Cytogenetic testing of pregnancy loss tissue: a meta-analysis

Smits, Myrthe A J; Maarle, Merel van; Hamer, Geert; Mastenbroek, Sebastiaan; Goddijn, Mariëtte; Wely, Madelon van

doi:10.1016/j.rbmo.2020.02.001

Cited by 32 publications

(22 citation statements)

References 75 publications

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“…Importantly, these are similar values to those previously published in prior studies using more conventional culture‐based karyotyping methods. 2 Additionally, the frequency of each chromosomal abnormality in our current sample series was also similar to that reported in these studies. Trisomy 16, 22, and 15 have been the most frequently observed of the autosomal aneuploidies in POC, 4 , 9 , 21 , 22 , 23 , 24 , 25 whereas trisomies 13, 18, and 21 are the commonly found neonatal chromosomal abnormalities.…”

Section: Discussionsupporting

confidence: 88%

“… 1 Many factors are known to cause miscarriages, but more than 50% are due to chromosomal abnormalities. 2 Chromosome testing of a product of conception (POC) reveals not only the cause of the miscarriage but also provides important clinical information to assist couples preparing for a subsequent pregnancy. 3 The most common chromosomal abnormality to cause a miscarriage is an autosomal trisomy, followed by monosomy X and then polyploidy.…”

Section: Introductionmentioning

confidence: 99%

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Usefulness of combined NGS and QF‐PCR analysis for product of conception karyotyping

Kato

Miyai

Suzuki³

et al. 2022

Reprod Medicine & Biology

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Purpose Since chromosomal abnormalities can be detected in more than half of miscarriages, cytogenetic testing of the product of conception (POC) can provide important information when preparing for a subsequent pregnancy. Conventional karyotyping is the common diagnostic method for a POC but can be problematic due to the need for cell culture. Methods We here conducted shallow whole‐genome sequencing (sWGS) using next‐generation sequencing (NGS) for alternative POC cytogenomic analysis. Since female euploidy samples can include 69,XXX triploidy, additional QF‐PCR was performed in these cases. Results We here analyzed POC samples from miscarriages in 300 assisted reproductive technology (ART) pregnancies and detected chromosomal abnormalities in 201 instances (67.0%). Autosomal aneuploidy (151 cases, 50.3%) was the most frequent abnormality, consistent with prior conventional karyotyping data. Mosaic aneuploidy was detected in seven cases (2.0%). Notably, the frequency of triploidy was 2.3%, 10‐fold lower than the reported frequency in non‐ART pregnancies. Structural rearrangements were identified in nine samples (3%), but there was no case of segmental mosaicism. Conclusions These data suggest that NGS‐based sWGS, with the aid of QF‐PCR, is a viable alternative karyotyping procedure that does not require cell culture. This method could also assist with genetic counseling for couples who undergoes embryo selection based on PGT‐A data.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Usefulness of combined NGS and QF‐PCR analysis for product of conception karyotyping

Kato

Miyai

Suzuki³

et al. 2022

Reprod Medicine & Biology

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“…The clinical use of testing for foetal chromosomal abnormality is also contentious. Although it was previously thought that women with RM and normal foetal karyotype had worse prognoses for future pregnancies compared with sporadic foetal aneuploidy ( Carp et al , 2001 ; Saravelos and Li, 2012 ), a systematic review found that incidence of chromosomal abnormalities, which accounted for 46% of RM, was not different from sporadic miscarriage ( Smits et al , 2020 ). Recent guidance published in the Lancet recommended that chromosomal testing could be performed for counselling purposes but little evidence is found on its value as a prognostic factor ( Coomarasamy et al , 2021 ).…”

Section: Discussionmentioning

confidence: 92%

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Woon

Greer

Shah

et al. 2022

Human Reproduction Update

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BACKGROUND Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal–foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls. OBJECTIVE AND RATIONALE The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls. SEARCH METHODS MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger’s test. OUTCOMES Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM. WIDER IMPLICATIONS The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

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“…Almost 50 years of cytogenetic studies of spontaneous abortions have demonstrated abnormality rates of around 50–60% [ 10 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Trisomies are the most frequently detected anomalies (58–61%), followed by monosomy X (8–13%), polyploidies (2–13%), and structural anomalies (7–9%) [ 11 , 12 , 41 ]. Autosomal monosomies are rare in spontaneous abortion material (0.8–1.5%), and found predominantly in mosaic state [ 13 , 47 , 48 , 49 ].…”

Section: Genetic Causes Of Miscarriagementioning

confidence: 99%

“…A significant proportion of miscarriages (50–70%) are caused by chromosomal abnormalities; in addition, more data have appeared on the associations between pregnancy loss and copy number variations (CNVs), gene mutations, methylation abnormalities, and other aberrations [ 10 , 11 , 12 , 13 , 14 , 15 ]. One can suggest that the increasing number of studied families and gene variants/CNVs founded in early pregnancy loss highlights the need for their functional assessment in trophoblast development to determine their role in adverse pregnancy outcomes.…”

Section: Introductionmentioning

confidence: 99%

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

Nikitina

Lebedev

2022

Cells

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Miscarriage affects approximately 15% of clinically recognized pregnancies, and 1–3% of couples experience pregnancy loss recurrently. Approximately 50–60% of miscarriages result from chromosomal abnormalities, whereas up to 60% of euploid recurrent abortions harbor variants in candidate genes. The growing number of detected genetic variants requires an investigation into their role in adverse pregnancy outcomes. Since placental defects are the main cause of first-trimester miscarriages, the purpose of this review is to provide a survey of state-of-the-art human in vitro trophoblast models that can be used for the functional assessment of specific abnormalities/variants implicated in pregnancy loss. Since 2018, when primary human trophoblast stem cells were first derived, there has been rapid growth in models of trophoblast lineage. It has been found that a proper balance between self-renewal and differentiation in trophoblast progenitors is crucial for the maintenance of pregnancy. Different responses to aneuploidy have been shown in human embryonic and extra-embryonic lineages. Stem cell-based models provide a powerful tool to explore the effect of a specific aneuploidy/variant on the fetus through placental development, which is important, from a clinical point of view, for deciding on the suitability of embryos for transfer after preimplantation genetic testing for aneuploidy.

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Cytogenetic testing of pregnancy loss tissue: a meta-analysis

Cited by 32 publications

References 75 publications

Usefulness of combined NGS and QF‐PCR analysis for product of conception karyotyping

Usefulness of combined NGS and QF‐PCR analysis for product of conception karyotyping

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

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