Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017.

INTRODUCTION: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. MATERIAL AND METHODS: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. RESULTS: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. CONCLUSION: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.

Incidence and outcome of arrhythmias and electrical disease in patients with Trisomy 18.

Patients with Trisomy 18 have a high incidence of cardiac anomalies and are associated with early death. Because of early mortality, electrical system disease and arrhythmia has been difficult to delineate and the incidence remain unknown. We sought to describe the association and clinical outcomes of electrical system disease and cardiac tachy-arrhythmias in patients with Trisomy 18. This was a retrospective, single institutional study. All patients with Trisomy 18 were included in the study. Patient characteristics, congenital heart disease (CHD), conduction system and clinical tachy-arrhythmia data were collected on all patients. Outcomes including cardiac surgical interventions, electrical system interventions and death were collected until the time of study. Patients with tachy-arrhythmias/electrical system involvement were compared to those without to identify potential associated variables. A total of 54 patients with Trisomy 18 were included in analysis. The majority of patients was female and had associated CHD. AV nodal conduction system abnormalities with either first or second degree AV block were common (15%) as was QTc prolongation (37%). Tachy-arrhythmias were common with 22% of patients having at least one form of tachy-arrhythmia and associated with concomitant conduction system disease (p = 0.002). Tachy-arrhythmias were typically treatable with monitoring or medication with eventual resolution without need for procedural intervention. Although early death was common, there were no causes of death associated with tachy-arrhythmia or conduction system disease. In conclusion, patients with Trisomy 18 have a high incidence of conduction system abnormalities and burden of clinical tachy-arrhythmias. Although frequent, electrical system disease did not affect patient outcome or difficultly of care delivery.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

The short-term mortality and morbidity of very low birth weight infants with trisomy 18 or trisomy 13 in Japan.

Trisomy 18 (T18) and trisomy 13 (T13) are major concerns in prenatal genetic testing due to their poor prognosis; very low birth weight (VLBW) is also a concern in neonatology. The aim of this study was to investigate the mortality and morbidity of VLBW infants diagnosed with T18/T13 in Japan, compared with those with no birth defects (BD-). Maternal and neonatal data were collected prospectively from infants weighing <1501 g and were admitted to centers of the Neonatal Research Network of Japan during 2003 to 2016. Among 60,136 infants, 563 and 60 was diagnosed with T18 and T13, respectively. Although the age of mothers of infants with T18/T13 was higher, the frequency of maternal complications was lower than those with BD-. With maternal and neonatal characteristic adjustments, T18/T13 had a higher incidence of each morbidity when compared with BD-. Mortality rates in the NICU were 70, 77, and 5.8% for T18, T13, and BD-, respectively, while the survival discharge rates of T18 and T13 were 29.5 and 23.3%, respectively, which was significantly higher than previous reports. This was the first nationwide survey for VLBW infants with T18/T13 in Japan; this novel data will be relevant and useful for prenatal genetic counseling and perinatal management. Although T18/T13 were considered to be fatal in the past, with proper epidemiological information, discussions with affected families, and compassionate patient care, the mortality rate of T18/T13 can be improved.

Clinical performance of non-invasive prenatal served as a first-tier screening test for trisomy 21, 18, 13 and sex chromosome aneuploidy in a pilot city in China.

BACKGROUND: Cell-free fetal DNA (cffDNA) has opened up new approaches for non-invasive prenatal testing (NIPT), and it is often used as the second-tier test for high-risk pregnant women in detecting trisomy (T) 21, T18, and T13 after serum biochemistry screening. This study aims to discuss the clinical performance of NIPT as an alternative first-tier screening test for pregnant women in detecting T21, T18, T13, and sex chromosome aneuploidies (SCAs) in China. METHODS: A total of 42,924 samples were recruited. The cell-free plasma DNA was directly sequenced. Each of the chromosome aneuploidies of PPV was analyzed. A total of 22 placental samples were acquired, including 14 FP and 8 TP samples. The placental verification of FP NIPT results was performed. RESULTS: Among 42,924 samples, 281 (0.65%) positive cases, including 87 of T21, 31 of T18, 22 of T13, and 141 of SCAs were detected. For the detection of T21, the positive predictive value (PPV) was 78.46%, for trisomy 18, 62.96%, for trisomy 13, 10.00%, for SCAs, 47.22% in the total samples. For trisomy 21, the PPV was 86.67%, for trisomy 18, 80.00%, for trisomy 13, 20.00%, for SCAs, 56.52% in advanced maternal age (AMA) women. The PPV of T21 increased with age. For T18, the PPV showed an overall upward trend. For T13 and SCAs, PPV was raised first and then lowered. Placental verification of false positive (FP) NIPT results confirmed confined placental mosaicism(CPM) was the reason for false positives. CONCLUSIONS: This study represents the first time that NIPT has been used as a first-tier screening test for fetal aneuploidies in a pilot city with large clinical samples in China. We propose that NIPT could replace serum biochemistry screening as a first-tier test.

