Disparities in access to reproductive genetic services associated with geographic location of residence and maternal race and ethnicity.

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.

Clinical outcomes following preimplantation genetic testing for monogenic conditions: a systematic review of observational studies.

OBJECTIVE: We aimed to report a summary of clinical outcomes following preimplantation genetic testing for monogenic conditions, by performing a systematic review of published literature on clinical pregnancy and live birth rates following preimplantation genetic testing due to a monogenic indication. Additionally, we aimed to undertake a subgroup analysis of clinical outcomes of concurrent monogenic and aneuploidy screening. DATA SOURCES: Three electronic databases (MEDLINE, EMBASE, and PubMed) were searched from inception to May 2024. STUDY ELIGIBILITY CRITERIA: Quantitative data audits, observational studies, and case series reporting clinical outcomes for individuals undergoing preimplantation genetic testing for a monogenic indication were included. Only studies using blastocyst biopsies with polymerase chain reaction-based or genome-wide haplotyping methods for molecular analysis were eligible to reflect current laboratory practice. METHODS: Quality assessment was performed following data extraction using an adaptation of the Joanna Briggs critical appraisal tool for case series. Results were extracted, and pooled mean clinical pregnancy rates and birth rates were calculated with 95% confidence intervals (95% CI). We compared outcomes between those with and without concurrent preimplantation genetic testing for aneuploidy. RESULTS: Our search identified 1372 publications; 51 were eligible for inclusion. Pooled data on 5305 cycles and 5229 embryo transfers yielded 1806 clinical pregnancies and 1577 births. This translated to clinical pregnancy and birth rates of 34.0% [95% CI: 32.8%-35.3%] and 29.7% [95% CI: 28.5%-31.0%] per cycle and 24.8% [95% CI: 23.6%-26.0%] and 21.7% [95% CI: 20.8%-23.1%] per embryo transfer. In studies with concurrent aneuploidy screening, clinical pregnancy and birth rates were 43.3% [95% CI: 40.2%-46.5%] and 37.6% [95% CI: 34.6%-40.8%] per cycle and 37.0% [95% CI: 33.9%-40.3%] and 31.8% [95% CI: 28.8%-35.0%] per embryo transfer. Studies without aneuploidy screening reported clinical pregnancy and birth rates of 32.5% [95% CI: 31.0%-34.1%] and 28.1% [95% CI: 26.6%-29.7%] per cycle and 21.2% [95% CI: 19.8%-22.6%] and 18.6% [95% CI: 17.3%-20.0%] per embryo transfer. CONCLUSION: This systematic review reveals promising clinical outcome figures for this indication group. Additionally, synthesizing the published scientific literature on clinical outcomes from preimplantation genetic testing for monogenic conditions provides a rigorous, noncommercial evidence base for counseling.

Uterine fibroids and non-informative cell-free DNA screening results.

OBJECTIVE: Uterine fibroids are monoclonal tumors, which are often genetically abnormal and associated with false-positive genome-wide cell-free DNA (cfDNA) screening results, particularly when large. It is plausible that fibroids may also increase the risk of cfDNA failure by affecting fetal fraction or due to their genetic anomalies confounding cfDNA algorithms. We aimed to investigate a possible association between fibroids and cfDNA non-informative results. METHODS: This was a retrospective cohort study of women undergoing cfDNA screening for fetal chromosomal abnormalities between 2013 and 2020, comparing pregnancies with vs without uterine fibroids recorded on any obstetric ultrasound before 24 weeks' gestation. Univariable and multivariable logistic regression models were used to investigate the association between fibroids and cfDNA failure, adjusting for gestational age, maternal age, weight and height at blood sampling, mode of conception, multiple gestation and test platform (chromosome-selective or genome-wide). Analyses were stratified according to the number of fibroids and total fibroid volume. The impact of fibroids on fetal fraction was assessed using linear regression, adjusting for the same covariates. RESULTS: Among 19 818 pregnancies undergoing cfDNA screening, fibroids were reported in 2038 (10.28%) and cfDNA failure at the first screening attempt occurred in 228 (1.15%) pregnancies. Non-informative results occurred in 1.96% of pregnancies with fibroids and 1.06% of pregnancies without fibroids (adjusted odds ratio (aOR), 2.40 (95% CI, 1.65-3.48)). The risk of failure in the first screening attempt increased progressively with the number of fibroids (aOR, 5.05 (95% CI, 2.29-11.13) in women with four or more fibroids) and total fibroid volume, with greater than a 5-fold and 14-fold increase in risk among women with fibroid volumes of 100.1-400 mL (aOR, 5.52 (95% CI, 2.30-13.25)) and > 400 mL (aOR, 14.80 (95% CI, 4.50-48.69)), respectively. Although test failure was more common with chromosome-selective than genome-wide screening, fibroids similarly increased the risk of failure of both screening platforms. Compared to pregnancies without fibroids, those with fibroids had a fetal fraction on average 0.61% lower (adjusted mean difference, -0.61% (95% CI, -0.77% to -0.45%)). CONCLUSION: Uterine fibroids are associated with lower fetal fraction and an increased risk of cfDNA screening failure. The strength of this association increases with increasing fibroid number and volume. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

