Evidence-based management of preimplantation chromosomal mosaicism: lessons from the clinic
2021; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2021.07.1182
ISSN1556-5653
AutoresAndria G. Besser, Emily L. Mounts, J. Grifo,
Tópico(s)Parvovirus B19 Infection Studies
ResumoMosaic results obtained through preimplantation genetic testing for aneuploidy pose ongoing challenges to clinical practice. Thorough genetic counseling for patients considering mosaic embryo transfer is consistently recommended by many best-practice statements, and providers are charged with the task of assessing and explaining potential prenatal, neonatal, and long-term risks. However, an increasing amount of outcome data from transferred embryos with mosaic results do not show any evidence of increased risk to ongoing pregnancies or newborns. This article examines how to reconcile these data with the current practices for patient education about preimplantation genetic testing for aneuploidy and mosaic embryo risk assessment, through an evidence-based lens. Mosaic results obtained through preimplantation genetic testing for aneuploidy pose ongoing challenges to clinical practice. Thorough genetic counseling for patients considering mosaic embryo transfer is consistently recommended by many best-practice statements, and providers are charged with the task of assessing and explaining potential prenatal, neonatal, and long-term risks. However, an increasing amount of outcome data from transferred embryos with mosaic results do not show any evidence of increased risk to ongoing pregnancies or newborns. This article examines how to reconcile these data with the current practices for patient education about preimplantation genetic testing for aneuploidy and mosaic embryo risk assessment, through an evidence-based lens. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33411 Counseling patients about results from preimplantation genetic testing (PGT) for aneuploidy (PGT-A) has become a daunting task, even for providers who are experienced in reproductive genetics. While PGT-A has always been characterized as a screening test, it is most often used as a diagnostic tool for selecting which embryos should or should not be transferred. Given that PGT laboratories often report results that are neither distinctly normal or abnormal, paired with the broader limitations of PGT-A, in vitro fertilization (IVF) providers face an increasing burden of interpreting complex results and are challenged to facilitate difficult embryo selection decisions within an evidence-based framework. Mosaic PGT-A results have caused extensive counseling dilemmas since the first reports of chromosomally normal newborns from mosaic embryos were published (1Greco E. Minasi M.G. Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts.N Engl J Med. 2015; 373: 2089-2090Crossref PubMed Scopus (331) Google Scholar). Although chromosomal mosaicism was initially described in embryos nearly 3 decades ago (2Munné S. Weier H.U. Grifo J. Cohen J. Chromosome mosaicism in human embryos.Biol Reprod. 1994; 51: 373-379Crossref PubMed Scopus (265) Google Scholar), its routine detection in clinical testing has only been enabled in recent years by the combination of trophectoderm biopsy and next-generation sequencing-based PGT-A technologies. The increased reporting of mosaic results has sparked many questions about the utility of these results for clinical decision making, particularly given a lack of consensus regarding laboratory practices for test validation, detection thresholds, and reporting schemes (3Capalbo A. Ubaldi F.M. Rienzi L. Scott R. Treff N. Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities.Hum Reprod. 2017; 32: 492-498PubMed Google Scholar, 4Weissman A. Shoham G. Shoham Z. Fishel S. Leong M. Yaron Y. Chromosomal mosaicism detected during preimplantation genetic screening: results of a worldwide Web-based survey.Fertil Steril. 2017; 107: 1092-1097Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar); that is, the significance of a mosaic result may differ based on which laboratory performed the analysis. As a result, providers often struggle with how to best communicate these results to patients, initially in the absence of clear outcome data to delineate specific risks. As mosaic embryo transfer has become more commonplace, counseling practices have evolved accordingly to accommodate the increasing knowledge base surrounding this topic; however, barriers to understand and effectively and consistently communicate these data to patients still exist, and both providers and patients alike continue to grapple with embryo transfer decisions. A recent statement by the Practice Committee and Genetic Counseling Professional Group of the American Society for Reproductive Medicine (ASRM) emphasizes the necessity for patient education before PGT-A (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The statement outlines the essential components of patient pretest counseling, including a review of the expected frequency of mosaic results at the laboratory used and the challenges associated with interpreting these results. Pretest patient education is an opportunity to clearly elucidate the primary purpose of PGT-A—that is, to maximize the chance of implantation and reduce the chance of spontaneous abortion by avoiding the transfer of aneuploid embryos—and to ensure that patients are prepared for the possibility that results may not always be straightforward or clearly inform embryo transfer decisions. The potential for genetic results that can generate more questions than answers may cause anxiety, and some patients may choose to decline PGT-A to avoid this potential situation (6Besser A.G. Mounts E.L. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening.Reprod Biomed Online. 2017; 34: 369-374Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). It is also essential to review any relevant clinical policies upfront with patients to ensure that there is an understanding about which options may or may not be available to them for storage or transfer of any embryos created. The task of reviewing PGT-A results with patients is one that many IVF providers find daunting, and mosaic results are among the most challenging to decipher and explain. The ASRM statement outlines necessary posttest counseling points on mosaic results, particularly for cases in which the transfer of such embryos may be considered (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Posttest counseling should include a discussion about current outcome data, address patient comfort levels with persisting uncertainty during pregnancy, and review prenatal testing options (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 6Besser A.G. Mounts E.L. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening.Reprod Biomed Online. 2017; 34: 369-374Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Ideally, counseling on mosaic results would be evidence-based and anchored not to current practices or the beliefs and biases of individual experts, but rather to pertinent experimental evidence (7Eddy D.M. Clinical decision making: from theory to practice. Practice policies--guidelines for methods.JAMA. 1990; 263: 1839-1841Crossref PubMed Scopus (111) Google Scholar). Through the integration of clinical expertise, the best available research data, and patient values, evidence-based medicine is a pillar of quality and patient-centered medical care (8Ioannidis J.P.A. Khoury M.J. Evidence-based medicine and big genomic data.Hum Mol Genet. 2018; 27: R2-R7Crossref PubMed Scopus (25) Google Scholar). While the ASRM statement addresses concerns about the possibility of adverse outcomes in live births from mosaic embryos and cites limited outcome data (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), there has since been additional published research on the outcomes of large numbers of mosaic embryo transfers (9Viotti M. Victor A.R. Barnes F.L. Zouves C.G. Besser A.G. Grifo J.A. et al.Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.Fertil Steril. 2021; 115: 1212-1224Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 10Lee C.I. Cheng E.H. Lee M.S. Lin P.Y. Chen Y.C. Chen C.H. et al.Healthy live births from transfer of low-mosaicism embryos after preimplantation genetic testing for aneuploidy.J Assist Reprod Genet. 2020; 37: 2305-2313Crossref PubMed Scopus (12) Google Scholar, 11Zhang Y.X. Chen J.J. Nabu S. Yeung Q.S.Y. Li Y. Tan J.H. et al.The pregnancy outcome of mosaic embryo transfer: a prospective multicenter study and meta-analysis.Genes (Basel). 2020; 11: 973Crossref PubMed Scopus (23) Google Scholar), and this concern may no longer be entirely valid. Viotti et al. (9Viotti M. Victor A.R. Barnes F.L. Zouves C.G. Besser A.G. Grifo J.A. et al.Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.Fertil Steril. 2021; 115: 1212-1224Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar) reported on outcomes associated with 1,000 mosaic embryos transferred, and found that mosaic results only affected implantation or early pregnancy viability, with no reports of fetal mosaicism in this large cohort. To date, there has been only a single report of fetal mosaicism resulting from an embryo identified as mosaic for the same chromosome (12Kahraman S. Cetinkaya M. Yuksel B. Yesil M. Pirkevi Cetinkaya C. The birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report.Hum Reprod. 2020; 35: 727-733Crossref PubMed Scopus (40) Google Scholar). This unique case confirms that, unsurprisingly, such an outcome is possible; however, it is also becoming increasingly evident that this is a statistically unlikely outcome, and that the vast majority of viable pregnancies from putative mosaic embryos are chromosomally normal. Genetic counseling about mosaic embryo transfer must evolve to accurately represent this outcome data while also addressing its limitations. Often, embryos with mosaic results are presented as being at risk of resulting in a fetus or baby with a chromosomal abnormality; yet, it must be acknowledged that there is currently no evidence demonstrating that pregnancies from embryos with mosaic results are at greater risk for this outcome compared with those conceived from euploid-result or untested