With improvements in overall health attributable to newly available medications called highly effective modulator therapy, an increasing number of people with cystic fibrosis (CF) are pursuing pregnancy. However, the safety of these medications for pregnant people with CF and the fetus remains largely unknown. Limited data demonstrate a decline in patients' health and well-being after withdrawal of highly effective modulator therapy during pregnancy; however, both animal and human studies suggest an association between highly effective modulator therapy and cataracts in the offspring that requires further investigation. Use of highly effective modulator therapy can also affect the results of newborn screening and may influence fetal outcomes among fetuses affected by CF as a result of transplacental passage of highly effective modulator therapy. An ongoing prospective cohort study will likely provide more information for pregnant people with CF. Until then, multidisciplinary counseling continues to be critical for people with CF who are of reproductive age.

PURPOSE:To describe the association between geographic location of residence and use of aneuploidy screening or prenatal genetic counseling and how it is modified by maternal race and ethnicity. METHODS:Retrospective cohort of individuals at a tertiary care center between 2017-2019. County of residence was classified as rural or metropolitan based in US Office of Management and Budget 2019 definitions. Maternal race and ethnicity were self-identified. Our composite outcome was defined as use of aneuploidy screening or genetic counseling visit. The composite outcome was compared by geographic location and ethnicity. Logistic regression was used to model the relationship between geographic location and the composite outcome. RESULTS:A total of 8774 pregnancies were included. Of these, 4770 (54%) had genetic screening, and 3781 (43%) had at least 1 genetic counseling visit. Rural patients were significantly less likely to have the composite outcome compared with metropolitan peers (37.1% vs 47.2%, P < .001). In addition, we identified differences in the composite outcome between White rural patients and LatinX rural patients (37.7% vs 35.6%, P < .001) and between Asian rural patients and LatinX and Black rural patients (41.0% vs 35.6%, P < .001; 41.0% vs 36.8%, P < .001). Logistic regression demonstrated that rural patients were significantly less likely to have the composite outcome compared with metropolitan peers, after adjusting for LatinX ethnicity and gestational age at first prenatal visit (OR 0.72, [0.55, 0.95], P = .002). CONCLUSION:Rural, minority patients were significantly less likely to receive reproductive genetic services compared with metropolitan peers extending our knowledge of disparities in maternity care.

As early diagnosis and management of inborn errors of metabolism (IEM) improves, more individuals with these conditions are pursuing pregnancy. There is limited data and available subspecialists to guide the complex aspects that may impact such pregnancies, such as partner carrier screening, preconception counseling, metabolic management of mother and fetus during pregnancy and postpartum, pre- and postnatal diagnosis of the fetus, and labor and delivery care. Here, we provide a description of the unique clinical setup of our adult reprogenetics/genomics clinic in collaboration with pediatric genetics and metabolism (PGM) on management of the complex mother/child dyad when an inborn error of metabolism is present.

Access to care with a genetics professional for reproductive aged women is limited. In addition, there are barriers to accessing a Maternal Fetal Medicine-Clinical Geneticist who can guide rare disease care in pregnancy and prenatal diagnosis, thus making maternity care for those with genetic conditions particularly limited. To address this issue, we established an Adult Reproductive Clinical Genetics & Genomics Clinic (MFM-CGG Clinic) in which families can establish genetic and high-risk pregnancy care in a single location with continuity of care.

PurposeTo describe psychological outcomes among people with recurrent anomalous pregnancies pursuing trio-exome sequencing (exome sequencing (ES)) compared to those with one affected. MethodsWe 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. ResultsOf 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. ConclusionsAll individuals experienced significant generalized psychological distress in the pre-ES period, extending our knowledge of how pregnancy history contributes to parental sequencing outcomes.

ObjectiveTo determine the cost-effectiveness of first-trimester ultrasound before fetal aneuploidy screening with cell-free DNA (cfDNA) compared with screening by cfDNA alone. MethodsA decision analytic model was constructed for 400 000 pregnant individuals with advanced maternal age who desired first-trimester aneuploidy screening with cfDNA in the USA, to compare two screening strategies: (1) cfDNA only and (2) ultrasound performed within 4 weeks before cfDNA. Input parameters included probability of fetal aneuploidy, cfDNA performance, desire for diagnostic testing, pregnancy outcomes, and pregnancy and lifetime costs and utilities. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), in terms of cost in 2020 US dollars (USD) per quality-adjusted life year (QALY) gained. Secondary outcomes included procedure-related loss, pregnancy termination, live birth with aneuploidy, live birth with structural anomaly and stillbirth. Discounting was performed at 3% per year with an estimated maternal lifespan of 81 years starting at the age of 35 years. One-way, multiway and Monte Carlo probabilistic sensitivity analyses were performed. All base-case estimates and ranges of uncertainty were derived from the literature. The willingness-to-pay threshold was set at 100 000 USD per QALY. ResultsIn the base-case analysis, ultrasound before cfDNA screening was more cost-effective than cfDNA screening without pretest ultrasound, with an ICER of 12 588 USD and higher net monetary benefit (24 241 vs 20 466). The strategy involving ultrasound before cfDNA was more costly by 544 USD but also more effective (by 0.04 QALY) compared with cfDNA alone. Base-case results were robust in sensitivity analyses with the strategy involving ultrasound before cfDNA always remaining the most cost-effective approach with the highest net monetary benefit. ConclusionFirst-trimester ultrasound before cfDNA is a more cost-effective strategy for non-invasive prenatal aneuploidy screening compared with cfDNA alone. (c) 2022 International Society of Ultrasound in Obstetrics and Gynecology.

