Search Results (147)

Background: Non-invasive prenatal testing (NIPT) examines cell-free DNA (cfDNA) in maternal serum, which includes both maternal DNA and apoptotic placental DNA. The presence of multiple aneuploidies or widespread abnormal patterns of gains and losses across chromosomes in a structurally normal fetus has been linked to maternal cancer. Case Presentation: The patient was a 22-year-old G1P0 with a history of classical Hodgkin’s lymphoma in remission. Her NIPT collected at 14 weeks and 3 days was reported as a “no call”. A second NIPT at a different laboratory showed multiple chromosomal aneuploidies (trisomy 18, 21, and monosomy X) with normal fetal anatomy on ultrasound. The patient was asymptomatic and was referred to hematology–oncology specifically to address the concern that these NIPT results could be related to cancer recurrence. Imaging was deferred as she was already on an established surveillance protocol for her Hodgkin’s lymphoma. At 26 weeks of gestation, the patient presented with a cough and dyspnea. Chest x-ray raised concern for disease recurrence, and biopsy confirmed recurrent Hodgkin’s lymphoma. She received two cycles of ICE chemotherapy. Cesarean delivery at 34 weeks and 2 days was performed for non-reassuring fetal heart tones. She continued chemotherapy, followed by BEAM conditioning and autologous stem cell transplantation. Genetic testing of the neonate revealed a normal karyotype; the placenta karyotype yielded no interpretable results. Discussion and Conclusions: Certain patterns of abnormal NIPT results may be associated with maternal malignancy and warrant further investigation. The absence of standardized protocols for reporting such NIPT results can complicate timely interdisciplinary evaluation and treatment. However, diagnostic testing should be offered with a positive NIPT result, a no-call or test failure, and abnormal ultrasound results, even with a “low-risk” NIPT result. Full article

Medical big data derived from clinical records, laboratory tests, sequencing outputs, and quality-control indicators provides new opportunities for individualized prenatal risk assessment and optimized screening strategies. This study proposes an interpretable computational framework for prenatal risk assessment and testing-time optimization by integrating ensemble learning, BMI-stratified analysis, and uncertainty evaluation. For male-fetus samples, Y-chromosome-related measurements were used as biologically meaningful proxies for fetal signal. Linear regression, polynomial regression, random forest regression, and least-squares boosting were evaluated using cross-validated root mean squared error and coefficient of determination. BMI-stratified monotonic success-rate functions across gestational age were then estimated using a sliding-window procedure to identify practical sampling windows. Monte Carlo perturbation and bootstrap resampling were further applied to assess robustness against measurement noise and threshold variation. Least-squares boosting achieved the best overall predictive performance. The estimated optimal sampling ages were approximately 10 weeks, 14 weeks + 5 days, and 23 weeks + 3 days for the low-, medium-, and high-BMI strata, respectively, with greater instability observed in the high-BMI stratum. For female-fetus samples, aneuploidy screening was formulated as a binary classification task. Random forest substantially outperformed logistic regression, with an ROC-AUC of 0.884 versus 0.538 and an average precision of 0.668 versus 0.070, and supported a decision threshold of 0.1437. These findings suggest that medical big data-driven methods can improve prenatal risk assessment, testing-time optimization, and uncertainty-aware decision support in prenatal screening. Full article

Background/Objectives: To compare the maternal, fetal, and neonatal outcomes of pregnancies undergoing amniocentesis with those undergoing non-invasive prenatal testing (NIPT), within a cohort of women with comparable clinical indications, aiming to evaluate differences in adverse outcomes in a risk-indicated population. Methods: In this retrospective cohort study, pregnancy outcomes of 2044 pregnant women who underwent amniocentesis and 7668 pregnant women who underwent NIPT were evaluated using single-center data. The analysis was restricted to pregnancies with normal/reportable test results and without structural or genetic anomalies. Pregnancy loss outcomes were evaluated in the full cohort, while perinatal outcomes were analyzed among cases with available delivery data (377 amniocentesis and 2063 NIPT cases). Pregnancy and perinatal outcomes, including miscarriage, intrauterine fetal demise (IUD), preterm birth (PTB), pregnancy-induced hypertensive diseases (PIHDs), gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), low birth weight (LBW), small for gestational age (SGA), and low APGAR scores (<7), were evaluated. Multivariate logistic regression analysis was performed to adjust for potential confounding factors, and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported. Results: Amniocentesis was associated with a significantly higher risk of an adverse outcome compared to NIPT in this risk-indicated cohort. The likelihood of miscarriage was significantly higher in the amniocentesis group (aOR: 1.91, 95% CI: 1.17–3.14, p = 0.025), as was the risk of IUD (aOR: 4.10, 95% CI: 2.05–8.20, p < 0.001). PTB risk was also increased (aOR: 1.96, 95% CI: 1.53–2.51, p < 0.001). LBW was significantly more prevalent in the amniocentesis group (aOR: 7.73, 95% CI: 5.40–11.05, p < 0.001), and the likelihood of delivering a SGA neonate was also increased (aOR: 1.45, 95% CI: 1.02–2.06, p = 0.040). A 1st-minute APGAR score < 7 was also more frequent in the amniocentesis group (aOR: 1.51, 95% CI: 1.06–2.16, p = 0.022), although the association with 5th-minute APGAR scores < 7 did not reach statistical significance (aOR: 1.45, 95% CI: 0.83–2.52, p = 0.193). Overall, the risk of composite maternal and perinatal adverse outcomes (aOR: 1.77, 95% CI: 1.41–2.22, p < 0.001) as well as composite fetal and neonatal adverse outcomes (aOR: 1.97, 95% CI: 1.50–2.58, p < 0.001) was significantly higher in the amniocentesis group compared to the NIPT group. No significant association was observed for PIHD, GDM, or ICP. Conclusions: Our findings showed that, apart from fetal loss, amniocentesis may be associated with adverse perinatal outcomes such as PTB, LBW, SGA and low APGAR scores. Full article