embryos. Various attempts have been made to stratify mosaic results into different risk categories, particularly with the use of chromosome number as a distinguishing factor (13PGDIS Newsletter, July 19, 2016PGDIS position statement on chromosome mosaicism and preimplantation aneuploidy testing at the blastocyst stage.http://pgdis.org/docs/newsletter_071816.htmlDate accessed: June 23, 2021Google Scholar, 14Virtual Academy of GeneticsCoGEN Statement. CoGEN position statement on chromosomal mosaicism detected in preimplantation blastocyst biopsies.https://ivf-worldwide.com/cogen/general/cogen-statement.htmlDate accessed: June 23, 2021Google Scholar, 15Grati F.R. Gallazzi G. Branca L. Maggi F. Simoni G. Yaron Y. An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening.Reprod Biomed Online. 2018; 36: 442-449Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). These rankings are available in widely accessible media for patients to consume, and both IVF providers and genetic counselors may feel pressure to use such resources in counseling patients who are desperate for embryo-specific risk information. However, these prioritization attempts are based only on theoretical risks that have been extrapolated from prenatal and postnatal data. Preimplantation data have not been incorporated into any currently available ranking schemes, and consequently, the existing models have not translated into real-world outcomes from mosaic embryo transfer. Given the lack of supporting evidence, the ASRM cautions against providing such "risk assessments" to patients (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). In contrast, attempts to stratify broad categories of mosaic results to the extent that they can predict embryo viability have been more successful: multiple studies have identified differences based on whether the suspected aneuploidy involves a full chromosome versus chromosomal segment (deletion or duplication), the estimated percentage of abnormal cells in the biopsy, and the total number of aneuploidies identified (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Although these studies have not all shown consistent results, patterns are emerging as sample sizes increase, and these data are likely to be at least partly useful in embryo selection decisions. Prenatal test recommendations after mosaic embryo transfer are another area in which evidence-based guidance is lacking. Most best-practice statements in this area uniformly recommend prenatal diagnosis by amniocentesis as the gold standard follow-up test (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 6Besser A.G. Mounts E.L. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening.Reprod Biomed Online. 2017; 34: 369-374Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 13PGDIS Newsletter, July 19, 2016PGDIS position statement on chromosome mosaicism and preimplantation aneuploidy testing at the blastocyst stage.http://pgdis.org/docs/newsletter_071816.htmlDate accessed: June 23, 2021Google Scholar, 14Virtual Academy of GeneticsCoGEN Statement. CoGEN position statement on chromosomal mosaicism detected in preimplantation blastocyst biopsies.https://ivf-worldwide.com/cogen/general/cogen-statement.htmlDate accessed: June 23, 2021Google Scholar), with some clinics even reporting to mandate prenatal diagnosis in such cases (16Yang M. Rito T. Metzger J. Naftaly J. Soman R. Hu J. et al.Depletion of aneuploid cells in human embryos and gastruloids.Nat Cell Biol. 2021; 23: 314-321Crossref PubMed Scopus (31) Google Scholar). On the surface, the rationale behind this recommendation is reasonable; if an embryo with a suspected chromosomal anomaly is being transferred, then it stands to reason that a resulting pregnancy, whether carried by an intended parent or a gestational carrier, should be tested with the most accurate diagnostic tool available. In contrast to chorionic villus sampling, which can be performed in the late first trimester, or cell-free DNA analysis, which has the added benefit of being noninvasive, amniocentesis is the only method by which DNA can be captured from fetal cells rather than placental tissues. Amniocentesis, like chorionic villus sampling, is an invasive procedure. Although it is largely safe, a risk of procedure-related spontaneous abortion still exists, and pregnancy loss has been documented after prenatal diagnosis done as a follow-up to mosaic embryo transfer (16Yang M. Rito T. Metzger J. Naftaly J. Soman R. Hu J. et al.Depletion of aneuploid cells in human embryos and gastruloids.Nat Cell Biol. 2021; 23: 314-321Crossref PubMed Scopus (31) Google Scholar, 17Besser AG, Plaut AC, Grifo JA. Results of prenatal diagnosis after mosaic embryo transfer indicate low risk of fetal chromosome abnormality. American Society for Reproductive Medicine conference, Baltimore, Maryland, October 2021. Accepted abstract.Google Scholar). Unfortunately, however, the aforementioned statements largely ignore this risk, and presume that the risk of miscarriage from a prenatal diagnostic procedure is outweighed by an elevated risk of fetal aneuploidy. Given the single isolated report of fetal aneuploidy after mosaic embryo transfer described above (12Kahraman S. Cetinkaya M. Yuksel B. Yesil M. Pirkevi Cetinkaya C. The birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report.Hum Reprod. 