IntroductionRapid 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. MethodsQualitative content analysis was conducted on a diverse population who were interviewed to explore their perceived experiences and preferences for prenatal screening educational delivery. ResultsTwenty-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/ConclusionOur 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.

Exome sequencing (ES), or sequencing of the protein coding regions of the genome, has revolutionized medicine and offers significant promise for prenatal diagnosis. Current studies emphasize the technical feasibility of ES.1Lord J. McMullan D.J. Eberhardt R.Y. et al.Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.Lancet. 2019; 393: 747-757Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar However, exploring the future impact of ES is critical to using this technology for fetal diagnosis. In particular, how ES informs future reproductive decisions has been understudied.2Best S. Wou K. Vora N. Van der Veyver I.B. Wapner R. Chitty L.S. Promises, pitfalls and practicalities of prenatal whole exome sequencing.Prenat Diagn. 2018; 38: 10-19Crossref PubMed Scopus (229) Google Scholar The objective of this study is to report how parents used diagnostic results from trio ES during an anomalous pregnancy to inform future diagnostic decisions. This was a case series of select patients in a prospective trio (sequencing of both parents and fetus) ES study (institutional review board grant number 13-4084) from July 2014 to July 2021. The study was eligible to patients with an anomalous pregnancy and nondiagnostic standard genetic testing (protocol provided in the Reference).3Vora N.L. Powell B. Brandt A. et al.Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges.Genet Med. 2017; 19: 1207-1216Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Following participation, some elected to provide information regarding subsequent pregnancies. Notably, this was volunteered by and was not systematically ascertained from all the participants. Data presented in this report include (1) postsequencing comments part of the study protocol and (2) volunteered information regarding future pregnancies. Overall 126 trios have been sequenced.4Talati A.N. Gilmore K.L. Hardisty E.E. Lyerly A.D. Rini C. Vora N.L. Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort.Genet Med. 2021; 23: 713-719Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Of those, 6 participants volunteered information on testing decisions in subsequent gestations. Notably, all 6 terminated the enrolled pregnancy and used ES diagnostic information in the next gestation (amniocentesis/chorionic villus sampling or preimplantation genetic testing for monogenic disorders) (Table). Other pregnancies may have occurred within the cohort but were not reported to the study personnel.TableFetal ultrasound findings, sequencing result, variant interpretation, and method of prenatal diagnosis in subsequent pregnancyID #Ultrasound-detected fetal anomalySequencing resultVariant interpretationPrenatal diagnosis in subsequent pregnancy1Nonimmune hydropsCompound heterozygous PIEZO1 variantsLP/VUSCVS2Cystic hygroma, omphalocele, broad abducted thumbs, hydrops, hydrocephalus, hypoplastic cerebellum, Chiari malformationCompound heterozygous WDR81 variantsLP/LPAmniocentesis3Micrognathia, heart defect, hypotonia. dysmorphic facial features, sacral dimpleDe novo KMT2A variantLPPGT-M4Arthrogryposis, hypoplastic right heart, enlarged liver, polyhydramniosDe novo HRAS and compound heterozygous HEXB variantsLP/LP (HEXB)LP (HRAS)CVS5Sloping forehead, micrognathia, IUGR, ambiguous genitalia, abnormal renal arteries, arthrogryposisCompound heterozygous TRAIP variantsP/VUSCVS6Fixed abnormally positioned upper extremities, rocker bottom feetHomozygous ADGRG6 (aka GPR126) variantVUS/VUSPGTCVS, chorionic villus sampling; IUGR, intrauterine growth restriction; LP, likely pathogenic; PGT, preimplantation genetic testing; PGT-M, preimplantation genetic testing for monogenic disorders; P, pathogenic; VUS, variant of uncertain significance.Talati. Exome sequencing and future pregnancies. Am J Obstet Gynecol 2022. Open table in a new tab CVS, chorionic villus sampling; IUGR, intrauterine growth restriction; LP, likely pathogenic; PGT, preimplantation genetic testing; PGT-M, preimplantation genetic testing for monogenic disorders; P, pathogenic; VUS, variant of uncertain significance. Talati. Exome sequencing and future pregnancies. Am J Obstet Gynecol 2022. All the participants provided pre- and post-ES comments. Pre-ES, 4 of them hoped to identify an etiology for pregnancy loss (eg: "we hope to understand why we lost the baby"); 1 described a search for closure, ("to get closure if there is an answer"); and 1 wanted information for future diagnosis ("guidance for future pregnancy testing"). Post-ES, 4 responded positively to the results (eg, "We now know the mutation we had. It's good that we know so we're not caught off guard in the future"). Although limited in sample size, our report demonstrates that receiving ES results impacts future pregnancy diagnostic decisions. However, this report is not without limitations. First, ES demonstrates a diagnostic yield of 15% to 19% when multisystem anomalies are present and standard testing is negative.1Lord J. McMullan D.J. Eberhardt R.Y. et al.Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.Lancet. 2019; 393: 747-757Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar Thus, most of the individuals had nondiagnostic results and did not contact us. Second, individuals in this report had access to early prenatal diagnosis. It is unlikely that ES would confer the same opportunity to those with barriers to care. Furthermore, the time to receive results with ES may be weeks. It requires complex genetic counseling and is costly; as such, its use for pregnancy management decisions in an ongoing pregnancy is uncertain.5Ferretti L. Mellis R. Chitty L.S. Update on the use of exome sequencing in the diagnosis of fetal abnormalities.Eur J Med Genet. 2019; 62: 103663Crossref PubMed Scopus (37) Google Scholar Finally, 1 person in our cohort had diagnostic testing on the basis of a variant of unknown significance (VUS), identifying an area where guidelines are unclear and decisions may be driven by test-related anxiety and distress.4Talati A.N. Gilmore K.L. Hardisty E.E. Lyerly A.D. Rini C. Vora N.L. Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort.Genet Med. 2021; 23: 713-719Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Given our expanding testing but limited correlation with the fetal phenotype and the significant distress associated with a diagnostic vs nondiagnostic result,4Talati A.N. Gilmore K.L. Hardisty E.E. Lyerly A.D. Rini C. Vora N.L. Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort.Genet Med. 2021; 23: 713-719Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar providers should recognize that there is currently no specific guidance on how a VUS may inform future pregnancy decisions, and this should be an area of focus for future studies.