OBJECTIVES: An increased nuchal translucency (NT) thickness of ≥ 3.5 mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks' gestation, but little is known about its performance as a screening tool before 11 weeks. We aimed to investigate, in a prospective setting, whether fetuses with increased NT before 11 weeks are at risk for adverse pregnancy outcome. METHODS: This was a prospective cohort study including pregnant women with a viable fetus with NT ≥ 2.5 mm and a crown-rump length (CRL) < 45 mm. All included women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after 1 week when the CRL was > 45 mm. Two groups were evaluated: cases with a normalized NT (< 3.5 mm) and cases with persistently increased NT (≥ 3.5 mm). The cases were monitored until 4 weeks after delivery. The main outcome was a composite adverse outcome of aneuploidy, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up. RESULTS: The study included 109 cases, of which 39 (35.8%) had an adverse pregnancy outcome. Of these, 64.1% (25/39) were aneuploid, corresponding to 22.9% (25/109) of the total study population. In the subgroups of NT thickness at inclusion of 2.5-3.4 mm, 3.5-4.4 mm and ≥ 4.5 mm, an adverse outcome was reported in 22.0% (9/41), 40.0% (18/45) and 52.2% (12/23), respectively. In fetuses with a normalized NT and without ultrasound abnormalities at the follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) cases were aneuploid. CONCLUSIONS: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening, such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased NT of ≥ 2.5 mm is observed before 11 weeks' gestation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Resultado adverso del embarazo en fetos con aumento precoz de la translucencia nucal: estudio prospectivo de cohortes OBJETIVOS: El aumento del grosor de la translucencia nucal (TN) de ≥3,5 mm es un marcador bien establecido de anomalías congénitas y resultados adversos del embarazo entre las semanas 11 y 14 de gestación, pero se sabe poco sobre su rendimiento como herramienta de cribado antes de las 11 semanas. El objetivo fue investigar, en un contexto prospectivo, si los fetos con aumento de la TN antes de las 11 semanas corren riesgo de presentar resultados adversos del embarazo. MÉTODOS: Se trató de un estudio prospectivo de cohortes que incluyó a embarazadas con un feto viable con una TN ≥2,5 mm y una longitud céfalo­caudal (LCC) <45 mm. Todas las mujeres incluidas fueron remitidas a una unidad de medicina fetal (UMF) y con cita para una prueba de seguimiento en la que se volvió a medir la TN al cabo de 1 semana cuando la LCC era >45 mm. Se evaluaron dos grupos: casos con una TN normalizada (<3.5 mm) y casos con una TN persistentemente aumentada (≥3,5 mm). A los casos se les dio seguimiento hasta 4 semanas después del parto. El resultado principal fue un resultado adverso compuesto de aneuploidía, otros trastornos genéticos, anomalías estructurales y pérdida del embarazo. Se realizaron análisis de subgrupos del grosor de la TN en el momento de la inclusión y de la TN normalizada o persistentemente aumentada en el seguimiento. RESULTADOS: El estudio incluyó 109 casos, de los cuales 39 (35,8%) tuvieron un resultado adverso del embarazo. De ellos, el 64,1% (25/39) eran aneuploides, lo que supone el 22,9% (25/109) de la población total del estudio. En los subgrupos de grosor de la TN en el momento de la inclusión de 2,5­3,4 mm, 3,5­4,4 mm y ≥4,5 mm, se notificó un resultado adverso en el 22,0% (9/41), el 40,0% (18/45) y el 52,2% (12/23), respectivamente. En los fetos con una TN normalizada y sin anomalías ecográficas en la ecografía de seguimiento, la incidencia de resultados adversos fue del 8,5% (5/59), de los cuales el 5,1% (3/59) de los casos eran aneuploides. CONCLUSIONES: Los fetos con un aumento precoz del grosor de la TN corren un riesgo considerable de sufrir un resultado adverso del embarazo, incluso si la TN se normaliza después de 11 semanas. No todas las anomalías congénitas pueden diagnosticarse con un cribado rutinario en el primer trimestre, como las pruebas prenatales no invasivas y/o una ecografía de anomalías en el primer trimestre. Por lo tanto, los futuros padres siempre deben ser remitidos a una UMF para una ecografía detallada. Se debería ofrecer una prueba prenatal invasiva si se observa un aumento de la TN de ≥2,5 mm antes de las 11 semanas de gestación.

genomeprofile: Unveiling the genomic profile for livestock breeding through comprehensive SNP array-based genotyping.

In livestock breeding, single nucleotide polymorphism arrays have become a cornerstone of modern livestock breeding. SNP arrays facilitate the identification of genetic markers linked to economically important traits and provide a powerful tool for predicting breeding values. However, conventional breeding programs often overlook additional genomic features contained in the SNP array data that can provide valuable insights into the genetic diversity, copy number variation, inbreeding levels and potential challenges in breeding lines. Here we present genomeprofile, a tool using SNP array-based genomic data, offering a comprehensive profile of breeding animals including the identification of copy number variants and runs of homozygosity, and screening for aneuploidy. By integrating these features into the breeding landscape, genomeprofile enables a more comprehensive picture of genomic variation, ultimately enhancing precision breeding strategies. To illustrate the practicality and efficacy of genomeprofile, we applied the tool to a dataset of four pig breeding lines. The genomeprofile tool is a user-friendly tool that processes genotype data in finalreport or plink ped format efficiently into useful output. The output contains copy number variations, runs of homozygosity, selection signatures, aneuploidy and inbreeding per individual and across populations. This allows breeding companies and researchers to identify unique individuals or regions in the genome of interest based on routinely collected data.

Non-invasive prenatal screening: Testing motivations and decision making in the low-risk population.

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) and questions to assess patients' motivations for cfDNA screening was offered at four MFM clinics following genetic counseling. It was found that 44% of participants (n = 100) made an uninformed decision about testing. Participants with private insurers were 4.25 times more likely to make an informed decision (95% CI = 1.10-16.37). Informed decision makers scored avoiding invasive procedures higher (p = 0.007) and ranked doing what family/friends desire lower (p = 0.005) than uninformed decision makers. While most participants scored receiving information about genetic conditions highest, 12% of participants reported fetal sex disclosure as a priority. However, this was not found to be associated with uninformed decision making. This study ultimately established that following genetic counseling, a low-risk population shared motivations with high-risk populations which highlights the importance of complete pre-test counseling for all. Future research should investigate the effect of modifying variables, such as socioeconomic status, on the performance of informed choice measures and critically evaluate the parameters that determine informed choice.