2020; 35: 727-733Crossref PubMed Scopus (40) Google Scholar), whether there truly is an increased risk of fetal abnormality has not yet been determined. Additionally, it must be acknowledged that more cases of confirmed fetal mosaicism have been identified to date from embryos diagnosed as euploid (18Friedenthal J. Maxwell S.M. Tiegs A.W. Besser A.G. McCaffrey C. Munné S. et al.Clinical error rates of next generation sequencing and array comparative genomic hybridization with single thawed euploid embryo transfer.Eur J Med Genet. 2020; 63103852Crossref PubMed Scopus (13) Google Scholar) than from those diagnosed as mosaic (n = 1). Therefore, the unequivocal recommendation for prenatal diagnosis warrants revisiting through an evidence-based lens. The American College of Obstetricians and Gynecologists recommends that all pregnant people be offered prenatal diagnosis, regardless of age, risk of chromosomal abnormality, or prior PGT, "given the personal nature of prenatal testing decision making" (19American College of Obstetricians and GynecologistsScreening for fetal chromosomal abnormalities: ACOG practice bulletin summary, Number 226.Obstet Gynecol. 2020; 136: 859-867Crossref PubMed Scopus (32) Google Scholar). Therefore, whether PGT-A results are mosaic or euploid, prenatal diagnosis should be offered—but is there justification in disproportionately making an unequivocal recommendation for invasive testing after mosaic embryo transfer, without any true evidence of higher risk? Recommendations have also been put forth regarding the types of analyses that should be performed on prenatal diagnostic samples (chorionic villi or amniocytes) obtained after mosaic embryo transfer. In addition to routine karyotyping, chromosomal microarray (CMA) and uniparental disomy (UPD) analyses are commonly cited as add-on tests to consider (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 6Besser A.G. Mounts E.L. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening.Reprod Biomed Online. 2017; 34: 369-374Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 20Del Gaudio D. Shinawi M. Astbury C. Tayeh M.K. Deak K.L. Raca G. ACMG Laboratory Quality Assurance CommitteeDiagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG).Genet Med. 2020; 22: 1133-1141Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Despite their potential utility in resolving uncertain preimplantation results, these tests also have the potential to yield additional unclear results. Chromosomal microarray analysis can identify deletions and duplications that are too small to be visualized by routine karyotyping and is therefore the diagnostic test of choice for the identification of segmental aneuploidy. However, CMA can also identify much smaller copy number variants that are often of unknown significance and are well below the resolution of any PGT-A platform (and therefore, would be unrelated to the original mosaic PGT-A result). These uncertain findings frequently contribute to anxiety and distress among patients (21Bernhardt B.A. Soucier D. Hanson K. Savage M.S. Jackson L. Wapner R.J. Women's experiences receiving abnormal prenatal chromosomal microarray testing results.Genet Med. 2013; 15: 139-145Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). Similarly, the American College of Medical Genetics and Genomics recently published updated recommendations for prenatal UPD testing, stating that the transfer of embryos with mosaic results involving certain chromosomes "should be followed by prenatal studies including UPD testing" (20Del Gaudio D. Shinawi M. Astbury C. Tayeh M.K. Deak K.L. Raca G. ACMG Laboratory Quality Assurance CommitteeDiagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG).Genet Med. 2020; 22: 1133-1141Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), and elected to uphold this recommendation (22Raca G. Shinawi M. Gaudio D.D. American College of Medical Genetics and Genomics. Response to Mounts and Besser.Genet Med. 2021; 23: 240-242Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar) despite a lack of evidence for any true increased UPD risk (23Mounts E.L. Besser A.G. Lack of evidence to support recommendation for prenatal uniparental disomy (UPD) analysis following mosaic embryo transfer.Genet Med. 2021; 23: 230-231Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Uniparental disomy testing relies on the identification of unique genetic markers that are maternally and paternally inherited, and similar to CMA, can be inconclusive when parents share similar haplotypes. Additionally, the clinical significance of UPD, even for imprinted chromosomes that have been associated with UPD syndromes, is not always entirely clear (24Eggermann T. Soellner L. Buiting K. Kotzot D. Mosaicism and uniparental disomy in prenatal diagnosis.Trends Mol Med. 2015; 21: 77-87Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). As there have not been any published