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Obstetrics and Gynecology Mar 2020Umbilical cord abnormalities are commonly cited as a cause of stillbirth, but details regarding these stillbirths are rare. Our objective was to characterize stillbirths...
OBJECTIVE
Umbilical cord abnormalities are commonly cited as a cause of stillbirth, but details regarding these stillbirths are rare. Our objective was to characterize stillbirths associated with umbilical cord abnormalities using rigorous criteria and to examine associated risk factors.
METHODS
The Stillbirth Collaborative Research Network conducted a case-control study of stillbirth and live births from 2006 to 2008. We analyzed stillbirths that underwent complete fetal and placental evaluations and cause of death analysis using the INCODE (Initial Causes of Fetal Death) classification system. Umbilical cord abnormality was defined as cord entrapment (defined as nuchal, body, shoulder cord accompanied by evidence of cord occlusion on pathologic examination); knots, torsions, or strictures with thrombi, or other obstruction by pathologic examination; cord prolapse; vasa previa; and compromised fetal microcirculation, which is defined as a histopathologic finding that represents objective evidence of vascular obstruction and can be used to indirectly confirm umbilical cord abnormalities when suspected as a cause for stillbirth. We compared demographic and clinical factors between women with stillbirths associated with umbilical cord abnormalities and those associated with other causes, as well as with live births. Secondarily, we analyzed the subset of pregnancies with a low umbilical cord index.
RESULTS
Of 496 stillbirths with complete cause of death analysis by INCODE, 94 (19%, 95% CI 16-23%) were associated with umbilical cord abnormality. Forty-five (48%) had compromised fetal microcirculation, 27 (29%) had cord entrapment, 26 (27%) knots, torsions, or stricture, and five (5%) had cord prolapse. No cases of vasa previa occurred. With few exceptions, maternal characteristics were similar between umbilical cord abnormality stillbirths and non-umbilical cord abnormality stillbirths and between umbilical cord abnormality stillbirths and live births, including among a subanalysis of those with hypo-coiled umbilical cords.
CONCLUSION
Umbilical cord abnormalities are an important risk factor for stillbirth, accounting for 19% of cases, even when using rigorous criteria. Few specific maternal and clinical characteristics were associated with risk.
Topics: Adult; Case-Control Studies; Female; Humans; Pregnancy; Stillbirth; Umbilical Cord; United States; Young Adult
PubMed: 32028503
DOI: 10.1097/AOG.0000000000003676 -
Lancet (London, England) Feb 2019Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which...
BACKGROUND
Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).
METHODS
In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.
FINDINGS
The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses).
INTERPRETATION
WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.
FUNDING
UK Department of Health and Social Care and The Wellcome Trust.
Topics: Abnormal Karyotype; Abortion, Eugenic; Abortion, Spontaneous; Congenital Abnormalities; DNA Copy Number Variations; Female; Fetal Development; Fetus; Humans; Infant, Newborn; Live Birth; Male; Nuchal Translucency Measurement; Parents; Perinatal Death; Pregnancy; Prospective Studies; Stillbirth; Exome Sequencing
PubMed: 30712880
DOI: 10.1016/S0140-6736(18)31940-8 -
Prenatal Diagnosis May 2022We conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal.
METHODS
Following electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta-analysis. Sub-group analyses investigated effects of case selection and fetal phenotype on diagnostic yield.
RESULTS
We identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%-36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre-selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub-groups, ranging from 53% (95% CI 42%-63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%-5%, p = 0.04) for isolated increased nuchal translucency.
CONCLUSION
Prenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non-diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre-selection of cases following multi-disciplinary review to determine that a monogenic cause is likely.
Topics: Exome; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prenatal Diagnosis; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 35170059
DOI: 10.1002/pd.6115 -
Genes Aug 2022Congenital malformations diagnosed by ultrasound screening complicate 3-5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of... (Review)
Review
Congenital malformations diagnosed by ultrasound screening complicate 3-5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of prenatally diagnosed fetal malformations are associated with aneuploidy or copy number variants, detected by conventional karyotyping, QF-PCR and microarray techniques, however monogenic disorders are not diagnosed by these tests. Next generation sequencing as a secondary prenatal genetic test offers additional diagnostic yield for congenital abnormalities deemed to be potentially associated with an underlying genetic aetiology, as demonstrated by two large cohorts: the 'Prenatal assessment of genomes and exomes' (PAGE) study and 'Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study' performed at Columbia University in the US. These were large and prospective studies but relatively 'unselected' congenital malformations, with little Clinical Genetics input to the pre-test selection process. This review focuses on the incremental yield of next generation sequencing in single system congenital malformations, using evidence from the PAGE, Columbia and subsequent cohorts, with particularly high yields in those fetuses with cardiac and neurological anomalies, large nuchal translucency and non-immune fetal hydrops (of unknown aetiology). The total additional yield gained by exome sequencing in congenital heart disease was 12.7%, for neurological malformations 13.8%, 13.1% in increased nuchal translucency and 29% in non-immune fetal hydrops. This demonstrates significant incremental yield with exome sequencing in single-system anomalies and supports next generation sequencing as a secondary genetic test in routine clinical care of fetuses with congenital abnormalities.
