Introduction: Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality, and low-dose aspirin (LDA) prophylaxis is the cornerstone of evidence-based prevention. Despite guideline recommendations, LDA adherence remains poor, with 10-25% of moderate-risk patients taking aspirin. Objective personalized risk stratification using biomarkers has been shown to motivate behavior change in other disease contexts. Survey data suggest that patients are more motivated to take aspirin if informed by an objective predictive test. Here, we report real-world LDA adherence among patients who received a high-risk result from a cell-free RNA (cfRNA) PE risk prediction test. Methods: This retrospective, observational survey study included asymptomatic patients of advanced maternal age (AMA; ≥ 35 years at delivery) with singleton pregnancies without USPSTF-defined preexisting high-risk conditions for PE who received the cfRNA PE risk prediction test. Patients who opted in to receive text message surveys were asked about LDA use following receipt of test results. High adherence was defined as reporting LDA use on at least 6 of 7 days per week at least 85% of the time surveyed. The primary analysis included patients with a high-risk test result and at least one LDA frequency survey response following receipt of test result. The observed proportion of adherent patients was compared to a baseline estimate of 25% using an exact binomial test. Results: Of 166 patients who received a cfRNA PE risk prediction test result, 48 (28.9%) received a high-risk result. Of these, 29 (60%) opted in and responded to at least one survey, constituting the primary analysis population. Twenty-seven of the 29 (93.1%; 95% CI: 78.0-98.1%) were classified as highly adherent, significantly higher than the 25% baseline adherence estimate for moderate-risk patients (p < 0.0001). Conclusion: Among surveyed patients who received a high-risk cfRNA PE test result, the proportion classified as highly adherent to LDA (93%) substantially exceeded published estimates of adherence in a similar patient population and met the clinically meaningful threshold of ≥ 80% associated with reduced risk of preterm preeclampsia. These findings indicate that objective and personalized biomarker risk testing may be a powerful driver of behavior change that current guidelines have failed to produce.

Preeclampsia affects ~8% of pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. From 2007 to 2019, rates of hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, doubled in the United States. This trend coincides with a rise in maternal mortality, which is now the highest among high-income nations. These statistics support the need to develop risk stratification tools that help to prevent and treat preeclampsia. Efforts to develop these risk assessments have not been successful in reproductive medicine, especially for preeclampsia. The US Preventive Services Task Force (USPSTF) has recommended a risk-based approach using clinical and demographic factors and, for individuals at increased risk, treatment with low-dose aspirin prophylaxis (AP) starting at 12 weeks of gestation. The aim of this study was to assess the proportions of a racially and geographically diverse population classified as low, moderate, or high risk for preeclampsia according to USPSTF criteria. This was a prospective cohort study conducted at 11 medical centers across the United States or through direct recruitment via social media. Included were individuals with singleton pregnancies who were 18 years or older and enrolled in the study before 22 weeks' gestation between July 2020 and March 2023. Participants were classified as high risk if they had at least 1 high-risk condition based on the USPSTF criteria. Participants were classified as moderate risk if they had ≥1 moderate risk factors but no high risk factors (moderate +1 risk category); this group was further subdivided into 2 categories: moderate 1 risk (defined as those with only 1 moderate risk factor) and moderate 2+ risk (those with ≥2 moderate risk factors). Those in the low-risk category had no high or moderate risk factors. AP recommendation with or without a prescription was the effect modification. The primary outcome was preeclampsia. A total of 5684 people were included in the analysis. The study population was identified as Asian (4.7%), black (21%), Hispanic (17.4%), white (48.6%), and other (8.3%). About 12% and 11% of participants were diagnosed with preeclampsia and gestational hypertension that progressed to preeclampsia, respectively. There were 18.5% in the high-risk category and 11.2% in the low-risk category. Approximately 70.3% were in the moderate +1 risk category, which was subdivided into the moderate risk 1 category (34.4%) and the moderate risk 2+ category (35.9%). While the incidence of preeclampsia varied by race, limited information was gleaned for sensitivity and specificity. A significantly increased risk of preeclampsia was observed in those with prior preeclampsia [risk ratio (RR), 1.44; 95% CI, 1.25-1.65; P<0.001] or chronic hypertension (RR, 1.26; 95% CI, 1.10-1.44; P=0.001). Much of the statistical significance was lost for moderate risk factors, and none of the racial categories were associated with increased risk. About 47% of participants with ≥1 risk factor received an AP recommendation. Those with a history of preeclampsia, chronic hypertension, diabetes, or a combination of these conditions before pregnancy were more likely to receive an AP recommendation. In conclusion, the USPSTF criteria for assessing the risk of developing preeclampsia were found to be associated with an increased risk of preeclampsia. The USPSTF risk assessment, examining the moderate risk for preeclampsia, was more weakly associated, and recommendations for AP were more effectively initiated in both high- and low-risk categories. (Abstracted from JAMA Network Open. 2025;8:32521792.).

