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1.
J Korean Med Sci ; 34(24): e172, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31222985

RESUMO

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.


Assuntos
Aberrações Cromossômicas , Síndrome de Down/diagnóstico , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Adulto , Aneuploidia , Estudos de Casos e Controles , Ácidos Nucleicos Livres/metabolismo , Síndrome de Down/genética , Feminino , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal , República da Coreia , Estudos Retrospectivos , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/epidemiologia , Adulto Jovem
2.
Clin Chim Acta ; 495: 263-268, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30998911

RESUMO

BACKGROUND: Noninvasive prenatal screening (NIPS) has higher sensitivity and specificity compared to traditional prenatal screening. Nevertheless, the discordant results between the NIPS and prenatal diagnosis were occasionally reported. In current study, we investigated the genetic basis of a T18 fetus with a discordant trisomy 5 (T5) positive and trisomy 18 (T18) negative NIPS result. METHODS: NIPS was used to detect fetal DNA in maternal circulating plasma based on semiconductor sequencing platform. The aneuploidies of the fetus and different part of placental tissues were investigated by copy number variation sequencing (CNV-seq) and chromosome microarray analysis (CMA). RESULTS: The positive result of T5 was detected for the pregnant woman in NIPS, while T18 was found in the fetal karyotyping analysis after amniocentesis. Furthermore, placental mosaicism of T5 and T18 was found by CNV-seq and CMA, which revealed the mosaic ratio of T5 was gradually increased from umbilical cord to the placenta center, while that of T18 was gradually decreased. CONCLUSION: For the reason of cell-free fetal DNA (cff DNA) in the maternal circulation originates from trophoblast cells of placenta, the level of placental mosaicism could cause false negative NIPS result in multiple aneuploidies. The present study proved that a discordant T5 positive and T18 negative NIPS result was caused by placental mosaicism. This study highlights placental mosaicism as a significant risk factor for discordant NIPS results. The result will be helpful for genetic counseling and clinical management of such pregnant woman.


Assuntos
Feto/metabolismo , Mosaicismo , Placenta/metabolismo , Diagnóstico Pré-Natal , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Adulto , Variações do Número de Cópias de DNA , Reações Falso-Positivas , Feminino , Humanos , Gravidez
3.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948683

RESUMO

We present a case in which a fetal diagnosis of complex congenital heart disease and trisomy 18 led to a series of decisions for an infant who was critically ill. The parents wanted everything done. The surgeons believed that surgery would be futile. The parents publicized the case on social media, which led to publicity and pressure on the hospital. The case reveals the intersection of parental values, clinical judgments, ethics consultation, insurance company decisions about reimbursement, and social media publicity. Together, these factors complicate the already delicate ethical deliberations and decisions.


Assuntos
Tomada de Decisão Clínica/ética , Consultoria Ética/ética , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Pais/psicologia , Mídias Sociais/ética , Síndrome da Trissomía do Cromossomo 18/cirurgia , Tomada de Decisão Clínica/métodos , Evolução Fatal , Humanos , Síndrome do Coração Esquerdo Hipoplásico/complicações , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico , Lactente , Masculino , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/diagnóstico
4.
Ont Health Technol Assess Ser ; 19(4): 1-166, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30847010