Neonatal mortality and morbidity in Down syndrome in the time of prenatal aneuploidy testing: a retrospective cohort study.

The total uptake of prenatal aneuploidy screening for Down syndrome (DS) is increasing worldwide. As a result of increasing prenatal diagnosis of DS and subsequent termination of pregnancy, livebirth prevalence of DS is decreasing. The aim of this study is to explore the impact of an increasing uptake of prenatal aneuploidy screening on the neonatal mortality and morbidity in DS. This is a retrospective cohort study of 253 neonates with DS born between 2012 and 2018 that were seen at the outpatient clinic of five hospitals in the Netherlands. The medical files were reviewed for maternal and neonatal characteristics and neonatal morbidities. The Dutch national birth registry (Perined) provided mortality numbers of neonates with DS. The results were interpreted in the context of other published studies. Neonatal mortality in DS remained stable, ranging from 1.4 to 3.6%. A congenital heart defect (CHD) was found in 138 of the 251 neonates (55.0%) with atrial septal defect, atrioventricular septal defect, and ventricular septal defect being the most common. The type of CHD in DS did not change over time. Gastro-intestinal defects were present in 22 of the 252 neonates with DS (8.7%), with duodenal atresia as the most reported anomaly. Persistent pulmonary hypertension of the neonate (PPHN) was found in 31 of the 251 infants (12.4%).  Conclusions: Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in DS appears to be stable. An increased incidence of PPHN was found. What is Known: • The total uptake of prenatal aneuploidy screening for Down syndrome is increasing worldwide. • As a result of increasing prenatal diagnosis of Down syndrome and subsequent termination of pregnancy, the livebirth prevalence of Down syndrome is decreasing. What is New: • Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in Down syndrome appears to be stable. • An increased incidence of persistent pulmonary hypertension of the neonate was found.

Association of maternal risk factors with fetal aneuploidy and the accuracy of prenatal aneuploidy screening: a correlation analysis based on 12,186 karyotype reports.

BACKGROUND: NIPT is becoming increasingly important as its use becomes more widespread in China. More details are urgently needed on the correlation between maternal risk factors and fetal aneuploidy, and how these factors affect the accuracy of prenatal aneuploidy screening. METHODS: Information on the pregnant women was collected, including maternal age, gestational age, specific medical history and results of prenatal aneuploidy screening. Additionally, the OR, validity and predictive value were also calculated. RESULTS: A total of 12,186 analysable karyotype reports were collected with 372 (3.05%) fetal aneuploidies, including 161 (1.32%) T21, 81 (0.66%) T18, 41 (0.34%) T13 and 89 (0.73%) SCAs. The OR was highest for maternal age less than 20 years (6.65), followed by over 40 years (3.59) and 35-39 years (2.48). T13 (16.95) and T18 (9.40) were more frequent in the over-40 group (P < 0.01); T13 (3.62/5.76) and SCAs (2.49/3.95) in the 35-39 group (P < 0.01). Cases with a history of fetal malformation had the highest OR (35.94), followed by RSA (13.08): the former was more likely to have T13 (50.65) (P < 0.01) and the latter more likely to have T18 (20.50) (P < 0.01). The sensitivity of primary screening was 73.24% and the NPV was 98.23%. The TPR for NIPT was 100.00% and the respective PPVs for T21, T18, T13 and SCAs were 89.92, 69.77, 53.49 and 43.24%, respectively. The accuracy of NIPT increased with increasing gestational age (0.81). In contrast, the accuracy of NIPT decreased with maternal age (1.12) and IVF-ET history (4.15). CONCLUSIONS: ①Pregnant patients with maternal age below 20 years had higher risk of aneuploidy, especially in T13; ②A history of fetal malformations is more risky than RSA, with the former more likely to have T13 and the latter more likely to have T18; ③Primary screening essentially achieves the goal of identifying a normal karyotype, and NIPT can accurately screen for fetal aneuploidy; ④A number of maternal risk factors may influence the accuracy of NIPT diagnosis, including older age, premature testing, or a history of IVF-ET. In conclusion, this study provides a reliable theoretical basis for optimizing prenatal aneuploidy screening strategies and improving population quality.

Aneuploidy screening after preimplantation genetic testing: a national survey of physician knowledge and practice.

PURPOSE: To assess the knowledge of generalist OB/GYN providers on aneuploidy screening recommendations for patients who utilized preimplantation genetic testing, and to survey providers' current practice habits. METHODS: A 12-question survey was distributed by email to OB/GYN physicians in the USA. Demographic information was also collected. RESULTS: A total of 178 survey responses were included for analysis. Sixty-seven percent correctly identified the current ACOG recommendation to offer additional aneuploidy screening/invasive diagnostic testing regardless of PGT status, and 66% said their practice is consistent with this recommendation. Ninety-one percent of responders correctly answered that in vitro fertilization does not always include PGT and 63% of responders were able to correctly identify the 3 available types of PGT. Thirty-three percent (n = 58) were attending physicians, and 67% (n = 120) were resident physicians. Most participants (81%, n = 145) stated they have been in practice 0-9 years, and the remaining 19% (n = 33) stated they have been in practice ≥ 10 years. CONCLUSION: Significant knowledge gaps of PGT and aneuploidy screening recommendations after PGT exist among generalist OB/GYN physicians. Efforts should be made to educate providers on the importance of offering aneuploidy screening and diagnostic testing to patients who utilized PGT to improve patient care.

