Prenatal Screening Strategies Research Articles

Noninvasive Evaluation of Fetal Zygosity in Twin Pregnancies Involving a Binary Analysis of Single-Nucleotide Polymorphisms

Twin pregnancy constitutes significant risks for maternal and fetal health, which is usually detected by ultrasound examination at early gestation. However, the imaging-based approach may not accurately identify all twins confounded by practical or clinical variables. The analysis of fetal cell-free DNA in noninvasive prenatal screening assays can completement the ultrasound method for twin detection, which differentiates fraternal or identical twins based on their distinct genotypes. Here, a new noninvasive prenatal screening employing high-coverage next-generation sequencing for targeted nucleotide polymorphisms was developed for detection of zygosity and determination of fetal fraction in twin pregnancies. This method utilizes a binary analysis of both the number and allelic fraction of fetus-specific single-nucleotide polymorphisms to infer the zygosity. In 323 samples collected from 215 singleton, 90 dizygotic, and 18 monozygotic twin pregnancies, all 90 dizygotic twins were correctly detected, with a 100% sensitivity and a 100% specificity. In addition, this method can detect complex pregnancies, such as egg donors, contamination, and twins with complete hydatidiform mole. The fetus-specific fetal fraction change was monitored in nine dizygotic twin pregnancies, which demonstrated highly variable dynamics of fetal cell-free DNA turnover up to 7 weeks after twin reduction. Overall, this study provides a new noninvasive prenatal screening strategy for the accurate identification of twin zygosity and quantification of fetal fraction, which has important clinical implications for the management of twin pregnancies.

A call for public funding of invasive and non-invasive prenatal testing.

For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test.

Universal prenatal screening: a initiative from Guanajuato, Mexico to improve equity in perinatal healthcare.

The prenatal approach from a preventive perspective is necessary to reduce perinatal complications. A perinatal care model with a holistic and horizontal approach is required. Mexico is currently considered an emerging market economy with inequality and an economic gap that impacts the accessibility and distribution of healthcare services. Guanajuato is one of the 32 states of Mexico and represents 1.6% of the country's surface. Strategies during the prenatal approach allow prediction, diagnosis, and anticipation of the principal causes of morbidity and mortality. Combining data from maternal characteristics and history with findings of biophysical and biochemical tests at 11 to 13 weeks of gestation can define the patient-specific risk for a large spectrum of complications that include miscarriage and fetal death, preterm delivery, preeclampsia, congenital disorders, and fetal growth abnormalities. We aim to describe the care model designed and implemented in the State Center for Timely Prenatal Screening of the Maternal and Child Hospital of Leon, Guanajuato, Mexico. Previous research showed there is a lack of information for low and middle-income countries regarding how to integrate prenatal screening strategies in the absence of resources to perform cell-free fetal DNA or biochemical serum markers in countries with emergent economies. This care model is carried out through horizontal processes where the screening is provided by trained and certified general practitioners who identify the population at risk in a timely manner for specialized care, and could help guide other Mexican states, and other countries with emergent economies with limited financial, professional, and infrastructural resources to improve prenatal care with a sense of equity, equality, and social inclusion as well as the timely evaluation of specialized perinatal care of high-risk patients.

Diagnosis of Congenital and Maternal Cytomegalovirus Infection—an Up-to-Date Review

Cytomegalovirus (CMV) is the most common congenital infection worldwide. Twenty percent of congenital CMV (cCMV) infections result in permanent disability, including hearing loss, cognitive deficits, cerebral palsy, and vision impairment, and 4% of cases result in death. Early recognition and diagnosis are imperative, as both antiviral treatment and non-pharmaceutical interventions can improve patient outcomes by reducing hearing loss, other symptomology, and overall disease severity. Specifically, evidence of effective therapy for symptomatic infants and, more recently, reduced fetal transmission following treatment of maternal primary infection may support expanded screening activities. Here, we present an overview of the clinical presentation, treatment and prevention of maternal CMV and cCMV infection. We discuss in detail new diagnostic methods for early and retrospective detection of congenital and maternal primary infections. Finally, we review proposed neonatal and prenatal screening strategies. Clinical laboratories should be aware of the latest clinical studies, the changing diagnostic landscape, and laboratory practices for cCMV and maternal CMV infection.