Survival outcomes of very low birth weight infants with trisomy 18.

Trisomy 18 (T18) is one of the most commonly diagnosed aneuploidies leading to poor survival outcome. However, little is known about the dual risk of T18 and very low birth weight (VLBW, weighing <1500 g at birth). We aimed to investigate the survival and clinical features of VLBW infants with T18. In this observational cohort study, infants with T18 admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2019 were eligible. Among 30 infants with T18 who were enrolled as study participants, 11 (37%) were born with VLBW. VLBW infants had lower gestational age (34.4 vs. 39.4 weeks, p < 0.01) and a higher incidence of esophageal atresia (64% vs. 11%, p < 0.01) than non-VLBW infants. The proportions of patients who underwent any surgery (55% vs. 5%, p < 0.01) and positive pressure ventilation (82% vs. 32%, p = 0.02) were higher in VLBW than non-VLBW infants. One-year overall survival rate (45% vs. 26%, p = 0.32 by log-rank test) did not differ between the two groups. In conclusion, being born at VLBW may not be fatal for infants with T18 undergoing active interventions.

The introduction of clinical genetic testing in Ethiopia: Experiences and lessons learned.

Limited data are available on genetic testing laboratories in low- and middle-income countries including those in sub-Saharan Africa (SSA). To characterize the need for genetic testing in SSA we describe the experience of MRC-ET Advanced Laboratory, a genetic testing laboratory in Ethiopia. Test results were analyzed based on indication(s) for testing, referral category, and diagnostic yield. A total of 1311 tests were run using the full MRC-Holland catalogue of Multiplex-Ligation Probe Amplification assays. Of all samples, 77% were postnatal samples, 15% products of conception (POC), and 8% amniotic samples. Of postnatal samples, the most common testing categories were multiple congenital anomalies (32%), disorders of sex development (17%), and Obstetrics/Gynecology (16%). Forty-three percent of postnatal samples were diagnostic, 11% were variants of uncertain significance (VUS), and 46% were normal with Trisomy 21 the most common diagnosis. Of POC samples, 10% were diagnostic, 34% revealed VUSs, and 55% were normal with Trisomy 18 the most common diagnosis. Of amniotic samples 17.5% were diagnostic, 3% revealed VUSs, and 79% were normal with Trisomy 18 the most common diagnosis. There is increasing demand for genetic testing in Ethiopia. Diagnostic genetic testing in SSA deserves increased attention as testing platforms become more affordable.

Insufficient development of vessels and alveoli in lungs of infants with trisomy 18-Features of pulmonary histopathological findings from lung biopsy.

The aim of this study was to evaluate the features of pulmonary histopathological changes in cases of trisomy 18 complicated with congenital heart disease and pulmonary arterial hypertension. Twenty-eight patients with trisomy 18 underwent open lung biopsy at the time of primary operation in our hospital between 2008 and 2019. We compared these histopathological findings with those from previously described groups without trisomy 18. Mean age at primary cardiac surgery was 37 days (range, 9-69 days). According to the Heath-Edwards (HE) classification, 1, 8, 12, and 5 patients were graded as 0, 1, 2, and 3, respectively, whereas 2 patients were not classifiable due to medial defects in the small pulmonary arteries (MD). Four (14.3%) and 13 (46.4%) patients presented with MD and hypoplasia of the small pulmonary arteries (HS). Fifteen (53.6%) and 21 (75.0%) patients presented with alveolar hypoplasia (AH) and alveolar wall thickening (AT). MD, HS, and AH in trisomy 18 were present frequently, differing significantly from previous reports. These findings might be associated with congenital inadequate development of vessels and alveoli in the lung, contributing to a high risk of PAH in trisomy 18.