Video education about genetic privacy and patient perspectives about sharing prenatal genetic data: a randomized trial.

BACKGROUND: Laboratories offering cell-free DNA often reserve the right to share prenatal genetic data for research or even commercial purposes, and obtain this permission on the patient consent form. Although it is known that nonpregnant patients are often reluctant to share their genetic data for research, pregnant patients' knowledge of, and opinions about, genetic data privacy are unknown. OBJECTIVE: We investigated whether pregnant patients who had already undergone cell-free DNA screening were aware that genetic data derived from cell-free DNA may be shared for research. Furthermore, we examined whether pregnant patients exposed to video education about the Genetic Information Nondiscrimination Act-a federal law that mandates workplace and health insurance protections against genetic discrimination-were more willing to share cell-free DNA-related genetic data for research than pregnant patients who were unexposed. STUDY DESIGN: In this randomized controlled trial (ClinicalTrials.gov Identifier: NCT04420858), English-speaking patients with singleton pregnancies who underwent cell-free DNA and subsequently presented at 17 0/7 to 23 6/7 weeks of gestation for a detailed anatomy scan were randomized 1:1 to a control or intervention group. Both groups viewed an infographic about cell-free DNA. In addition, the intervention group viewed an educational video about the Genetic Information Nondiscrimination Act. The primary outcomes were knowledge about, and willingness to share, prenatal genetic data from cell-free DNA by commercial laboratories for nonclinical purposes, such as research. The secondary outcomes included knowledge about existing genetic privacy laws, knowledge about the potential for reidentification of anonymized genetic data, and acceptability of various use and sharing scenarios for prenatal genetic data. Eighty-one participants per group were required for 80% power to detect an increase in willingness to share data from 60% to 80% (α=0.05). RESULTS: A total of 747 pregnant patients were screened, and 213 patients were deemed eligible and approached for potential study participation. Of these patients, 163 (76.5%) consented and were randomized; one participant discontinued the intervention, and two participants were excluded from analysis after the intervention when it was discovered that they did not fulfill all eligibility criteria. Overall, 160 (75.1%) of those approached were included in the final analysis. Most patients in the control group (72 [90.0%]) and intervention (76 [97.4%]) group were either unsure about or incorrectly thought that cell-free DNA companies could not share prenatal genetic data for research. Participants in the intervention group were more likely to incorrectly believe that their prenatal genetic data would not be shared for nonclinical purposes than participants in the control group (28.8% in the control group vs 46.2% in the intervention; P=.03). However, video education did not increase participant willingness to share genetic data in multiple scenarios. Non-White participants were less willing than White participants to allow sharing of genetic data specifically for academic research (P<.001). CONCLUSION: Most participants were unaware that their prenatal genetic data may be used for nonclinical purposes. Pregnant patients who were educated about the Genetic Information Nondiscrimination Act were not more willing to share genetic data than those who did not receive this education. Surprisingly, video education about the Genetic Information Nondiscrimination Act led patients to falsely believe that their data would not be shared for research, and participants who identified as racial minorities were less willing to share genetic data. New strategies are needed to improve pregnant patients' understanding of genetic privacy.

The impact of preimplantation genetic testing for aneuploidy on prenatal screening.

OBJECTIVES: To determine whether preimplantation genetic testing for aneuploidy (PGT-A) is associated with a reduced risk of abnormal conventional prenatal screening results in singleton pregnancies conceived using in vitro fertilization (IVF). METHODS: This was a retrospective cohort study of singleton IVF pregnancies conceived from a single tertiary care center between January 2014 and September 2019. Exclusion criteria included mosaic embryo transfers, vanishing twin pregnancies, and cycles with missing outcome data. Two cases of prenatally diagnosed aneuploidy that resulted in early voluntary terminations were also excluded. The primary outcome of abnormal first or second-trimester combined screening results was compared between two groups: pregnancy conceived after transfer of a euploid embryo by PGT-A vs. transfer of an untested embryo. Multivariable backwards-stepwise logistic regression with Firth method was used to adjust for potential confounders. RESULTS: Of the 419 pregnancies included, 208 (49.6%) were conceived after transfer of a euploid embryo by PGT-A, and 211 (50.4%) were conceived after transfer of an untested embryo. PGT-A was not associated with a lower likelihood of abnormal first-trimester (adjusted OR 1.64, 95% CI 0.82-3.39) or second-trimester screening results (adjusted OR 0.96, 95% CI 0.56-1.64). The incidences of cell-free DNA testing, fetal sonographic abnormalities, genetic counseling, and invasive prenatal diagnostic testing were similar between the two groups. CONCLUSIONS: Our data suggest that PGT-A is not associated with a change in the likelihood of abnormal prenatal screening results or utilization of invasive prenatal diagnostic testing. Counseling this patient population regarding the importance of prenatal screening and prenatal diagnostic testing, where appropriate, remains essential.

Audit of the first > 7500 noninvasive prenatal aneuploidy tests in a Swiss genetics center.