RESUMO

Background: Pregnant people have a risk of carrying a fetus affected by a chromosomal anomaly. Prenatal screening is offered to pregnant people to assess their risk. Noninvasive prenatal testing (NIPT) has been introduced clinically, which uses the presence of circulating cell-free fetal DNA in the maternal blood to quantify the risk of a chromosomal anomaly. At the time of writing, NIPT is publicly funded in Ontario for pregnancies at high risk of a chromosomal anomaly. Methods: We completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, budget impact, and patient preferences related to NIPT. We performed a systematic literature search for studies on NIPT for trisomies 21, 18, and 13, sex chromosome aneuploidies, and microdeletions in the average-risk or general population. We evaluated the cost-effectiveness of traditional prenatal screening, NIPT as a second-tier test (performed after traditional prenatal screening), and NIPT as a first-tier test (performed instead of traditional prenatal screening). We also conducted a budget impact analysis to estimate the additional costs of funding first-tier NIPT. We interviewed people who had lived experience with NIPT and people living with the conditions NIPT screens for, or their families. Results: The pooled clinical sensitivity of NIPT in the average-risk or general population was 99.5% (95% confidence interval [CI] 81.8%-99.9%) for trisomy 21, 93.1% (95% CI 75.9%-98.3%) for trisomy 18, and 92.7% (95% CI 81.6%-99.9%) for trisomy 13. The clinical specificity for any trisomy was 99.9% (95% CI 99.8%-99.9%). Compared with traditional prenatal screening, NIPT was more accurate in detecting trisomies 21, 18, and 13, and decreased the need for diagnostic testing. We found limited evidence on NIPT for sex chromosome aneuploidies or microdeletions in the average-risk or general population. Positive NIPT results should be confirmed by diagnostic testing.Compared with traditional prenatal screening, second-tier NIPT detected more affected fetuses, substantially reduced the number of diagnostic tests performed, and slightly reduced the total cost of prenatal screening. Compared with second-tier NIPT, first-tier NIPT detected more affected cases, but also led to more diagnostic tests and additional budget of $35 million per year for average-risk pregnant people in Ontario.People who had undergone NIPT were largely supportive of the test and the benefits of earlier, more accurate results. However, many discussed the need for improved pre- and post-test counselling and raised concerns about the quality of the information they received from health care providers about the conditions NIPT can screen for. Conclusions: NIPT is an effective and safe prenatal screening method for trisomies 21, 18, and 13 in the average-risk or general population. Compared with traditional prenatal screening, second-tier NIPT improved the overall performance of prenatal screening and slightly decreased costs. Compared with second-tier NIPT, first-tier NIPT detected more chromosomal anomalies, but resulted in a considerable increase in the total budget. Interviewees were generally positive about NIPT, but they raised concerns about the lack of good informed-choice conversations with primary care providers and the quality of the information they received from health care providers about chromosomal anomalies.


Assuntos
Síndrome de Down/diagnóstico , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Análise Custo-Benefício , Testes Diagnósticos de Rotina , Feminino , Custos de Cuidados de Saúde , Humanos , Gravidez , Diagnóstico Pré-Natal/economia , Diagnóstico Pré-Natal/normas , Sensibilidade e Especificidade
5.
Clin Rheumatol ; 38(5): 1251-1255, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30919147

RESUMO

BACKGROUND: Prenatal diagnosis of fetal trisomy 21 and other chromosomal abnormalities is based on invasive tests, such as amniocentesis and chorionic villus sampling, which are carried out in women identified through screening as being at high risk for these abnormalities. The most widely used method of screening is the first-trimester combined test which utilizes maternal age, and measurements of fetal nuchal translucency thickness (NT) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free ß-human chorionic gonadotropin (hCG). OBJECTIVES: To assess the influence of SLE on the levels of NT, PAPP-A, and ß-hCG and whether any alterations in such levels may increase the rate of false positives and the subsequent number of invasive tests. METHOD: This was a prospective first-trimester screening study for trisomies 21, 18, and 13 by a combination of maternal age, fetal nuchal translucency thickness, and serum PAPP-A and ß-hCG at King's College Hospital, London, between March 2006 and February 2011. The study population included 47 cases with maternal SLE and 45,493 without SLE. The results of biomarkers in the SLE and non-SLE groups were compared. RESULTS: In the SLE group, compared to the non-SLE group, there were no significant differences in median maternal age, fetal NT, or serum PAPP-A MoM, but serum free ß-hCG MoM was increased (1.402, IQR 0.872-2.290 vs 0.994, IQR 0.676-1.508). CONCLUSION: In first trimester screening for trisomies, the measured value of free ß-hCG should be adjusted for maternal SLE to avoid false positive results and overuse of invasive tests.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Doenças Fetais/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Medição da Translucência Nucal , Proteína Plasmática A Associada à Gravidez/análise , Adulto , Síndrome de Down/diagnóstico , Feminino , Humanos , Londres , Gravidez , Complicações na Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Medição de Risco , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico
6.
Medicine (Baltimore) ; 98(12): e14773, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896619

