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Purpose: To present results from a large cohort of individuals receiving expanded carrier screening (CS) in the United States., Methods: Single-gene disorder carrier status for 381,014 individuals was determined using next-generation sequencing (NGS) based CS for up to 274 genes. Detection rates were compared with literature-reported values derived from disease prevalence and carrier frequencies. Combined theoretical affected pregnancy rates for the 274 screened disorders were calculated., Results: For Ashkenazi Jewish (AJ) diseases, 81.6% (4434/5435) of carriers identified did not report AJ ancestry. For cystic fibrosis, 44.0% (6260/14,229) of carriers identified had a variant not on the standard genotyping panel. Individuals at risk of being a silent spinal muscular atrophy carrier, not detectable by standard screening, comprised 1/39 (8763/344,407) individuals. For fragile X syndrome, compared with standard premutation screening, AGG interruption analysis modified risk in 83.2% (1128/1356) premutation carriers. Assuming random pairing across the study population, approximately 1/175 pregnancies would be affected by a disorder in the 274-gene screening panel., Conclusion: Compared with standard screening, NGS-based CS provides additional information that may impact reproductive choices. Pan-ethnic CS leads to substantially increased identification of at-risk couples. These data support offering NGS-based CS to all reproductive-aged women.

Purpose: To assess the association between confined placental mosaicism (CPM) and adverse pregnancy outcome., Methods: A retrospective cohort study was carried out evaluating the outcome of pregnancies with and without CPM involving a rare autosomal trisomy (RAT) or tetraploidy. Birthweight, gestational age at delivery, fetal growth restriction (FGR), Apgar score, neonatal intensive care admission, preterm delivery, and hypertensive disorders of pregnancy were considered., Results: Overall 181 pregnancies with CPM and 757 controls were recruited. Outcome information was available for 69% of cases (n = 124) and 62% of controls (n = 468). CPM involving trisomy 16 (T16) was associated with increased incidence of birthweight <3rd centile (P = 0.007, odds ratio [OR] = 11.2, 95% confidence interval [CI] = 2.7-47.1) and preterm delivery (P = 0.029, OR = 10.2, 95% CI = 1.9-54.7). For the other RATs, an association with prenatally diagnosed FGR was not supported by birthweight data and there were no other strong associations with adverse outcomes., Conclusion: Excluding T16, the incidence of adverse pregnancy outcomes for pregnancies carrying a CPM is low. RATs can also be identified through genome-wide cell-free DNA screening. Because most of these will be attributable to CPMs, we conclude that this screening is of minimal benefit.

Objective: Non-invasive prenatal testing (NIPT) through the analysis of cell-free DNA in maternal plasma has bee expanded to include clinically-relevant microdeletions such as the 22q11.2 deletion syndrome (22q11.2DS)., Case Report: We present a pregnancy where the fetus was affected with 22q11.2DS based on chromosome microarray analysis. Discordant results were obtained through two different NIPT methodologies. The pregnancy was identified as high risk by a SNP-based approach but low risk using a genome-wide counting methodology. A review of the technical methods used for these tests provides insight into why they may provide conflicting results and emphasizes the importance of chromosome microarray studies for diagnostic confirmation and defining the deletion., Conclusion: Currently available NIPT for 22q11.2DS use different technologies that are not equivalent. The genome-wide counting methodology has the potential to detect deletions outside the critical 22q11.2 A-D region but current data suggests it may have a lower sensitivity for deletions within the critical region., (Copyright © 2018. Published by Elsevier B.V.)