Evaluation of the Z-score accuracy of noninvasive prenatal testing for fetal trisomies 13, 18 and 21 at a single center.

OBJECTIVE: To assess the correlation between Z-scores of positive noninvasive prenatal testing (NIPT) results and the positive predictive value (PPV) of NIPT. METHODS: Pregnancies with positive NIPT results at Guangzhou Women and Children's Medical Centre between July 2017 and May 2020 were included in this study. Fetal karyotyping or microarray analysis was provided to patients with abnormal NIPT results for confirmatory testing. Logistic regression analyses was applied to study the relationship between the Z scores and the PPV performance. The optimal cutoff values for indicating fetal common trisomies were obtained based on receiver operating characteristic (ROC) curve analysis, and then the PPV were calculated in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value and in patients with a Z-score between 3 and cutoff value respectively. RESULTS: A total of 214 pregnancies with positive NIPT results for fetal common trisomies were validated by invasive prenatal diagnosis and follow up in this study. Of these, NIPT indicated trisomy 13 in 25 cases, trisomy 18 in 54 cases and trisomy 21 in 135 patients. Logistic regression analyses showed a significant association (p < 0.05) between the Z-scores and true positive results for T21 and T18. For T13, the significant association was not observed (p > 0.05). The ROC curve analysis showed that the optimal cutoff Z-score for indicating fetal trisomies 13, 18, and 21 were 6.889, 7.574 and 6.612 respectively, and the corresponding area under curve were 0.706, 0.916, and 0.954. In this cohort with abnormal NIPT results, the cutoff values revealed a sensitivity of 96.8% and a specificity of 90% for indicating trisomies 21, and a sensitivity of 88.9% and a specificity of 92.6% for trisomies 18. However, probably due to the sample size, the sensitivity and specificity for indicating trisomy 13 were lower (85.7% and 61.1%) than that for trisomies 21 and 18. The PPVs in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value were 99.18% (121/122) for trisomy 21, 92.31% (24/26) for trisomy 18 and 46.15% (6/13) for trisomy 13. In patients with a Z-score between 3 and cutoff Z-score, the PPV of NIPT for trisomies 21, 18, and 13 were 30.77% (4/13), 10.71% (3/28), and 8.33% (1/12) respectively. Moreover, by classifying Z scores as 3 ≤ Z < 5, 5 ≤ Z < 10, and Z ≥ 10, the majority of Z scores were above 10 with a PPV of 99% for T21 and just 5.2% were between 3 and 5 with a PPV of 14.3%. In contrast for T18, over a third of tests had Z scores between 3 and 5. The PPV in this group is just over 5%. CONCLUSIONS: The present results show that the PPV performance of NIPT for fetal trisomies 13, 18, and 21 are closely associated with Z-score. The higher the Z-score, the greater the likelihood that the aneuploidy result is correct. Our experience in evaluating the Z-score accuracy of NIPT in this study could be of use in similar work.

Cytogenomic results following high-chance non-invasive prenatal testing: a UK national audit.

OBJECTIVE: Non-invasive prenatal testing (NIPT) is increasingly being adopted as a screening test in the UK and is currently accessed through certain National Health Service healthcare systems or by private provision. This audit aims to describe reasons for and results of cytogenomic investigations carried out within UK genetic laboratories following an NIPT result indicating increased chance of cytogenomic abnormality ('high-chance NIPT result'). METHOD: A questionnaire was sent out to 24 genetics laboratories in the UK and completed by 18/24 (75%). RESULTS: Data were returned representing 1831 singleton pregnancies. A total of 1329 (73%) invasive samples were taken following NIPT results showing a high chance of trisomy 21; this was confirmed in 1305 (98%) of these by invasive sampling. Trisomy 21 was confirmed in >99% of patients who also had high-screen risk results or abnormal scan findings. Amongst invasive samples taken due to NIPT results indicating a high chance of trisomy 18, 84% yielded a compatible result, and this number dropped to 49% for trisomy 13 and 51% for sex chromosomes. CONCLUSION: In the UK, the majority of patients having invasive sampling for high-chance NIPT results are doing so following an NIPT result indicating an increased chance of common trisomies (92%). In this population, NIPT performs particularly well for trisomy 21, but less well for other indications.