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

BackgroundNIPT 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.MethodsInformation 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.ResultsA 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).Conclusions①Pregnant 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.

A novel heterozygous mutation of the NPHS1 gene in a Chinese child with congenital nephrotic syndrome: A case report.

Congenital nephrotic syndrome (CNS) is a heterogeneous disorder in which massive proteinuria, hypoproteinemia, and hyperlipidemia and marked edema are the main manifestations before 3 months-of-age. Here, we present a case involving the genetic diagnosis of a child with CNS. A 31-day-old male infant with diarrhea for 25 days and generalized edema for more than 10 days. There was no family history of kidney disease. On proband whole exome sequencing, a compound heterozygous mutation of the NPHS1 gene was identified, including a novel in-frame mutation in exon 14 (c.1864_1866dupACC p. T622dup) and a missense mutation in exon 8 (c.928G>A p. D310N). Based on the clinical and genetic findings, this patient was finally diagnosed with CNS. The main treatment options for the patient were 2-fold: anti-infective treatment and symptomatic treatment. The patient died in follow-up 2 months later; the specific reason for death was unclear. Whole exome sequencing and Sanger sequencing confirmed that the infant had CNS. Our study identified a novel mutation in an infant, thus expanding the gene-mutation spectrum of the NPHS1 gene, thus providing an efficient prenatal screening strategy and early genetic counseling.

Health economic evaluation of four prenatal screening strategies for Down syndrome in Changsha, China

To compare the clinical application and health economic values of non-invasive prenatal testing (NIPT) and second trimester serum screening (STSS). A retrospective analysis was carried out on 54 026 singleton pregnant women undergoing NIPT and STSS from March 1, 2018 to December 31, 2019 in Changsha Maternal and Child Health Care Hospital. For pregnant women with high-risk results of NIPT, prenatal diagnosis and follow-up of pregnancy outcomes were conducted. The data was grouped to 4 screening models, and their cost-benefit was analyzed. The sensitivity, specificity and positive predictive value of NIPT were all higher than STSS. Screening models 1 to 4 have prevented the birth of 71, 29, 52 and 54 patients with Down syndrome, respectively. The safety index of screening models 1 to 4 were 0.0036, 0.3944, 02215 and 0.1281, respectively. When the price of NIPT was decreased to 600 RMB, the cost-benefit of the screening models 1 to 4 was 0.46, 0.65, 0.44 and 0.40 million RMB, respectively. NIPT has a better detection performance than STSS. When the price of NIPT is 600 RMB, screening model 1 has the best screening effect and the highest accuracy, safety index and health economical value.

The Blood Group Serology Combined Irregular Antibody Prenatal Screening Strategies for RhD-Pregnant Women in Xiamen

To investigate the distribution of Rh phenotype, irregular antibodies screenting and postpartum follow-up of RhD- pregnant women in Xiamen. The samples of 313 RhD- pregnant women from June 2018 to May 2020 were collected. Rh serotype phenotypes were identified by tube physiological saline method, irregular antibodies were screened and confirmed by DiaMed Low ion indirect anti-human gel card. By recording the medical，the pregnant women production process and the occurrence of HDN were investigated. The Rh serological phenotypes of 313 RhD- pregnant women were ccdee 180 cases (57.51%), Ccdee 97 cases (30.99%), ccdEe 10 cases(3.19%), CCdee 21 cases (6.71%), CcdEe 5 cases (1.60%), the ccdee and ccdee were the most common in the serological phenotype. Eleven irregular antibodies were detected in 313 RhD- pregnant women, accounting for 351% of the total. There were 8 cases of anti-D antibody, 1 case of anti-E antibody, and 2 cases of anti-D combined with anti-C antibody. The medical records of 21 RhD- pregnant women were reviewed, 19 cases of RhD+ and 2 RhD- newborns were successfully delivered, in which 2 cases developed RhD-HDN, 1 case developed RHE-HDN, and the remaining 18 cases did not develop HDN. The Rh serological phenotype of RhD- pregnant women in Xiamen area is mainly for ccdee. Maternal history and blood transfusion history are the main causes of irregular RhD- pregnant antibodies. It is recommended that serological phenotype combined with irregular antibody screening should be applied for RhD- pregnant women in clinic, to reduce the risk of RhD-HDN and ensure the safety of RhD- blood transfusion.

