Impact of early preeclampsia prediction on medication adherence and behavior change: a survey of pregnant and recently-delivered individuals.

BACKGROUND: Behavior change and medication adherence represent potential barriers to optimal prevention of pregnancy complications including preeclampsia. We sought to evaluate baseline sentiments on pregnancy care and medication amenability, and how these measures would be impacted by early predictive testing for preeclampsia. METHODS: We developed a digital survey to query participants' baseline sentiments on pregnancy care, knowledge about pregnancy complications, and views on a hypothetical test to predict preeclampsia. The survey was administered online to pregnant and recently-delivered individuals in the United States. Survey data were analyzed using pooled two-sample proportion z-tests with adjustment for multiple comparisons. RESULTS: One thousand and twenty-two people completed the survey. 84% reported they were satisfied with their pregnancy care. Self-assessed knowledge about preeclampsia was high, with 75% of respondents reporting they have a "good understanding" of preeclampsia, but measured knowledge was low, with only 10% able to identify five common signs/symptoms of preeclampsia. Notably, 40% of participants with prior preeclampsia believed they were at average or below-average risk for recurrence. 91% of participants desired early pregnancy predictive testing for preeclampsia. If found to be at high risk for preeclampsia, 88% reported they would be more motivated to follow their provider's medication recommendations and 94% reported they would desire home blood pressure monitoring. Increased motivation to follow clinicians' medication and monitoring recommendations was observed across the full spectrum of medication amenability. Individuals who are more medication-hesitant still reported high rates of motivation to change behavior and adhere to medication recommendations if predictive testing showed a high risk of preeclampsia. Importantly, a high proportion of medication-hesitant individuals reported that if a predictive test demonstrated they were at high risk of preeclampsia, they would feel more motivated to take medications (83.0%) and aspirin (75.9%) if recommended. CONCLUSION: While satisfaction with care is high, participants desire more information about their pregnancy health, would value predictive testing for preeclampsia, and report they would act on this information. Improved detection of at-risk individuals through objective testing combined with increased adherence to their recommended care plan may be an important step to remedy the growing gap in prevention.

Predictive RNA profiles for early and very early spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth remains the main driver of childhood morbidity and mortality. Because of an incomplete understanding of the molecular pathways that result in spontaneous preterm birth, accurate predictive markers and target therapeutics remain elusive. OBJECTIVE: This study sought to determine if a cell-free RNA profile could reveal a molecular signature in maternal blood months before the onset of spontaneous preterm birth. STUDY DESIGN: Maternal samples (n=242) were obtained from a prospective cohort of individuals with a singleton pregnancy across 4 clinical sites at 12-24 weeks (nested case-control; n=46 spontaneous preterm birth <35 weeks and n=194 term controls). Plasma was processed via a next-generation sequencing pipeline for cell-free RNA using the Mirvie RNA platform. Transcripts that were differentially expressed in next-generation sequencing cases and controls were identified. Enriched pathways were identified in the Reactome database using overrepresentation analysis. RESULTS: Twenty five transcripts associated with an increased risk of spontaneous preterm birth were identified. A logistic regression model was developed using these transcripts to predict spontaneous preterm birth with an area under the curve =0.80 (95% confidence interval, 0.72-0.87) (sensitivity=0.76, specificity=0.72). The gene discovery and model were validated through leave-one-out cross-validation. A unique set of 39 genes was identified from cases of very early spontaneous preterm birth (<25 weeks, n=14 cases with time to delivery of 2.5±1.8 weeks); a logistic regression classifier on the basis of these genes yielded an area under the curve=0.76 (95% confidence interval, 0.63-0.87) in leave-one-out cross validation. Pathway analysis for the transcripts associated with spontaneous preterm birth revealed enrichment of genes related to collagen or the extracellular matrix in those who ultimately had a spontaneous preterm birth at <35 weeks. Enrichment for genes in insulin-like growth factor transport and amino acid metabolism pathways were associated with spontaneous preterm birth at <25 weeks. CONCLUSION: Second trimester cell-free RNA profiles in maternal blood provide a noninvasive window to future occurrence of spontaneous preterm birth. The systemic finding of changes in collagen and extracellular matrix pathways may serve to identify individuals at risk for premature cervical remodeling, with growth factor and metabolic pathways implicated more often in very early spontaneous preterm birth. The use of cell-free RNA profiles has the potential to accurately identify those at risk for spontaneous preterm birth by revealing the underlying pathophysiology, creating an opportunity for more targeted therapeutics and effective interventions.

Results of the Genetic Counselor SARS-CoV-2 Impact Survey from the National Society of Genetic Counselors: Progress and penalty during the COVID-19 pandemic.

The Genetic Counselor SARS-CoV-2 Impact Survey (GCSIS) describes the impact of the pandemic on genetic counselors and genetic counseling services. With this information, the National Society of Genetic Counselors (NSGC) can better: (1) support advocacy and access efforts for genetic counseling services at both federal- and state-level; (2) promote effective billing and reimbursement for genetic counseling services provided via telemedicine; and (3) make decisions about how to best support genetic counselors. The survey was hosted on a novel data collection and analysis platform from LunaDNA and was open to all genetic counselors (n = 5,531 based on professional society membership). Survey response rate was approximately 3.8% (n = 212/5,531), with a demographic distribution broadly representative of the North American genetic counseling field. Genetic counselors remained largely employed, providing genetic counseling services throughout the pandemic, although almost one in five respondents (17%, n = 35/211) reported experiencing some degree of pandemic-related financial hardship. Nearly all respondents (90%, n = 104/115) transitioned, at least in part, to remote work settings, with about half (47%. n = 88/189) reporting restrictions in the care they were able to provide. These shifts came at a cost: existing gaps in Medicare status for genetic counselors and attendant reimbursement concerns led to uncertainty about whether genetic counselors' work will be reimbursed. Outside of work, caregiving responsibilities increased for 34% (n = 74/212) of respondents. The results of the GCSIS amplify the importance of federal- and state-level advocacy efforts for genetic counselors and their employers. They also highlight the impact of broader cultural intransigence on our majority-female profession. During the pandemic, genetic counselors continued to provide care, but without consistent financial support or expectation of reimbursement. The ability to attract and retain talented professionals to the genetic counseling field will hinge on the success of continued advocacy efforts.