Cell-free DNA screening for aneuploidies in 7113 pregnancies: single Italian centre study.

INTRODUCTION: Non-invasive prenatal testing (NIPT) using cell-free foetal DNA has been widely accepted in recent years for detecting common foetal chromosome aneuploidies, such as trisomies 13, 18 and 21, and sex chromosome aneuploidies. In this study, the practical clinical performance of our foetal DNA testing was evaluated for analysing all chromosome aberrations among 7113 pregnancies in Italy. METHODS: This study was a retrospective analysis of collected NIPT data from the Ion S5 next-generation sequencing platform obtained from Altamedica Medical Centre in Rome, Italy. RESULTS: In this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomies 13, 18 and 21. Out of the 7113 samples analysed, 74 cases (1%) were positive by NIPT testing; foetal karyotyping and follow-up results validated 2 trisomy 13 cases, 5 trisomy 18 cases, 58 trisomy 21 cases and 10 sex chromosome aneuploidy cases. There were no false-negative results. CONCLUSION: In our hands, NIPT had high sensitivity and specificity for common chromosomal aneuploidies such as trisomies 13, 18 and 21.

Prevalence of mosaicism in uncultured chorionic villus samples after chromosomal microarray and clinical outcome in pregnancies affected by confined placental mosaicism.

OBJECTIVE: To evaluate the prevalence of mosaicism in chorionic villus sampling (CVS) samples after chromosomal microarray (CMA) and clinical outcome of pregnancies affected by confined placental mosaicism. METHOD: We retrieved all results from CMA, array-based comparative genomic hybridization, on CVS samples from January 2011 to November 2017 from Central and North Denmark Regions. Mosaic results from uncultured chorionic villi, cytotrophoblasts and mesenchymal cells, after CVS and follow-up on amniocytes, fetal tissue, or postnatal blood were studied and matched with clinical data from The Danish Fetal Medicine Database. RESULTS: Prevalence of mosaicism was 93 out of 2,288 (4.1%) CVS samples of which 17 (18.3%) concerned submicroscopic copy number variations (CNVs) <10 Mb. Follow-up analyses were performed in 62 cases. True fetal mosaicism (TFM) was confirmed in 18.4% (7/38) when mosaicism involved whole chromosome aneuploidy and in 25.0% (6/24), when involving a CNV (P = .59). Median birth weight z-score was higher in cases of confined placental mosaicism for a CNV (0.21) than cases involving whole chromosomes (-0.74) (P = .02). CONCLUSION: Prevalence of mosaicism in CVS samples is higher after CMA on uncultured tissue than after conventional karyotyping on cultured tissue. The risk of TFM is equally high in cases of mosaicism for CNVs and whole chromosomes.

Prenatal ultrasound findings of holoprosencephaly spectrum: Unusual associations.

OBJECTIVE: The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly (HPE). METHODS: Fetal neurosonograms, postnatal assessment, and chromosomal analysis were performed in a cohort of 25 fetuses with HPE. RESULTS: The prevalence of HPE in high-risk pregnancies was 4.4:10 000. The alobar subtype was the most frequently encountered, with 17 cases (68%). Interestingly, among them, four cases (16%) presented with the rare agnathia-otocephaly complex. Chromosomal abnormalities were detected in 11 cases (44%), the most frequent being trisomy 13 in seven cases (five alobar, one semilobar, and one lobar HPE), followed by trisomy 18 in two cases with semilobar HPE. One case of alobar HPE had 45, XX, t(18;22) (q10;q10), -18p karyotyping, and one case of semilobar HPE was associated with triploidy. Facial malformations in HPE spectrum ranged from cyclopia, proboscis, and arrhinia that were associated with the alobar subtype to hypotelorism and median cleft that were frequent among the semilobar and lobar subtypes. Associated neural tube defects were identified in 12% of cases. CONCLUSION: Our study illustrates the clinical and genetic heterogeneity of HPE and describes different chromosomal abnormalities associated with HPE.