Screening for Alcohol Use in Pregnancy: a Review of Current Practices and Perspectives.

Global trends of increasing alcohol consumption among women of childbearing age, social acceptability of women’s alcohol use, as well as recent changes in alcohol use patterns due to the COVID-19 pandemic may put many pregnancies at higher risk for prenatal alcohol exposure (PAE), which can cause fetal alcohol spectrum disorder (FASD). Therefore, screening of pregnant women for alcohol use has become more important than ever and should be a public health priority. This narrative review presents the state of the science on various existing prenatal alcohol use screening strategies, including the clinical utility of validated alcohol use screening instruments. It also discusses barriers for alcohol use screening in pregnancy, such as practitioner constraints, unplanned pregnancies, delayed access to prenatal care, and stigma associated with substance use in pregnancy, providing recommendations to address these barriers. By implementing consistent alcohol use screening, prenatal care providers have the opportunity to facilitate access to counseling and brief interventions and thus, to prevent new cases of FASD and improve maternal and child health.

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;

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).

Is it time to adopt routine cytomegalovirus screening in pregnancy? No!

Congenital cytomegalovirus is caused by maternal primary or nonprimary infection during pregnancy and is a major preventable cause of neurodisability. The proposed strategies to reduce congenital cytomegalovirus include primary prevention with maternal hygiene measures and secondary prevention by serologic screening for detecting maternal primary infection. A recent randomized trial found that high-dose valaciclovir treatment resulted in a significant reduction in fetal infection after first-trimester maternal primary infection, leading to calls to start routine serologic screening in pregnancy. Previously, observational studies have found a reduction in fetal infection with after maternal primary cytomegalovirus infection when hyperimmune globulin is administered twice weekly during the first trimester of pregnancy; however, this has not been replicated in randomized trials that have used different regimens. Furthermore, some evidence from a single intervention trial and observational studies do not provide us with the necessary data required for rolling out an appropriate screening program. All screening tests may be associated with harm; in the case of congenital cytomegalovirus, there is the well-recognized potential for increasing terminations of pregnancy without diagnostic confirmation of fetal infection or sequelae. Although valaciclovir and hyperimmune globulin treatments may significantly reduce fetal infection rates, they do not prevent severe cytomegalovirus-related fetal brain damage in all pregnancies. Therefore, it is not clear that the offer of a prenatal intervention will provide sufficient reassurance to screen-positive women. In addition, the effectiveness of a prenatal screening and treatment strategy is predicated on a high rate of maternal primary infection, which is limited to regions with low cytomegalovirus seroprevalence, such as Western Europe. In some countries, such as the United States, Finland, and Brazil, nonprimary maternal infections are responsible for most congenital cytomegalovirus health burdens, limiting the potential impact of pregnancy screening. In this invited clinical perspective, we reviewed the evidence and outlined the steps needed to be taken before determining whether the benefits of routine screening for cytomegalovirus in pregnancy outweigh the harms. Until we have the necessary evidence, we should follow the current advice of multiple national health authorities and focus on promoting primary prevention through maternal hygiene precautions.