RESUMO

BACKGROUND AND OBJECTIVE: Ductus venosus (DV) Doppler has been suggested as a biomarker for the early screening of trisomy diseases. However, results from different studies have been largely inconsistent. This study aimed to investigate the relationship between DV and top 3 fetal aneuploidies by a systematical meta-analysis: trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13). METHODS: We performed a literature search covering articles from Medline, PubMed, RePORTER, and Elsevier publications. DV-T21/T18/T13 relation data were extracted from 9, 7, and 6 previous studies, respectively, including 31,053, 28,092 and 26,721 pregnant women worldwide. Both random-effects and fixed-effect model were used to study the log odds ratio (LOR) of T21, T18, and T13 in case of DV. Four potential influential factors were studied using a multiple linear regression (MLR) model, including maternal age, data age, sample size, and population region. RESULTS: DV was significantly related to T21, T18, and T13 (LOR = 3.44, 3.89 and 3.46; P value <2.1E-13). Significant between-study variance was observed for T21 (P value <1.71E-14), but not for T18 (P value >.05) and T13 (P value >.87). MLR results suggested that significant influential factors could include population region (P value <.0021), but not sample size, data age, and maternal age (P value >.078). CONCLUSIONS: Integrating DV could help in the detection of trisomy. However, accuracy and validity may vary depending on the population regions, which need further study.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Síndrome de Down/diagnóstico , Feto/irrigação sanguínea , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Ultrassonografia Pré-Natal/métodos , Biomarcadores , Feminino , Humanos , Idade Materna , Gravidez , Primeiro Trimestre da Gravidez , Características de Residência , Ultrassonografia Doppler
7.
BMC Pregnancy Childbirth ; 19(1): 27, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642270

RESUMO

BACKGROUND: Non-invasive prenatal testing (NIPT) can be used to accurately detect fetal chromosomal anomalies early in pregnancy by assessing cell-free fetal DNA present in maternal blood. The rapid diffusion of NIPT, as well as the ease and simplicity of the test raises concerns around informed decision-making and the potential for routinization. Introducing NIPT in a way that facilitates informed and autonomous decisions is imperative to the ethical application of this technology. We approach this imperative by systematically reviewing and synthesizing primary qualitative research on women's experiences with and preferences for informed decision-making around NIPT. METHODS: We searched multiple bibliographic databases including Ovid MEDLINE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), and ISI Web of Science Social Sciences Citation Index (SSCI). Our review was guided by integrative qualitative meta-synthesis, and we used a staged coding process similar to that of grounded theory to conduct our analysis. RESULTS: Thirty empirical primary qualitative research studies were eligible for inclusion. Women preferred to learn about NIPT from their clinicians, but they expressed dissatisfaction with the quality and quantity of information provided during counselling and often sought information from a variety of other sources. Women generally had a good understanding of test characteristics, and the factors of accuracy, physical risk, and test timing were the critical information elements that they used to make informed decisions around NIPT. Women often described NIPT as easy or just another blood test, highlighting threats to informed decision-making such as routinization or a pressure to test. CONCLUSIONS: Women's unique circumstances modulate the information that they value and require most in the context of making an informed decision. Widened availability of trustworthy information about NIPT as well as careful attention to the facilitation of counselling may help facilitate informed decision-making. TRIAL REGISTRATION: PROSPERO 2018 CRD42018086261 .