Topics: Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Hydrops Fetalis; Infant, Newborn; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Ultrasonography, Prenatal
PubMed: 36140685
DOI: 10.3390/genes13091517 -
Clinical Epidemiology 2016The aim of this study is to set up a database in order to monitor the detection rates and false-positive rates of first-trimester screening for chromosomal abnormalities... (Review)
Review
AIM
The aim of this study is to set up a database in order to monitor the detection rates and false-positive rates of first-trimester screening for chromosomal abnormalities and prenatal detection rates of fetal malformations in Denmark.
STUDY POPULATION
Pregnant women with a first or second trimester ultrasound scan performed at all public hospitals in Denmark are registered in the database.
MAIN VARIABLES/DESCRIPTIVE DATA
Data on maternal characteristics, ultrasonic, and biochemical variables are continuously sent from the fetal medicine units' Astraia databases to the central database via web service. Information about outcome of pregnancy (miscarriage, termination, live birth, or stillbirth) is received from the National Patient Register and National Birth Register and linked via the Danish unique personal registration number. Furthermore, results of all pre- and postnatal chromosome analyses are sent to the database.
CONCLUSION
It has been possible to establish a fetal medicine database, which monitors first-trimester screening for chromosomal abnormalities and second-trimester screening for major fetal malformations with the input from already collected data. The database is valuable to assess the performance at a regional level and to compare Danish performance with international results at a national level.
PubMed: 27822088
DOI: 10.2147/CLEP.S99477 -
International Journal of General... 2021This study aims to investigate the formation factors that affect the angle of nuchal cord and explore the types of nuchal cord that exist and the process of standardized...
OBJECTIVE
This study aims to investigate the formation factors that affect the angle of nuchal cord and explore the types of nuchal cord that exist and the process of standardized ultrasound diagnosis of nuchal cord.
METHODS
Ultrasonography was performed on 707 fetuses with nuchal cord, to observe the direction of the coil, determine the type of coil, and analyze the correlation between the fetal position, placental location, and the direction of the coil with the angle of the umbilical cord.
RESULTS
Among the 707 fetuses, those with 1 loop accounted for 89.67%, fetuses with 2 loops accounted for 6.08%, fetuses with 3 loops accounted for 0.28%, and fetuses with partial draping of the umbilical cord accounted for 3.96%. Nuchal cord mostly occurred in fetuses where the placenta was attached to the anterior wall of the uterus, and the α-shaped and C-shaped types were in the majority. The C-shaped type accounted for 43.14%, the α-shaped type for 40.88%, the O-shaped type for 12.02%, and the L-shaped type for 3.96%.
CONCLUSION
The direction of the coil of the umbilical cord can be determined by blood flow vector observation. The fetal position, placental location, and the direction of the coil are the three factors affecting the coiling angle of the umbilical cord. Ultrasonic classification of nuchal cord can provide detailed information, which can be used by physicians when performing surgery on the fetus. The advances in the diagnosis procedure allow the diagnosis of nuchal cord to be carried out in an orderly manner, making it more accurate and standardized.
PubMed: 34557033
DOI: 10.2147/IJGM.S322713 -
BMC Pregnancy and Childbirth Aug 2021The prenatal test of cell-free fetal DNA (cffDNA) is also known as noninvasive prenatal testing (NIPT) with high sensitivity and specificity. This study is to evaluate...
BACKGROUND
The prenatal test of cell-free fetal DNA (cffDNA) is also known as noninvasive prenatal testing (NIPT) with high sensitivity and specificity. This study is to evaluate the performance of NIPT and its clinical relevance with various clinical indications.
METHODS
A retrospective analysis was conducted on 14,316 pregnant women with prenatal indications, including advanced maternal age (≥35 years), maternal serum screening abnormalities, the thickened nuchal translucency (≥2.5 mm) and other ultrasound abnormalities, twin pregnancy/IVF-ET pregnancy, etc. The whole-genome sequencing (WGS) of maternal plasma cffDNA was employed in this study.
RESULTS
A total of 189 (1.32%) positive NIPT cases were identified, and 113/189 (59.79%)cases were confirmed by invasive prenatal testing. Abnormal serological screening (53.14%) was the most common indication, followed by elderly pregnancy (23.02%). The positive prediction value for T21, T18, T13, sex chromosome abnormalities, other autosomal aneuploidy abnormalities, and CNV abnormalities were 91.84, 68.75,37.50, 66.67, 14.29, and 6.45%, respectively. The positive rate and the true positive rate of nuchal translucency (NT) thickening were the highest (4.17 and 3.33%), followed by the voluntary requirement group (3.49 and 1.90%) in the various prenatal screening indications. The cffDNA concentration was linearly correlated with gestational age (≥10 weeks) and the positive NIPT group's Z-score values.