Economic Impact of Coverage Expansion for Non-invasive Prenatal Testing Through a Performance-Based Risk-Sharing Agreement.

BackgroundHarvard Pilgrim Health Care expanded coverage for non-invasive prenatal testing (NIPT) to include all pregnant, single-gestation women aged < 35 years, through a performance-based risk-sharing (PBRS) agreement with Illumina to offset costs from coverage expansion. NIPT analyzes cell-free DNA fragments from a maternal blood sample to screen for fetal aneuploidies and is considered a more accurate screening method than conventional serum biochemical screening and nuchal translucency ultrasound-based approaches.ObjectiveThis study assessed the impact of NIPT coverage expansion on prenatal screening strategies and payer expenditures.MethodsThis was a real-world comparison of utilization and expenditures of prenatal screening and diagnostic testing in pregnant women aged < 35 years pre- (1 March 2016–28 February 2018) and post- (1 March 2018–30 September 2019) coverage expansion. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were estimated to compare changes in utilization of conventional and NIPT-based prenatal screening methods. Change in per member per month (PMPM) expenditures in $US year 2020 were assessed post-coverage expansion using a budget impact model.ResultsA total of 5041 and 4109 distinct pregnancies were identified in pre- and post-coverage expansion periods, respectively. Mean ± standard deviation maternal age was consistent between pre- and post-coverage expansion periods (30.35 ± 3.35 and 30.33 ± 3.28, respectively). Screening orders for conventional methods decreased, with an adjusted IRR in the post-expansion period of 0.87 (95% CI 0.85–0.90) times the rate in the pre-expansion period; orders for NIPT increased, with an adjusted IRR in the post-expansion period of 1.41 (95% CI 1.32–1.51) times the rate in the pre-expansion period. Invasive diagnostic testing was low at baseline (1.0%) and did not change post-coverage expansion. The change in PMPM is estimated at $US0.026 post-coverage expansion.ConclusionThe PBRS agreement to expand NIPT coverage for women aged < 35 years was associated with an increase in NIPT utilization, decreases in conventional screening methods, and a modest increase in PMPM expenditures.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-021-00261-y.

OP354 Cost-Effectiveness Analysis Of Different Prenatal Screening Strategies For Down Syndrome In China: Data From Shandong Province

IntroductionThere are large differences between the prenatal screening strategies for Down Syndrome (DS) in different provinces in China. In Henan province there is a serological triple screening in the second trimester (STS) strategy, while in Shandong province contingent non-invasive prenatal testing (NIPT) screening strategy (NIPT delivered to older pregnant women) is used, and there is a universal NIPT screening strategy in Anhui province. Moreover, many factors varied widely in different regions, such as the proportion of older pregnant woman and the ability of people to pay. This study aimed to determine the cost-effectiveness of current strategy in Shandong compared with strategies in other provinces.MethodsA decision tree model was developed according to the screening strategies in different provinces. Four screening strategies were involved, universal STS strategy, contingent STS strategy, contingent NIPT strategy, and universal NIPT strategy. Cost-effectiveness analysis was conducted from a societal perspective in a simulated cohort of 100,000 pregnant women. The data of costs and epidemiologic parameters were collected from field surveys in Shangdong and a literature review.ResultsThe universal STS strategy, contingent STS strategy, contingent NIPT strategy, and universal NIPT strategy could prevent 17.0, 40.0, 46.2, and 53.6 DS births, respectively. There was no strategy dominated by others. The universal NIPT strategy and contingent NIPT strategy would decrease invasive procedures for prenatal diagnosis, resulting in fewer procedure-related miscarriages. The sensitivity analysis showed that the effectiveness of the screening strategy is significantly influenced by the resident's acceptance of NIPT.ConclusionsFrom the perspective of maximizing the effect, the universal NIPT strategy is the optimal strategy. But taking into account the resident's and government's ability to pay, contingent NIPT Strategy may be appropriate for the current situation in Shandong. To ensure a better cost-effective advantage in the universal NIPT strategy, the government should provide health education to increase the acceptance of NIPT while controlling the price of NIPT.

Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies

BackgroundPrenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary.MethodsWe modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population.ResultsAt an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3–5%, it was more costly and more women required diagnostic testing.ConclusionReflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal screening and diagnosis of genetic abnormalities: SEGO, SEQCML, AEDP consensus recommendations.

In this paper, the scientific societies SEGO, SEQCML and AEDP provide a series of consensus-based recommendations for prenatal screening and diagnosis of genetic abnormalities. A set of evaluation indicators are also proposed as a means to improve the quality of the biochemical, ultrasound, and genetic processes involved in prenatal screening and diagnosis of genetic anomalies. Some recommendations are also proposed in relation to invasive prenatal diagnostic procedures, more specifically regarding sample collection and genetic testing. The purpose of this proposal is to unify performance criteria and quality indicators at national level, with audits performed on a regular basis. It is strongly recommended that a national prenatal screening strategy be established and provided with the resources necessary to evaluate the performance of quality indicators and diagnostic procedures under the supervision of health authorities. Protocols should be revised on a regular basis to consider the incorporation of new cost-effective technologies.

A Hierarchical Bayes Approach to Modeling Heterogeneity in Discrete Choice Experiments: An Application to Public Preferences for Prenatal Screening.

Previous studies assessing preferences for prenatal screening have focused on preferences of the affected population and have largely assumed homogeneous preferences. We aimed to estimate public preferences and willingness to pay for prenatal screening and diagnosis from a Canadian general population sample, and to model preferences at the individual level. A discrete choice experiment was used to elicit preferences for different aspects of prenatal screening and diagnostic strategies. Strategies differed in five attributes: timing of the results, false-negative rate, false-positive rate, risk of miscarriage, and out-of-pocket cost. Respondents made forced and unforced choices using a dual response approach. Hierarchical Bayes analysis was applied to estimate individual-level part-worth utilities. Individual probability and expected uptake of prenatal screening under different scenarios were also assessed. Subgroup analyses were conducted using individual-level preferences. The final analyses were based on a sample of 4601 respondents. Results showed that the two most important attributes were false-negative rate and miscarriage risk. There was significant heterogeneity in preferences among respondents. Individuals' perception of the risk of pregnancy with chromosomal abnormalities affected their preferences for screening. The relatively high uptake of safe and accurate screening among all groups of respondents indicated people's desire for information about the health of their unborn baby regardless of their decision to continue the pregnancy. Our findings are consistent with previous studies based on affected-population preferences. This concordance should be reassuring from a policy perspective and can inform the design of publicly funded prenatal screening programs.

Cost-effectiveness of prenatal screening and diagnostic strategies for Down syndrome: A microsimulation modeling analysis

ObjectivesDown syndrome (DS) is the most frequently occurring fetal chromosomal abnormality and different prenatal screening strategies are used for determining risk of DS worldwide. New non-invasive prenatal testing (NIPT), which uses cell-free fetal DNA in maternal blood can provide benefits due to its higher sensitivity and specificity in comparison to conventional screening tests. This study aimed to assess the cost-effectiveness of using population-level NIPT in fetal aneuploidy screening for DS.MethodsWe developed a microsimulation decision-analytic model to perform a probabilistic cost-effectiveness analysis (CEA) of prenatal screening and diagnostic strategies for DS. The model followed individual simulated pregnant women through the pregnancy pathway. The comparators were serum-only screening, contingent NIPT (i.e., NIPT as a second-tier screening test) and universal NIPT (i.e., NIPT as a first-tier screening test). To address uncertainty around the model parameters, the expected values of costs and quality-adjusted life-years (QALYs) in the base case and all scenario analyses were obtained through probabilistic analysis from a Monte Carlo simulation.ResultsBase case and scenario analyses were conducted by repeating the micro-simulation 1,000 times for a sample of 45,605 pregnant women per the population of British Columbia, Canada (N = 4.8 million). Preliminary results of the sequential CEAs showed that contingent NIPT was a dominant strategy compared to serum-only screening. Compared with contingent NIPT, universal NIPT at the current test price was not cost-effective with an incremental cost-effectiveness ratio over $100,000/QALY. Contingent NIPT also had the lowest cost per DS case detected among these three strategies.ConclusionIncluding NIPT in existing prenatal screening for DS is shown to be beneficial over conventional testing. However, at current prices, implementation of NIPT as a second-tier screening test is more cost-effective than deploying it as a universal test.