Assuntos
Tomada de Decisões , Consentimento Livre e Esclarecido , Gestantes , Diagnóstico Pré-Natal/psicologia , Ácidos Nucleicos Livres/sangue , Comportamento de Escolha , Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Feminino , Humanos , Preferência do Paciente , Gravidez , Pesquisa Qualitativa , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/sangue , Síndrome da Trissomía do Cromossomo 18/diagnóstico
8.
BMC Pregnancy Childbirth ; 19(1): 22, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630440

RESUMO

BACKGROUND: Canadian policies regarding the implementation and public coverage of non-invasive prenatal testing (NIPT) are heterogeneous and shifting, with NIPT being publicly covered for high-risk pregnancies in some provinces, but not others. Such a diverse and evolving policy landscape provides fertile ground for examining the preferences of pregnant women, their partners, and health professionals regarding the implementation and coverage of NIPT by the public healthcare system, as well as the factors influencing their preferences, which is what the present study does. METHODS: In this paper, we report the results of three-large scale Canadian surveys, in which 882 pregnant women, 395 partners of pregnant women, and 184 healthcare professionals participated. RESULTS: The paper focuses on preferences regarding how and when NIPT should be used, as well as the factors influencing these preferences, and how coverage for NIPT should be provided. These are correlated with respondents' levels of knowledge about Down syndrome and testing technologies and with their stated intended use of NIPT results. CONCLUSION: Salient is the marked difference between the preferences of prospective parents and those of healthcare professionals, which has potential implications for Canadian policy regarding NIPT implementation and insurance coverage.


Assuntos
Atitude do Pessoal de Saúde , Ácidos Nucleicos Livres/sangue , Síndrome de Down/diagnóstico , Preferência do Paciente , Gestantes , Diagnóstico Pré-Natal , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto , Canadá , Síndrome de Down/sangue , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Política de Saúde , Humanos , Cobertura do Seguro , Masculino , Pessoa de Meia-Idade , Gravidez , Gravidez de Alto Risco , Sensibilidade e Especificidade , Cônjuges , Inquéritos e Questionários , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomía do Cromossomo 18/sangue
9.
Ultrasound Obstet Gynecol ; 53(1): 73-79, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30014528

RESUMO

OBJECTIVE: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF). METHODS: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively. RESULTS: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%). CONCLUSIONS: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.


Assuntos
Algoritmos , Ácidos Nucleicos Livres/análise , Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Adolescente , Adulto , Transtornos Cromossômicos/sangue , Transtornos Cromossômicos/genética , Estudos de Coortes , Síndrome de Down/diagnóstico , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gravidez , Fatores de Risco , Sensibilidade e Especificidade , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto Jovem
10.
Ultrasound Obstet Gynecol ; 53(2): 208-213, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353581

RESUMO

OBJECTIVE: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13, contingent on the results of the first-trimester combined test in twin pregnancy. METHODS: Screening for trisomies 21, 18 and 13 was carried out in 959 twin pregnancies by assessment of a combination of maternal age, fetal nuchal translucency thickness, and serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-13 weeks' gestation in two UK NHS hospitals. Women in the high-risk group (risk ≥ 1 in 100) were offered the option of invasive testing, cfDNA testing or no further testing, and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates. RESULTS: In 42 (4.4%) of the 959 pregnancies, there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow-up. The 917 pregnancies with known trisomic status of both twins included six that were discordant for trisomy 21, four that were discordant for trisomy 18 and 907 with no trisomy 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.1%) and 667 (72.7%) of the pregnancies were classified as high risk, intermediate risk and low risk, respectively. The high-risk group included five (83.3%) cases of trisomy 21 and three (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included six pregnancies with trisomy 21, three with trisomy 18 and 206 with no trisomy 21, 18 or 13. The cfDNA test classified correctly as screen positive all six cases of trisomy 21 and two of the three with trisomy 18, and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening led to prenatal detection of all cases of trisomy 21 and three of four with trisomy 18. CONCLUSION: This study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.