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.

Area of residence affects access to prenatal care and may affect use of reproductive genetic services. The purpose of this study is to describe the association between rural or urban county of residence and use of reproductive genetic services. Retrospective cohort study of individuals who sought prenatal and delivery care at a quarternary care center in NC between 2017-2019. Patient county of residence was classified as rural or urban based on definitions from the Core Based Statistical Areas of the US Office of Management and Budget 2019. Metropolitan counties are defined as urban; micropolitan and rural are defined as rural. Uptake of genetic screening and genetic counseling services were compared by patient county of residence. Logistic regression using backwards, stepwise elimination was used to model the association between rural county and use of genetic services. 8774 pregnancies were included in the dataset. Of those, 4770 (54%) had genetic screening or diagnostic testing and 3,781 (43%) had at least one genetic counseling visit. Rural patients less frequently spoke English as their primary language and were less likely to be insured, receive genetic counseling, or have aneuploidy screening; also, they more often started prenatal care at a later gestational age (Table 1). Cell free DNA screening for aneuploidy was more frequently used by urban patients; by contrast, quad screen was more frequently used by rural patients (Figure 1). In regression analyses, rural residence was significantly associated with decreased odds of aneuploidy screening after adjusting for age above 35, gestational age at first prenatal visit, and at least one genetic counseling visit (OR 0.81 [0.69, 0.96], p< 0.001]; this was not seen for genetic counseling. Patients in rural counties less frequently used genetic services; this may be driven by later presentations to care. Further studies assessing factors influencing this inequity are needed.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

To assess if method of pregnancy management impacts psychological outcomes among patients pursuing trio-ES for genetic diagnosis. Secondary analysis of a prospective trio-ES study, enrolling patients with a pregnancy with any major fetal anomaly and normal microarray after genetic counseling. All patients decided on pregnancy termination or continuation prior to enrolling. Patients agreed to learn: (1) findings that explain the fetal phenotype, (2) medically actionable secondary findings in a parent, or (3) carrier couple status for significant autosomal recessive conditions. Variants resulting from ES were interpreted as likely pathogenic, pathogenic, or of uncertain significance. The pregnant patient from each trio completed validated scales and short-free responses before and after sequencing. Psychological outcomes were compared between those who terminated or continued. Thematic content in free responses was analyzed. 190 trios are enrolled; 153 (81%) have been sequenced. 90 patients provided information about pregnancy management. 60 (67%) elected to terminate a pregnancy and 30 elected to continue. Those who terminated were more likely to be employed, have income >$75,000, and were less likely to have a prior anomalous pregnancy (Table 1). There was no difference in genetic knowledge or anxiety and depression scores between groups pre-sequencing. 29 (32%) received an informative result from ES; of those, 24 had terminated. After sequencing, all who had terminated were less certain about test results and had worse psychological adaptation scores compared to those who continued. Overall and subscale scores did not differ based on specific ES results. There was no difference in decisional conflict between groups (Table 1). In free response, patients hoped ES would support a pregnancy management decision (Table 2). Reproductive decision-making is closely tied to uptake of ES and adaptation of genetic results, expanding our knowledge of pre and post-test counseling needs.View Large Image Figure ViewerDownload Hi-res image Download (PPT)