The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).
ABSTRACT Noninvasive prenatal screening has become a valuable tool in detecting a variety of disorders and abnormalities, including sex chromosome aneuploidies (SCAs). The test uses cell-free DNA (cfDNA) analysis to identify risk for chromosomal abnormalities, which can then be more fully investigated using other tests. Much of previous research focused on cfDNA has assessed autosomal aneuploidies, but few studies have specifically focused on SCAs. The aim of this systematic review and meta-analysis was to assess the accuracy of cfDNA testing in identifying SCAs in singleton pregnancies. Studies were identified by keywords associated with cfDNA, SCA, and noninvasive prenatal testing, and studies were included based on relevance. Inclusion criteria were limited to singleton pregnancies that underwent cfDNA testing with confirmation by diagnostic genetic testing between January 1, 2010 and December 1, 2021. A total of 21 articles were selected for the final meta-analysis. All included studies reported results for monosomy X (45,X), representing nearly 13,000 tests with 254 confirmed positive results, 133 false-positives, and 18 false-negatives. Estimated sensitivity based on this sample was 98.8%, with specificity of 99.4%. Positive and negative predictive values were 14.5% and 100%, respectively. Of the 21 included studies, 16 also reported results for Klinefelter syndrome (47,XXY), representing just over 11,000 tests with 62 confirmed positive results, 10 false-positives, and 11 false-negatives. Estimated sensitivity was 100% and specificity was 100%, with positive predictive value of 97.7% and negative predictive value of 100%. Thirteen of 21 studies included reported results for triple X syndrome (47,XXX), representing roughly 10,000 tests with 38 confirmed positive results, 18 false-positives, and 1 false-negative. This showed an estimated sensitivity of 100% and specificity of 99.9%, with positive predictive value of 61.6% and negative predictive value of 100%. Finally, 9 of the studies included in this meta-analysis reported results for Jacobs syndrome (47,XYY), representing approximately 8500 tests with 22 confirmed positive results, 2 false-positives, and no false-negatives. This led to an estimated sensitivity and specificity of 100%, with positive and negative predictive values also 100%. These results provide evidence that cfDNA testing is effective in identification of SCAs in pregnancies at high risk. This particular population limits the generalizability of the findings but adds to the literature surrounding the effectiveness and accuracy of this method. The analysis used strict criteria to define the studies that were included, yet still included a large sample of tests (12,000), which adds to the statistical and practical significance of the analysis. Generalizing the findings of this study is difficult based on both the fact that the sample did not include low-risk individuals and that positive predictive values varied greatly with prevalence, impacting clinical significance. Overall, cfDNA testing for SCAs has both high sensitivity and specificity, along with a high negative predictive value of 99.99% or above for each SCA examined. Further research is needed to confirm these findings and extend knowledge to a more diverse population.
Cardiopulmonary resuscitation can be a difficult topic to discuss. The barriers surrounding its discussion are well documented in human medicine but have not previously been examined in veterinary medicine. The objectives of this study is to describe the perceptions, practices and preferences of veterinarians and registered veterinary nurses towards discussing cardiopulmonary resuscitation with pet owners.
Abstract Objective There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies. Method We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics. Results Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers. Conclusion Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.
Objective. To determine the utility of fundal height in screening for small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates at term.Study design. This was a retrospective cohort study of 3627 women at University of California, San Francisco from 2002 to 2006 with term, singleton pregnancies specifically examining the 448 who had third trimester ultrasounds for size unequal to dates by fundal height. χ2 analyses determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of fundal height as a screening tool for abnormal intrauterine growth.Results. The sensitivity of fundal height was 16.6% for detecting actual birthweight (BWt) > 90th percentile (p < 0.001) and 17.3% for < 10th percentile (p < 0.001). Specificity ranged from 92.4 to 95.4%. Significant differences existed among subgroups by maternal weight, parity, age, and ethnicity. Sensitivity was lower for SGA among overweight/obese women but higher among multiparous women. Additionally, women ≥35 years showed higher sensitivity for extreme LGA, and several notable differences were found by ethnicity such as higher sensitivity for extreme LGA among Caucasian women.Conclusion. The sensitivity of fundal height for detecting abnormal intrauterine growth was less than 35% for all subgroups, although specificity was more ideal at >90%. Other modalities should be considered to screen for growth abnormalities.
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