Assuntos
Ácidos Nucleicos Livres/sangue , Síndrome de Down , Gravidez de Gêmeos/estatística & dados numéricos , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Adulto , Estatura Cabeça-Cóccix , Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Humanos , Programas de Rastreamento/métodos , Idade Materna , Testes para Triagem do Soro Materno/estatística & dados numéricos , Medição da Translucência Nucal , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez/sangue , Estudos Prospectivos , Medição de Risco , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/sangue , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
11.
Expert Rev Mol Diagn ; 19(2): 189-196, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582381

RESUMO

OBJECTIVES: This study was aimed to report the clinical characteristics of fetal chromosomal aneuploidy diseases using noninvasive prenatal testing (NIPT) in twin pregnancies and analyze the results in terms of chorionicity, conception, and fetal fraction. METHODS: A total of 1160 women with twin pregnancies were recruited from 1 October 2015, to 1 August 2017. Next-generation sequencing technology was used to detect fetal aneuploidies, such as trisomy 21, trisomy 18, trisomy 13 and trisomy X. RESULTS: Aneuploidy was detected using NIPT in 26 fetuses, among which 18 fetal aneuploidies occurred in only one fetus of the twins. The rate of aneuploidy was 1.3% for dichorionic diamniotic twins and 0.5% for monochorionic diamniotic twins, respectively. The rate of aneuploidy was 1.2% for spontaneous pregnancy group and 1.1% for assisted reproductive technologies group. CONCLUSION: In this study, detection of trisomy 21, trisomy 18, trisomy 13, and X abnormality in twin pregnancies was confirmed to be accurate. The aneuploidies mostly occurred in only one fetus of the twins, and trisomy 21 was the most common type. The prenatal diagnostic standard for NIPT in singleton pregnancies could perform well in twin pregnancies, which means NIPT can be popularized as routine prenatal screening in twin pregnancies.


Assuntos
Síndrome de Down , Doenças Fetais , Gravidez de Gêmeos , Diagnóstico Pré-Natal , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Trissomia , Cromossomos Humanos X/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Testes Genéticos , Humanos , Gravidez , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/diagnóstico , Trissomia/genética , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
12.
Rev Med Liege ; 73(12): 640-644, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30570236

RESUMO

Screening for chromosomal abnormality such as trisomy 18 in a bichorial-biamniotic twin pregnancy is based on ultrasound and a non-invasive prenatal test (NIPT) from 12 weeks of gestation. An invasive examination such as amniocentesis is necessary for a diagnostic confirmation. The management of these complicated cases consists in performing a selective feticide in the first or third trimester of pregnancy. Trisomy 18 most often results from a chromosomal nondisjunction of maternal origin. Indeed, advanced maternal age is a major cause of chromosomal abnormality and a promoting factor of twin pregnancies. This is a severe condition with a very high stillbirth rate, even though there are certain cases where babies have managed to survive for several years.


Assuntos
Gravidez de Gêmeos , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto , Amniocentese , Feminino , Humanos , Gravidez , Redução de Gravidez Multifetal , Diagnóstico Pré-Natal
13.
PLoS One ; 13(12): e0207840, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30517156

RESUMO

With the advance of next-generation sequencing (NGS) technologies, non-invasive prenatal testing (NIPT) has been developed and employed in fetal aneuploidy screening on 13-/18-/21-trisomies through detecting cell-free fetal DNA (cffDNA) in maternal blood. Although Z-test is widely used in NIPT NGS data analysis, there is still necessity to improve its accuracy for reducing a) false negatives and false positives, and b) the ratio of unclassified data, so as to lower the potential harm to patients as well as the induced cost of retests. Combining the multiple Z-tests with indexes of clinical signs and quality control, features were collected from the known samples and scaled for model training using support vector machine (SVM). We trained SVM models from the qualified NIPT NGS data that Z-test can discriminate and tested the performance on the data that Z-test cannot discriminate. On screenings of 13-/18-/21-trisomies, the trained SVM models achieved 100% accuracies in both internal validations and unknown sample predictions. It is shown that other machine learning (ML) models can also achieve similar high accuracy, and SVM model is most robust in this study. Moreover, four false positives and four false negatives caused by Z-test were corrected by using the SVM models. To our knowledge, this is one of the earliest studies to employ SVM in NIPT NGS data analysis. It is expected to replace Z-test in clinical practice.


