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.     

Diagnostic yield of exome sequencing in isolated fetal growth restriction: Systematic review and meta-analysis

The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with isolated fetal growth restriction (FGR). This was a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies included those with (a) only fetuses with FGR in the absence of fetal structural anomalies and (b) negative CMA or karyotyping results. Only positive variants classified as likely pathogenic or pathogenic determined as causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Eight studies with data on ES diagnostic yield, including 146 fetuses with isolated FGR, were identified. Overall, a pathogenic variant determined as potentially causative of the fetal phenotype was found in 17 cases, resulting in a 12% (95% CI: 7%–18%) incremental performance pool of ES. The vast majority were studied before 32 weeks'gestation. In conclusion, a monogenic disorder was prenatally found in association with apparently isolated FGR in 12% of these fetuses.     

Isolated fetal hydrothorax with hydrops: a systematic review of prenatal treatment options

Objective To evaluate the effect of prenatal therapeutic interventions on perinatal outcome in pregnancies complicated by isolated fetal hydrothorax with hydrops. Methods A systematic review of the literature from January 1982 to January 2006 of perinatal outcome in pregnancies with isolated fetal hydrothorax with hydrops with any form of prenatal treatment was conducted. Results Forty-four articles met our selection criteria, reporting a total of 172 fetuses treated prenatally. Reported treatment options were single (n = 13) or serial thoracocentesis (n = 18), thoraco-amniotic shunt placement (n = 100) or a combination of thoracocentesis and shunting (n = 36). Four case-reports described pleurodesis with OK-432, (n = 3) and intrapleural injection of autologous blood (n = 2). Overall survival rate was 63%, ranging from 54% for single thoracocentesis to 80% in the 5 cases treated with pleurodesis, without statistically significant differences between the treatment modalities. Shunt-placement with or without prior thoracocentesis was most often described, with survival rates of 67 and 61% respectively. Discussion The available literature consists exclusively of case reports and case series. This systematic review suggests that with prenatal intervention, perinatal survival rates around 63% are possible. There is a need for prospective, adequately controlled studies with long-term follow-up to determine the best treatment and more reliable outcome data in pregnancies complicated by fetal hydrothorax with hydrops. Copyright © 2007 John Wiley & Sons, Ltd.     

Factors affecting the clinical use of non-invasive prenatal testing: a mixed methods systematic review

Non-invasive prenatal testing has been in clinical use for a decade; however, there is evidence that this technology will be more widely applied within the next few years. Guidance is therefore required to ensure that the procedure is offered in a way that is evidence based and ethically and clinically acceptable. We conducted a systematic review of the current relevant literature to ascertain the factors that should be considered when offering non-invasive prenatal testing in a clinical setting. We undertook a systematic search of relevant databases, journals and reference lists, and from an initial list of 298 potential papers, identified 11 that were directly relevant to the study. Original data were extracted and presented in a table, and the content of all papers was analysed and presented in narrative form. Four main themes emerged: perceived attributes of the test, regulation and ethical issues, non-invasive prenatal testing in practice and economic considerations. However, there was a basic difference in the approach of actual or potential service users, who were very positive about the benefits of the technology, compared with other research participants, who were concerned with the potential moral and ethical outcomes of using this testing method. Recommendations for the appropriate use of non-invasive prenatal testing are made. © 2013 John Wiley & Sons, Ltd.     

Monochorionic and dichorionic twin pregnancies discordant for fetal anencephaly: a systematic review of prenatal management options

The aim of this study was to evaluate the effect of selective feticide (SF) compared to expectant management (EM) on perinatal outcome in dichorionic and monochorionic twins discordant for anencephaly. For this purpose, we conducted a systematic review of literature and added ten unpublished cases. As a result, we found that in dichorionic twins, mean gestational age (GA) at birth in the SF group was 38.0 weeks versus 34.9 weeks (P = 0.0002). Mean birth weight was 2922 g in the SF group versus 2474 g (P = 0.03). In monochorionic twins, mean GA at birth was 35.2 weeks versus 32.7 weeks (P = 0.1). Mean birth weight was 2711 g versus 1667 g (P = 0.0001). We conclude that while SF does not reduce perinatal mortality, it does result in significantly longer gestations and higher birth weight, and appears to be the management of choice in dichorionic twins discordant for anencephaly. In monochorionic twins, SF also increases birth weight, but in view of the complexity of this group, no clear recommendations can be made. Copyright © 2008 John Wiley & Sons, Ltd.     

Obstetrical outcomes following amniocentesis performed after 24 weeks of gestation: A systematic review and meta-analysis

To evaluate obstetrical outcomes for women having late amniocentesis (on or after 24 weeks). Electronic databases were searched from inception to January 1st, 2023. The obstetrical outcomes evaluated were gestational age at delivery, preterm birth (PTB) < 37 weeks, PTB within 1 week from amniocentesis, premature prelabor rupture of membranes (pPROM), chorionamnionitis, placental abruption, intrauterine fetal demise (IUFD) and termination of pregnancy (TOP). The incidence of PTB <37 weeks was 4.85% (95% CI 3.48–6.56), while the incidence of PTB within 1 week was 1.42% (95% CI 0.66–2.45). The rate of pPROM was 2.85% (95% CI 1.21–3.32). The incidence of placental abruption was 0.91% (95% CI 0.16–2.25), while the rate of IUFD was 3.66% (95% CI 0.00–14.04). The rate of women who underwent TOP was 6.37% (95%CI 1.05–15.72). When comparing amniocentesis performed before or after 32 weeks, the incidence of PTB within 1 week was 1.48% (95% CI 0.42–3.19) and 2.38% (95% CI 0.40–5.95). Amniocentesis performed late after 24 weeks of gestation is an acceptable option for patients needing prenatal diagnosis in later gestation.     

Non-invasive prenatal testing (NIPT) in twin pregnancies affected by early single fetal demise: A systematic review of NIPT and vanishing twins

The screening performance of non-invasive prenatal testing (NIPT) in vanishing twin (VT) pregnancies is relatively unknown. To close this knowledge gap, we conducted a systematic review of the available literature. Studies describing the test performance of NIPT for trisomy 21, 18, 13, sex chromosomes and additional findings in pregnancies with a VT were retrieved from a literature search with a publication date until October 4, 2022. The methodological quality of the studies was assessed with the quality assessment tool for diagnostic accuracy studies-2 (QUADAS-2). The screen positive rate of the pooled data and the pooled positive predictive value (PPV) were calculated using a random effects model. Seven studies, with cohort sizes ranging from 5 to 767, were included. The screen positive rate of the pooled data for trisomy 21 was 35/1592 (2.2%), with a PPV of 20% (confirmation in 7/35 cases [95% CI 9.8%–36%]). For trisomy 18, the screen positive rate was 13/1592 (0.91%) and the pooled PPV 25% [95% CI 1.3%–90%]. The screen positive rate for trisomy 13 was 7/1592 (0.44%) and confirmed in 0/7 cases (pooled PPV 0% [95% CI 0%–100%]). The screen positive rate for additional findings was 23/767 (2.9%), of which none could be confirmed. No discordant negative results were reported. There is insufficient data to fully evaluate NIPT performance in pregnancies with a VT. However, existing studies suggest that NIPT can successfully detect common autosomal aneuploidies in pregnancies affected by a VT but with a higher false positive rate. Further studies are needed to determine the optimal timing of NIPT in VT pregnancies.