Solid tumor screening recommendations in trisomy 18.

The purpose of this study was to determine whether trisomy 18 patients are at an increased risk of tumor development and require formal tumor screening recommendations. A literature search of trisomy 18 patients with reports of tumors or malignancies, and compilation of all previously reported as well as new unreported cases was performed. 67 patients with trisomy 18 were found to have documented malignancies. 44 patients had hepatoblastomas, 21 patients had Wilms tumors, one patient had a functional neurogenic neoplasia, and one patient had Hodgkins lymphoma. The increasing numbers of reported malignancies in patients with trisomy 18 supports the indication for an early screening process. Specific screening recommendations are outlined consisting of imaging exams and laboratory values performed at specific intervals.

Trisomy 13 and 18-Prevalence and mortality-A multi-registry population based analysis.

The aim of the study is to determine the prevalence, outcomes, and survival (among live births [LB]), in pregnancies diagnosed with trisomy 13 (T13) and 18 (T18), by congenital anomaly register and region. Twenty-four population- and hospital-based birth defects surveillance registers from 18 countries, contributed data on T13 and T18 between 1974 and 2014 using a common data-reporting protocol. The mean total birth prevalence (i.e., LB, stillbirths, and elective termination of pregnancy for fetal anomalies [ETOPFA]) in the registers with ETOPFA (n = 15) for T13 was 1.68 (95% CI 1.3-2.06), and for T18 was 4.08 (95% CI 3.01-5.15), per 10,000 births. The prevalence varied among the various registers. The mean prevalence among LB in all registers for T13 was 0.55 (95%CI 0.38-0.72), and for T18 was 1.07 (95% CI 0.77-1.38), per 10,000 births. The median mortality in the first week of life was 48% for T13 and 42% for T18, across all registers, half of which occurred on the first day of life. Across 16 registers with complete 1-year follow-up, mortality in first year of life was 87% for T13 and 88% for T18. This study provides an international perspective on prevalence and mortality of T13 and T18. Overall outcomes and survival among LB were poor with about half of live born infants not surviving first week of life; nevertheless about 10% survived the first year of life. Prevalence and outcomes varied by country and termination policies. The study highlights the variation in screening, data collection, and reporting practices for these conditions.

Cost-effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model-based analysis.