Assuntos
Síndrome de Down/diagnóstico , Diagnóstico Pré-Natal/métodos , Máquina de Vetores de Suporte , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto , Diagnóstico por Computador/métodos , Diagnóstico por Computador/estatística & dados numéricos , Diagnóstico Diferencial , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Aprendizado de Máquina , Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Estudos Retrospectivos , Análise de Sequência de DNA , Adulto Jovem
14.
Medicine (Baltimore) ; 97(35): e12045, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30170416

RESUMO

To establish gestational age-specific and body weight-specific mid-trimester normal median equations for the prenatal serum markers α-fetoprotein (AFP), free ß subunit human chorionic gonadotropin (fßHCG), and unconjugated oestriol (uE3) for a Chinese population; to compare and replace the median equations built in LifeCycle software; to evaluate the effect of equations used for gestation correction on estimating risk in Down's syndrome, Edward's syndrome, and neural tube defect (NTD).A total of 353,065 cases of prenatal screening data of pregnant women were screened by 13 prenatal screening institutions in China. The local median equations of each institution and the large data were fitted by the least square regression, and then the difference was compared between large data equations and local median equations. The applicability of the localized median equations was evaluated by the determination coefficient. Based on the established median equations, multiples of median (MoM) of each values were calculated and compared with the latest Down's syndrome quality assurance support service (DQASS).There is no significant difference between the local median equations of each institution and the large sample median equations, which are various from LifeCycle built-in median equations. Besides, the determination coefficient of localized median equations are >0.99. 97.0% MoM medians obtained by using local median equations are consistent with latest standard of DQASS.The median established by large sample data represents the median level of a Chinese population, and can be used to replace the software built-in median equations to achieve better screening results.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Estriol/sangue , Diagnóstico Pré-Natal/métodos , alfa-Fetoproteínas/análise , Adulto , Biomarcadores , China , Diagnóstico Diferencial , Síndrome de Down , Feminino , Idade Gestacional , Humanos , Defeitos do Tubo Neural/diagnóstico , Gravidez , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal/normas , Valores de Referência , Síndrome da Trissomía do Cromossomo 18/diagnóstico
16.
J Obstet Gynaecol Can ; 40(10): 1295-1301, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30025867

RESUMO

OBJECTIVES: To assess the performance of first trimester combined screening (FTS) when enhanced with placental growth factor and alpha feto-protein in the detection of trisomies 18 and 13. METHODS: A retrospective case-control study. Marker parameters were derived using frozen serum samples. Multivariate Gaussian modelling predicted the detection rate (DR) and false-positive rate (FPR) for trisomies 18 and 13 with FTS and enhanced first trimester screening (eFTS) using the risk of trisomy 21 alone and an additional risk cut-off for trisomy 18, or trisomies 18 or 13. RESULTS: There were 83 trisomy 18, 22 trisomy 13, and 588 controls. The median placental growth factor levels in trisomies 18 and 13 were 0.75 and 0.65 multiple of the median of controls, respectively (both P < 0.0001). There were no statistically significant differences in alpha feto-protein levels. Modelling predicts that using a trisomy 21 risk cut-off alone, at FPR of 3%, eFTS increases the DR for trisomies 18 and 13 by 0.6-0.8% compared with FTS. Additionally using a trisomy 18 risk cut-off, at an extra FPR of 0.2%, eFTS increased the DR by 0.6-0.9% over FTS; using a trisomy 18 or 13 risk cut-off did not further increase detection for FTS or eFTS. The increase in DR was greater at higher FPR. CONCLUSION: eFTS increases the detection of trisomies 18 and 13 to a small extent.