OBJECTIVES: Noninvasive prenatal testing (NIPT) is actually the most accurate method of screening for fetal chromosomal aberration (FCA). We used pregnancy outcome record to evaluate a complete data set of single nucleotide polymorphism-based test results performed by a Swiss genetics center. MATERIALS AND METHODS: The Panorama® test assesses the risk of fetal trisomies (21, 18 and 13), gonosomal aneuploidy (GAN), triploidy or vanishing twins (VTT) and five different microdeletions (MD). We evaluated all 7549 test results meeting legal and quality requirements taken in women with nondonor singleton pregnancies between April 2013 and September 2016 classifying them as high or low risk. Follow-up ended after 9 months, data collection 7 months later. RESULTS: The Panorama® test provided conclusive results in 96.1% of cases, detecting 153 FCA: T21 n = 76, T18 n = 19, T13 n = 15, GAN n = 19, VTT n = 13 and MD n = 11 (overall prevalence 2.0%). Pregnancy outcome record was available for 68.6% of conclusive laboratory results, including 2.0% high-risk cases. In this cohort the Panorama® test exhibited 99.90% sensitivity for each trisomy; specificity was 99.90% for T21, 99.98% for T18 and 99.94% for T13. False positive rate was 0.10% for T21, 0.02% for T18 and 0.06% for T13. CONCLUSION: SNP-based testing by a Swiss genetics center confirms the expected accuracy of NIPT in FCA detection.

Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester: (Replaces Consults #10, Single umbilical artery, October 2010; #16, Isolated echogenic bowel diagnosed on second-trimester ultrasound, August 2011; #17, Evaluation and management of isolated renal pelviectasis on second-trimester ultrasound, December 2011; #25, Isolated fetal choroid plexus cysts, April 2013; #27, Isolated echogenic intracardiac focus, August 2013).

Soft markers were originally introduced to prenatal ultrasonography to improve the detection of trisomy 21 over that achievable with age-based and serum screening strategies. As prenatal genetic screening strategies have greatly evolved in the last 2 decades, the relative importance of soft markers has shifted. The purpose of this document is to discuss the recommended evaluation and management of isolated soft markers in the context of current maternal serum screening and cell-free DNA screening options. In this document, "isolated" is used to describe a soft marker that has been identified in the absence of any fetal structural anomaly, growth restriction, or additional soft marker following a detailed obstetrical ultrasound examination. In this document, "serum screening methods" refers to all maternal screening strategies, including first-trimester screen, integrated screen, sequential screen, contingent screen, or quad screen. The Society for Maternal-Fetal Medicine recommends the following approach to the evaluation and management of isolated soft markers: (1) we do not recommend diagnostic testing for aneuploidy solely for the evaluation of an isolated soft marker following a negative serum or cell-free DNA screening result (GRADE 1B); (2) for pregnant people with no previous aneuploidy screening and isolated echogenic intracardiac focus, echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1B); (3) for pregnant people with no previous aneuploidy screening and isolated thickened nuchal fold or isolated absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening through cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (4) for pregnant people with no previous aneuploidy screening and isolated choroid plexus cysts, we recommend counseling to estimate the probability of trisomy 18 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive (GRADE 1C); (5) for pregnant people with negative serum or cell-free DNA screening results and an isolated echogenic intracardiac focus, we recommend no further evaluation as this finding is a normal variant of no clinical importance with no indication for fetal echocardiography, follow-up ultrasound imaging, or postnatal evaluation (GRADE 1B); (6) for pregnant people with negative serum or cell-free DNA screening results and isolated fetal echogenic bowel, urinary tract dilation, or shortened humerus, femur, or both, we recommend no further aneuploidy evaluation (GRADE 1B); (7) for pregnant people with negative serum screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend counseling to estimate the probability of trisomy 21 and discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening through cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference (GRADE 1B); (8) for pregnant people with negative cell-free DNA screening results and isolated thickened nuchal fold or absent or hypoplastic nasal bone, we recommend no further aneuploidy evaluation (GRADE 1B); (9) for pregnant people with negative serum or cell-free DNA screening results and isolated choroid plexus cysts, we recommend no further aneuploidy evaluation, as this finding is a normal variant of no clinical importance with no indication for follow-up ultrasound imaging or postnatal evaluation (GRADE 1C); (10) for fetuses with isolated echogenic bowel, we recommend an evaluation for cystic fibrosis and fetal cytomegalovirus infection and a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C); (11) for fetuses with an isolated single umbilical artery, we recommend no additional evaluation for aneuploidy, regardless of whether results of previous aneuploidy screening were low risk or testing was declined. We recommend a third-trimester ultrasound examination to evaluate growth and consideration of weekly antenatal fetal surveillance beginning at 36 0/7 weeks of gestation (GRADE 1C); (12) for fetuses with isolated urinary tract dilation A1, we recommend an ultrasound examination at ≥32 weeks of gestation to determine if postnatal pediatric urology or nephrology follow-up is needed. For fetuses with urinary tract dilation A2-3, we recommend an individualized follow-up ultrasound assessment with planned postnatal follow-up (GRADE 1C); (13) for fetuses with isolated shortened humerus, femur, or both, we recommend a third-trimester ultrasound examination for reassessment and evaluation of growth (GRADE 1C).

United States' experience in nuchal translucency measurement: variation according to provider characteristics in over five million ultrasound examinations.

