Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US.

OBJECTIVE: There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies. METHOD: We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics. RESULTS: Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers. CONCLUSION: Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing

Degrees of disclosure: a study of women's covert use of the diaphragm in an HIV prevention trial in sub-Saharan Africa.

In sub-Saharan Africa more women are infected with HIV/AIDS than men and new prevention methods are urgently needed. One major attribute of female-initiated HIV prevention methods is that they can be used covertly, without a male partner's knowledge. Using mixed methods, we explored the predictors and dimensions of covert use of the diaphragm in a randomized controlled trial that tested its effectiveness for HIV prevention. The Methods for Improving Reproductive Health in Africa (MIRA) trial was conducted in Zimbabwe and South Africa, and data collection took place between September 2003 and January 2007. This study is a secondary analysis of quantitative and qualitative data from participants randomized to the intervention group, and their male partners. It includes survey data from 2316 women (mean age=28.3), 14 focus group discussions (FGD) conducted with 104 women, and 7 FGD and 10 in-depth interviews with 37 male partners. The median follow-up for trial participation was 21 months (range: 12-24). At their final visit, approximately 9% of women had never disclosed to their primary partners that they were using the diaphragm (covert use). In multivariate analysis, predictors of covert use included being older, not co-habiting with the partner, having a partner who did not use condoms, and being from South Africa. Qualitative analysis revealed that covert use was not dichotomous, but ranged along a continuum, which we categorized into five levels (i.e. full disclosure; mostly open use; occasional covert use; mostly covert use; and completely covert use). We discuss the critical role of the option of covert use for many women in the context of an HIV prevention trial, as well as gender power dynamics which may influence women's decisions about disclosure

Parental Hopes and Understandings of the Value of Prenatal Diagnostic Genomic Sequencing: A Qualitative Analysis.

Objective: To provide qualitative empirical data on parental expectations of diagnostic prenatal genomic sequencing and the value of the results to families. Methods: We interviewed 15 families-mothers and/or fathers-who had had prenatal genomic sequencing about their expectations and their respective evaluations of the benefits of genomic sequencing. Results: Families' hopes for genetic sequencing clustered around three themes: hoping to identify the cause of the fetal anomaly in a terminated pregnancy; hopes for guidance as to the likely outcome of current pregnancy; and hopes for information to support future family planning. In addition, hopes were discussed in terms of the potential for results to be beneficial in acquiring greater knowledge, while at the same time recognizing that new knowledge may raise more questions. Assessment of the value of sequencing largely mirrored these expectations when positive results seen. Negative results can also be seen as valuable in ruling out a genetic cause and in providing certainty that families had done everything that they could to know about the cause of fetal demise. Conclusion: It would appear that with guidance from genetic counsellors, families were largely able to navigate the many uncertainties of prenatal genomic sequencing and thus see themselves as benefitting from sequencing. However, support structures are essential to guide them through their expectations and interpretations of results to minimize possible harms. Engaging in the process of genomic sequencing was seen as beneficial in of itself to families who would otherwise be left without any options to seek diagnostic answers

Making Abortion Safer in Rwanda: Operationalization of the Penal Code of 2012 to Expand Legal Exemptions and Challenges

Penal code was revised in Rwanda in 2012 allowing legal termination of pregnancy resulting from rape, incest, forced marriage, or on medical grounds. An evaluation was conducted to assess women‘s access to abortion services as part of an ongoing program to operationalize the new exemptions for legal abortion. Data was collected from eight district hospitals; seven gender-based violence (GBV) centers and six intermediate courts. Three focus group discussions and 22 in-depth interviews were conducted with key informants. At hospitals, of the 2,644 uterine evacuation records (July 2012-June 2014), and 312 monitoring cases (August-December 2014), majority of all uterine evacuations (97% and 85% respectively, for the two periods) were for obstetric conditions, and induced abortion on medical grounds accounted for 2% vs. 15% respectively. Medical abortion was the prominent method of uterine evacuation. At the GBV centers, 3,763 records were identified retrospectively; 273 women were pregnant. Since the legal reform there was only one abortion for a pregnancy resulting from rape. Abortion stigma and court order requirement are major barriers to access services. The operationalization program has made significant contributions to make abortion safer in Rwanda but this evaluation demonstrates that further work is required to reach the goal of providing safe abortion services to all eligible women. Addressing abortion stigma at the community, organizational and structural levels; further strengthening of service provision; and streamlining legal requirements to protect particularly young women from sexual violence and making abortion a realistic option for GBV victims are some of the important next steps. Keywords: Rwanda, abortion, law, rape, gender-based violence, stigm

