High positive predictive value 22q11.2 microdeletion screening by prenatal cell-free DNA testing that incorporates fetal fraction amplification.

OBJECTIVE: 22q11.2 deletion syndrome (DS) is a serious condition with a range of features. The small microdeletion causing 22q11.2DS makes it technically challenging to detect using standard prenatal cfDNA screening. Here, we assess 22q11.2 microdeletion clinical performance by a prenatal cfDNA screen that incorporates fetal fraction (FF) amplification. METHODS: The study cohort consisted of patients who received Prequel (Myriad Genetics, Inc.), a prenatal cfDNA screening that incorporates FF amplification, and met additional eligibility criteria. Pregnancy outcomes were obtained via a routine process for continuous quality improvement. Samples with diagnostic testing results were used to calculate positive predictive value (PPV). RESULTS: 379,428 patients met study eligibility criteria, 76 of whom were screen-positive for a de novo 22q11.2 microdeletion. 22 (29.7%) had diagnostic testing results available, and all 22 cases were confirmed as true positives, for a PPV of 100% (95% CI 84.6%-100%). This performance was based on cases that ranged broadly across FF (5.9%-41.1%, mean 23.0%), body mass index (22.3-44.8, mean 29.9), and gestational age at testing (10.0w-34.6w, median 12.7w). Ultrasound findings in screen-positive pregnancies were consistent with those known to be associated with 22q11.2DS. CONCLUSION: 22q11.2 microdeletion screening that incorporates FF amplification demonstrated high PPV across both general and high-risk population cohorts.

Inclusion of sex chromosomes in noninvasive prenatal testing in Asia, Australia, Europe and the USA: A survey study.

OBJECTIVE: To examine the extent to which sex chromosomes are included in current noninvasive prenatal testing (NIPT) and the reporting practices with respect to fetal chromosomal sex and sex chromosome aberrations (SCAs), in addition to an update on the general implementation of NIPT. METHOD: A questionnaire addressing the research objectives was distributed by email to fetal medicine and clinical genetics experts in Asia, Australia, Europe and the USA. RESULTS: Guidelines on NIPT are available in the majority of the included countries. Not all existing guidelines address reporting of fetal chromosomal sex and SCAs. In most settings, NIPT frequently includes sex chromosomes (five Australian states, China, Hong Kong, Israel, Singapore, Thailand, USA and 23 of 31 European countries). This occurs most often by default or when parents wish to know fetal sex. In most settings, a potential SCA is reported by stating the risk hereof as "low" or "high" and/or by naming the SCA. Less than 50% of all pregnant women receive NIPT according to respondents from three Australian states, China, Israel, Singapore, Thailand and 24 of 31 European countries. However, this percentage, the genomic coverage of NIPT and its application as primary or secondary screening vary by setting. CONCLUSION: In most of the studied countries/states, NIPT commonly includes sex chromosomes. The reporting practices concerning fetal chromosomal sex and SCAs are diverse and most commonly not addressed by guidelines. In general, NIPT is variably implemented across countries/states.

Genome-wide cell-free DNA screening: a focus on copy-number variants.

PURPOSE: Of 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. METHODS: Cases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. RESULTS: CNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1-79.5%) and 71.8% (95% CI: 65.5-77.4%) for "fetal-only" events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5-68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6-97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. CONCLUSION: Genome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

Developmental considerations with regard to so-called absence of the leaflets of the arterial valves.