OBJECTIVE: The Nuchal Translucency Quality Review (NTQR) program has provided standardized education, credentialing and epidemiological monitoring of nuchal translucency (NT) measurements since 2005. Our aim was to review the effect on NT measurement of provider characteristics since the program's inception. METHODS: We evaluated the distribution of NT measurements performed between January 2005 and December 2019, for each of the three primary performance indicators of NT measurement (NT median multiples of the median (MoM), SD of log10 NT MoM and slope of NT with respect to crown-rump length (CRL)) for all providers within the NTQR program with more than 30 paired NT/CRL results. Provider characteristics explored as potential sources of variability included: number of NT ultrasound examinations performed annually (annual scan volume of the provider), duration of participation in the NTQR program, initial credentialing by an alternative pathway, provider type (physician vs sonographer) and number of NT-credentialed providers within the practice (size of practice). Each of these provider characteristics was evaluated for its effect on NT median MoM and geometric mean of the NT median MoM weighted for the number of ultrasound scans, and multiple regression was performed across all variables to control for potential confounders. RESULTS: Of 5 216 663 NT measurements from 9340 providers at 3319 sites, the majority (75%) of providers had an NT median MoM within the acceptable range of 0.9-1.1 and 85.5% had NT median MoM not statistically significantly outside this range. Provider characteristics associated with measurement within the expected range of performance included higher volume of NT scans performed annually, practice at a site with larger numbers of other NT-credentialed providers, longer duration of participation in the NTQR program and alternative initial credentialing pathway. CONCLUSIONS: Annual scan volume, duration of participation in the NTQR program, alternative initial credentialing pathway and number of other NT-credentialed providers within the practice are all associated with outcome metrics indicating quality of performance. It is critical that providers participate in ongoing quality assessment of NT measurement to maintain consistency and precision. Ongoing assessment programs with continuous feedback and education are necessary to maintain quality care. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Decision-making for prenatal genetic screening: how will pregnant women navigate a growing number of aneuploidy and carrier screening options?

BACKGROUND: Prenatal genetic screens, including carrier screening (CS) and aneuploidy screening (AS), comprise an important component of reproductive healthcare delivery. Clinical practice guidelines emphasize the importance of informed decision-making and patient's preferences regarding the use of these screens. Yet, it is unclear how to achieve this ideal as prenatal genetic screening options rapidly become more complex and increasingly available to patients. With increased complexity and availability of reproductive testing options, decision-support strategies are critical to prepare patients to consider AS and/or CS. METHODS: A self-administered survey evaluated knowledge and decision-making preferences for expanded carrier (CS) and aneuploidy (AS) prenatal screening. The survey was administered to participants before their first prenatal visit to assess baseline decision-making needs and preference at the initiation of prenatal care. Analysis was approached as a descriptive process. RESULTS: Participants had similar familiarity with the concepts associated with AS compared to CS; mean knowledge scores for CS was 0.59 [possible range 0.00 to 1.00] and 0.55 for AS. Participants reported preferences to learn about a range of conditions, including those with severe or mild impact, childhood-onset, and adult-onset. Decision-making preference with respect to learning about the associated disease phenotypes for the contained on AS and CS panel shifted with the complexity of the panel, with a greater preference to learn about conditions post-test compared pre-test education as panels increased from 5 to 100 conditions. CONCLUSION: Patients' baseline knowledge of prenatal genetic screens coupled with evolving decision-making preferences presents challenges for the delivery of prenatal genetic screens. This calls for the development and implementation of innovative approaches to support pregnant patients' decision-making commensurate with advances in prenatal genomics.

Uptake of fetal aneuploidy screening after the introduction of the non-invasive prenatal test: A national population-based register study.

INTRODUCTION: The introduction of the non-invasive prenatal test (NIPT) has shifted the prenatal screening landscape. Countries are exploring ways to integrate NIPT in their national prenatal screening programs, either as a first- or second-tier test. This study aimed to describe how the uptake of fetal aneuploidy screening changed after the introduction of NIPT as a second-tier and as a first-tier test within the national prenatal screening program of the Netherlands. MATERIAL AND METHODS: A population-based register study in the Netherlands, recording uptake of fetal aneuploidy screening. Data from all pregnant women choosing to have the first-trimester combined test (FCT) or first-tier NIPT between January 2007 and March 2019 were retrospectively collected using national registration systems. Uptake percentages for fetal aneuploidy screening (FCT and NIPT) were calculated and stratified by region and maternal age. Statistical significance was determined using trend analysis and chi-squared tests. RESULTS: Between 2007 and 2013 FCT uptake increased from 14.8% to 29.5% (P = .004). In April 2014 NIPT was introduced as a second-tier test for high-risk women after FCT (TRIDENT-1 study). FCT uptake rose from 29.5% in 2013 to 34.2% in 2015 (P < .0001). After the introduction of NIPT as a first-tier test for all women in April 2017 (TRIDENT-2 study), FCT uptake declined significantly from 35.8% in 2016 to 2.6% in 2018 (P < .0001). NIPT uptake increased to 43.4% in 2018. Regionally, NIPT uptake ranged from 31.8% to 67.9%. Total uptake (FCT and NIPT) between 2007 and 2018 increased significantly from 14.8% to 45.9% (P < .0001). However, total uptake stabilized at 46% for both years of TRIDENT-2 (April 2017-March 2019). CONCLUSIONS: An increase in total fetal aneuploidy screening uptake up to 45.9% was observed after the introduction of NIPT. Uptake appears to have stabilized within a year after introducing first-tier NIPT.

PGT-SR (reciprocal translocation) using trophectoderm sampling and next-generation sequencing: insights from a virtual trial.