Noninvasive prenatal screening (NIPS) for fetal chromosome defects has high sensitivity and specificity but is not fully diagnostic. In response to a desire to provide more information to individual women with positive NIPS results, 2 online calculators have been developed to calculate posttest risk (PTR). Use of these calculators is critically reviewed. There is a mathematically dictated requirement for a precise estimate for the specificity to provide an accurate PTR. This is illustrated by showing that a 0.1% decrease in the value for specificities for trisomies 21, 18, and 13 can reduce the PTR from 79-64% for trisomy 21, 39-27% for trisomy 18, and 21-13% for trisomy 13, respectively. Use of the calculators assumes that sensitivity and specificity are constant for all women receiving the test but there is evidence that discordancy between screening results and true fetal karyotype is more common for older women. Use of an appropriate value for the prior risk is also important and for rare disorders there is considerable uncertainty regarding prevalence. For example, commonly used rates for trisomy 13, monosomy-X, triploidy, and 22q11.2 deletion syndrome can vary by >4-fold and this can translate into large differences in PTR. When screening for rare disorders, it may not be possible to provide a reliable PTR if there is uncertainty over the false-positive rate and/or prevalence. These limitations, per se, do not negate the value of screening for rare conditions. However, counselors need to carefully weigh the validity of PTR before presenting them to patients. Additional epidemiologic and NIPS outcome data are needed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to estimate the performance of a single-nucleotide polymorphism (SNP)-based noninvasive prenatal test for 5 microdeletion syndromes., Study Design: Four hundred sixty-nine samples (358 plasma samples from pregnant women, 111 artificial plasma mixtures) were amplified with the use of a massively multiplexed polymerase chain reaction, sequenced, and analyzed with the use of the Next-generation Aneuploidy Test Using SNPs algorithm for the presence or absence of deletions of 22q11.2, 1p36, distal 5p, and the Prader-Willi/Angelman region., Results: Detection rates were 97.8% for a 22q11.2 deletion (45/46) and 100% for Prader-Willi (15/15), Angelman (21/21), 1p36 deletion (1/1), and cri-du-chat syndromes (24/24). False-positive rates were 0.76% for 22q11.2 deletion syndrome (3/397) and 0.24% for cri-du-chat syndrome (1/419). No false positives occurred for Prader-Willi (0/428), Angelman (0/442), or 1p36 deletion syndromes (0/422)., Conclusion: SNP-based noninvasive prenatal microdeletion screening is highly accurate. Because clinically relevant microdeletions and duplications occur in >1% of pregnancies, regardless of maternal age, noninvasive screening for the general pregnant population should be considered., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to report on laboratory and clinical experience following 6 months of clinical implementation of a single-nucleotide polymorphism-based noninvasive prenatal aneuploidy test in high- and low-risk women., Study Design: All samples received from March through September 2013 and drawn ≥9 weeks' gestation were included. Samples that passed quality control were analyzed for trisomy 21, trisomy 18, trisomy 13, and monosomy X. Results were reported as high or low risk for fetal aneuploidy for each interrogated chromosome. Relationships between fetal fraction and gestational age and maternal weight were analyzed. Follow-up on outcome was sought for a subset of high-risk cases. False-negative results were reported voluntarily by providers. Positive predictive value (PPV) was calculated from cases with an available prenatal or postnatal karyotype or clinical evaluation at birth., Results: Samples were received from 31,030 patients, 30,705 met study criteria, and 28,739 passed quality-control metrics and received a report detailing aneuploidy risk. Fetal fraction correlated positively with gestational age, and negatively with maternal weight. In all, 507 patients received a high-risk result for any of the 4 tested conditions (324 trisomy 21, 82 trisomy 18, 41 trisomy 13, 61 monosomy X; including 1 double aneuploidy case). Within the 17,885 cases included in follow-up analysis, 356 were high risk, and outcome information revealed 184 (51.7%) true positives, 38 (10.7%) false positives, 19 (5.3%) with ultrasound findings suggestive of aneuploidy, 36 (10.1%) spontaneous abortions without karyotype confirmation, 22 (6.2%) terminations without karyotype confirmation, and 57 (16.0%) lost to follow-up. This yielded an 82.9% PPV for all aneuploidies, and a 90.9% PPV for trisomy 21. The overall PPV for women aged ≥35 years was similar to the PPV for women aged <35 years. Two patients were reported as false negatives., Conclusion: The data from this large-scale report on clinical application of a commercially available noninvasive prenatal test suggest that the clinical performance of this single-nucleotide polymorphism-based noninvasive prenatal test in a mixed high- and low-risk population is consistent with performance in validation studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to determine changes in screening and performance of invasive diagnostic procedures for Down syndrome between 2001 and 2007., Study Design: The Society for Maternal-Fetal Medicine members completed a survey in 2007 regarding screening tests and diagnostic procedures for Down syndrome. With the use of descriptive statistics, the chi(2) test, and the Student t test, responses from 2007 were compared with responses from a similar 2001 survey., Results: Performance of first-trimester screening more than doubled from 2001-2007 (43.1% in 2001, 97.3% in 2007; P < .0001). Between 2001 and 2007, the use of the quad screen increased 10-fold (8.5% in 2001, 85.6% in 2007; P < .0001). There was an estimated 20% decrease in invasive diagnostic procedures that were performed in risk-positive women (53.7% in 2001, 34.2% in 2007; P < .0001). In 2007, the average fetal loss rates that were quoted by maternal-fetal medicine specialists after chorionic villous sampling was 1:160 and after an amniocentesis was 1:493., Conclusion: Down syndrome screening evolved from 2001-2007, with an increasing emphasis on first-trimester screening. With more efficacious screening, the number of invasive procedures has declined.

Objective: The purpose of this study was to evaluate stepwise sequential screening for fetal aneuploidy., Study Design: Women who received first-trimester screening were also offered second-trimester tests with second-trimester risks that were based on both sets of markers. Screen-positive rates, use of second-trimester testing and invasive testing, sensitivity, and changes in risks were evaluated., Results: Of 1528 women who received first-trimester screening, 133 women (8.7%) had an indication for invasive testing that was based on first-trimester results alone; 1173 women (76.8%) received second-trimester tests, which reduced the net number of women with an indication for invasive testing to 105 (6.9%). In unaffected pregnancies, the addition of the second-trimester testing reduced the median Down syndrome risk from 1:2368 to 1:10,301. Six of 10 chromosome abnormalities (60%) were identified by first-trimester screening, and 9 of 10 chromosome abnormalities (90%) were identified by sequential screening., Conclusion: Sequential screening can be introduced successfully into clinical practice, is effective, and can reduce the number of invasive tests that are performed.

Purpose: To identify trends in the utilization of second trimester maternal serum screening, follow-up amniocenteses, and the detection of Down syndrome-affected pregnancies between 1991 and 2003., Methods: We reviewed all triple and quadruple maternal serum screening tests referred to the University of Connecticut screening laboratory from women with singleton pregnancies. For each calendar year, the total number of tests, proportion to women aged 35 or older, number of follow-up amniocenteses, and the number of prenatally and postnatally diagnosed Down syndrome cases were recorded., Results: A total of 109,469 women received screening. In 1991, the proportion of older women who received screening was 58% of that present in the Connecticut population but by 2003 this had increased to 83% (P < 0.001). In Down syndrome screen-positive pregnancies, there was no significant change in the rate of amniocentesis utilization (average 73%), but in false-positives, there was a decline from 70% in 1991 to 27% in 2003 (P < 0.001)., Conclusion: Increased use of maternal serum screening by older women, use of second trimester ultrasound, and improvements in screening methodology have resulted in sharply reduced numbers of amniocenteses in unaffected pregnancies.

Objective: We investigated the observed and expected Down syndrome livebirths in the US from 1989 to 2001., Study Design: Using birth certificate data, we recorded maternal age-specific live births from 1989 to 2001, and stratified them by women 15 to 34 and 35 to 49 years old. We estimated Down syndrome live births from 1989 to 2001, assuming no terminations. We recorded Down syndrome live births by year from 1989 to 2001., Results: Despite an expected 1.32-fold increase in Down syndrome live birth rates from 1989 to 2001, Down syndrome live births actually declined. In 1989, the rate of Down syndrome cases was 15% lower than expected, decreasing to 51% by 1998. Women 15 to 34 had 45% fewer affected pregnancies in 2001, while women 35 to 49 had 53% fewer in 2001. We estimated that Down syndrome live births decreased from 3962 in 1989 to 3654 in 2001., Conclusion: Down syndrome live births declined in the US despite an expected increase caused by delayed or extended childbearing.