Technology-Driven Noninvasive Prenatal Screening Results Disclosure and Management.

Background: Noninvasive prenatal screening (NIPS) utilization has grown dramatically and is increasingly offered to the general population by nongenetic specialists. Web-based technologies and telegenetic services offer potential solutions for efficient results delivery and genetic counseling. Introduction: All major guidelines recommend patients with both negative and positive results be counseled. The main objective of this study was to quantify patient utilization, motivation for posttest counseling, and satisfaction of a technology platform designed for large-scale dissemination of NIPS results. Methods: The technology platform provided general education videos to patients, results delivery through a secure portal, and access to telegenetic counseling through phone. Automatic results delivery to patients was sent only to patients with screen-negative results. For patients with screen-positive results, either the ordering provider or a board-certified genetic counselor contacted the patient directly through phone to communicate the test results and provide counseling. Results: Over a 39-month period, 67,122 NIPS results were issued through the platform, and 4,673 patients elected genetic counseling consultations; 95.2% (n = 4,450) of consultations were for patients receiving negative results. More than 70% (n = 3,370) of consultations were on-demand rather than scheduled. A positive screen, advanced maternal age, family history, previous history of a pregnancy with a chromosomal abnormality, and other high-risk pregnancy were associated with the greatest odds of electing genetic counseling. By combining web education, automated notifications, and telegenetic counseling, we implemented a service that facilitates results disclosure for ordering providers. Discussion: This automated results delivery platform illustrates the use of technology in managing large-scale disclosure of NIPS results. Further studies should address effectiveness and satisfaction among patients and providers in greater detail. Conclusions: These data demonstrate the capability to deliver NIPS results, education, and counseling-congruent with professional society management guidelines-to a large population.

Noninvasive prenatal screening for patients with high body mass index: Evaluating the impact of a customized whole genome sequencing workflow on sensitivity and residual risk.

OBJECTIVE: Women with high body mass index (BMI) tend to have reduced fetal fraction (FF) during cell-free DNA-based noninvasive prenatal screening (NIPS), causing test failure rates up to 24.3% and prompting guidelines that recommend aneuploidy screening other than NIPS for patients with significant obesity. Because alternatives to NIPS are only preferable if they perform better, we compared the respective sensitivities at different BMI levels of traditional aneuploidy screening and a customized whole-genome sequencing NIPS. METHOD: The relationship between FF, aneuploidy, and BMI was quantified from 58 105 patients screened with a customized NIPS that does not fail samples because of low FF alone. Expected analytical sensitivity as a function of aneuploidy and BMI (eg, trisomy 18 sensitivity when BMI = 35) was determined by scaling the BMI- and aneuploidy-specific FF distribution by the FF- and aneuploidy-specific sensitivity calculated from empirically informed simulations. RESULTS: Across all classes of obesity and assuming zero FF-related test failures, analytical sensitivity for the investigated NIPS exceeded that of traditional aneuploidy screening for trisomies 13, 18, and 21. CONCLUSION: Relative to traditional aneuploidy screening, a customized NIPS with high accuracy at low FF and a low test-failure rate is a superior screening option for women with high BMI.

Correction: Inaccuracies and shortcomings in "Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations".

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY-NC-ND 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens.

BACKGROUND: Noninvasive prenatal screening (NIPS) of common aneuploidies using cell-free DNA from maternal plasma is part of routine prenatal care and is widely used in both high-risk and low-risk patient populations. High specificity is needed for clinically acceptable positive predictive values. Maternal copy-number variants (mCNVs) have been reported as a source of false-positive aneuploidy results that compromises specificity. METHODS: We surveyed the mCNV landscape in 87,255 patients undergoing NIPS. We evaluated both previously reported and novel algorithmic strategies for mitigating the effects of mCNVs on the screen's specificity. Further, we analyzed the frequency, length, and positional distribution of CNVs in our large dataset to investigate the curation of novel fetal microdeletions, which can be identified by NIPS but are challenging to interpret clinically. RESULTS: mCNVs are common, with 65% of expecting mothers harboring an autosomal CNV spanning more than 200 kb, underscoring the need for robust NIPS analysis strategies. By analyzing empirical and simulated data, we found that general, outlier-robust strategies reduce the rate of mCNV-caused false positives but not as appreciably as algorithms specifically designed to account for mCNVs. We demonstrate that large-scale tabulation of CNVs identified via routine NIPS could be clinically useful: together with the gene density of a putative microdeletion region, we show that the region's relative tolerance to duplications versus deletions may aid the interpretation of microdeletion pathogenicity. CONCLUSIONS: Our study thoroughly investigates a common source of NIPS false positives and demonstrates how to bypass its corrupting effects. Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.

Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods.

OBJECTIVE: Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies. METHODS: Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. RESULTS: The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. CONCLUSION: The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.