OBJECTIVE: To evaluate the cost-effectiveness of five prenatal screening strategies for trisomies (13/18/21) and other unbalanced chromosomal abnormalities (UBCA), following the introduction of cell-free DNA (cfDNA) analysis. METHODS: A model-based cost-effectiveness analysis was performed to estimate prevalence, safety, screening-program costs and healthcare costs of five different prenatal screening strategies, using a virtual cohort of 652 653 pregnant women in France. Data were derived from the French Biomedicine Agency and published articles. Uncertainty was addressed using one-way sensitivity analysis. The five strategies compared were: (i) cfDNA testing for women with a risk following first-trimester screening of ≥ 1/250; (ii) cfDNA testing for women with a risk of ≥ 1/1000 (currently recommended); (iii) cfDNA testing in the general population (regardless of risk); (iv) invasive testing for women with a risk of ≥ 1/250 (historical strategy); and (v) invasive testing for women with a risk of ≥ 1/1000. RESULTS: In our virtual population, at similar risk thresholds, cfDNA testing compared with invasive testing was cheaper but less effective. Compared with the historical strategy, cfDNA testing at the ≥ 1/1000 risk threshold was a more expensive strategy that detected 158 additional trisomies, but also 175 fewer other UBCA. Implementation of cfDNA testing in the general population would give an incremental cost-effectiveness ratio of €9 166 689 per additional anomaly detected compared with the historical strategy. CONCLUSION: Extending cfDNA to lower risk thresholds or even to all pregnancies would detect more trisomies, but at greater expense and with lower detection rate of other UBCA, compared with the historical strategy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Relación costo-eficacia de cinco estrategias de cribado prenatal para trisomías y otras anomalías cromosómicas no equilibradas: un análisis basado en modelos OBJETIVO: Evaluar la eficacia en función de los costos de cinco estrategias de cribado prenatal para trisomías (13/18/21) y otras anomalías cromosómicas no equilibradas (UBCA, por sus siglas en inglés), tras la introducción del análisis de ADN fetal (cfDNA, por sus siglas en inglés). MÉTODOS: Se realizó un análisis de la relación costo-eficacia basado en modelos para estimar la prevalencia, la seguridad, los costos de los programas de cribado y los costos sanitarios de cinco estrategias diferentes de cribado prenatal, para lo cual se usó una cohorte virtual de 652 653 mujeres embarazadas en Francia. Los datos se obtuvieron de la Agencia Francesa de Biomedicina y de artículos publicados. La incertidumbre se abordó mediante un análisis de sensibilidad unidireccional. Las cinco estrategias comparadas fueron: (i) pruebas de cfDNA para mujeres con un riesgo ≥1/250 después del examen del primer trimestre; (ii) pruebas de cfDNA para mujeres con un riesgo ≥1/1000 (las recomendadas actualmente); (iii) pruebas de cfDNA en la población general (independientemente del riesgo); (iv) pruebas invasivas para mujeres con un riesgo ≥1/250 (estrategia histórica); y (v) pruebas invasivas para mujeres con un riesgo ≥1/1000. RESULTADOS: En esta población virtual, con umbrales de riesgo similares, la prueba de cfDNA fue más barata pero menos efectiva en comparación con la prueba invasiva. En comparación con la estrategia histórica, la prueba de cfDNA para el umbral de riesgo de ≥1/1000 fue una estrategia más costosa que detectó 158 trisomías adicionales, pero también 175 menos de otras UBCA. La aplicación de las pruebas de cfDNA en la población general daría una relación costo-eficacia incremental de 9 166 689 EUR por cada anomalía adicional detectada en comparación con la estrategia histórica. CONCLUSIÓN: Extender las pruebas de cfDNA a umbrales de riesgo más bajos o incluso a todos los embarazos detectaría más trisomías, pero a un costo mayor y con una tasa de detección más baja de otras UBCA, en comparación con la estrategia histórica.

Clinical Validation of Non-Invasive Prenatal Testing for Fetal Common Aneuploidies in 1,055 Korean Pregnant Women: a Single Center Experience.

BACKGROUND: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA from maternal plasma for fetal aneuploidy identification is expanding worldwide. The objective of this study was to evaluate the clinical utility of NIPT for the detection of trisomies 21, 18, and 13 of high-risk fetus in a large Korean population. METHODS: This study was performed retrospectively, using stored maternal plasma from 1,055 pregnant women with singleton pregnancies who underwent invasive prenatal diagnosis because of a high-risk indication for chromosomal abnormalities. The NIPT results were confirmed by karyotype analysis. RESULTS: Among 1,055 cases, 108 cases of fetal aneuploidy, including trisomy 21 (n = 57), trisomy 18 (n = 42), and trisomy 13 (n = 9), were identified by NIPT. In this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomy 21, and 92.9% sensitivity and 100% specificity for trisomy 18, and 100% sensitivity and 99.9% specificity for trisomy 13. The overall positive predictive value (PPV) was 98.1%. PPVs for trisomies 21, 18, and 13 ranged from 90.0% to 100%. CONCLUSION: This study demonstrates that our NIPT technology is reliable and accurate when applied to maternal DNA samples collected from pregnant women. Further large prospective studies are needed to adequately assess the performance of NIPT.

Epidemiology of chromosomal trisomies in the East of Ireland.

Background: Chromosomal trisomies are associated with advancing maternal age. In Ireland, information on the total prevalence and outcome of trisomy affected pregnancies is unavailable. This study aimed to ascertain more precise data on Trisomies 21, 18 and 13 in a large Irish region during the period 2011-2013. Methods: Multiple information sources were used in case finding, including a regional congenital anomaly register, all maternity and paediatric hospitals in the region and the regional Department of Clinical Genetics. Results: There were 394 trisomy cases from 80 894 total births, of which 289 were Trisomy 21, 75 were Trisomy 18 and 30 were Trisomy 13. The total prevalence rate was 48.9/10 000 births, 35.7, 9.3 and 3.7 for Trisomies 21, 18 and 13, respectively. Over 90% of Trisomies 18/13 and 47% of Trisomy 21 were diagnosed prenatally; 61% of Trisomy 21 cases and nearly 30% of Trisomies 18/13 were live births; 38% all trisomy affected pregnancies ended in a termination. Conclusions: This study provides precise data on the total prevalence and outcome of trisomy affected pregnancies in the East of Ireland. Total prevalence rates were higher than previously reported. Prenatal diagnosis had a significant impact on outcome. These data provide a better basis for planning of services for live-born children affected by trisomy.

