Understanding the experiences and perspectives of prenatal screening among a diverse cohort.

INTRODUCTION: Rapid advances in prenatal genetic screening technology make it difficult for providers to deliver adequate prenatal counseling. The aim of this study was to understand how prenatal screening educational approaches can meet the needs of patients. METHODS: Qualitative content analysis was conducted on a diverse population who were interviewed to explore their perceived experiences and preferences for prenatal screening educational delivery. RESULTS: Twenty-two women from three US sites were interviewed. Participants were racially/ethnically diverse with 22.7% identifying as Black or African American (n = 5), 40.9% as Hispanic (n = 9), and 4.5% as Pacific Islander (n = 1). Four themes were identified: prenatal screening education, prenatal screening decision-making, return of results, and suggestions for creating a decision aid. Most results were consistent with previous research not targeting a diverse population. DISCUSSION/CONCLUSION: Our results indicate that learning style preferences vary between patients and that current methods are not consistently satisfying patient's desire for understanding, particularly with 'high-risk' results, suggesting that a standardized tool could improve knowledge and decrease decisional conflict. This diverse cohort suggested a list and description of each of the testing options offered, information about each condition being screened for, a timeline for the testing and return of results, costs associated, and non-technical language.

Diagnostic yield and psychological outcomes among women pursuing trio-exome sequencing: Do women with recurrent anomalous fetal phenotypes experience more negative psychological outcomes?

PURPOSE: To describe psychological outcomes among people with recurrent anomalous pregnancies pursuing trio-exome sequencing (exome sequencing (ES)) compared to those with one affected. METHODS: We analyzed data from a prospective ES cohort, enrolling patients with major fetal anomaly and normal microarray. Participants completed validated scales before and after ES. We (1) compared responses of those with multiple anomalous pregnancies to those with one affected and (2) conducted linear regression to examine associations between multiple affected pregnancies and post-ES constructs. RESULTS: Of 166 trios, 61 (37%) received results from ES. Forty (24%) had more than one affected pregnancy and 45% of those received a result explaining the fetal phenotype. All participants had clinically significant presequencing generalized psychological distress. For the 93 who completed the post-ES surveys, those with multiple affected pregnancies had higher psychological adaptation scores but worse test related distress scores (9.3 (6.2) versus 7.1(5.6), p = 0.12) and (14.3 (1.5) versus 15.4 (1.4), p = 0.01). In linear regression models, there were no significant differences in post-ES constructs after adjusting for clinically relevant covariates. CONCLUSIONS: All individuals experienced significant generalized psychological distress in the pre-ES period, extending our knowledge of how pregnancy history contributes to parental sequencing outcomes.

Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions.

PURPOSE: The purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening. METHODS: An unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies. RESULTS: Overall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected. CONCLUSION: Although traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (∼10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.

Parental motivations for and adaptation to trio-exome sequencing in a prospective prenatal testing cohort: Beyond the diagnosis.

PURPOSE: To understand motivations for and parental interpretation of results from trio-exome sequencing (ES) for fetal anomalies with a negative standard genetic diagnosis. METHODS: Analysis of an ongoing, prospective prenatal trio-ES study of pregnancies with ultrasound-identified congenital anomalies and lack of a standard genetic diagnosis. After determination of pregnancy disposition, participants completed questionnaires and a semi-structured interview pre- and post-sequencing. Interviews were analyzed using a constructivist grounded theory methodology to identify themes. Associations between themes and ES result were also examined. RESULTS: One hundred twenty-six trios have been sequenced. Of those, 45 (36%) resulted in fetal diagnosis. One hundred twenty-five women completed pre-sequencing surveys, and 91 women completed post-sequencing surveys. The main themes identified include (1) variable reasons to pursue ES, (2) limited expectations but high hopes from ES, (3) parental adaptation to uncertain results, (4) impact on personal health and reproduction, and (5) gratitude for the process. CONCLUSION: Participants pursued ES for various reasons, most often to identify a diagnosis and guide reproduction. Post-sequencing, most participants described the process, their interpretation of results, and the impact of receiving the results. Less frequently, but of most concern, participants expressed anxiety about testing and implications for themselves, relationships, and other family members, thus identifying an area of high need for additional support among patients undergoing prenatal ES.

Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort.