reports to date of an ongoing pregnancy with a segmental aneuploidy or UPD related to an initial mosaic PGT-A result, the recommendation for CMA or UPD testing in the absence of a well-defined risk must be weighed against the potential for results of uncertain significance that are unrelated to the primary test "indication." Such unclear results, if unable to be resolved, could prompt additional costly prenatal evaluations and difficult decisions about pregnancy termination. Although the ASRM encourages all clinics to draft internal policies regarding the transfer and storage of mosaic embryos, in many cases clinics have put in place policies that are not evidence based. In 2018, Kim et al. (25Kim T.G. Neblett M.F. Shandley L.M. Omurtag K. Hipp H.S. Kawwass J.F. National mosaic embryo transfer practices: a survey.Am J Obstet Gynecol. 2018; 219: 602.e1-602.e7Abstract Full Text Full Text PDF Scopus (15) Google Scholar) found that just over half of the clinics surveyed permitted mosaic embryo transfer, and 2 years later, a smaller study found that 70% would perform such transfers (26Ren C. Besser A.G. Weil J. Hull R. Youngblom J. Embryo transfer based on preimplantation genetic testing: A critical assessment of current practice and policy guidelines.Fertil Steril. 2020; 114: e19Abstract Full Text Full Text PDF Google Scholar). Given an increasing amount of outcome data, a lack of consistency between laboratories in defining a mosaic result, and a paucity of evidence showing an increased risk of adverse outcomes compared with pregnancies conceived from euploid or untested embryos (the latter of which are routinely transferred without additional counseling, despite the potential to be aneuploid or mosaic), one must consider whether a policy barring mosaic embryo transfer is justified. Additionally, some clinics will agree to transfer embryos with certain types of mosaic results but prohibit the transfer of others, such as those displaying a higher estimated percentage of mosaicism or those involving specific chromosomes. It is questionable how such policies can be developed in the absence of any data supporting the notion that certain mosaic results confer additional risk and warrant withholding from transfer. Evidence-based development of embryo transfer policies may assist providers with managing more complex patient requests, for example, to prioritize an embryo with a mosaic result over one with a euploid result because of preferences for embryo sex or differing results of PGT for monogenic disorders, to transfer mosaic and euploid embryos simultaneously, or to preferentially transfer a mosaic embryo for the purpose of reserving remaining euploids for a future gestational carrier (27Besser A.G. McCulloh D.H. Grifo J.A. What are patients doing with their mosaic embryos? Decision making after genetic counseling.Fertil Steril. 2019; 111: 132-137.e1Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). These situations are likely to become increasingly commonplace as the landscape of IVF and PGT-A continues to evolve. The scarcity of information regarding the long-term health outcomes in offspring is also frequently cited as a concern regarding mosaic embryo transfer. Now, well over a thousand putative mosaic embryos have been transferred, with prospective outcome data demonstrating a potential higher chance of failed implantation and early spontaneous abortion compared with euploid embryos. Of note, however, there has been no published evidence of adverse effects of mosaicism beyond its possible influence on embryonic implantation and/or early development, including a lack of identified fetal, maternal, and neonatal risks. Nonetheless, critics of mosaic embryo transfer practices frequently cite a risk of possible long-term or even subclinical consequences of mosaicism after the neonatal period. For this concern to be valid, a stated goal of PGT-A would need to be maximizing the chance of healthy offspring and reducing lifetime health risks. In fact, despite common misconceptions (28Quinn M.M. Juarez-Hernandez F. Dunn M. Okamura R.J. Cedars M.I. Rosen M.P. Decision-making surrounding the use of preimplantation genetic testing for aneuploidy reveals misunderstanding regarding its benefit.J Assist Reprod Genet. 2018; 35: 2155-2159Crossref PubMed Scopus (11) Google Scholar), PGT-A has never possessed this ability, as the vast majority of long-term health risks are not caused by chromosomal aneuploidy. Therefore, there is no logical reason to expect that an apparently healthy newborn, especially with normal karyotypic or CMA studies, would be at greater risk for future health problems had they been conceived from a mosaic embryo transfer rather than from a euploid embryo transfer. Although there is always a theoretical risk of undetected aneuploidy in untestable fetal tissues or very low-level mosaicism, this is a risk for every pregnancy and child and is not unique to those conceived from putative mosaic embryos. A lack of evidence-based risk assessment and counseling of patients has become increasingly evident as patients, likely frustrated by mixed messaging