Komal Bajaj

ACMG statement on noninvasive prenatal screening for fetal aneuploidy

Noninvasive assessment of the fetal genome is now possible using next-generation sequencing technologies. The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening. However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice. Once informed, clinicians can provide efficient pretest and posttest counseling with the goal of avoiding patient harm. It is in the public’s best interest that test results contain key elements and that laboratories adhere to established quality control and proficiency testing standards. The analysis of cell-free fetal DNA in maternal circulation for fetal aneuploidy screening is likely the first of major steps toward the eventual application of whole fetal genome/whole fetal exome sequencing.Genet Med 2013:15(5):395–398

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.

Disclaimer: This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9–10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.Genet Med 18 10, 1056–1065.

Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results

Purpose:Noninvasive prenatal screening for fetal aneuploidy analyzes cell-free fetal DNA circulating in the maternal plasma. Because cell-free fetal DNA is mainly of placental trophoblast origin, false-positive and false-negative findings may result from placental mosaicism. The aim of this study was to calculate the potential contribution of placental mosaicism in discordant results of noninvasive prenatal screening.Methods:We performed a retrospective audit of 52,673 chorionic villus samples in which cytogenetic analysis of the cytotrophoblast (direct) and villus mesenchyme (culture) was performed, which was followed by confirmatory amniocentesis in chorionic villi mosaic cases. Using cases in which cytogenetic discordance between cytotrophoblast and amniotic fluid samples was identified, we calculated the potential contribution of cell line–specific mosaicism to false-positive and false-negative results of noninvasive prenatal screening.Results:The false-positive rate, secondary to the presence of abnormal cell line with common trisomies in cytotrophoblast and normal amniotic fluid, ranged from 1/1,065 to 1/3,931 at 10% and 100% mosaicism, respectively; the false-negative rate was calculated from cases of true fetal mosaicism, in which a mosaic cell line was absent in cytotrophoblast and present in the fetus; this occurred in 1/107 cases.Conclusion:Despite exciting advances, underlying biologic mechanisms will never allow 100% sensitivity or specificity.Genet Med 16 8, 620–624.Genetics in Medicine (2014); 16 8, 620–624. doi:10.1038/gim.2014.3

The type of feto‐placental aneuploidy detected by cfDNA testing may influence the choice of confirmatory diagnostic procedure

Cell‐free DNA (cfDNA) screening can provide false positive/negative results because the fetal fraction originates primarily from trophoblast. Consequently, invasive diagnostic testing is recommended to confirm a high‐risk result. Currently, there is debate about the most appropriate invasive method. We sought to estimate the frequency in which a chorionic villus sampling (CVS) performed after a high‐risk cfDNA result would require a follow‐up amniocentesis due to placental mosaicism.

Rapid and novel prenatal molecular assay for detecting aneuploidies and microdeletion syndromes

To develop a targeted aneuploidy and microdeletion detection platform for use in the prenatal setting, to assess the integrity of the platform with a robust validation system, and to prospectively determine the performance of the platform under routine clinical conditions.

Carrier Screening: Past, Present, and Future

To date, preconceptual and prenatal patients have been offered gene-by-gene, disorder-by-disorder carrier screening. Newer techniques allow screening of many disorders at one time. The goal of this review is to provide an overview of the current practice and future direction of carrier screening within the preconceptual/prenatal setting.

Frequency of fetal karyotype abnormalities in women undergoing invasive testing in the absence of ultrasound and other high-risk indications†

No previous studies have reported the frequencies of individual chromosomal anomalies in normal‐appearing fetuses stratified by maternal age (MA) and gestational age (GA).

Clinical utility of chromosomal microarray analysis in prenatal diagnosis: report of first 6 months in clinical practice

Abstract Objective: We studied the clinical utility of chromosomal microarray analysis (CMA) in prenatal diagnosis in a clinical setting in New York City. Methods: Our center began offering CMA to pregnant women undergoing invasive diagnostic procedures for an abnormal structural finding on ultrasound, maternal age of 35 years or older, or elevated risk on aneuploidy screening, beginning March 2012. Our first six months experience is reported. Results: Benign familial variants were the most common finding (16/22 fetuses). Variants of uncertain significance were frequent, especially when fathers were not available for testing (4/22 fetuses). Most patients undertook CMA as part of evaluation of an ultrasound anomaly (52%). One patient terminated a pregnancy based on an ultrasound finding in the setting of a benign familial variant on CMA, and a second terminated a pregnancy based on a copy number variant identified on CMA. Conclusion: For CMA to be maximally useful in prenatal diagnosis, parental DNA samples as well as robust datasets to provide predictive phenotypic information are required. The most common reason for undertaking CMA was to evaluate an ultrasound anomaly, and benign familial variants were a common finding. Genetic services are required to provide pre- and post-test genetic counseling and help families interpret results.

Working memory is limited: improving knowledge transfer by optimising simulation through cognitive load theory

This analysis explores how to optimise knowledge transfer in healthcare simulation by applying cognitive load theory to curriculum design and delivery for both novice and expert learners. This is particularly relevant for interprofessional learning which is team-based, as each participant comes to the simulation experience with different levels of expertise. Healthcare simulation can offer opportunities to create complex and dynamic experiences that replicate real clinical situations. Understanding Cognitive Load Theory can foster the acquisition of complex knowledge, skills and abilities required to deliver excellence in patient care without overwhelming a learners ability to handle new materials due to working memory limitations. The 2 aspects of working memory that will be explored in this paper are intrinsic load and extrinsic load. These will be addressed in terms of the learners level of expertise and how to consider these elements to enhance the learning environment in simulation scenario development and delivery. By applying the concepts of Cognitive Load Theory, this paper offers educators a method to tailor their curricula to navigate working memory and optimise the opportunity for knowledge transfer.

Validating Obstetric Emergency Checklists using Simulation: A Randomized Controlled Trial

Background The World Health Organizations Surgical Safety Checklist has demonstrated significant reduction in surgical morbidity. The American Congress of Obstetricians and Gynecologists District II Safe Motherhood Initiative (SMI) safety bundles include eclampsia and postpartum hemorrhage (PPH) checklists. Objective To determine whether use of the SMI checklists during simulated obstetric emergencies improved completion of critical actions and to elicit feedback to facilitate checklist revision. Study Design During this randomized controlled trial, teams were assigned to use a checklist during one of two emergencies: eclampsia and PPH. Raters scored teams on critical step completion. Feedback was elicited through structured debriefing. Results In total, 30 teams completed 60 scenarios. For eclampsia, trends toward higher completion were noted for blood pressure and airway management. For PPH, trends toward higher completion rates were noted for PPH stage assessment and fundal massage. Feedback resulted in substantial checklist revision. Participants were enthusiastic about using checklists in a clinical emergency. Conclusion Despite trends toward higher rates of completion of critical tasks, teams using checklists did not approach 100% task completion. Teams were interested in the application of checklists and provided feedback necessary to substantially revise the checklists. Intensive implementation planning and training in use of the revised checklists will result in improved patient outcomes.