CONCLUSIONS
whole-genome sequencing of cffDNA has extremely high sensitivity and specificity for T21, high sensitivity for T18, sex chromosome abnormalities, and T13. It also provides evidence for other abnormal chromosomal karyotypes (CNV and non-21/18/13 autosomal aneuploidy abnormalities). The cffDNA concentration is closely related to the gestational age and determines the specificity of NIPT. Our results highlight NIPT's clinical significance, which is an effective prenatal screening tool for high-quality care of pregnancy.
Topics: Adolescent; Adult; China; Chromosome Aberrations; Chromosome Disorders; Female; Humans; Middle Aged; Noninvasive Prenatal Testing; Predictive Value of Tests; Pregnancy; Pregnancy, High-Risk; Retrospective Studies; Sensitivity and Specificity; Whole Genome Sequencing; Young Adult
PubMed: 34429082
DOI: 10.1186/s12884-021-04044-5 -
Head and Neck Pathology Mar 2020Fibroblastic and myofibroblastic neoplasms of the head and neck encompass a group of rare tumor types with often overlapping clinicopathologic features that range in... (Review)
Review
Fibroblastic and myofibroblastic neoplasms of the head and neck encompass a group of rare tumor types with often overlapping clinicopathologic features that range in biologic potential from benign to overtly malignant. Even neoplasms with no metastatic potential may provide significant therapeutic challenges in this region due to the unique anatomy of the head and neck. This review will cover the following entities, highlighting important clinical aspects of each neoplasm and then focusing on their characteristic histomorphology, immunophenotype, and molecular alterations: nodular and cranial fasciitis, fibrous hamartoma of infancy, nasopharyngeal angiofibroma, nuchal-type and Gardner fibromas, desmoid fibromatosis, dermatofibrosarcoma protuberans and giant cell fibroblastoma, solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, infantile fibrosarcoma, low-grade fibromyxoid sarcoma, and sclerosing epithelioid fibrosarcoma. While some of these neoplasms characteristically arise in the head and neck, others are rarely described in this anatomic region and may therefore be particularly difficult to recognize. Distinction between these entities, however, is crucial, particularly as the molecular pathogenetic basis for these neoplasms are being rapidly elucidated, in some instances allowing for targeted therapeutic approaches.
Topics: Head and Neck Neoplasms; Humans; Neoplasms, Fibrous Tissue; Soft Tissue Neoplasms
PubMed: 31950474
DOI: 10.1007/s12105-019-01104-3 -
MMWR. Morbidity and Mortality Weekly... Sep 2011In late December 2010, a male resident of Wisconsin, aged 70 years, sought treatment for progressive right shoulder pain, tremors, abnormal behavior, and dysphagia at an...
In late December 2010, a male resident of Wisconsin, aged 70 years, sought treatment for progressive right shoulder pain, tremors, abnormal behavior, and dysphagia at an emergency department (ED). He was admitted for observation and treated with benzodiazepines and haloperidol, a neuroleptic, for presumed alcohol withdrawal syndrome. The next day, he had rhabdomyolysis, fever, and rigidity, and neuroleptic malignant syndrome was diagnosed. The neuroleptic was discontinued, but the patient's clinical status worsened, with encephalopathy, respiratory failure, acute renal failure requiring hemodialysis, and episodes of cardiac arrest. With continued clinical deterioration, additional causes were considered, including rabies. On hospital day 12, rabies virus antigens and nucleic acid were detected in the nuchal skin biopsy and rabies virus nucleic acid in saliva specimens sent to CDC. A rabies virus variant associated with silver-haired bats (Lasionycteris noctivagans) was identified. The patient died on hospital day 13. His spouse reported that they had been selling firewood, and bats had been present in the woodpile; however, the man had not reported a bat bite. Two relatives and five health-care workers potentially exposed to the man's saliva received postexposure prophylaxis. This case highlights the variable presentations of rabies and the ease with which a diagnosis of rabies can be missed in a clinically challenging patient with comorbidities. Clinicians should consider rabies in the differential diagnosis for patients with progressive encephalitis or neurologic illness of unknown etiology and caregivers should take precautions to avoid exposure to body fluids. Continued public education regarding risks for rabies virus exposure during interactions with wildlife, particularly bats, is important.
Topics: Aged; Alcohol Withdrawal Delirium; Animals; Antipsychotic Agents; Biopsy; Chiroptera; Deglutition Disorders; Diagnosis, Differential; Encephalitis; Fatal Outcome; Humans; Male; Neuroleptic Malignant Syndrome; Post-Exposure Prophylaxis; Rabies; Rabies virus; Wisconsin
PubMed: 21881547
DOI: No ID Found