from different providers, often seek second opinions and advice from peers or social media (29Reich J, Besser AG, Blakemore JK. Mosaic embryo: an analysis of the social media content surrounding embryonic mosaicism. American Society for Reproductive Medicine conference, Baltimore, Maryland, October 2021. Accepted abstract.Google Scholar). The ASRM attempts to resolve this issue and standardize counseling by recommending referral to a clinical genetics specialist, "who has specific knowledge of perinatal and pediatric outcomes associated with chromosomal mosaicism" (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). However, recent outcome studies have demonstrated that prenatal and pediatric data are likely irrelevant to most preimplantation mosaic diagnoses (5Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive MedicineClinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.Fertil Steril. 2020; 114: 246-254Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 9Viotti M. Victor A.R. Barnes F.L. Zouves C.G. Besser A.G. Grifo J.A. et al.Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.Fertil Steril. 2021; 115: 1212-1224Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 10Lee C.I. Cheng E.H. Lee M.S. Lin P.Y. Chen Y.C. Chen C.H. et al.Healthy live births from transfer of low-mosaicism embryos after preimplantation genetic testing for aneuploidy.J Assist Reprod Genet. 2020; 37: 2305-2313Crossref PubMed Scopus (12) Google Scholar). When providers with focused expertise in prenatal and pediatric genetics are called upon to counsel these patients, given the backdrop of their clinical experience with mosaicism and without necessarily having PGT-specific knowledge, they may provide exceptionally cautionary counseling that is inconsistent with the current data on mosaic embryo outcomes. While genetic counselors' expertise in navigating complex genetic information with patients and facilitating reproductive decision making is undoubtedly of value, these skills are unable to overcome the underlying problem: there is still a paucity of data about specific risk factors and outcomes for different mosaic results. Unfortunately, these limitations simply cannot be resolved through referrals to genetics providers alone. The importance of evidence-based PGT-A counseling extends beyond mosaicism, as recent studies are similarly highlighting the complexities of other types of PGT-A results. Several groups have now demonstrated that a single trophectoderm biopsy showing an apparently nonmosaic segmental aneuploid result is less likely to be concordant with the inner cell mass compared with biopsies showing full monosomies or trisomies (30Girardi L. Serdarogullari M. Patassini C. Poli M. Fabiani M. Caroselli S. et al.Incidence, origin, and predictive model for the detection and clinical management of segmental aneuploidies in human embryos.Am J Hum Genet. 2020; 106: 525-534Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 31Navratil R. Horak J. Hornak M. Kubicek D. Balcova M. Tauwinklova G. et al.Concordance of various chromosomal errors among different parts of the embryo and the value of re-biopsy in embryos with segmental aneuploidies.Mol Hum Reprod. 2020; 26: 269-276Crossref PubMed Scopus (20) Google Scholar), and therefore may be more likely to represent a mitotic error or even false-positive result (32Goodrich D. Xing T. Tao X. Lonczak A. Zhan Y. Landis J. et al.Evaluation of comprehensive chromosome screening platforms for the detection of mosaic segmental aneuploidy.J Assist Reprod Genet. 2017; 34: 975-981Crossref PubMed Scopus (28) Google Scholar). Additionally, there have been reports of chromosomally normal live births from embryos with nonmosaic segmental aneuploid results (16Yang M. Rito T. Metzger J. Naftaly J. Soman R. Hu J. et al.Depletion of aneuploid cells in human embryos and gastruloids.Nat Cell Biol. 2021; 23: 314-321Crossref PubMed Scopus (31) Google Scholar, 33Gleicher N. Vidali A. Braverman J. Kushnir V.A. Barad D.H. Hudson C. et al.International PGS Consortium Study GroupAccuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos.Reprod Biol Endocrinol. 2016; 14: 54Crossref PubMed Scopus (78) Google Scholar, 34Tiegs A.W. Tao X. Zhan Y. Whitehead C. Kim J. Hanson B. et al.A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy.Fertil Steril. 2021; 115: 627-637Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar), and these cases are likely to occur at a much higher rate compared with those with nonmosaic whole chromosome aneuploidies. It is, therefore, reasonable to question whether this is yet another category of embryos that, while having historically been deemed abnormal on PGT-A and unsuitable for transfer, in fact, have some reproductive potential. As our knowledge about what constitutes "normal" or "abnormal" continues to evolve and as the interpretation of PGT-A results becomes more complex, evidence-based counseling of patients has ultimately become a more daunting task, but one that is more necessary than ever. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33411
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