Objective: Our objectives were to determine patterns of antenatal Down syndrome screening and risk adjustment by maternal-fetal medicine specialists in the United States in 2001., Study Design: A survey to investigate Down syndrome screening practice patterns was mailed to the 1,638 members of the Society of Maternal-Fetal Medicine in the United States. Practice demographics, screening patterns, and the numeric risks quoted in counseling were analyzed., Results: Five hundred forty-three specialists (33.2%) responded; 530 of these specialists (97.6%) performed antenatal Down syndrome screening; all of them offered second-trimester screening, and 247 of them (45.5%) offered first-trimester screening. With the use of second-trimester ultrasonography, risk was increased by 69.4% of respondents and decreased by 33.1%. Amniocentesis was the most frequently used diagnostic test (83.2%), with loss rates quoted at 1:100 to 1:1,000., Conclusion: Maternal-fetal medicine specialists show a wide in variation practices used for Down syndrome screening, modification of risk, and quoted procedure-related loss rates. This information calls for a consensus regarding risks that are quoted in Down syndrome counseling.

Background: The acceptability of prenatal screening and diagnosis of Down syndrome is dependent, in part, on the gestational age at which the testing is offered. First trimester screening could be advantageous if it has sufficient efficacy and can be effectively delivered., Issues: Two first trimester maternal serum screening markers, pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG), are useful for identifying women at increased risk for fetal Down syndrome. In addition, measurement of an enlarged thickness of the subcutaneous fluid-filled space at the back of the neck of the developing fetus (referred to as nuchal translucency or NT) has been demonstrated to be an indicator for these high-risk pregnancies. When these three parameters are combined, estimates for Down syndrome efficacy exceed those currently attainable in the second trimester. Women who are screen-positive in the first trimester can elect to receive cytogenetic testing of a chorionic villus biopsy. The first trimester tests could also, theoretically, be combined with the second trimester maternal serum screening tests (integrated screening) to obtain even higher levels of efficacy. There are, however, several practical limitations to first trimester and integrated screening. These include scheduling of testing within relatively narrow gestational age intervals, availability of appropriately trained ultrasonographers for NT measurement, risks associated with chorionic villus biopsy, and costs. There is also increasing evidence that an enlarged NT measurement is indicative of a high risk for spontaneous abortion and for fetal abnormalities that are not detectable by cytogenetic analysis. Women whose fetuses show enlarged NT, therefore, need first trimester counseling regarding their Down syndrome risks and the possibility of other adverse pregnancy outcomes. Follow-up ultrasound and fetal echocardiography in the second trimester are also indicated., Conclusion: First trimester screening appears to be a highly effective method to screen for Down syndrome. Women with screen-positive results based on NT measurement appear to be at increased risk for diverse fetal abnormalities. The finding of a normal fetal karyotype may not, therefore, carry a high level of reassurance for a normal baby., (Copyright 2002 Elsevier Science B.V.)

Background: Down syndrome is one of the most important causes of mental retardation in the population. In the absence of prenatal screening and diagnosis, prevalence at birth in the United States would currently exceed 1:600. The purpose of prenatal screening is to identify those women at the increased risk for an affected pregnancy and to maximize the options available to these women., Tests Available: Second trimester serum screening involves combining the maternal age-specific risk for an affected pregnancy with the risks associated with the concentrations of maternal serum alpha-fetoprotein (MSAFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) (triple testing). A forth analyte, inhibin-A (INH-A), is increasingly being utilized (quadruple testing). Optimal second trimester screening requires the integration of a number of clinical variables, the most important of which is an accurate assessment of gestational age. In addition to Down syndrome, the triple and quadruple tests preferentially identify fetal trisomy 18, Turner syndrome, triploidy, trisomy 16 mosaicism, fetal death, Smith-Lemli-Opitz syndrome, and steroid sulfatase deficiency. Some programs modify the Down syndrome risks generated through maternal serum screening tests with fetal biometric data obtained by ultrasound. Other second trimester tests have shown promise, including the analysis of maternal urine and fetal cells in the maternal circulation, but none are in routine clinical use., Conclusion: The second trimester triple and quadruple tests provide benchmarks for evaluating new screening protocols. The combination of fetal biometry, new test development as well as clarification of the role of co-factors that affect the concentrations of analytes in existing tests should lead to greater efficacy in second trimester screening for Down syndrome.