Cost‐effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model‐based analysis

To evaluate the cost-effectiveness of five prenatal screening strategies for trisomies (13/18/21) and other unbalanced chromosomal abnormalities (UBCA), following the introduction of cell-free DNA (cfDNA) analysis. A model-based cost-effectiveness analysis was performed to estimate prevalence, safety, screening-program costs and healthcare costs of five different prenatal screening strategies, using a virtual cohort of 652 653 pregnant women in France. Data were derived from the French Biomedicine Agency and published articles. Uncertainty was addressed using one-way sensitivity analysis. The five strategies compared were: (i) cfDNA testing for women with a risk following first-trimester screening of ≥ 1/250; (ii) cfDNA testing for women with a risk of ≥ 1/1000 (currently recommended); (iii) cfDNA testing in the general population (regardless of risk); (iv) invasive testing for women with a risk of ≥ 1/250 (historical strategy); and (v) invasive testing for women with a risk of ≥ 1/1000. In our virtual population, at similar risk thresholds, cfDNA testing compared with invasive testing was cheaper but less effective. Compared with the historical strategy, cfDNA testing at the ≥ 1/1000 risk threshold was a more expensive strategy that detected 158 additional trisomies, but also 175 fewer other UBCA. Implementation of cfDNA testing in the general population would give an incremental cost-effectiveness ratio of €9 166 689 per additional anomaly detected compared with the historical strategy. Extending cfDNA to lower risk thresholds or even to all pregnancies would detect more trisomies, but at greater expense and with lower detection rate of other UBCA, compared with the historical strategy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Budget impact of incorporating non-invasive prenatal testing in prenatal screening for Down syndrome in Turkey

ObjectivesTo provide information to the government about the budget impact of implementing non-invasive prenatal testing (NIPT) into prenatal screening strategies to detect Down syndrome (DS) in singleton pregnancies in Turkey; the likely costs or savings associated with NIPT in comparison to the current practice were calculated. MethodsA decision-analytic model was developed to calculate the cost estimates for 1,309,771 women who gave birth in 2016; 84.8% of whom were <35-years-of-age. The superior combined test (CT) among current strategies is compared with contingent NIPT for women < 35-years-of-age; and usual practice of amniocentesis (AC) for women ≥ 35 years-of-age was replaced with universal NIPT. ResultsWhen the market price of NIPT (1,077 PPPUS$) is used, contingent NIPT offered to high-risk women < 35-years-of-age adds 34,907,225 PPPUS$; and for women-35 ≥ years-of-age the universal NIPT leads to 142,785,818 PPPUS$ more cost to the government compared to current strategies. The additional costs with NIPT are partially compensated by the cost-savings due to reduction of the number of invasive tests and procedure related losses (17,826,476 PPPUS$ for women < 35-years-of-age and 37,070 PPPUS$ for women ≥ 35-years-of-age). Results are sensitive to the NIPT costs; with a lower cost of NIPT, a total saving would be 33,116,046 PPPUS$ with new strategies. ConclusionsNIPT might be the choice of prenatal screening strategies if its price is lowered to economically acceptable levels. Until that time, currently accepted protocols seem to be more realistic. On the other hand, decision makers should also consider possible savings and the women's quality of life that can be improved with the new technology.