Prevalence and clinical characterization of oral clefts in patients with chromosome trisomy 18.

OBJECTIVE: To verify the prevalence and perform the clinical characterization of oral clefts in a sample of patients with trisomy of chromosome 18 in Southern Brazil. METHODS: This was a retrospective cross-sectional study, performed in a reference clinical genetic service in Southern Brazil. The initial sample consisted of 77 patients diagnosed in the neonatal period with trisomy 18 treated at the Clinical Genetics Service of a referral hospital at Federal University of Health Sciences of Porto Alegre (UFCSPA). The patients' diagnosis was confirmed by karyotype and care was provided during their stay in the intensive care unit (ICU) of the hospital that is a reference in Southern Brazil for care for malformed patients. The period covered was from 1975 to 2020. RESULTS: During the study period, 77 patients diagnosed with trisomy 18 were treated, most of them in the ICU. Of these, 13 individuals were excluded due to incomplete data. The final sample consisted of 64 patients with an average age of 2.4 years of life, ranging from one day to 16 years old, the majority of whom were female. Regarding face dysmorphisms identified in the sample, three (4,68%) patients had cleft lip and two (3,11%) had cleft lip and palate. CONCLUSIONS: This study contributed to the recognition of the characteristics and prevalence of oral clefts in individuals with trisomy 18 in a sample of patients from Southern Brazil. In addition, we described the clinical alterations found in patients with oral clefts, as well as other associated comorbidities, such as cardiac, neurological and pulmonary comorbidities, as well as cranial and facial dysmorphisms.

Prenatal screening tests and prevalence of fetal aneuploidies in a tertiary hospital in Thailand.

This study evaluated prenatal screening test performance and the prevalence of common aneuploidies at Siriraj Hospital, Thailand. We collected data from screening tests which are first-trimester test, quadruple test, and noninvasive prenatal tests (NIPT) between January 2016 and December 2020. Thirty percent (7,860/25,736) of pregnancies received prenatal screening tests for aneuploidies disorders, and 17.8% underwent prenatal diagnosis tests without screening. The highest percentage of screening tests was first-trimester test (64.5%). The high-risk results were 4% for first-trimester test, 6.6% for quadruple test, and 1.3% for NIPT. The serum screening tests for trisomy 13 and 18 had no true positives; therefore, we could not calculate sensitivity. For the first-trimester test, the sensitivity for trisomy 21 was 71.4% (95% confidence intervals (CI) 30.3-94.9); specificity for trisomy 13 and 18 was 99.9% (95% CI 99.8-99.9); and for trisomy 21 was 96.1% (95% CI 95.6-96.7). For the quadruple test, the specificity for trisomy 18 was 99.6% (95% CI 98.9-99.8), while the sensitivity and specificity for trisomy 21 were 50% (95% CI 26.7-97.3) and 93.9% (95% CI 92.2-95.3), respectively. NIPT had 100% sensitivity and specificity for trisomy 13, 18 and 21, and there were neither false negatives nor false positives. For pregnant women < 35 years, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.28 (95% CI 0.12-0.67), 0.28 (95% CI 0.12-0.67), and 0.89 (95% CI 0.54-1.45), respectively. For pregnant women ≥35 years, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.26 (95% CI 0.06-1.03), 2.59 (95% CI 1.67-4.01), and 7.25 (95% CI 5.58-9.41), respectively. For all pregnancies, the prevalence of trisomy 13, 18, and 21 per 1,000 births was 0.27 (95% CI 0.13-0.57), 0.97 (95% CI 0.66-1.44), 2.80 (95% CI 2.22-3.52), respectively.