BACKGROUND: Absent arterial valve leaflets are rare anomalies. On the basis of our understanding of the normal development of the arterial valves, we draw inferences that might offer clues to their morphogenesis. METHODS: We describe the findings from four human fetal autopsies with so-called "absent" arterial valvar leaflets. We then make inferences relative to these finding on the basis of our current understanding of normal development, the latter obtained by analysis of episcopic data sets from a large series of mouse embryos. RESULTS: The fetuses had died between 12 and 15 weeks of gestation. In two cases, we found absence of the leaflets of the pulmonary valve, with patency of the arterial duct, but otherwise normal hearts. In a third case, there was absence of the leaflets of both arterial valves, along with a perimembranous ventricular septal defect and a "window-type" arterial duct. This fetus had a completely muscular subaortic infundibulum. The last fetus had a pulmonary dominant common arterial trunk, with absence of the truncal valvar leaflets, but again with a muscular subtruncal infundibulum. Findings from the analysis of the mouse embryos reveal that the arterial valvar leaflets are formed from the distal outflow cushions, but that the cushions have a separate function in septating the arterial roots and the proximal outflow tracts. CONCLUSIONS: When interpreting the fetal findings in the light of development, we conclude that there had been normal fusion of the major outflow cushions, but failure in excavation of their peripheral margins in three of the cases. In the fourth case, however, the cushions had not only failed to excavate but had also failed to separate the arterial roots.

Society for Maternal-Fetal Medicine (SMFM) Special Report: Current approaches to measuring quality of care in obstetrics.

Heath care measurement and evaluation is an integral piece of the health care system. The creation and assessment of care performance metrics are important and relevant for the obstetric community including both clinicians and patients. Careful deliberation is required to create a measurement system that results in optimal care for women and families. This article reviews the current approaches to measuring quality in obstetrics.

Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.

Maternal source of false-positive fetal sex chromosome aneuploidy in noninvasive prenatal testing.

BACKGROUND: The intent of noninvasive prenatal testing is to screen for fetal aneuploidies. The assumption is that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. CASES: We report three cases in which maternal sex chromosome aneuploidy (confirmed by karyotype), two cases of which were previously unknown, resulted in false-positive results. In each, results were positive for fetal aneuploidy, but neonatal karyotypes confirmed normal karyotype. CONCLUSION: Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Intrinsic to the analysis is that the underrepresentations and overrepresentations are of fetal origin. We present three cases in which this assumption is not valid. We suggest that maternal sex chromosome aneuploidy be considered when results suggest fetal sex chromosome aneuploidies.

Standardized severe maternal morbidity review: rationale and process.

Severe maternal morbidity and mortality have been rising in the United States. To begin a national effort to reduce morbidity, a specific call to identify all pregnant and postpartum women experiencing admission to an intensive care unit or receipt of four or more units of blood for routine review has been made. While advocating for review of these cases, no specific guidance for the review process was provided. Therefore, the aim of this expert opinion is to present guidelines for a standardized severe maternal morbidity interdisciplinary review process to identify systems, professional, and facility factors that can be ameliorated, with the overall goal of improving institutional obstetric safety and reducing severe morbidity and mortality among pregnant and recently pregnant women. This opinion was developed by a multidisciplinary working group that included general obstetrician­gynecologists, maternal­fetal medicine subspecialists, certified nurse­midwives, and registered nurses all with experience in maternal mortality reviews. A process for standardized review of severe maternal morbidity addressing committee organization, review process, medical record abstraction and assessment, review culture, data management, review timing, and review confidentiality is presented. Reference is made to a sample severe maternal morbidity abstraction and assessment form.

Standardized severe maternal morbidity review: rationale and process.

Severe maternal morbidity and mortality have been rising in the United States. To begin a national effort to reduce morbidity, a specific call to identify all pregnant and postpartum women experiencing admission to an intensive care unit or receipt of 4 or more units of blood for routine review has been made. While advocating for review of these cases, no specific guidance for the review process was provided. Therefore, the aim of this expert opinion is to present guidelines for a standardized severe maternal morbidity interdisciplinary review process to identify systems, professional, and facility factors that can be ameliorated, with the overall goal of improving institutional obstetric safety and reducing severe morbidity and mortality among pregnant and recently pregnant women. This opinion was developed by a multidisciplinary working group that included general obstetrician-gynecologists, maternal-fetal medicine subspecialists, certified nurse-midwives, and registered nurses all with experience in maternal mortality reviews. A process for standardized review of severe maternal morbidity addressing committee organization, review process, medical record abstraction and assessment, review culture, data management, review timing, and review confidentiality is presented. Reference is made to a sample severe maternal morbidity abstraction and assessment form.