Genetic ancestry and diagnostic yield of exome sequencing in a diverse population

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations

Degrees of disclosure: A study of women's covert use of the diaphragm in an HIV prevention trial in sub-Saharan Africa

In sub-Saharan Africa more women are infected with HIV/AIDS than men and new prevention methods are urgently needed. One major attribute of female-initiated HIV prevention methods is that they can be used covertly, without a male partner's knowledge. Using mixed methods, we explored the predictors and dimensions of covert use of the diaphragm in a randomized controlled trial that tested its effectiveness for HIV prevention. The Methods for Improving Reproductive Health in Africa (MIRA) trial was conducted in Zimbabwe and South Africa, and data collection took place between September 2003 and January 2007. This study is a secondary analysis of quantitative and qualitative data from participants randomized to the intervention group, and their male partners. It includes survey data from 2316 women (mean age = 28.3), 14 focus group discussions (FGD) conducted with 104 women, and 7 FGD and 10 in-depth interviews with 37 male partners. The median follow-up for trial participation was 21 months (range: 12-24). At their final visit, approximately 9% of women had never disclosed to their primary partners that they were using the diaphragm (covert use). In multivariate analysis, predictors of covert use included being older, not co-habiting with the partner, having a partner who did not use condoms, and being from South Africa. Qualitative analysis revealed that covert use was not dichotomous, but ranged along a continuum, which we categorized into five levels (i.e. full disclosure; mostly open use; occasional covert use; mostly covert use; and completely covert use). We discuss the critical role of the option of covert use for many women in the context of an HIV prevention trial, as well as gender power dynamics which may influence women's decisions about disclosure.Diaphragm HIV prevention Covert use Female-initiated methods Zimbabwe South Africa Women

"Let's Just Wait Until She's Born": Temporal Factors That Shape Decision-Making for Prenatal Genomic Sequencing Amongst Families Underrepresented in Genomic Research.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research. Drawing on the views of 18 prenatal families who agreed to be interviewed after enrolling (n = 15) or declining to enroll (n = 3) in P3EGS, we observed that the timing of sequencing, coupled with unique considerations around experiences of time during pregnancy and prenatal testing, intersect with structural supports beyond the clinic to produce preferences for and against prenatal sequencing and to contain the threat of unwelcome, uncertain knowledge. Particularly for those without structural supports, finding out consequential information may be more palatable after the birth, when the first stage of the uncertain future has been revealed. Future research should examine the role of temporality in decision-making around prenatal genomic sequencing across diverse population cohorts, in order to observe more precisely the role that structural barriers play in patient preferences

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach

PurposePatients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.MethodsWe explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.ResultsUnderrepresented minorities made up 75% of the probands. In total, 150 families (79%) accepted SF as part of their child/fetus's ES. Most families (63%) wanted all categories of H-SF. Those who declined SF as part of ES were less likely to want H-SF across all categories. Interview findings indicate that some families did not recall their SF decision. Preparing for the future was a major motivator for accepting SF, and concerns about privacy, discrimination, and psychological effect drove decliners.ConclusionA notable subset of families (37%) did not want at least 1 category of H-SF, suggesting more hesitancy about receiving all available results than previously reported. The lack of recollection of SF decisions suggests a need for alternative communication approaches. Results highlight the importance of the inclusion of diverse populations in genomic research

Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations