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.

Falsos positivos del cribado de trisomía 21 y 18 del primer trimestre y complicaciones obstétricas / Adverse outcomes in pregnancies with false positive trisomy 21 and 18 screening results

OBJETIVO: Analizar si los casos positivos de cribado combinado de trisomía 21 (t21) o trisomía 18 (t18) en ausencia de aneuploidía (falsos positivos- FP) se relacionan con complicaciones de la gestación, ajustando por factores demográficos y clínicos de riesgo. MATERIAL Y MÉTODOS: Estudio retrospectivo de casos y controles anidado en una cohorte de pacientes que acudieron para cribado del primer trimestre. Los casos fueron las pacientes con FP de riesgo combinado de t21 superior a 1/270 o riesgo de t18 superior a 1/100. Se consideraron complicaciones de la gestación: óbito fetal, parto prematuro menor de 34 semanas o prematuro menor de 37 semanas, preeclampsia, retrasos de crecimiento, pequeño para la edad gestacional (CIR, PEG) y diabetes gestacional (DG). Se ajustó por obesidad, edad, paridad, tabaquismo, y técnicas de reproducción asistida. RESULTADO: Se obtuvieron 204 casos de FP, 149 FP para trisomía 21, 41 para trisomía 18, y 14 FP para ambos riesgos. Se encontró asociación estadísticamente significativa de FP t21 con óbito fetal (OR=3,5; ic95% 1,4-8,7; p=0,01), parto prematuro menor de 37 semanas (OR=2,2; IC95% 1,4-3,4; p=0,001), preeclampsia (OR =2,6; IC95% 1,17-6,1; p=0,02), PEG (OR =2,2; IC95% 1,2-4,1; p=0,02), CIR (OR=2,8; IC95% 1,6-5,1; p=0,001), y DG (OR=2,1; IC95% 1,2-3,7; p=0,01). Los FP t18 se asociaron con óbito (OR=8,9; IC95% 2,9-27; p=0,002). CONCLUSIÓN: Los FP del cribado del primer trimestre, para trisomía 21 y trisomía 18, se asocian con resultados obstétricos adversos.

We have studied whether positive cases of combined trisomy 21 (t21) or 18 (t18) screening in the absence of aneuploidy (false positives -FP-) are related to pregnancy complications adjusting for demographic and clinical risk factors. METHODS: Retrospective case-control study nested in a cohort of patients who came for first trimester aneuploidy screening. The cases were patients with FP combined risk of t21 (greater than 1/270) or t18 risk (greater than 1/100). The control group was a sample of patients with low-risk screening. We considered pregnancy complications: stillbirth, premature delivery before 34 and 37 weeks, preeclampsia, growth retardation, small for gestational age (FGR, SGA), and gestational diabetes (GD). Or were adjusted for obesity, age, parity, smoking, and assisted reproduction techniques. RESULTS: 204 cases of FP were obtained, 149 FP for trisomy 21, 41 for trisomy 18, and 14 FP for both risks. A statistically significant association between t21 FP was found with stillbirth (OR = 3.5; 95% CI 1.4-8.7; p = 0.01), preterm delivery less than 37 weeks (OR = 2.2; 95% CI 1.4-3.4; p = 0.001), preeclampsia (OR = 2.6; 95% CI 1.17-6.1; p = 0.02), SGA (OR = 2.2; 95% CI 1, 2-4.1; p = 0.02), FGR (OR = 2.8; 95% CI 1.6-5.1; p = 0.001), and GD (OR = 2.1; 95% CI 1.2 −3.7; p = 0.01). FP t18s were associated with fetal loss (OR= 8.9 (95% CI 2.9-27) p = 0.002. CONCLUSION: FP from first trimester screening for t21 and t18 are associated with adverse obstetric outcomes.

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.

Trisomía 9, trisomía 13 y trisomía 18: resultados del análisis citogenético prenatal, Hospital Clínico Universidad de Chile, años 2000-2017 / Trisomy 9, trisomy 13 and trisomy 18: results of the prenatal cytogenical analysis, Hospital Clínico Universidad de Chile, years 2000-2017

INTRODUCCIÓN: En Chile, la norma técnica de la Ley N° 21.030 de 2017 considera tres aneuploidías como letales; las trisomías 9, 13 y 18, cuyo diagnóstico se confirma con un cariograma. No existe a la fecha registro nacional de frecuencia prenatal de estas patologías. OBJETIVO: Determinar la frecuencia de trisomías 9, 13 y 18 en los estudios citogenéticos prenatales en muestras de células obtenidas con amniocentesis y cordocentesis, procesados en el Laboratorio de Citogenética del Hospital Clínico Universidad de Chile. MATERIALES Y MÉTODOS: Estudio descriptivo y retrospectivo de los resultados de cariograma de líquido amniótico (LA) y sangre fetal (SF), procesados desde enero de 2000 a diciembre de 2017. RESULTADOS: Se incluyeron 2.305 muestras (402 de SF y 1.903 de LA), de ellas 442 (19%) fueron trisomías letales (TL), dentro de ellas fueron TL libres 416 (95%), TL estructurales 15 (2,7%) y mosaicos 11 (2,3%). La trisomía 18 fue en ambos tipos de muestra la más frecuente (73,5%), seguida de trisomía 13 (24,2%) y trisomía 9 (2,3%). Se desglosan resultados conforme al tipo de TL, muestra, motivo de derivación, edad materna y edad gestacional. CONCLUSIONES: El cariograma confirma el diagnóstico de aneuploidías y aporta datos relevantes para el consejo genético. La cromosomopatía letal más frecuente fue la trisomía 18. Se observó que uno de cada cinco cariogramas referidos por anomalías congénitas y/o marcadores de aneuploidía revelaban una TL.

INTRODUCTION: In Chile, the technical standard of Law No. 21,030 of 2017 considers three aneuploidies as lethal; trisomies 9, 13 and 18, whose diagnosis is confirmed with a Karyotype. To date there is not a national registry of prenatal frequency of these pathologies. OBJECTIVE: To determine the frequency of trisomies 9, 13 and 18 in prenatal cytogenetic studies in samples of cells obtained with amniocentesis and cordocentesis, processed in the Cytogenetics Laboratory of the Universidad de Chile Clinical Hospital. MATERIALS AND METHODS: Descriptive and retrospective study of the results of karyotypes of amniotic fluid (LA) and fetal blood (SF) processed from January 2000 to December 2017. Results: 2,305 samples (402 of SF and 1,903 of LA) were included, of which 438 (19%) were lethal trisomies (TL), corresponding to free TL 416 (95%), structural TL 12 (2,7%) and mosaics 10 (2.3%). Trisomy 18 was the most frequent in both types of sample (73,5 %), followed by trisomy 13 (24,2%) and trisomy 9 (2.3%). RESULTS are shown according to the type of TL, sample, reason for referral, maternal age and gestational age. CONCLUSIONS: The karyotype confirms the diagnosis of aneuploidies and provides relevant data for genetic counseling. The most frequent lethal chromosomopathy was trisomy 18. It was observed that one in five karyotypes referred for congenital anomalies and / or aneuploidy markers revealed a TL.

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.

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.

The indications for early prenatal diagnosis of trisomy 18: a 7-year experience at mainland China.

Objective: To report the experience with first-trimester prenatal detection of pregnancies complicated by trisomy 18.Study design: Proven cases of trisomy 18 identified between 11 and 14 weeks of gestation were retrospectively reviewed. Information on maternal demographics, prenatal sonographic findings, indications for prenatal diagnosis and chromosomal analysis results was obtained by reviewing medical records.Results: During the 7-year period from January 2011 to December 2017, 89 cases of full trisomy 18 had first-trimester indications for prenatal diagnosis at Guangzhou Women and Children's Medical Center. Eighty-five (95.5%) had abnormal sonographic findings in the first trimester. The most common finding was increased nuchal translucency (55.1%), followed by cystic hygroma (18.0%), omphalocele (14.6%), and fetalis hydrops (11.2%). Four cases (4.5%) were not associated with any abnormal first-trimester sonographic finding, and were diagnosed because of routine positive screening results for trisomy 18. A single case was diagnosed because of a positive cell-free DNA (cfDNA) result.Conclusion: These results demonstrate that a large number of fetuses with trisomy 18 have abnormal sonographic findings in the first trimester, and support the continued utility of first-trimester sonographic examination in the diagnosis of this trisomy even with the availability of cfDNA.

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.

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.

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.

The prevalence of selected major birth defects in the United States.

Although collectively they are fairly common, birth defects receive limited attention as a group of outcomes either clinically or from a public health perspective. This article provides an overview of the prevalence, trends and selected socio-demographic risk factors for several major birth defects, including neural tube defects, cranio-facial anomalies, congenital heart defects, trisomies 13, 18, and 21, and gastroschisis and omphalocele. Attention should focus on strengthening existing registries, creating birth defects surveillance programs in states that do not have them, and standardizing registry methods so that broadly national data to monitor these trends are available.