the concordance of TE with the ICM is considered, mosaic TE biopsies poorly correlate with the chromosomal status of the remaining embryo, displaying mostly ICM aneuploidy in cases of TE high-range mosaics diagnosis and euploidy when mosaicism grade in TE is less than 50% (low-mid range mosaicism), which implies an evident overestimation of mosaicism results. Indeed, a binary classification of NGS profiles that excludes mosaic ranges, including only euploid and aneuploid diagnosis, provides higher specificity and accuracy in identifying abnormal embryos and discarding them. As intermediate copy number profiles do not represent strong evidence of mosaicism but only an inaccurate and misleading assumption, and considering that no increased risk has been reported in the offspring, until diagnosis specificity is improved and its clinical implications are determined, laboratories should consider limiting predictions to euploid and aneuploid and stop reporting mosaicism.
... If an ongoing pregnancy is achieved after MET, the most likely outcome is a newborn with a normal karyotype (1,5,10). However, there is the rare possibility of a newborn with a mosaic or aneuploid karyotype (11,12). Furthermore, fetal mosaicism is impossible to definitively rule out, and if it is confirmed, phenotypic effects are difficult to predict (13). ...
Objective
To survey genetic counselors (GCs) who have counseled about mosaic embryos regarding the challenges they faced in counseling this patient population and assess their need for more resources to support their practice.
Design
Self-administered online survey.
Setting
Academic university.
Study Population
Seventy-eight GCs primarily from the United States and Canada.
Intervention(s)
Genetic counselors completed a quantitative survey with an embedded qualitative component. Quantitative data were analyzed by descriptive statistics. An inductive thematic analysis was performed on open-text responses.
Main Outcome Measure(s)
Genetic counselors were asked what clinical activities relating to mosaic embryos they performed. They were then asked to rate how challenging each activity was to perform using a 5-point scale; a rating of 4 or 5 was defined as highly challenging. Open-text questions enabled GCs to describe factors that they felt contributed to these challenges.
Result(s)
The challenges reported by GCs included the uncertainty of outcomes in offspring after mosaic embryo transfer, limited guidelines available to assist clinicians with counseling about mosaic embryos, and ranking mosaic embryos by suitability for transfer. The contributing factors suggested by participants included limited outcome data, limited GC involvement in pretest counseling for preimplantation genetic testing for aneuploidy (PGT-A), and perceived inconsistency in counseling practices across clinics. Genetic counselors differed in their genetic testing recommendations for pregnancies conceived after mosaic embryo transfer. Amniocentesis and postnatal assessment were recommended by 85% and 49% of GCs, respectively, and 15% recommended chorionic villus sampling and noninvasive prenatal testing. Almost all (92%) reported a need for more resources, such as standardized guidelines, more outcome data, and continuing education on PGT-A and mosaicism.
Conclusion(s)
This study describes challenges experienced by GCs while they counseled about mosaic embryos. Our findings demonstrate a need for more outcome data on mosaic embryo pregnancies and for evidence-based clinical guidelines. The differing recommendations for prenatal genetic testing among GCs in the study warrant further research into contributing factors. We strongly recommend that pretest counseling, including a discussion regarding mosaicism, is provided to all couples considering PGT-A to reduce counseling challenges and to promote patients’ informed decision-making.
... In 2021, in a systematic review of clinical outcomes after the transfer of mosaic embryos, Treff and Marin summarized that an ongoing pregnancy was achieved in 38% of cases [86]. To date, only two mosaic case has been confirmed prenatally [86,88,89]. However, mosaic embryos were expected to have less favorable clinical outcomes compared with euploid embryos (low implantation rate, high miscarriage rate) with the poorest outcomes when the abnormal cell population is > 50% (high range) [89]. ...
... However, it allows a follow-up of the trophectoderm result in an earlier gestational age [95] without any risk for the pregnancy. So far, only two cases have been reported showing a postnatal confirmation of the mosaicism, one after the transfer of a low-range (35%) mosaicism of monosomy 2 [88] and the other after the transfer of high-level mosaic for trisomy 15 and partial monosomy 20 [89]. ...
Preimplantation genetic testing for aneuploidy (PGT-A) has evolved over recent years, including improvements in embryo culture, biopsy, transfer, and genetic testing. The application of new comprehensive chromosome screening analysis has improved the accuracy in determining the chromosomal status of the analyzed sample, but it has brought new challenges such as the management of partial aneuploidies and mosaicisms. For the past two decades, PGT-A has been involved in a controversy regarding its efficiency in improving IVF outcomes, despite its widespread worldwide implementation. Understanding the impact of embryo aneuploidy in IVF (in vitro fertilization) should theoretically allow improving reproductive outcomes. This review of the literature aims to describe the impact of aneuploidy in human reproduction and how PGT-A was introduced to overcome this obstacle in IVF (in vitro fertilization). The article will try to analyze and summarize the evolution of the PGT-A in the recent years, and its current applications and limitations, as well as the controversy it generates. Conflicting published data could indicate the lacking value of a single biopsied sample to determine embryo chromosomal status and/or the lack of standardized methods for embryo culture and management and genetic analysis among other factors. It has to be considered that PGT-A may not be a universal test to improve the reproductive potential in IVF patients, rather each clinic should evaluate the efficacy of PGT-A in their IVF program based on their population, skills, and limitations.
... These findings, for the first time, report that human blastocysts with single chromosome mosaicism or segmental abnormalities present indistinguishable telomere lengths, telomerase gene expression, and telomerase activity compared with euploid blastocysts. These findings indicate the similarity of developmental patterns between euploid and mosaic or segmental blastocysts, which could explain why mosaic and segmental embryo transfers result in healthy infants undergoing IVF treatment [40,41]. Hence, our work provides direct molecular evidence justifying the transfer of mosaic or segmental embryos in patients who have no other embryos. ...
The telomere length of human blastocysts exceeds that of oocytes and telomerase activity increases after zygotic activation, peaking at the blastocyst stage. Yet, it is unknown whether aneuploid human embryos at the blastocyst stage exhibit a different profile of telomere length, telomerase gene expression, and telomerase activity compared to euploid embryos. In present study, 154 cryopreserved human blastocysts, donated by consenting patients, were thawed and assayed for telomere length, telomerase gene expression, and telomerase activity using real-time PCR (qPCR) and immunofluorescence (IF) staining. Aneuploid blastocysts showed longer telomeres, higher telomerase reverse transcriptase (TERT) mRNA expression, and lower telomerase activity compared to euploid blastocysts. The TERT protein was found in all tested embryos via IF staining with anti-hTERT antibody, regardless of ploidy status. Moreover, telomere length or telomerase gene expression did not differ in aneuploid blastocysts between chromosomal gain or loss. Our data demonstrate that telomerase is activated and telomeres are maintained in all human blastocyst stage embryos. The robust telomerase gene expression and telomere maintenance, even in aneuploid human blastocysts, may explain why extended in vitro culture alone is insufficient to cull out aneuploid embryos during in vitro fertilization.
