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Background This study aimed to evaluate the efficiency of noninvasive prenatal screening (NIPS) technology in screening for microdeletions in the 7q11.23 region.Methods 19,607 pregnant women underwent NIPS in our hospital. Maternal peripheral cell-free foetal DNA (cffDNA) was routinely screened for aneuploidy by cffDNA enrichment and simultaneously analyzed for pathogenic copy number variants (CNVs). The Williams syndrome (WS) 7q11.23 region was targeted in this study. Chromosomal microarray analysis (CMA) was used to verify the screen-positive samples.Results The mean concentration of cffDNA before and after enrichment increased from 9.44% to 19.32%, with a statistically significant difference. Two out of 19,607 samples tested for CNVs were found to have a heterozygous deletion at the 7q11.23 region, indicating a high risk for WS. CMA results confirmed the 1.5 megabase (Mb) deletions at the 7q11.23 region in amniotic fluid samples. One of the two WS foetuses had a small left ventricle by ultrasound screening, and the other did not have a significant cardiovascular abnormality phenotype.Conclusions NIPS screening for Williams syndrome can be achieved by enriching cell-free foetal DNA and improving bioinformatic analysis algorithms.

Background: As a screening method, inaccuracies in noninvasive prenatal screening (NIPS) exist, which are often attributable to biological factors. One such factor is the history of transplantation. However, there are still limited reports on such NIPS cases. Methods: We report an NIPS case of a pregnant woman who had received a stem cell transplant from a male donor. To determine the karyotype in the woman's original cell, we performed chromosome microarray analysis (CMA) on her postnatal blood and oral mucosa. To comprehensively estimate the cell‐free DNA (cfDNA) composition, we further performed standard NIPS procedures on the postnatal plasma. Moreover, we reviewed all published relevant NIPS case reports about pregnant women with transplantation history. Results: NIPS showed a low‐risk result for common trisomies with a fetal fraction of 65.80%. CMA on maternal white blood cells showed a nonmosaic male karyotype, while the oral mucosa showed a nonmosaic female karyotype. The proportion of donor's cfDNA in postnatal plasma was 94.73% based on the Y‐chromosome reads ratio. The composition of cfDNA in maternal plasma was estimated as follows: prenatally, 13.60% maternal, 65.80% donor, and 20.60% fetal/placental, whereas postnatally, 5.27% maternal and 94.73% donor. Conclusions: This study expanded our understanding of the influence of stem cell transplantation on NIPS, allowing us to optimize NIPS management for these women. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening (NIPS) has shown good performance in screening common aneuploidies. However, its performance in detecting fetal sex chromosome aneuploidies (SCAs) needs to be evaluated in a large cohort. In this retrospective observation, a total of 116,862 women underwent NIPS based on DNA nanoball sequencing from 2015 to 2022. SCAs were diagnosed based on karyotyping or chromosomal microarray analysis (CMA). Among them, 2,084 singleton pregnancies received karyotyping and/or CMA. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NIPS for fetal SCAs were evaluated. The sensitivity was 97.7% (95%CI, 87.7–99.9), 87.3% (95% CI, 76.5–94.4), 96.1% (95%CI, 86.5–99.5), and 95.7% (95% CI, 78.1–99.9), the PPV was 25.8% (95%CI, 19.2–33.2), 80.9% (95%CI, 69.5–89.4), 79.0% (95%CI, 66.8–88.3), and 53.7% (95%CI, 37.4–69.3) for 45,X, 47,XXY, 47,XXX, and 47,XYY, respectively. The specificity was 94.1% (95%CI, 93.0–95.1) for 45,X, and more than 99.0% for sex chromosome trisomy (SCT). The NPV was over 99.0% for all. NIPS screening for fetal SCAs has high sensitivity, specificity and NPV. The PPV of SCAs was moderate, but that of 45,X was lower than that of SCTs. Invasive prenatal diagnosis should be recommended for high-risk patients. [ABSTRACT FROM AUTHOR]

Abstract Background Pathogenic (P) copy number variants (CNVs) may be associated with second-trimester ultrasound soft markers (USMs), and noninvasive prenatal screening (NIPS) can enable interrogate the entire fetal genome to screening of fetal CNVs. This study evaluated the clinical application of NIPS for detecting CNVs among fetuses with USMs in pregnant women not of advanced maternal age (AMA). Results Fetal aneuploidies and CNVs were identified in 6647 pregnant women using the Berry Genomics NIPS algorithm.Those with positive NIPS results underwent amniocentesis for prenatal diagnosis. The NIPS and prenatal diagnosis results were analyzed and compared among different USMs. A total of 96 pregnancies were scored positive for fetal chromosome anomalies, comprising 37 aneuploidies and 59 CNVs. Positive predictive values (PPVs) for trisomy 21, trisomy 18, trisomy 13, and sex chromosome aneuploidies were 66.67%, 80.00%, 0%, and 30.43%, respectively. NIPS sensitivity for aneuploidies was 100%. For CNVs, the PPVs were calculated as 35.59% and false positive rate of 0.57%. There were six P CNVs, two successfully identified by NIPS and four missed, of which three were below the NIPS resolution limit and one false negative. The incidence of aneuploidies was significantly higher in fetuses with absent or hypoplastic nasal bone, while that of P CNVs was significantly higher in fetuses with aberrant right subclavian artery (ARSA), compared with other groups. Conclusions NIPS yielded a moderate PPV for CNVs in non-AMA pregnant women with fetal USM. However, NIPS showed limited ability in identifying P CNVs. Positive NIPS results for CNVs emphasize the need for further prenatal diagnosis. We do not recommend the use of NIPS for CNVs screening in non-AMA pregnant women with fetal USM, especially in fetuses with ARSA.

Abstract Background Copy number variation (CNV) of X chromosome can lead to a variety of neonatal abnormalities, especially for male fetuses. In recent years, due to the high sensitivity and high specificity of NIPS, its application has gradually expanded from chromosome aneuploidy to CNV. Few prenatal cases involving the detection of Xq duplication and deletion by NIPS have been reported, but it is of great significance for genetic counseling. Case presentation A 36-year-old woman was referred for prenatal diagnosis and genetic counseling at 17 weeks of gestation because of abnormal result of noninvasive prenatal screening (NIPS). Multiple congenital malformations, hydrocephalus, and enlarged gallbladder were observed by prenatal ultrasound. Amniocentesis revealed the karyotype of the fetus as 46, XN, add(X) (p22.2) and the result of chromosomal microarray analysis was arr[hg19] Xq27.1q28(138,506,454–154896094) × 2 and arr[hg19] Xp22.33p22.32(168,551–5,616,964) × 1. CNV-seq showed that the mother shares a 16.42 Mb duplication in the Xq27.1-q28 region and a 2.97 Mb deletion in the Xp22.33-p22.32 region. After genetic counseling, the couple chose to terminate the pregnancy. Conclusion The combination of NIPS and CMA would be of values in detection of subchromosomal duplications and/or deletions at fetal stage. The detection of X chromosome aberration in a male fetus should give suspicion of the possibility of maternal inheritance.

Abstract Background As a screening method, inaccuracies in noninvasive prenatal screening (NIPS) exist, which are often attributable to biological factors. One such factor is the history of transplantation. However, there are still limited reports on such NIPS cases. Methods We report an NIPS case of a pregnant woman who had received a stem cell transplant from a male donor. To determine the karyotype in the woman's original cell, we performed chromosome microarray analysis (CMA) on her postnatal blood and oral mucosa. To comprehensively estimate the cell‐free DNA (cfDNA) composition, we further performed standard NIPS procedures on the postnatal plasma. Moreover, we reviewed all published relevant NIPS case reports about pregnant women with transplantation history. Results NIPS showed a low‐risk result for common trisomies with a fetal fraction of 65.80%. CMA on maternal white blood cells showed a nonmosaic male karyotype, while the oral mucosa showed a nonmosaic female karyotype. The proportion of donor's cfDNA in postnatal plasma was 94.73% based on the Y‐chromosome reads ratio. The composition of cfDNA in maternal plasma was estimated as follows: prenatally, 13.60% maternal, 65.80% donor, and 20.60% fetal/placental, whereas postnatally, 5.27% maternal and 94.73% donor. Conclusions This study expanded our understanding of the influence of stem cell transplantation on NIPS, allowing us to optimize NIPS management for these women.

Abstract Objective This study aimed to establish a cell-free fetal DNA (cffDNA) assay using multiplex digital PCR (dPCR) for identifying fetuses at increased risk of 22q11.2 deletion/duplication syndrome. Methods Six detection sites and their corresponding probes were designed for the 22q11.2 recurrent region. A dPCR assay for the noninvasive screening of 22q11.2 deletion/duplication syndrome was established. A total of 130 plasma samples from pregnant women (including 15 samples with fetal 22q11.2 deletion/duplication syndrome) were blindly tested for evaluating the sensitivity and specificity of the established assay. Results DNA with different sizes of 22q11.2 deletion/duplication was detected via dPCR, indicating that the designed probes and detection sites were reasonable and effective. In the retrospective clinical samples, 11 out of 15 samples of pregnant women with 22q11.2 deletion/duplication were detected during the cffDNA assay, and accurate regional localization was achieved. Among the 115 normal samples, 111 were confirmed to be normal. Receiver operating characteristic curves were used for assessing the cut-off values and AUC for these samples. The sensitivity, specificity, and positive as well as negative predictive values were 73.3%, 96.5%, 73.3%, and 96.5%, respectively. Conclusion The cffDNA assay based on dPCR technology for the noninvasive detection of 22q11.2 recurrent copy number variants in fetuses detected most affected cases, including smaller but relatively common nested deletions, with a low false-positive rate. It is a potential, efficient and simple method for the noninvasive screening of 22q11.2 deletion/duplication syndrome.

Aim: To investigate the detectability of noninvasive prenatal screening (NIPS) with conventional sequencing depth to detect fetal copy number variants. Methods: We performed a retrospective study in a total of 19 144 pregnant women. Their cell‐free plasma DNA were assessed for trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies, and genome‐wide copy number variants by NIPS at conventional sequencing depth. Results: Three hundred seventy‐four cases (2.0%, 374/19 144) with abnormal results were detected, which including 84 cases (0.4%, 84/19 144) with high risk of trisomy 21, 18, and 13, 90 cases (0.5%, 90/19 144) with high risk of sex chromosome abnormalities (SCA), and 44 cases (0.2%, 44/19 144) with high risk of other chromosome aneuploidies. One hundred fifty‐six cases (0.8%, 156/19 144) with high risk of copy number variations (CNVs) were also detected. In following prenatal diagnosis, composite positive predictive value (PPV) of trisomy 21, 18, and 13 was 69.6% (48/69). The PPV of SCAs was 37.3% (19/51). And the PPVs for CNVs was detected as 51.0% (<5 Mb), 71.4% (5 Mb ≤ CNV ≤10 Mb), 56.5% (>10 Mb). Finally, a follow‐up about the pregnancy outcomes were conducted for all available cases. Conclusions: NIPS yielded high PPVs for trisomy 21, 18, and 13 aneuploidies and moderate PPVs for SCAs and CNVs. The screening effectiveness was closely related to the size of CNV fragments. Larger CNVs, especially larger than 5 Mb, could be detected more accurately by NIPS in our analytic technique. Meanwhile, diagnostic confirmation by microarray analysis was highly recommended. [ABSTRACT FROM AUTHOR]

Background: Combined first‐trimester screening (cFTS) for fetal anomalies involves maternal serum screening for biochemical markers and measurement of the nuchal translucency (NT) by ultrasound. Noninvasive prenatal screening (NIPS) analyses cell‐free DNA present in a maternal blood sample for presence of fetal chromosomal aneuploidies. Aims: To compare NIPS with cFTS as frontline screening in a public hospital in Australia. Materials and methods: Women were offered NIPS in addition to the usual cFTS routinely offered to all women at a public hospital in NSW, Australia. The cFTS sample was collected at ten weeks' gestation and the NIPS sample at 12 weeks' gestation at the ultrasound appointment. Results: In a low‐risk population of 997 women, frontline NIPS had a screen‐positive rate of 0.5% (5/997) vs 4.2% (42/997) with cFTS. cFTS correctly identified one trisomy 21 case and one trisomy 18 case; however, there were two trisomy 18 false negatives. Of five positive NIPS calls, four were correctly identified as trisomy 21 (one) and trisomy 18 (three); there were no NIPS false negatives. Overall, the false‐positive rate with NIPS was 0.1% vs 4.0% by cFTS. Conclusions: The lower screen‐positive rate with NIPS for common trisomies was a result of the significantly lower false‐positive rate with NIPS. Consequently, NIPS as first‐line screening, even if funded by the hospital, may provide cost savings. We believe NIPS should be used from ten weeks' gestation in conjunction with morphology ultrasound for routine first‐trimester prenatal management. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening (NIPS) with predicted fetal sex chromosomes included in the results has become increasingly available for pregnant individuals. Predicted fetal sex chromosome results from NIPS are interpreted so as to equate sex chromosomes with sex and gender. As pediatric endocrinologists, we worry about how this use of NIPS harmfully reinforces sex and gender binaries and sets potentially inaccurate assumptions about what the identified chromosomes mean. We use a hypothetical case based on our clinical experience in which the NIPS report of fetal sex does not conform to expectations at birth to highlight ethical concerns surrounding this practice. The use of NIPS for fetal sex chromosome prediction has the potential to perpetuate stigma and bring psychological harm to parents and their future children, particularly those who are intersex, transgender, and gender diverse. The medical community should adopt an approach to the use of NIPS for fetal sex chromosome prediction that recognizes the spectrums of sex and gender to avoid reproducing stigma towards sex‐ and gender‐diverse individuals and associated harms. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to establish a cell-free fetal DNA (cffDNA) assay using multiplex digital PCR (dPCR) for identifying fetuses at increased risk of 22q11.2 deletion/duplication syndrome. Methods: Six detection sites and their corresponding probes were designed for the 22q11.2 recurrent region. A dPCR assay for the noninvasive screening of 22q11.2 deletion/duplication syndrome was established. A total of 130 plasma samples from pregnant women (including 15 samples with fetal 22q11.2 deletion/duplication syndrome) were blindly tested for evaluating the sensitivity and specificity of the established assay. Results: DNA with different sizes of 22q11.2 deletion/duplication was detected via dPCR, indicating that the designed probes and detection sites were reasonable and effective. In the retrospective clinical samples, 11 out of 15 samples of pregnant women with 22q11.2 deletion/duplication were detected during the cffDNA assay, and accurate regional localization was achieved. Among the 115 normal samples, 111 were confirmed to be normal. Receiver operating characteristic curves were used for assessing the cut-off values and AUC for these samples. The sensitivity, specificity, and positive as well as negative predictive values were 73.3%, 96.5%, 73.3%, and 96.5%, respectively. Conclusion: The cffDNA assay based on dPCR technology for the noninvasive detection of 22q11.2 recurrent copy number variants in fetuses detected most affected cases, including smaller but relatively common nested deletions, with a low false-positive rate. It is a potential, efficient and simple method for the noninvasive screening of 22q11.2 deletion/duplication syndrome. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening with cell-free DNA is now considered a first-line screening for common aneuploidies. Advancements in existing laboratory techniques now allow to interrogate the entirety of the fetal genome, and many commercial laboratories have expanded their screening panels to include screening for rare autosomal aneuploidies and copy number variants. Here, we review the currently available data on the performance of fetal cell-free DNA to detect rare autosomal aneuploidies and copy number variants that are associated with clinically significant microdeletion and microduplication syndromes and the current position of medical societies on routine screening for these syndromes. [ABSTRACT FROM AUTHOR]

To assess the diagnostic accuracy of noninvasive prenatal screening (NIPS) in screening for copy number variations (CNVs). We conducted a systematic review and meta-analysis by combining our study results with those reported in other articles. We retrospectively collected the data of pregnant women with NIPS testing in the Hangzhou Women's Hospital from December 2019 to February 2022. Simultaneously, a systematic search of PubMed, EMBASE, and Web of Science was carried out to identify all relevant peer-reviewed publications. Statistical analysis was performed based on the random-effects model to determine a pooled estimate of the positive predictive value (PPV). A total of 29 studies involving 2,667 women were included for analysis. The pooled PPV of NIPS in the detection of CNVs was 32.86% (95% confidence interval [24.61–41.64]). Statistical heterogeneity was high, while no significant publication bias was found in this meta-analysis. There were insufficient data to accurately determine sensitivity and specificity, as most studies only performed confirmatory tests on high-risk women. The PPV of NIPS in screening for CNVs was approximately 33%. Cautions should be kept in mind for the pretest guidance and subsequent after-test counseling when offering such genome-wide NIPS tests. [ABSTRACT FROM AUTHOR]

Background Noninvasive prenatal screening is more effective in screening for fetal aneuploidy than does traditional serological screening. We attempted to analyze the real-world data about the positive predictive value (PPV) for chromosome aneuploidy, and chromosome copy number variation (CNV) obtained by noninvasive prenatal testing (NIPT) , and to explore the pregnancy outcome for fetuses with sex chromosome aneuploidies and chromosome microdeletion or microduplication determined by pregnant women. Objective To assess the clinical value of karyotype analysis and chromosomal microarray analysis (CMA) of the testing results of NIPT. Methods Five-hundred and twenty-eight pregnant women who were found with a fetus at high risk of chromosome aneuploidy, and CNV by NIPT were selected from Department of Reproductive and Genetic Medicine, Hebei General Hospital, from January 1, 2014 to December 31, 2018. Amniocentesis or umbilical vein puncture was performed in them to obtain fetal cells for a definite prenatal diagnosis using karyotype analysis and CMA. All delivered cases were followed up by telephone within one year after childbirth to understand the pregnancy outcome. Results Prenatal diagnosis analysis revealed that 447 fetuses were at high risk of chromosome aneuploidy. And PPVs for the risk of trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies, and other chromosome aneuploidy were 82.86% (174/210) , 51.52% (34/66) , 12.50% (4/32) , 50.82% (62/122) , and 5.88% (1/17) , respectively. Another 81 fetuses were at high risk of CNVs. CMA suggested that copy number variations were found in 28 cases (PPV 34.57%) , and the proportion with a clear pathogenic significance reached 24.69% (20/81) . Among the subjects under 35 years and 35 years or older, the proportions of abnormal results confirmed by prenatal diagnosis were 48.51% (147/303) and 70.22% (158/225) , respectively, showing statistically significant difference (χ2=24.938, P

BackgroundGenetic factors are important causes of birth defects. Noninvasive prenatal screening (NIPS) is widely used for prenatal screening of trisomy 21, trisomy 18, and trisomy 13, which are the three most common fetal aneuploidies. Fetal fraction refers to the proportion of cell-free fetal DNA in maternal plasma, which can influence the accuracy of NIPS. Elucidating the factors that influence fetal fraction can provide guidance for the interpretation of NIPS results and genetic counseling. However, there is currently no broad consensus on the known factors that influence fetal fraction.ObjectiveThe study aimed to explore the maternal and fetal factors influencing fetal fraction.MethodsA total of 153,306 singleton pregnant women who underwent NIPS were included. Data on gestational age; maternal age; body mass index (BMI); z-scores for chromosomes 21, 18, and 13; and fetal fraction in NIPS were collected from the study population, and the relationships between fetal fraction and these factors were examined. The relationship between fetal fraction and different fetal trisomy types was also analyzed.ResultsThe results showed that the median gestational age, maternal age, and BMI of the pregnant women were 18 (16, 20) weeks, 29 (25, 32) years, and 22.19 (20.40, 24.24) kg/m2, respectively. The median fetal fraction was 11.62 (8.96, 14.7)%. Fetal fraction increased with gestational age and decreased with maternal age and BMI (P

Sex chromosome aneuploidies (SCAs), including 47,XXY, 47,XXX, 47,XYY, and supernumerary variants, occur collectively in approximately one of 500 live births. Clinical phenotypes are highly variable resulting in previous ascertainment rates estimated to be only 10%–25% during a lifetime. Historically, prenatal SCA diagnoses were incidental findings, accounting for ≤10% of cases, with the majority of diagnoses occurring postnatally during evaluations for neurodevelopmental, medical, or infertility concerns. The initiation of noninvasive prenatal screening (NIPS) in 2012 and adoption into standardized obstetric care provides a unique opportunity to significantly increase prenatal ascertainment of SCAs. However, the impact NIPS has had on ascertainment of SCAs is understudied, particularly for those who may defer diagnostic testing until after birth. This study evaluates the timing of diagnostic testing following positive NIPS in 152 infants with SCAs and potential factors influencing this decision. Eighty‐seven (57%) elected to defer diagnostic testing after a positive NIPS until birth, and 8% (7/87) of those confirmed after birth were found to have discordant results on postnatal diagnostic testing, most of which would have influenced genetic counseling. [ABSTRACT FROM AUTHOR]

Diagnosis of a chromosome 22q11.2 microdeletion and its associated deletion syndrome (22q11.2DS) is optimally made early. We reviewed the available literature to provide contemporary guidance and recommendations related to the prenatal period. Indications for prenatal diagnostic testing include a parent or child with the 22q11.2 microdeletion or suggestive prenatal screening results. Definitive diagnosis by genetic testing of chorionic villi or amniocytes using a chromosomal microarray will detect clinically relevant microdeletions. Screening options include noninvasive prenatal screening (NIPS) and imaging. The potential benefits and limitations of each screening method should be clearly conveyed. NIPS, a genetic option available from 10 weeks gestational age, has a 70–83% detection rate and a 40–50% PPV for most associated 22q11.2 microdeletions. Prenatal imaging, usually by ultrasound, can detect several physical features associated with 22q11.2DS. Findings vary, related to detection methods, gestational age, and relative specificity. Conotruncal cardiac anomalies are more strongly associated than skeletal, urinary tract, or other congenital anomalies such as thymic hypoplasia or cavum septi pellucidi dilatation. Among others, intrauterine growth restriction and polyhydramnios are additional associated, prenatally detectable signs. Preconception genetic counselling should be offered to males and females with 22q11.2DS, as there is a 50% risk of transmission in each pregnancy. A previous history of a de novo 22q11.2 microdeletion conveys a low risk of recurrence. Prenatal genetic counselling includes an offer of screening or diagnostic testing and discussion of results. The goal is to facilitate optimal perinatal care. [ABSTRACT FROM AUTHOR]

Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12 to 16 weeks of gestation when there is evidence for its effectiveness, and enables the guidance of appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA screening. Secondary outcomes were prediction of early-onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). This secondary analysis of a prospective, multicenter, observational prenatal cell-free DNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and 2 characteristics of cell-free DNA (total cell-free DNA and fetal fraction) were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the "reference" classifier was a shallow logistic regression model. We also explored several feedforward (nonlinear) neural network architectures with ≥1 hidden layers, and compared their performance with the logistic regression model. We selected a simple neural network model built with 1 hidden layer and made up of 15 units. Of the 17,520 participants included in the final analysis, 72 (0.4%) developed early-onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cell-free DNA measurement was 12.6 weeks, and 2155 (12.3%) had their cell-free DNA measurement at ≥16 weeks' gestation. Preeclampsia was associated with higher total cell-free DNA (median, 362.3 vs 339.0 copies/mL cell-free DNA; P <.001) and lower fetal fraction (median, 7.5% vs 9.4%; P <.001). The expected, cross-validated area under the curve scores for early-onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively, for the logistic regression model, and 0.797, 0.800, and 0.713, respectively, for the neural network model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% confidence interval, 0.569–0.599) for the logistic regression model and 59.3% (95% confidence interval, 0.578–0.608) for the neural network model. The contribution of both total cell-free DNA and fetal fraction to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cell-free DNA and fetal fraction features from the neural network model was associated with a 6.9% decrease in sensitivity at a 15% screen-positive rate, from 54.9% (95% confidence interval, 52.9–56.9) to 48.0% (95% confidence interval, 45.0–51.0). Routinely available patient characteristics and cell-free DNA markers can be used to predict preeclampsia with performance comparable to that of other patient characteristic models for the prediction of preterm preeclampsia. Logistic regression and neural network models showed similar performance. [Display omitted] [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the effects of white blood cell (WBC) count on fetal fraction (FF), which is an essential quality control for obtaining reliable results, and on the rate of screen failures in noninvasive prenatal screening (NIPS).MethodsNoninvasive prenatal screening, serum lipid and liver enzyme level measurements, and WBC count were performed for 4,281 pregnancies with male fetuses. After adjusting for confounders, including the maternal characteristics and alanine aminotransferase (ALT) levels, the effect of WBC count on FF and test failure rate was measured by linear and logistic regression analyses.ResultsFetal fraction was negatively associated with BMI, ALT, IVF conceptions, and WBC count and positively correlated with gestational age in the multivariate linear regression model. Moreover, WBC count was the most important factor affecting FF after BMI according to the standardization coefficient analysis. In the 4,281 pregnancy samples with male fetuses, FF decreased with WBC count from 11.45% at ≤8 to 9.02% at >12, and FF markedly decreased to 7.40% in pregnancies with a higher WBC count (>12) and higher BMI (≥25 kg/m2). Meanwhile, the test failure rates were significantly higher in the WBC count > 12 group (4.29%) than in the WBC count ≤ 8 group (0.89%). Notably, when the BMI of pregnancies with a WBC count of >12 was >25, the rate reached 7.53%. Subsequently, multivariate logistic regression analysis further confirmed that an increased BMI and WBC count were independently and significantly associated with the test failure rates.ConclusionAn increased WBC count was associated with lower FF and higher test failure rates, suggesting that these important factors should be carefully considered during genetic counseling in pregnant women who decide to undergo blood collection or resampling.

Increased fetal nuchal translucency (NT) is a common ultrasonic manifestation during pregnancy. Many studies have confirmed that NT ≥ 3 mm is a high risk factor for adverse pregnancy outcome. However, when NT is between 2.5 and 2.9 mm, will it increase the risk of fetal chromosome abnormalities and other diseases? What is the most appropriate method for prenatal chromosome evaluation? At present, it has not been widely reported in the literature, and the conclusion is also controversial. This prospective cohort study included fetal samples from women who underwent amniocentesis from 2017 to 2020. The samples of the experimental group were fetuses with NT ≥ 2.5 mm at 11 to 13 + 6 weeks of gestation, with or without ultrasonographic anomaly. The control group contained fetal NT < 2.5 mm without ultrasonographic anomalies. All amniotic fluid samples were tested by copy number variants sequencing. In 262 fetal samples with isolated NT from 2.5 to 2.9 mm, the detection rate of aneuploidy was 3.4% (9/262), and the risk of aneuploidy was significantly higher than that of the control group (1.4%, 32/2331) (relative risk 2.5, 95% CI 1.2–5.2). The detection rates of other pathogenic/likely pathogenic copy number variants in the two groups were 0.8% (2/262) and 1.3% (31/2331), respectively, which was not statistically significant (relative risk 0.6, 95% CI 0.1–2.4). Our results showed that isolated NT from 2.5 to 2.9 mm increased the risk of fetal chromosome aneuploidy. Therefore, noninvasive prenatal screening is recommended as the first choice for prenatal chromosome evaluation in this population. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the efficiency of noninvasive prenatal screening (NIPS) technology in screening for microdeletions in the 7q11.23 region., Methods: 19,607 pregnant women underwent NIPS in our hospital. Maternal peripheral cell-free foetal DNA (cffDNA) was routinely screened for aneuploidy by cffDNA enrichment and simultaneously analyzed for pathogenic copy number variants (CNVs). The Williams syndrome (WS) 7q11.23 region was targeted in this study. Chromosomal microarray analysis (CMA) was used to verify the screen-positive samples., Results: The mean concentration of cffDNA before and after enrichment increased from 9.44% to 19.32%, with a statistically significant difference. Two out of 19,607 samples tested for CNVs were found to have a heterozygous deletion at the 7q11.23 region, indicating a high risk for WS. CMA results confirmed the 1.5 megabase (Mb) deletions at the 7q11.23 region in amniotic fluid samples. One of the two WS foetuses had a small left ventricle by ultrasound screening, and the other did not have a significant cardiovascular abnormality phenotype., Conclusions: NIPS screening for Williams syndrome can be achieved by enriching cell-free foetal DNA and improving bioinformatic analysis algorithms.

To assess the clinical performance of noninvasive prenatal screening (NIPS) for both common trisomy and sex chromosome aneuploidy (SCA). We recruited 71,888 pregnant women to undergo NIPS testing from December 2015 to June 2021. Demographic characteristics, diagnostic results, and follow-up outcomes were collected. There were a total of 381 high-risk cases for common trisomy and 343 positive screens for SCA. Invasive prenatal diagnosis (IPD) was performed in 507 (70.0%) participants. The positive predictive value (PPV) was 83.7% for T21, 72.5% for T18, 14.3% for T13, 31.9% for 45,X, 72.0% for 47,XXX, 89.8% for 47,XXY, and 72.2% for 47,XYY, respectively. Logistic regression analysis presented a significant association between Z-score and PPV in common trisomy (P < 0.05) while not in SCA (P > 0.05). PPV in the high-risk group (Z-score ≥ cutoff) was superior to that in the intermediate risk group (3 ≤ Z-score < cutoff) for T21/T18/T13. PPV for 45,X, 47,XXY, and 47,XYY tended to be higher with the increasing Z-score, except for 47,XXX. NIPS would be a valuable strategy in prenatal screening, while cautions should be kept in mind for subsequent genetic consulting about the risk of Z-score. [ABSTRACT FROM AUTHOR]

Background: Rolling-circle replication (RCR) is a novel technology that has not been applied to cell-free DNA (cfDNA) testing until recently. Given the cost and simplicity advantages of this technology compared to other platforms currently used in cfDNA analysis, an assessment of RCR in clinical laboratories was performed. Here, we present the first validation study from clinical laboratories utilizing RCR technology. Methods: 831 samples from spontaneously pregnant women carrying a singleton fetus, and 25 synthetic samples, were analyzed for the fetal risk of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), by three laboratories on three continents. All the screen-positive pregnancies were provided post-test genetic counseling and confirmatory diagnostic invasive testing (e.g., amniocentesis). The screen-negative pregnancies were routinely evaluated at birth for fetal aneuploidies, using newborn examinations, and any suspected aneuploidies would have been offered diagnostic testing or confirmed with karyotyping. Results: The study found rolling-circle replication to be a highly viable technology for the clinical assessment of fetal aneuploidies, with 100% sensitivity for T21 (95% CI: 82.35–100.00%); 100.00% sensitivity for T18 (71.51–100.00%); and 100.00% sensitivity for T13 analyses (66.37–100.00%). The specificities were >99% for each trisomy (99.7% (99.01–99.97%) for T21; 99.5% (98.62–99.85%) for T18; 99.7% (99.03–99.97%) for T13), along with a first-pass no-call rate of 0.93%. Conclusions: The study showed that using a rolling-circle replication-based cfDNA system for the evaluation of the common aneuploidies would provide greater accuracy and clinical utility compared to conventional biochemical screening, and it would provide comparable results to other reported cfDNA methodologies.

Background: This study aims to evaluate prenatal diagnosis methods following positive noninvasive prenatal screening (NIPS) results. Methods: According to the positive noninvasive prenatal screening results, 926 pregnant women were divided into three groups: main target disease group (high risk for trisomy 21, trisomy 18, or trisomy 13), sex chromosome aneuploidy (SCA) group, and other chromosomal abnormalities group [abnormal Z-scores for chromosomes other than trisomy (T)21/T18/T13 or SCAs]. The verification methods and results were then retrospectively analysed. Results: In the main target disease group, the positive rate of chromosomal abnormalities confirmed by quantitative fluorescence polymerase chain reaction (QF-PCR) was 75.18% (212/282), which was not significantly different from that by karyotyping (79.36%, 173/218) and copy number variation (CNV) detection methods (71.43%, 65/91). The positive rate of additional findings confirmed by karyotyping and copy number variation detection methods in main target disease group was 0.46% (1/218) and 8.79% (8/91), respectively. The positive rate of chromosomal abnormalities confirmed by karyotyping and CNV detection methods were 27.11% (45/166) and 38.46% (95/247) in the SCA group and 4.17% (1/24) and 20% (36/180) in the other chromosomal abnormalities group, respectively. Fetal sex chromosome mosaicism was detected in 16.13% (20/124) of the confirmed SCA cases. There were no significant differences in the detection rates of chromosomal microarray analysis (CMA) and CNV sequencing (CNVseq) among the three groups (p > 0.05). Conclusion: QF-PCR can quickly and accurately identify aneuploidies following NIPS-positive results for common aneuploidy, and in combination with karyotyping and CNV detection techniques can provide more comprehensive results. With the NIPS-positive results for SCA or other abnormalities, CMA and CNVseq may have the same effect on increasing the detection rate. The addition of fluorescence in situ hybridization assay may help to identify true fetal mosaicism. [ABSTRACT FROM AUTHOR]

A paradigm shift in noninvasive prenatal screening has been made with the discovery of cell-free fetal DNA in maternal plasma. Noninvasive prenatal screening is primarily used to screen for fetal aneuploidies, and has been used globally. Fetal fraction, an important parameter in the analysis of noninvasive prenatal screening results, is the proportion of fetal cell-free DNA present in the total maternal plasma cell-free DNA. It combines biological factors and bioinformatics algorithms to interpret noninvasive prenatal screening results and is an integral part of quality control. Maternal and fetal factors may influence fetal fraction. To date, there is no broad consensus on the factors that affect fetal fraction. There are many different approaches to evaluate this parameter, each with its advantages and disadvantages. Different fetal fraction calculation methods may be used in different testing platforms or laboratories. This review includes numerous publications that focused on the understanding of the significance, influencing factors, and interpretation of fetal fraction to provide a deeper understanding of this parameter.

Background: This study aims to evaluate prenatal diagnosis methods following positive noninvasive prenatal screening (NIPS) results.Methods: According to the positive noninvasive prenatal screening results, 926 pregnant women were divided into three groups: main target disease group (high risk for trisomy 21, trisomy 18, or trisomy 13), sex chromosome aneuploidy (SCA) group, and other chromosomal abnormalities group [abnormal Z-scores for chromosomes other than trisomy (T)21/T18/T13 or SCAs]. The verification methods and results were then retrospectively analysed.Results: In the main target disease group, the positive rate of chromosomal abnormalities confirmed by quantitative fluorescence polymerase chain reaction (QF-PCR) was 75.18% (212/282), which was not significantly different from that by karyotyping (79.36%, 173/218) and copy number variation (CNV) detection methods (71.43%, 65/91). The positive rate of additional findings confirmed by karyotyping and copy number variation detection methods in main target disease group was 0.46% (1/218) and 8.79% (8/91), respectively. The positive rate of chromosomal abnormalities confirmed by karyotyping and CNV detection methods were 27.11% (45/166) and 38.46% (95/247) in the SCA group and 4.17% (1/24) and 20% (36/180) in the other chromosomal abnormalities group, respectively. Fetal sex chromosome mosaicism was detected in 16.13% (20/124) of the confirmed SCA cases. There were no significant differences in the detection rates of chromosomal microarray analysis (CMA) and CNV sequencing (CNVseq) among the three groups (p > 0.05).Conclusion: QF-PCR can quickly and accurately identify aneuploidies following NIPS-positive results for common aneuploidy, and in combination with karyotyping and CNV detection techniques can provide more comprehensive results. With the NIPS-positive results for SCA or other abnormalities, CMA and CNVseq may have the same effect on increasing the detection rate. The addition of fluorescence in situ hybridization assay may help to identify true fetal mosaicism.

Background: We aimed to assess the clinical application of noninvasive prenatal screening (NIPS) based on second-trimester ultrasonographic soft markers (USMs) in low-risk pregnant women. Methods: Data of pregnant women between April 2015 and December 2019 were retrospectively analyzed. Pregnant women [age at expected date of confinement (EDC) of <35 years; low risks for trisomy 21 (T21) and trisomy 18 (T18) based on maternal serum screening; presenting second-trimester USMs (7 types)] who successfully underwent NIPS and had available follow-up information were included in our study. Cases with positive NIPS results were prenatally diagnosed. All patients were followed up for 6 months to 2 years after NIPS, and their clinical outcomes were obtained. Subgroup analyses were performed according to the different USMs. Results: NIPS suggested that among a total of 10,023 cases, 37 (0.37%) were at high risk of aneuploidy, including 4 T21, 6 trisomy 13 (T13), and 27 sex chromosome abnormalities (SCA). Ten cases with aneuploidy (0.10%) were confirmed by prenatal diagnosis, consisting of two T21 and eight SCA. The eight fetuses with SCA consisted of one monosomy X, two XXY, one XXXY, one XXX, one XYY, and two mosaicisms. T21 was detected in one fetus with absent or hypoplastic nasal bone and one fetus with echogenic intracardiac focus (EICF). SCA was detected in five fetuses with EICF, two fetuses with multiple soft markers, and one fetus with echogenic bowel. The positive rate of chromosomal aneuploidy was significantly higher in fetuses with absent or hypoplastic nasal bone (6.25 vs. 0.10%, p = 0.017), echogenic bowel (3.7 vs. 0.10%, p = 0.029), and multiple soft markers (0.678 vs. 0.10%, p = 0.045) than in the total fetuses. The positive predictive values (PPVs) of NIPS in these three groups were 100%, 50%, and 100%, respectively. EICF accounted for 93.25% (9,346/10,023) of the study population, whereas the PPV of NIPS was only 20%. Conclusion: NIPS is an advanced screening test for low-risk pregnant women. In the 10,023 pregnant women sampled, SCA were more common than autosomal trisomy, and EICF was the most frequent USM but the least predictive aneuploidy. Further aneuploidy evaluation is suggested for low-risk pregnant women whose ultrasound indicates absent or hypoplastic nasal bone, echogenic bowel, or multiple soft markers. NIPS can serve as a second-line complementary screening for these women. [ABSTRACT FROM AUTHOR]

BackgroundNoninvasive prenatal screening (NIPS) by next-generation sequencing of cell-free DNA (cfDNA) in maternal plasma is used to screen for common aneuploidies such as trisomy 21 in high risk pregnancies. NIPS can identify fetal genomic microdeletions; however, sensitivity and specificity have not been systematically evaluated. Commercial companies have begun to offer expanded panels including screening for common microdeletion syndromes such as 22q11.2 deletion (DiGeorge syndrome) without reporting the genomic coordinates or whether the deletion is maternal or fetal. Here we describe a phenotypically normal mother and fetus who tested positive for atypical 22q deletion via maternal plasma cfDNA testing.MethodsWe performed cfDNA sequencing on saved maternal plasma obtained at 11 weeks of gestation from a phenotypically normal woman with a singleton pregnancy whose earlier screening at a commercial laboratory was reported to be positive for a 22q11.2 microdeletion. Fluorescence in situ hybridization and chromosomal microarray diagnostic genetic tests were done postnatally.ConclusionNIPS detected a 22q microdeletion that, upon diagnostic workup, did not include the DiGeorge critical region. Diagnostic prenatal or postnatal testing with chromosomal microarray and appropriate parental studies to determine precise genomic coordinates and inheritance should follow a positive microdeletion NIPS result.

Background: We aimed to assess the clinical application of noninvasive prenatal screening (NIPS) based on second-trimester ultrasonographic soft markers (USMs) in low-risk pregnant women.Methods: Data of pregnant women between April 2015 and December 2019 were retrospectively analyzed. Pregnant women [age at expected date of confinement (EDC) of

ObjectiveTo evaluate the accuracy of Z-scores of noninvasive prenatal screening (NIPS) in predicting 21, 18 trisomy, and X chromosome aneuploidy.MethodsA total of 39,310 prenatal women were recruited for NIPS from September 2015 to September 2020. Interventional prenatal diagnosis was applied to verify the diagnosis of NIPS-positive results. Logistic regression analysis was employed to relate the Z-scores to the positive predictive value (PPV) of NIPS-positive results. Using receiver operating characteristic (ROC) curves, we calculated the optimal cutoff value of Z-scores to predict fetal chromosome aneuploidy. According to the cutoff value, NIPS-positive results were divided into the medium Z-value (MZ) and high Z-value (HZ) groups, and PPV was calculated to access the accuracy of Z-scores.ResultsA total of 288 effective values of Z-scores were used as the final data set. The logistics regression analysis revealed that Z-scores were significantly associated with true-positive results for 21 trisomy (T21) and 18 trisomy (T18) (P < 0.05), whereas the same was not observed for X chromosome aneuploids (P > 0.05). The optimal cutoff value of the Z-score for T21, T18, XO, XXX, and XXY indicated by ROC curve analysis were 5.79, 6.05, −9.56, 5.89, and 4.47, and the area under the curve (AUC) were 0.89, 0.80, 0.48, 0.42, and 0.45, respectively. PPV in the HZ group was higher than that in the MZ group, and the application of the cutoff value reduced the false discovery rate (FDR), which was only 2.9% in the HZ group compared with 61.1% in the MZ group for T21 and T18. The difference in total PPV between the MZ and HZ groups for X chromosome aneuploids was statistically significant. Moreover, the PPV for XXX and XXY seemed to increase with Z-scores but not for XO.ConclusionThe Z-score is helpful for the accurate judgment of NIPS results and for clinical prenatal counseling. Especially for T21 and T18, Z-scores have an excellent clinical association, which is superior to that seen with X chromosome aneuploids. In addition, using Z-scores to judge NIPS results offers a certain reference value for XXX and XXY but not for XO.

Objective: To evaluate the clinical application of expanded noninvasive prenatal screening (eNIPS) for genome-wide large copy number variation (CNV), i.e. chromosomal deletion/duplication >5 Mb, and aneuploidy; also to provide practical information for counseling eNIPS positive cases. Method: We recruited 34,620 women with singleton pregnancy for genome-wide cell-free plasma DNA sequencing. Screening positive cases were verified by karyotyping and/or SNP array. Result: A total of 461 (1.33%) positive cases were identified through our cfDNA screening including 209 cases of common trisomies (0.60%), 124 cases of sex chromosomal abnormalities (SCA) (0.36%), 71 cases of other autosomal anueploidies (OAA) (0.21%), and 57 CNVs larger than 5Mb (0.16%). The predictive positive values (PPV) were 70.06% in general for common trisomies with as high as 91.67% for Trisomy21 (T21), 40.22% in general for SCAs with as high as 100% for Jacob Syndrome (XYY). The PPV for OAAs was 5.45%, and T7/T8/T16/T22 were the most frequent OAAs (n=15, 9, 9, 8, respectively). The PPV for CNVs larger than 5Mb was 51.22% (n=57) with the CNV mostly detected on Chr5/Chr4/Chr2/Chr7 (n=10, 8, 5, 5, respectively). Conclusion: The expanded NIPS had shown promising PPVs for CNVs (large than 5 Mb), SCAs and common trisomies, yet this method required higher efficacy in screening for OAAs. The post-test genetic counseling for expanded NIPS should be tailored to the types of positive cases and also address the origin of abnormal signals (fetal vs. maternal). [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy of Z-scores of noninvasive prenatal screening (NIPS) in predicting 21, 18 trisomy, and X chromosome aneuploidy. Methods: A total of 39,310 prenatal women were recruited for NIPS from September 2015 to September 2020. Interventional prenatal diagnosis was applied to verify the diagnosis of NIPS-positive results. Logistic regression analysis was employed to relate the Z-scores to the positive predictive value (PPV) of NIPS-positive results. Using receiver operating characteristic (ROC) curves, we calculated the optimal cutoff value of Z-scores to predict fetal chromosome aneuploidy. According to the cutoff value, NIPS-positive results were divided into the medium Z-value (MZ) and high Z-value (HZ) groups, and PPV was calculated to access the accuracy of Z-scores. Results: A total of 288 effective values of Z-scores were used as the final data set. The logistics regression analysis revealed that Z-scores were significantly associated with true-positive results for 21 trisomy (T21) and 18 trisomy (T18) (P < 0.05), whereas the same was not observed for X chromosome aneuploids (P > 0.05). The optimal cutoff value of the Z-score for T21, T18, XO, XXX, and XXY indicated by ROC curve analysis were 5.79, 6.05, −9.56, 5.89, and 4.47, and the area under the curve (AUC) were 0.89, 0.80, 0.48, 0.42, and 0.45, respectively. PPV in the HZ group was higher than that in the MZ group, and the application of the cutoff value reduced the false discovery rate (FDR), which was only 2.9% in the HZ group compared with 61.1% in the MZ group for T21 and T18. The difference in total PPV between the MZ and HZ groups for X chromosome aneuploids was statistically significant. Moreover, the PPV for XXX and XXY seemed to increase with Z-scores but not for XO. Conclusion: The Z-score is helpful for the accurate judgment of NIPS results and for clinical prenatal counseling. Especially for T21 and T18, Z-scores have an excellent clinical association, which is superior to that seen with X chromosome aneuploids. In addition, using Z-scores to judge NIPS results offers a certain reference value for XXX and XXY but not for XO. [ABSTRACT FROM AUTHOR]

Sex chromosome aneuploidies (SCAs) are among the most common chromosome abnormalities observed in humans. Manifestations include low fertility, infertility, delayed language development, and dysfunction in motor development. Noninvasive prenatal screening (NIPS) based on cell-free fetal DNA from the peripheral blood of pregnant women is increasingly used for the screening of fetal chromosome abnormalities, including screening for fetal gender and fetal sex chromosome aneuploidy. A systematic review of the literature about NIPS for SCAs is needed. This review evaluated a vast array of published studies focusing on the clinical significance, detection methods, performance of NIPS for SCAs, and the management of positive SCA results following screening with the aim of facilitating a comprehensive and systematic understanding of NIPS for SCAs. Looking forward, NIPS is expected to become the primary screening test for common aneuploidies as well as other chromosome abnormalities, including some micro-deletions and micro-duplications, with the potential to transition from a screening test to a prenatal diagnosis method. Ultimately, the goal is to provide a safe and accurate method for increasing early diagnosis to improve long-term outcomes for the SCA patients and families by well- informed health care providers. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening using cell-free DNA involves analysis of a sample of maternal blood for DNA fragments of fetal chromosomes from the fetal-placental unit to detect common chromosome abnormalities, trisomy 21, trisomy 13, trisomy 18, and sex chromosomes as early as 10 weeks' gestation when the fetal fraction is usually more than 4%. It is the most sensitive and specific prenatal screening option for these conditions. Because it is a screening test, false-positive and false-negative results can occur. Positive screen results necessitate further evaluation for diagnosis to confirm a medical condition, before critical decisions regarding pregnancy are made. Professional organizations provide clinical recommendations to providers regarding prescreen and postscreen counseling and management of results. [ABSTRACT FROM AUTHOR]

Abstract Background To review the performance of noninvasive prenatal screening (NIPS) using targeted single‐nucleotide polymorphisms (SNPs) approach in mixed‐risk Thai women. Methods Retrospective analysis of data for detection of trisomy 21 (T21), 18 (T18), 13 (T13), monosomy X (XO), other sex chromosome aneuploidies (SCA), and triploidy/vanishing twins (VT) from a single commercial laboratory. Results Mean (±SD) gestational age and maternal weight were 13.2 (±2.1) weeks and 125.7 (±22.4) pounds, respectively (n = 8,572). From 462/8,572 (5.4%) no‐calls; 1/462 (0.2%) was uninformative SNPs, and 1/462 chose amniocentesis. Redraw settled 323/460 (70%) samples with low fetal fraction (FF); and 8,434/8,572 (98.4%) were finally reportable, with 131 high risks (1.6%). The median (min‐max) FF of reportable (n = 8,434) and unreportable samples (n = 137) samples were 10.5% (2.6–37.9) and 3.8% (1–14.1), respectively (p

Abstract Background Noninvasive prenatal screening (NIPS) of common aneuploidies using cell-free DNA from maternal plasma is part of routine prenatal care and is widely used in both high-risk and low-risk patient populations. High specificity is needed for clinically acceptable positive predictive values. Maternal copy-number variants (mCNVs) have been reported as a source of false-positive aneuploidy results that compromises specificity. Methods We surveyed the mCNV landscape in 87,255 patients undergoing NIPS. We evaluated both previously reported and novel algorithmic strategies for mitigating the effects of mCNVs on the screen’s specificity. Further, we analyzed the frequency, length, and positional distribution of CNVs in our large dataset to investigate the curation of novel fetal microdeletions, which can be identified by NIPS but are challenging to interpret clinically. Results mCNVs are common, with 65% of expecting mothers harboring an autosomal CNV spanning more than 200 kb, underscoring the need for robust NIPS analysis strategies. By analyzing empirical and simulated data, we found that general, outlier-robust strategies reduce the rate of mCNV-caused false positives but not as appreciably as algorithms specifically designed to account for mCNVs. We demonstrate that large-scale tabulation of CNVs identified via routine NIPS could be clinically useful: together with the gene density of a putative microdeletion region, we show that the region’s relative tolerance to duplications versus deletions may aid the interpretation of microdeletion pathogenicity. Conclusions Our study thoroughly investigates a common source of NIPS false positives and demonstrates how to bypass its corrupting effects. Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.

Prenatal genetic screening should be an informed, autonomous patient choice. Extrinsic factors which influence patient decision‐making threaten the ethical basis of prenatal genetic screening. Prior research in the area of medical decision‐making has identified that labeling may have unanticipated effects on patient perceptions and decision‐making processes. This Internet‐administered study explored the impact of option labeling on the noninvasive prenatal screening (NIPS) selections of US adults. A total of 1,062 participants were recruited through Amazon Mechanical Turk (MTurk) and randomly assigned to one of three possible label sets reflecting provider‐derived and industry‐derived option labels used in prenatal screening. Multinomial logistic regression analysis showed option labeling had a statistically significant impact on the NIPS selections of study participants (p =.0288). Outcomes of the Satisfaction with Decision Scale (SWD) indicated option labels did not play a role in participant satisfaction with screening selection. The results of this study indicate a need for further evaluation of the impact NIPS option labeling has on patient screening decisions in real‐world clinical interactions. Clinical providers and testing laboratories offering NIPS should give careful consideration to the option labels used with prenatal screening so as to minimize influence on patient screening selection and decision‐making processes. [ABSTRACT FROM AUTHOR]

Background: To review the performance of noninvasive prenatal screening (NIPS) using targeted single‐nucleotide polymorphisms (SNPs) approach in mixed‐risk Thai women. Methods: Retrospective analysis of data for detection of trisomy 21 (T21), 18 (T18), 13 (T13), monosomy X (XO), other sex chromosome aneuploidies (SCA), and triploidy/vanishing twins (VT) from a single commercial laboratory. Results: Mean (±SD) gestational age and maternal weight were 13.2 (±2.1) weeks and 125.7 (±22.4) pounds, respectively (n = 8,572). From 462/8,572 (5.4%) no‐calls; 1/462 (0.2%) was uninformative SNPs, and 1/462 chose amniocentesis. Redraw settled 323/460 (70%) samples with low fetal fraction (FF); and 8,434/8,572 (98.4%) were finally reportable, with 131 high risks (1.6%). The median (min‐max) FF of reportable (n = 8,434) and unreportable samples (n = 137) samples were 10.5% (2.6–37.9) and 3.8% (1–14.1), respectively (p <.05). Fetal karyotypes were available in 106/131 (80.9%) and 52/138 (37.7%) high risk and repeated no‐calls, respectively. The positive predictive values (PPVs) for T21 (n = 47), T18 (n = 15), T13 (n = 7), XO (n = 8), other SCA (n = 7), and triploidy/VT were 94%, 100%, 58.3%, 66.7%, 70%, and 57.1%, respectively. None of repeated no‐calls had aneuploidies. Conclusion: SNP‐based NIPS has high PPVs for T21 and T18. Although the proprietary SNPs library is not population‐specific, uninformative SNPs are uncommon. [ABSTRACT FROM AUTHOR]

Background: With the increasing availability of noninvasive prenatal screening (NIPS) and high‐resolution ultrasound, more cases of sex discordance are being identified in routine clinical practice. This can be a source of much concern for families and clinicians. Knowledge about the limitations of NIPS and reasons for discordant results are critical for counseling parents. Aims: Here, we present three cases from a single tertiary care referral center. We also review the literature to address potential limitations of NIPS in correctly identifying fetal sex chromosomes. Materials and Methods: After Institutional Review Board approval, cases of discordant fetal sex were identified using ICD‐9 and ICD‐10 codes. In addition, departmental counseling database and cytogenetics laboratory logbooks were reviewed. Results: In our first case, a 37‐year‐old G4 P2012 underwent NIPS at 11 weeks gestation and Monosomy X (associated with Turner syndrome) was identified. Morphological sonographic assessment at 20 weeks gestation was consistent with a female fetus following an amniocentesis at 16 weeks that revealed normal 46, XX karyotype. During the third trimester, the patient was diagnosed with Stage IV invasive ductal carcinoma of the breast. Postnatal follow‐up of the neonate was consistent with a phenotypic female. In the second case, a 22‐year‐old G2 P1001 obese female underwent NIPS at 14 weeks gestation and normal 46, XY karyotype was identified. Morphological sonographic assessment at 20 weeks was not consistent with a male fetus. The patient declined invasive testing. Postnatally, the karyotype was 46, XX and the neonate was phenotypically female. The reason for the discordant results was not identified. In the third case, a 25‐year‐old G1 P0 obese female underwent NIPS at 13 weeks gestation and normal 46, XY karyotype was identified. Morphological sonographic assessment at 20 weeks was indeterminate; however, follow‐up at 24 weeks was consistent with a female fetus. The patient declined invasive prenatal testing. Postnatally, the karyotype was 46, XX, and the neonate was phenotypically female with uterus present on ultrasound. The reason for the discordant results was not identified. Discussion: Our cases demonstrate possible limitations of NIPS in correctly identifying sex chromosomes. Conclusions: Providers and patients need to be aware of these limitations, and invasive diagnostic prenatal testing should be offered in cases of discordance between NIPS and sonographic sex assessment. [ABSTRACT FROM AUTHOR]