Assuntos
Fator de Crescimento Placentário/sangue , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , alfa-Fetoproteínas/análise , Adulto , Aneuploidia , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomía do Cromossomo 18/sangue
17.
J Med Screen ; 25(4): 169-173, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30049248

RESUMO

OBJECTIVE: To assess whether the accuracy of risk estimation in antenatal screening for trisomy 18 using the Combined test can be improved by revising the truncation limits of two serum markers. METHODS: In an audit of data from 420 trisomy 18 and 573,754 unaffected singleton pregnancies screened at the Wolfson Institute of Preventive Medicine, London (March 2003 to June 2017), the accuracy of risk estimation was assessed by inspection of a validation plot (the median predicted late first trimester Combined test risk plotted against observed prevalence within categories of predicted risk estimates). Using validation and probability plots, we assessed whether the revised pregnancy-associated plasma protein A (PAPP-A) and free ß-human chorionic gonadotrophin (free ß-hCG) truncation limits led to more accurate risk estimation and improved screening performance. RESULTS: With the lower truncation limits currently used for PAPP-A and free ß-hCG (0.15 and 0.30 multiples of the median [MoM], respectively), risk was underestimated. Revised lower truncation limits of 0.05 MoM for both PAPP-A and free ß-hCG led to greater accuracy, with an increase in the number of trisomy 18 pregnancies detected (from 85.4% to 90.2%) for a small increase in the false-positive rate (from 0.20% to 0.29%) at a 1 in 100 late first trimester risk cut-off. CONCLUSION: The revised truncation limits for PAPP-A and free ß-hCG increase the accuracy of trisomy 18 risk estimation and improve screening performance using the Combined test. Validation and probability plots are useful in setting screening marker truncation limits.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/sangue , Testes para Triagem do Soro Materno , Proteína Plasmática A Associada à Gravidez/análise , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Biomarcadores/sangue , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Valores de Referência , Risco
18.
Am J Obstet Gynecol ; 219(3): 287.e1-287.e18, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29852155

RESUMO

BACKGROUND: Next-generation sequencing is emerging as a viable alternative to chromosome microarray analysis for the diagnosis of chromosome disease syndromes. One next-generation sequencing methodology, copy number variation sequencing, has been shown to deliver high reliability, accuracy, and reproducibility for detection of fetal copy number variations in prenatal samples. However, its clinical utility as a first-tier diagnostic method has yet to be demonstrated in a large cohort of pregnant women referred for fetal chromosome testing. OBJECTIVE: We sought to evaluate copy number variation sequencing as a first-tier diagnostic method for detection of fetal chromosome anomalies in a general population of pregnant women with high-risk prenatal indications. STUDY DESIGN: This was a prospective analysis of 3429 pregnant women referred for amniocentesis and fetal chromosome testing for different risk indications, including advanced maternal age, high-risk maternal serum screening, and positivity for an ultrasound soft marker. Amniocentesis was performed by standard procedures. Amniocyte DNA was analyzed by copy number variation sequencing with a chromosome resolution of 0.1 Mb. Fetal chromosome anomalies including whole chromosome aneuploidy and segmental imbalances were independently confirmed by gold standard cytogenetic and molecular methods and their pathogenicity determined following guidelines of the American College of Medical Genetics for sequence variants. RESULTS: Clear interpretable copy number variation sequencing results were obtained for all 3429 amniocentesis samples. Copy number variation sequencing identified 3293 samples (96%) with a normal molecular karyotype and 136 samples (4%) with an altered molecular karyotype. A total of 146 fetal chromosome anomalies were detected, comprising 46 whole chromosome aneuploidies (pathogenic), 29 submicroscopic microdeletions/microduplications with known or suspected associations with chromosome disease syndromes (pathogenic), 22 other microdeletions/microduplications (likely pathogenic), and 49 variants of uncertain significance. Overall, the cumulative frequency of pathogenic/likely pathogenic and variants of uncertain significance chromosome anomalies in the patient cohort was 2.83% and 1.43%, respectively. In the 3 high-risk advanced maternal age, high-risk maternal serum screening, and ultrasound soft marker groups, the most common whole chromosome aneuploidy detected was trisomy 21, followed by sex chromosome aneuploidies, trisomy 18, and trisomy 13. Across all clinical indications, there was a similar incidence of submicroscopic copy number variations, with approximately equal proportions of pathogenic/likely pathogenic and variants of uncertain significance copy number variations. If karyotyping had been used as an alternate cytogenetics detection method, copy number variation sequencing would have returned a 1% higher yield of pathogenic or likely pathogenic copy number variations. CONCLUSION: In a large prospective clinical study, copy number variation sequencing delivered high reliability and accuracy for identifying clinically significant fetal anomalies in prenatal samples. Based on key performance criteria, copy number variation sequencing appears to be a well-suited methodology for first-tier diagnosis of pregnant women in the general population at risk of having a suspected fetal chromosome abnormality.