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.

Importance:The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility. Objective:To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations. Design, Setting, and Participants:This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via convenience sampling. Exposure:The exposures were clinical factors abstracted from medical records by research coordinators, which were stratified according to USPSTF definitions of low, moderate (parity, advanced maternal age [AMA], race, and body mass index), and high (chronic hypertension, prior preeclampsia, type 1 or 2 diabetes, kidney disease, and/or autoimmune conditions) risk. Main Outcomes and Measures:Data collected included AP recommendation, presence of USPSTF-defined moderate risk factors or high risk factors, and any preeclampsia diagnosis. Effect sizes and relative risk (RR) were calculated within risk strata. Results:Of 5684 participants (median [IQR] age, 30.9 [26.4-34.6] years; 267 [4.1%] Asian; 1191 [21.0%] Black; 990 Hispanic [17.4%]; 2764 [48.6%] White; and 472 [8.3%] with other race or ethnicity), 5046 (88.8%) were at increased risk of preeclampsia (3996 [70.3%] at moderate risk and 1050 [18.5%] at high risk). A total of 2438 participants (43.1%) received an AP recommendation. The overall preeclampsia rate was 12.1% (685 participants). The PE rates specific to USPSTF categories were 3.0% for those at low risk (19 of 638 participants), 10.5% for those at moderate risk (419 of 3996 patients), and 23.5% for those at high risk (247 of 1050 participants). Among individuals with 2 or more moderate risk factors but without any high risk factor, nulliparity was associated with significantly increased risk of preeclampsia (RR, 1.48; 95% CI, 1.35-1.62; P < .001), while AMA was associated with decreased risk (RR, 0.79; 95% CI, 0.65-0.96; P = .02); there was no association with obesity (RR, 1.11; 95% CI, 1.01-1.22; P = .048) or Black race (RR, 0.95; 95% CI, 0.80-1.14; P = .63). Of 1044 participants with any high risk factors, 856 (82.0%) were recommended AP and of 634 at low risk, 538 (85.9%) were not recommended AP. In contrast, of 1942 participants with 1 moderate risk factor, 463 (23.8%) were recommended AP, and of 2032 with 2 or more moderate risk factors, 1024 (50.4%) were recommended AP. Conclusions and Relevance:In this prospective cohort study of 5684 singleton pregnancies, 89% of the population was assessed as having increased risk (moderate or high) of preeclampsia by USPSTF criteria. These findings suggest that moderate risk factors in the absence of high risk factors show no or low value for estimating the risk of developing preeclampsia, leading to nonspecific recommendations of AP in the moderate risk category.

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.

INTRODUCTION: The same factors contributing to disproportionately worse health outcomes are also barriers to inclusion in research for Black, Hispanic, and Indigenous patients. In this subanalysis of a large, multisite prospective cohort study of maternal plasma mRNA signatures and adverse pregnancy outcomes (APOs), we sought to determine whether equitable representation was aided by the inclusion of a large community hospital as an enrollment site. METHODS: Pregnant persons between 18 and 45 year old with a singleton pregnancy eligible to enroll in this IRB-approved prospective cohort study at Woman’s Hospital (Baton Rouge, Louisiana). A hybrid of indirect and direct recruitment strategies, bolstered by text message communication and gift card compensation, were deployed to facilitate enrollment that mirrored the community’s diversity. RESULTS: Two thousand five hundred twenty-two participants have been enrolled over 22 months (18% of the hospital’s eligible patient population): 41% of participants are Black, 9% are of Hispanic origin, 50% are White, and 9% Other race. This identically mirrors the demographics of the hospital obstetric patient population (38% Black, 7% Hispanic, 49% White, and 13% Other). CONCLUSION: Participants overall mirrored the diverse population served. Inclusion of study sites outside of the traditional academic setting is an effective strategy for promoting equitable access to clinical research, combating barriers to inclusion in research faced by the populations that are disproportionately affected by APOs.