PURPOSE: To evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy. METHODS: Trio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two timepoints: pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared with post-sequencing responses; post-sequencing responses were stratified by women who received trio-ES results that may explain fetal findings, secondary findings (medically actionable or couples with heterozygous variants for the same recessive disorder), or negative results. RESULTS: One hundred fifteen trios were enrolled. Of those, 41/115 (35.7%) received results from trio-ES, including 36 (31.3%) who received results that may explain the fetal phenotype. These women had greater post-sequencing distress compared with women who received negative results, including generalized distress (p = 0.03) and test-related distress (p = 0.2); they also had worse psychological adaptation to results (p = 0.001). Genomic knowledge did not change from pre- to post-sequencing (p = 0.51). CONCLUSION: Women show more distress after receiving trio-ES results compared with those who do not, suggesting that women receiving results may need additional support or counseling to inform current and future reproductive decisions.

Correction: An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

PURPOSE: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing. METHODS: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions. RESULTS: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition. CONCLUSION: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.

Use of a novel computerized decision aid for aneuploidy screening: a randomized controlled trial.

PURPOSE: To assess whether knowledge following use of a decision aid (DA) for aneuploidy screening and testing is inferior to knowledge in women who saw a genetic counselor (GC) only. METHODS: This is a randomized controlled noninferiority trial of pregnant women at ≤22 weeks. Women who were scheduled for GC were randomly allocated to use a DA before GC or to GC alone. The primary outcome was knowledge score, comparing women who had used the DA only to those who saw GC alone. Analysis was by intent to treat. RESULTS: Between January and October 2017, 197 women were randomized, 105 to GC only and 92 to DA use before GC. Demographics and baseline knowledge were similar between groups. Mean knowledge score following DA use was not inferior to mean knowledge score following GC only (10.4 vs. 10.6, p = 0.306). Decisional conflict was similar following completion of the DA to following GC only, but was reduced following completion of both the DA and GC compared with GC only (0.22 vs. 1.74, p = 0.003). CONCLUSION: Knowledge surrounding aneuploidy screening in women who used a DA was not inferior to knowledge in women who underwent GC. Use of the DA in addition to GC reduced decisional conflict.

Ethical and counseling challenges in prenatal exome sequencing.

OBJECTIVE: Ethical and counseling challenges are expected with the introduction of prenatal whole exome sequencing. In this study, we describe specific challenges identified through the UNC-Chapel Hill Prenatal Exome Sequencing Study. METHODS: Participants were a subset of women participating in the fetal exome study, which has enrolled 73 mother-father-fetus trios in pregnancies diagnosed with structural anomalies and normal standard genetic testing results. In this descriptive study, cases were reviewed by members of the research team, including a bioethicist, to identify counseling challenges. Illustrative cases were chosen by group consensus. RESULTS: Four illustrative cases were identified for further analysis. Challenges included need for adequate counseling and informed consent, challenges in prenatal variant interpretation, performing prenatal diagnosis in subsequent pregnancies, inability to identify a genetic etiology, and identifying parental secondary findings. CONCLUSION: Our study illustrates several challenges identified in an ongoing prenatal exome study. While genomic medicine is a powerful tool for prenatal diagnosis, it is important that clinicians understand the ethical implications and parental perceptions of this testing modality.

Maternal Malignancy Evaluation After Discordant Cell-Free DNA Results.

Cell-free DNA screening for fetal aneuploidy is a commonly used testing strategy in pregnancies at high risk for fetal aneuploidy. The use of cell-free DNA screening is expanding to the low-risk population, because the detection rate for trisomy 21 surpasses that of traditional screening modalities. Although the sensitivity and specificity of cell-free DNA are superior to traditional screening, false-positive results do occur and may indicate an adverse maternal health condition, including maternal mosaicism or, rarely, malignancy. The risk of maternal cancer is significantly elevated when more than one aneuploidy is detected that is discordant from fetal karyotype. Given this risk as well as the rising incidence of cancer in pregnancy, patient counseling and malignancy evaluation should be considered in women when more than one aneuploidy is detected. We reviewed the published literature and developed an algorithm to evaluate women when these results are identified.

Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges.

PurposeWe investigated the diagnostic and clinical performance of exome sequencing in fetuses with sonographic abnormalities with normal karyotype and microarray and, in some cases, normal gene-specific sequencing.MethodsExome sequencing was performed on DNA from 15 anomalous fetuses and from the peripheral blood of their parents. Parents provided consent to be informed of diagnostic results in the fetus, medically actionable findings in the parents, and their identification as carrier couples for significant autosomal recessive conditions. We assessed the perceptions and understanding of exome sequencing using mixed methods in 15 mother-father dyads.ResultsIn seven (47%) of 15 fetuses, exome sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1 and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that exome sequencing would explain the results (5.2 on a 10-point scale) was higher than the approximately 30% diagnostic yield discussed in pretest counseling.ConclusionExome sequencing had diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy and variant interpretation must be addressed by highly tailored pre- and posttest genetic counseling.

Development, Implementation, and Assessment of a Genetics Curriculum Across Institutions.