PURPOSE: The objective of this virtual study was to simulate a full cycle and assess the costs and benefits to a couple with a reciprocal translocation, using current techniques for preimplantation genetic testing and comparing reporting every chromosome with only reporting those involved in the rearrangement. METHODS: A simulation was constructed for women under the age of 35 years, where vitrified-warmed embryos were transferred one at a time in a first full cycle following preimplantation genetic testing using next-generation sequencing and sampling the trophectoderm at the blastocyst stage. The effect on pregnancy outcomes (live birth, clinical miscarriage and biochemical pregnancy) was evaluated for different reporting strategies for embryo transfer to (i) report only the rearranged chromosomes and transfer embryos with a normal or balanced test result for the translocation (targeted), or (ii) report every chromosome and exclude from transfer all embryos with an abnormal test result (exclusion), or (iii) exclude only those consistent with an unbalanced translocation and/or unrelated non-mosaic whole-chromosome aneuploidy and assign those with samples consistent with a normal or balanced translocation complement and unrelated mosaic aneuploidy or segmental imbalance (embryos of uncertain reproductive potential) a lower transfer priority (ranking). The number of individual women whom might benefit by avoiding an adverse pregnancy outcome (biochemical pregnancy, clinical miscarriage) or be disadvantaged by not achieving a live birth was evaluated. The financial cost of the different reporting strategies and the time taken to complete a cycle were also considered. RESULTS: The simulation showed that compared to only reporting the translocation chromosomes (targeted reporting), testing every chromosome and ranking embryos by test result for transfer was a cost-effective strategy to avoid an adverse pregnancy without compromising the chance of a live birth. Excluding from transfer embryos with a test result consistent with a normal or balanced translocation complement of uncertain reproductive potential was an inferior strategy because it resulted in fewer live births from a full cycle. Reporting only the translocation chromosomes was an inferior strategy because it was less effective than ranked reporting of every chromosome to avoid an adverse pregnancy. Compared to targeted reporting, the ranked and exclusion strategies marginally reduced the overall cost and time taken to complete a full cycle. The ranking strategy avoided 1 adverse pregnancy for 12 cycles started, compared to 1 in 10 for the exclusion strategy which also resulted in 1 in 22 fewer women achieving a live birth. A minority (< 10%) of couples benefited by avoiding at least 1 adverse pregnancy whilst also reducing the time and cost for a complete cycle; most (> 70% ) couples received no benefit additional to targeted reporting and had the same outcome for pregnancy, time and cost. CONCLUSIONS: The primary objective of PGT-SR for couples with a reciprocal translocation is to avoid a pregnancy with a chromosomally unbalanced product of the translocation and to reduce the risk of miscarriage, at least to that expected for couples with normal karyotypes. Trophectoderm sampling at the blastocyst stage with testing using NGS is an effective approach; however, ranking and excluding from transfer embryos with abnormal test results for unrelated chromosomes is problematical and is likely to be detrimental to achieving a live birth. Targeted reporting, where only the results of the chromosomes involved in the translocation are known, should be preferred to achieve a live birth. A best effort should be made to follow up and investigate all pregnancies following PGT-SR. Once the reproductive outcome is known (biochemical pregnancy, clinical pregnancy, live birth), the chromosomes unrelated to the rearrangement can be analysed as an experimental study. The risk/benefit of avoiding an adverse pregnancy vs reducing the chance of a healthy delivery should be a decision for each individual couple and informed by appropriate genetic counselling for their specific translocation and history.

Perceptions, motivations and decision regret surrounding preimplantation genetic testing for aneuploidy.

STUDY QUESTION: Is there a difference in level of decision regret following IVF treatment between those who choose to complete or not complete preimplantation genetic testing for aneuploidy [PGT-A]? SUMMARY ANSWER: Approximately one-third of the participants expressed moderate to severe regret (MSR) following their decision to either complete or not complete PGT-A; notably, decision regret was higher in those who chose not to complete PGT-A, primarily driven by significantly higher regret scores in those that experienced a miscarriage after not testing. WHAT IS KNOWN ALREADY: Previous research has found that 39% of participants who completed PGT-A expressed some degree of decision regret and that negative clinical outcomes, such as lack of euploid embryos, negative pregnancy test or miscarriage, were associated with a higher level of decision regret. To date, there are no published studies assessing the possible disparity in decision regret surrounding PGT-A in a population of IVF patients that either chose to pursue PGT-A or not. STUDY DESIGN, SIZE, DURATION: An anonymous online survey was distributed to 1583 patients who underwent IVF with or without PGT-A at a single university institution between January 2016 and December 2017. In total, 335 women accessed the survey, 220 met eligibility criteria and 130 completed the full study survey. Six participants were excluded due to refusal of medical record review, and nine participants were excluded after record review due to not meeting eligibility based on cycle start date or completing only embryo banking without attempting transfer. One hundred and fifteen participants were included in the final analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 115 participants included, 55 (48%) completed PGT-A and 60 (52%) did not complete PGT-A. The online survey included four sections: Demographics; Perceptions about PGT-A risks and benefits [scale from 0 (absolutely not true) to 100 (absolutely true)]; Decision-making factors [scale from 0 (not important) to 100 (very important)]; and Brehaut Decision Regret Scale [DRS] [range 0-100, with >25 indicating MSR]. A retrospective chart review was conducted to confirm study eligibility and collect cumulative clinical outcomes of consenting participants who completed the survey. MAIN RESULTS AND THE ROLE OF CHANCE: Demographics of the PGT-A and no PGT-A cohorts were similar, with the majority of respondents being Caucasian or Asian, unaffiliated with any religion and with a graduate or professional degree. The two groups differed significantly in mean age, with the PGT-A group being slightly older (mean ± SD: 37 ± 3.7 versus 36 ± 3.4; P = 0.048), and in rate of miscarriages, with fewer participants in the PGT-A cohort experiencing a miscarriage (5% versus 22%; P = 0.012). The majority of participants in both PGT-A and no PGT-A cohorts strongly believed in the purported benefits of PGT-A, including that it decreases the risk of birth defects (median 82 versus 77; P = 0.046), improves the chances of having a healthy baby (median 89 versus 74; P = 0.002) and selects the best embryo for transfer (median 85 versus 80; P = 0.049). When asked to report their motivating factors for decision-making, both groups cited physician counseling as important (median 70 versus 71; P = 0.671); however, the PGT-A cohort was more strongly motivated by a desire to not transfer abnormal embryos (median 84 versus 53; P = 0.0001). Comparison of DRS score between those who did or did not undergo PGT-A showed significantly higher median DRS score after not completing PGT-A (median 15 versus 0; P = 0.013). There was a significantly higher proportion of participants who did not complete PGT-A that expressed mild (36% versus 16%) and MSR (32% versus 24%) compared to those who completed PGT-A (χ2 = 9.03, df = 2; P = 0.011). Sub-group analyses of DRS scores by outcomes of clinical pregnancy, miscarriage and live birth revealed that the higher DRS score in those not completing PGT-A was driven by a large increase in regret noted by those with history of a miscarriage (median 45 versus 0; P = 0.018). Multivariate logistic regression modeling found no evidence that any specific demographic factor, clinical outcome or perception/motivation surrounding PGT-A was independently predictive of increased risk for MSR. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of data collection incurs the possibility of sampling and recall bias. As only 59% of eligible respondents completed the full survey, it is possible that mainly those with very positive or negative sentiments following treatment felt compelled to complete their response. This bias, however, would apply to the whole of the population, and not simply to those who did or did not complete PGT-A. WIDER IMPLICATIONS OF THE FINDINGS: The proportion of participants expressing any degree of decision regret in this PGT-A cohort was 40%, which is comparable to that shown in prior research. This study adds to prior data by also assessing decision regret experienced by those who went through IVF without PGT-A, and showed that 68% expressed some level of regret with their decision-making. These results should not be interpreted to mean that all patients should opt for PGT-A to pre-emptively mitigate their risk of regret. Instead, it suggests that drivers of decision regret are likely multifactorial and unique to the experience of one's personal expectations regarding PGT-A, motivations for pursuing or not pursuing it and resultant clinical outcome. Highlighting the complex nature of regret, these data should encourage physicians to more carefully consider individual patient values toward risk-taking or risk-averse behavior, as well as their own positions regarding PGT-A. Until there are clear recommendations regarding utilization of PGT-A, a strong collaboration between physicians and genetic counselors is recommended to educate patients on the risks and potential benefits of PGT-A in a balanced and individualized manner. STUDY FUNDING/COMPETING INTEREST(S): No funding was utilized for study completion and the authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