Physiological systems vary from day to night in response to differing biological demands. In various nonpregnant populations, these changes may be reflected in RNA expression patterns measured in blood samples. This study sought to identify whether time of blood draw and circadian rhythm can be revealed through cell free RNA analysis of maternal blood plasma in a pregnant population. This was a prospective, observational study of a cell-free RNA platform utilizing direct-to-participant recruitment efforts from July 2020 to December 2021. The IRB-approved study was open to patients ages 18-45 with a singleton pregnancy in the United States. Samples were grouped by time of blood draw into morning (6am-10am, n=121), midday (10am-2pm, n=303) and afternoon (2pm-6pm, n=113). We ran differential gene expression (DGE) analyses to test the impact of time of day. A quasi-likelihood negative binomial generalized log-linear model was fit to count data using edgeR package (v. 3.38.1) and DGE were discovered with an empirical Bayes quasi-likelihood F-test (edgeR) in all 3 possible pairwise comparisons. When looking for DGE between the morning and afternoon groups we identify 5,729 genes (Figure 1) or 43% of all analyzed genes as significantly differentially expressed. For morning vs midday the number is 4,278 (32%) and finally midday vs afternoon has 15 (0.1%) DGE. The three sets have very high overlap, ranging from 73% - 87% (p < 10-30), and among the genes with highest separation we find those reported with circadian rhythm (PER1, PER3, DDIT4, FKBP5). The cell-free RNA platform revealed that time of sample collection has a predictable impact on RNA expression patterns. This is the first evidence of this phenomenon demonstrated in a pregnant population, and particularly the morning group is differentiated from later blood draws. The effect of circadian rhythm is an important consideration in current and future development of biomarkers making the time of sample collection an important variable to collect and analyze.

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.

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.

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.

ABSTRACT Objective To describe our clinical experience across the entire range of fetal‐fraction (FF) measurements of a non‐invasive prenatal screen (NIPS) that uses whole‐ genome sequencing (WGS). Methods We analyzed retrospectively results from 58 105 singleton pregnancies that underwent NIPS on a customized WGS platform during an 8‐month period and assessed clinical test performance for trisomy 21, trisomy 18 and trisomy 13. Pregnancy outcomes were sought for all screen‐positive patients and for 18% of screen‐negative patients. As differences in outcome‐collection response rates could artificially impact test‐performance calculations, we computed inferred sensitivity, specificity, positive predictive values (PPV) and negative predictive values adjusted for ascertainment bias. Results The screening test yielded a result for 99.9% ( n = 58 048) of patients, meaning that approximately 1 in 1000 patients received a test failure (i.e. test failure rate = 0.1%). Of pregnancies with a test result, 572 (1%) screened positive for one of the common aneuploidies (362 for trisomy 21, 142 for trisomy 18 and 68 for trisomy 13). Informative outcomes were received for 237 (41.4%) patients with a screen‐positive result and 3258 (5.7%) of those with a screen‐negative result. In the full cohort, inferred sensitivities for trisomy 21, trisomy 18 and trisomy 13 were 99.7%, 96.8% and 94.3%, respectively, and PPVs were 93.1%, 85.2% and 48.4%, respectively. If a FF threshold of 4% had been employed to guard against false negatives, calculated sensitivities for the three aneuploidies would not have changed significantly, yet, importantly, the overall test‐failure rate would have increased to 6.6% ( n = 3829), impacting 1 in 15 women. Conclusions Our clinical experience demonstrates that a customized WGS‐based NIPS without a FF threshold achieves high accuracy while maintaining a low test‐failure rate of 0.1%. As such, alternative strategies to ensure high accuracy of detection of common aneuploidies in samples with low FF (such as redraw after test failure, redrawing at a later gestational age, risk scoring based on FF) are not necessary for this screening approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

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.