Assuntos
Transtornos Cromossômicos/diagnóstico , Variações do Número de Cópias de DNA/genética , Adulto , Amniocentese , Aneuploidia , China , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Síndrome de Down/diagnóstico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Análise em Microsséries , Gravidez , Diagnóstico Pré-Natal , Estudos Prospectivos , Análise de Sequência de DNA , Aberrações dos Cromossomos Sexuais , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico
19.
Aust N Z J Obstet Gynaecol ; 58(4): 397-403, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29900540

RESUMO

Cell-free DNA screening has quickly become established in Australia as an accurate - albeit costly - prenatal screening test for trisomy 21, 18 and 13. It is also commonly used for the detection of sex chromosome abnormalities. The increasing number of prenatal screening pathways available to women has increased the complexity of pretest counselling. Concurrent advances in diagnostic testing with the widespread use of chromosomal microarrays create further challenges for the continuing education of clinicians and health consumers. This article aims to answer common clinical questions in this rapidly evolving field and complements the recently updated Royal Australian and New Zealand College of Obstetricians and Gynaecologists Statement on Prenatal Screening for Fetal Chromosome and Genetic Conditions.


Assuntos
Ácidos Nucleicos Livres , Transtornos Cromossômicos/diagnóstico , Testes Genéticos , Diagnóstico Pré-Natal , Austrália , Síndrome de Down/diagnóstico , Feminino , Humanos , Valor Preditivo dos Testes , Gravidez , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico
20.
DNA Cell Biol ; 37(7): 626-633, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29957029

RESUMO

Massively parallel sequencing of circulating fetal DNA in the plasma of pregnant women is a common method for noninvasive prenatal testing (NIPT) of fetal trisomy 13, 18, and 21. However, circulating DNA is not restricted to pregnant women, with increased levels of plasma DNA also frequently detected in the plasma of cancer patients. Among pregnant women whose NIPT results were inconsistent with the fetal karyotype, a small number of patients have subsequently been diagnosed with a previously undetected malignancy. However, the extent to which circulating tumor DNA (ctDNA) affects the results of NIPT is still unclear. We examined serum from 50 nonpregnant women with breast tumors by NIPT. These samples were then added to serum containing trisomy 13, 18, and 21 fetal DNA to figure out the extent to which maternal tumors can interrupt NIPT results in pregnant women with breast tumors. Concentrations of cell-free DNA (cfDNA) were higher in both pregnant women and breast tumor patients, relative to nonpregnant healthy controls. Among the 50 samples evaluated, 3 produced false positive NIPT results for trisomy 13, 18, or 21, indicating that genomic copy number variations (CNVs) had occurred. Simulation testing also showed that ctDNA can increase the standard deviation of the associated z-scores, which lower absolute z-scores by decreasing the proportion of circulating fetal DNA relative to total DNA. Of the 50 samples tested, 9 fell within the equivocal range and 8 produced false negative results for trisomy 13, 18, or 21. Data presented here show for the first time that ctDNA is able to affect NIPT results in two ways. First, ctDNA can lead to false positive results due to the detection of genomic CNVs in tumor DNA. Alternatively, ctDNA can increase the likelihood of a false negative by decreasing the proportion of circulating fetal DNA in serum.


Assuntos
Neoplasias da Mama/diagnóstico , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Síndrome de Down/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/normas , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto , Artefatos , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Estudos de Casos e Controles , Ácidos Nucleicos Livres/sangue , DNA Tumoral Circulante/sangue , Variações do Número de Cópias de DNA , Síndrome de Down/sangue , Síndrome de Down/genética , Reações Falso-Negativas , Feminino , Feto , Humanos , Gravidez , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/sangue , Síndrome da Trissomía do Cromossomo 18/genética
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