INTRODUCTION: In assisted reproductive technology, aneuploidy is considered a primary cause of failed embryo implantation. This has led to the implementation of preimplantation genetic testing for aneuploidy in some clinics. The prevalence of aneuploidy and the use of aneuploidy screening during preimplantation genetic testing for inherited disorders has not previously been reviewed. Here, we systematically review the literature to investigate the prevalence of aneuploidy in blastocysts derived from patients carrying or affected by an inherited disorder, and whether screening for aneuploidy improves clinical outcomes. MATERIAL AND METHODS: PubMed and Embase were searched for articles describing preimplantation genetic testing for monogenic disorders and/or structural rearrangements in combination with preimplantation genetic testing for aneuploidy. Original articles reporting aneuploidy rates at the blastocyst stage and/or clinical outcomes (positive human chorionic gonadotropin, gestational sacs/implantation rate, fetal heartbeat/clinical pregnancy, ongoing pregnancy, miscarriage, or live birth/delivery rate on a per transfer basis) were included. Case studies were excluded. RESULTS: Of the 26 identified studies, none were randomized controlled trials, three were historical cohort studies with a reference group not receiving aneuploidy screening, and the remaining were case series. In weighted analysis, 34.1% of 7749 blastocysts were aneuploid. Screening for aneuploidy reduced the proportion of embryos suitable for transfer, thereby increasing the risk of experiencing a cycle without transferable embryos. In pooled analysis the percentage of embryos suitable for transfer was reduced from 57.5% to 37.2% following screening for aneuploidy. Among historical cohort studies, one reported significantly improved pregnancy and birth rates but did not control for confounding, one did not report any statistically significant difference between groups, and one properly designed study concluded that preimplantation genetic testing for aneuploidy enhanced the chance of achieving a pregnancy while simultaneously reducing the chance of miscarriage following single embryo transfer. CONCLUSIONS: On average, aneuploidy is detected in 34% of embryos when performing a single blastocyst biopsy derived from patients carrying or affected by an inherited disorder. Accordingly, when screening for aneuploidy, the risk of experiencing a cycle with no transferable embryos increases. Current available data on the clinical effect of preimplantation genetic testing for aneuploidy performed concurrently with preimplantation genetic testing for inherited disorders are sparse, rendering the clinical effect from preimplantation genetic testing for aneuploidy difficult to access.

A tale of two studies: now is no longer the best of times for preimplantation genetic testing for aneuploidy (PGT-A).

Preimplantation genetic testing for aneuploidy (PGT-A) does not create normal embryos, but selecting a viable embryo for a fresh transfer has the potential to deliver an extra effect for live birth from a stimulated cycle by evading the attrition associated with embryo cryopreservation. Improved genetic tests are now available for selecting viable embryos; however, current embryo cryopreservation techniques also have a superior survival rate, which means it is now possible to transfer most morphologically suitable embryos from a stimulated cycle one at a time. The cumulative live birth rate from a stimulated cycle is now unlikely to be superior compared with morphological assessment alone, with any benefit likely to be associated with a reduction in the risk of miscarriage and the time to pregnancy. This communication offers a perspective on the likely benefit and disbenefit of PGT-A based on the outcome of modern-day clinical studies. Caution should be advised regarding offering PGT-A to every woman. Quantifying the likely miscarriage benefit and live birth disbenefit for an appropriate patient group may help to better inform couples who might be considering adding aneuploidy screening to their treatment cycle.