INTRODUCTION: Describe clinical performance of a whole genome sequencing-based noninvasive prenatal screen (NIPS) in pregnancies achieved via assisted reproductive technology (ART). METHODS: After securing IRB-exempt status, we retrospectively analyzed results from 58,105 patients who underwent NIPS during a nine-month period to assess clinical performance of Trisomy 21, 18, and 13 in singleton pregnancies. Four percent (2,435 pregnancies) reported being conceived via ART. Fetal fraction (FF) was measured for all patients but was not used as a stand-alone reason for test failure. We sought pregnancy outcomes for all patients who screened positive and for 10% of those who screened negative. Voluntarily reported outcomes were also accepted. Concordance of results was determined with respect to pregnancy outcome. Clinical sensitivities and specificities were calculated, adjusting cohort size for ascertainment bias. RESULTS: The total patient cohort included average-risk (43%, n=24,751) and high-risk patients (57%, n=33,354). For the ART population, median maternal age was 36 years and median gestational age was 12.0 weeks. The screen yielded a result for 99.7% of ART patients; no result was issued for the remaining 0.3% of samples (n=7). Screen positive rate was 0.7%. Informative outcomes were received for 50% of positive results in the ART cohort; nine true positives and one false positive. Observed sensitivities for Trisomy 21 and Trisomy 18 were 100% and 100%, respectively, in ART pregnancies. No patients screened positive for Trisomy 13. No false negatives were reported. CONCLUSION: Results demonstrate that NIPS in our laboratory achieves high accuracy while maintaining a low test-failure rate in pregnancies conceived via ART.

Noninvasive Prenatal Screening (NIPS) via cell-free DNA analysis (cfDNA) has been rapidly incorporated into prenatal care since 2011. The Counsyl Prelude Prenatal Screen utilizes a widely reported whole genome sequencing (WGS) approach to NIPS. Here we describe the clinical experience of offering Prelude in our laboratory. We retrospectively analyzed results from 58,028 patients who underwent NIPS over a nine month period to assess clinical performance for identifying Trisomy 21, Trisomy 18, and Trisomy 13 in singleton pregnancies. We sought pregnancy outcomes for all positive results and 10% of negative results. Voluntarily reported false negatives were also included. The patient cohort included average-risk (41%, n=23,735) and high-risk patients (59%, n=34,293). Median maternal age was 34 years (interquartile range (IQR): 29-37 years). Median gestational age was 12.4 weeks (IQR: 11.3-13.7 weeks). Unlike several NIPS offerings that do not provide a result when fetal fraction (FF) is below a specified threshold, Prelude does not fail samples solely based on fetal fraction. As such, the screen yielded a result for 99.9% of patients; no result was issued for 0.1% of cases (n=59) due to technical reasons. Median turnaround time was three days (IQR: 2-4 days). 572 cases (1%) screened positive ("aneuploidy detected" or "aneuploidy suspected") with 362 positive for Trisomy 21, 142 positive for Trisomy 18, and 68 positive for Trisomy 13. "Aneuploidy suspected" reports accounted for 6.5% of positive results (n=37), 0.06% of the total cohort. Informative clinical outcomes were received for 244 (42.7%) positive results and 1,510 negative results (23% of those requested). Based on cytogenetically confirmed cases and adjusting cohort size for ascertainment bias, observed sensitivities for Trisomy 21, Trisomy 18, and Trisomy 13 were 99.3%, 95.9%, and 94.4%, respectively. Twenty-nine false positives were identified (seven Trisomy 21, seven Trisomy 18, and fifteen Trisomy 13). Prelude clinical performance is consistent with the NIPS literature, and is achieved without a FF failure threshold. Our results demonstrate that Prelude achieves high accuracy and a low test-failure rate in a large general obstetric population.

Reports of rare autosomal aneuploidy (RAA) from noninvasive prenatal screening (NIPS) via whole-genome sequencing (WGS) have important clinical implications due to placental mosaicism, uniparental disomy (UPD), and true fetal aneuploidy. We explored the prevalence of RAA and relative degree of mosaicism (DOM) detected via NIPS for RAA versus for common aneuploidies (13, 18, 21) and the effect on results interpretation. To characterize prevalence and the degree of mosaicism in all aneuploidies, a retrospective analysis of 48,965 sequential prenatal NIPS samples processed via WGS was performed. Aneuploidy was identified using a z-score that reflected the significance of enrichment or depletion in WGS read density. For the purposes of this study, we examined high confidence positives defined as having |z| > 6. DOM is defined as the ratio of the fetal fraction estimated from WGS read-density enrichment on the positive chromosome (FF_pos) to the orthogonal, regression- based fetal fraction measurement inferred from the collection of read density values across all autosomes (FF_inferred). DOM less than 0.5 was chosen for the threshold at which a positive RAA call was qualified as being mosaic. 266 out of 48,965 samples (0.5%) had an RAA. The most common RAAs occurred in chromosomes 7, 8, 15, 16, and 20. Near zero prevalences of RAAs on chromosomes 1, 11, 17, and 19 are consistent with previous reports. We showed that the frequency of mosaicism differed between common aneuploidies and RAAs; 4.44% of samples positive for chromosome 21 were estimated to have DOM less than 0.5. In contrast, for chromosome 7, 87.69% of positive samples were estimated to have DOM less than 0.5. Our findings suggest that mosaicism may be common—not an edge case—in RAA and, therefore, must be taken into account when reporting positives. Accurate screen-positive calls for RAA and common aneuploidy therefore uniquely depend on established laboratory criteria for DOM. Interpreting these results in the same manner as those for common aneuploidies may otherwise compromise the clinical value of screening for RAA due to potential false negatives.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

INTRODUCTION: Non-invasive prenatal screening (NIPS) and expanded carrier screening (ECS) have widened the scope of information available to patients and providers alike, underscoring the importance of timely results delivery. We describe an automated system utilizing online education and tele-genetic counseling to aid women's health professionals in effectively delivering genetic testing results. METHODS: Providers are notified upon availability of results. For ECS results indicating a high reproductive risk, patients receive an automated email directing them to schedule a consultation with a laboratory-based genetic counselor. Screen-positive NIPS results are delivered to the ordering provider, who may request that a laboratory-based genetic counselor contact the patient. All other results can be viewed directly by the patient in an online portal with educational resources. Regardless of result type, patients can speak to a genetic counselor, either on-demand or by scheduling an appointment. This study was IRB exempt. RESULTS: Through December 2017, 278,318 ECS results and 67,122 NIPS results were issued via the system. Of these, 41,050 patients (15%) ECS patients and 4,673 (7%) NIPS patients elected genetic counseling, resulting in a total of 47,793 consultations. A number of patients electing genetic consultations received negative results (∼50% ECS, 95% NIPS). Patients frequently utilized on-demand services (32% ECS, 70% NIPS). Median consultation duration times were ten minutes and nine minutes for ECS and NIPS results, respectively. CONCLUSION: We describe a system that can provide large-scale prenatal genetic testing results delivery, education, and counseling congruent with clinical guidelines; imperative to quality care as uptake grows among the obstetric population.

Purpose/AimExamine how well noninvasive prenatal screening (NIPS) performs in women across body mass index (BMI) classes.HypothesisNIPS via whole genome sequencing better serves all women, regardless of BMI, compared with traditional maternal serum screening.Significance/BackgroundNoninvasive Prenatal Screening (NIPS), increasingly offered as a first‐line aneuploidy screen, has superior performance compared with maternal serum screening (MSS). Fetal fraction (FF) is one of the many factors that influence the performance of NIPS. Low FF is associated with early gestational age, a compromised placenta (eg, from triploidy and certain aneuploidies), and high BMI. By far, the most common driver of low FF is high BMI. The most recent American College of Medical Genetics and Genomics statement recommends “offering aneuploidy screening other than NIPS in cases of significant obesity.” However, patients with high BMI constitute approximately25% of US pregnancies, creating a significant disparity in care based on weight.Methods58,639 patients who received NIPS were stratified into standard BMI classes. For each BMI group, the aggregate analytical sensitivity was calculated by summing—over the range of FF values—the product of 1) the sensitivity for a given FF and depth based on a model of whole‐genome sequencing (WGS) NIPS and 2) the BMI‐specific probability of observing a patient at that FF. Scaled sensitivities were incorporated into residual‐risk calculations to assess impact on patient results reporting.FindingsDue to downward shifts in the FF distribution, NIPS sensitivity drops as BMI increases: non‐obese analytical sensitivity for T21 is 99.5%, whereas for class III it is 94.1%. Nevertheless, even patients with class III BMI have expected T21 sensitivity in excess of that obtainable via standard MSS (92.9%). Sensitivity for T13 and T18 was also higher across the BMI spectrum for WGS‐based NIPS relative to MSS.DiscussionWGS‐based NIPS with high performance at low FF is a high‐quality aneuploidy screening option for all women, regardless of BMI. Providers can therefore offer the same high level of care to all patients, regardless of body habitus.