Objective Many residency programs offer limited exposure and minimal didactic time genetics, despite its frequent use in obstetrics and gynecology. The objective of this study was to develop, pilot, and assess a three-module women's health genetics curriculum for residents that was easily transferable between institutions. Methods An interactive three-module genetics curriculum covering basic principles, prenatal screening/diagnosis, and cancer genetics was developed. A pre- and posttests were used to assess improvement in knowledge. Subjective feedback was obtained to assess curricular satisfaction. The data were analyzed with descriptive statistics. Results The curriculum was administered at two institutions. Forty-eight residents attended ≥ 1 session. Twenty completed the pretest, and 23 completed the posttest. At the first institution, using audience response system, the percentage correct per question increased on 10/14 questions between pre- and posttests. All students felt the curriculum was useful and would strongly recommend to other residents. At the second institution, pre/posttests were distributed on paper. Mean scores significantly improved between pre- and posttests (p = 0.007). On the pretest, no residents scored > 70%. However, 8/13 scored > 70% on the posttest (p = 0.002). Instructors at both institutions described the curriculum as easy to use/implement. Conclusion This three-module workshop on women's health genetics was easily implemented across institutions and led to increased knowledge.

Cell-Free DNA Screening: Complexities and Challenges of Clinical Implementation.

Screening for fetal aneuploidy in pregnant women using cell-free DNA has increased dramatically since the technology became commercially available in 2011. Since that time, numerous trials have demonstrated high sensitivity and specificity to screen for common aneuploidies in high-risk populations. Studies assessing the performance of these tests in low-risk populations have also demonstrated improved detection rates compared with traditional, serum-based screening strategies. Concurrent with the increased use of this technology has been a decrease in invasive procedures (amniocentesis and chorionic villus sampling). As the technology becomes more widely understood, available, and utilized, challenges regarding its clinical implementation have become apparent. Some of these challenges include test failures, false-positive and false-negative results, limitations in positive predictive value in low-prevalence populations, and potential maternal health implications of abnormal results. In addition, commercial laboratories are expanding screening beyond common aneuploidies to include microdeletion screening and whole genome screening. This review article is intended to provide the practicing obstetrician with a summary of the complexities of cell-free DNA screening and the challenges of implementing it in the clinical setting.

Attitudes and Knowledge of Maternal-Fetal Medicine Fellows Regarding Noninvasive Prenatal Testing.

Using cell-free DNA in maternal serum to detect fetal aneuploidy has been shown to have high sensitivity and specificity. The purpose of this study was to assess attitudes and knowledge of Maternal-Fetal Medicine (MFM) fellows regarding noninvasive prenatal testing (NIPT). A 13 question survey was sent via listserv to US-based MFM fellows. One hundred sixteen fellows responded, a 42.3% response rate, with >75% reporting they are comfortable ordering NIPT. Most (82%) preferred that a patient discuss options with a provider or genetic counselor. Three common methods used to learn about NIPT were: formal educational activities (n = 78, 69%), self-review of the literature (n = 76, 67%), and discussions with peers (n = 73, 65%). On questions related to trisomy 21, accuracy was >70%. However, accuracy was lower regarding use in twin pregnancies (42%) and monosomy X screening (50%).

Cell free DNA testing-interpretation of results using an online calculator.

All pregnant women, regardless of age, should be offered screening or invasive testing for chromosomal abnormalities at <20 weeks' gestation. Noninvasive prenatal screening for fetal aneuploidy with the use of cell-free DNA (cfDNA) is a screening method that offers high sensitivity and specificity in validation studies and has reduced the need for unnecessary invasive procedures. Laboratories often advertise and report a test's sensitivity and specificity as a means to describe the test's accuracy. The positive predictive value (PPV) of a screening test (the proportion of positive results that are truly positive) is a function of the prevalence of the condition in a population and often is not reported in direct-to-patient advertising. False-positive cfDNA screening tests have been reported, and there is evidence that some women are deciding to terminate their pregnancy without confirmatory testing. We believe that laboratories should disclose the patient-specific PPV of cfDNA screening for aneuploidy on result reports. To assist with counseling patients about the benefits, risks, and limitations of aneuploidy screening with the use of cfDNA and to demonstrate the relationship between an a priori risk and PPV, we developed a web-based calculator to estimate the PPV of the 4 commercially available cfDNA testing platforms for which data have been published. Estimates are made with the use of a patient's age and gestational age-related risk of trisomy 21, 18 and 13 or an a priori risk that is based on other findings. This web-based calculator is an aid for providers and genetic counselors to illustrate the relationship between disease prevalence and a test's PPV. It has enhanced our counseling of patients both before they elect noninvasive prenatal screening and after they receive a positive result.