Background: Increased nuchal translucency (NT) is associated with an elevated risk of genetic abnormalities and structural malformations. The clinical utility of invasive testing and the optimal diagnostic approach in mildly increased NT (3.0–3.4 mm) is debated. This study aimed to evaluate genetic and ultrasound findings in this subgroup and to assess the diagnostic yield of advanced genetic testing. Methods: We retrospectively included a total of 107 fetuses with NT between 3.0 and 3.4 mm from a single fetal medicine unit. Complete outcome data were available for 97 pregnancies. Invasive prenatal testing with standard karyotype, chromosomal microarray analysis (CMA) and RASopathy panel testing were offered. All patients underwent detailed ultrasound examination to detect structural abnormalities at 16 and 20 weeks, regardless of whether invasive testing was performed. Results: Invasive prenatal testing, amniocentesis or chorionic villus sampling, (CVS), was performed in 77/97 cases (79.4%). Genetic abnormalities were detected in 28/97 (28.9%). Overall, five rare genetic anomalies were identified; none would have been detected by quantitative fluorescent polymerase chain reaction (QF-PCR) or non-invasive prenatal testing (NIPT). Two anomalies were detectable by standard karyotype, two exclusively by CMA and one exclusively by RASopathy panel. When considering all cases undergoing advanced genetic testing (CMA or RASopathy panel, n = 35) the overall diagnostic yield was 8.5% (3/35). When calculated across the entire cohort with complete follow-up, the additional diagnostic yield was 3.1% (3/97). Major structural malformations were identified in 17/97 cases (17.5%), of which 10 (58.8%) were associated with genetic abnormalities. Conclusions: Fetuses with NT measurements between 3.0 and 3.4 mm show a substantially increased risk of genetic abnormalities and structural malformations. These findings support a comprehensive prenatal evaluation, including invasive testing with advanced genetic analysis and detailed ultrasound assessment, to optimize diagnosis and counseling. Full article

Objectives: This study aimed to characterize the types and frequencies of sex chromosome aneuploidies (SCAs) detected through invasive prenatal testing, evaluate the concordance between non-invasive prenatal testing (NIPT) and confirmatory diagnostic methods, and assess the challenges faced during genetic counseling following SCA diagnosis. Study Design: A retrospective review was conducted on 842 prenatal samples collected between 2020 and 2024 in a tertiary private medical center. Samples included amniotic fluid, chorionic villi, and products of conception. Testing involved rapid QF-PCR for aneuploidy detection, followed by SNP-based chromosomal microarray analysis (CMA). NIPT results with high risk for sex chromosomes aneuploidies were correlated with invasive testing outcomes in 19 cases. Results: Sex chromosome aneuploidies were identified in 67 cases (7.96%), with Turner syndrome (45, X) being the most frequent (23 cases, including six mosaics), followed by Klinefelter syndrome (18 cases), 47, XYY (14 cases), and trisomy X (12 cases). Among 19 NIPT-tested cases, 10 were true positives, 5 false positives, and 4 false negatives, including two mosaic Turner syndrome cases undetected by NIPT. Discordances were attributed to factors such as mosaicism and placental anomalies. Conclusions: Prenatal diagnosis of SCAs via invasive testing remains crucial due to NIPT’s limited sensitivity for mosaicism and false positives. Comprehensive genetic counseling is essential to navigate diagnostic uncertainties and optimize prenatal management and postnatal outcomes. Full article

Background: Prader–Willi syndrome (PWS) is a multisystemic complex imprinting disorder. Prenatal diagnosis of PWS is still a challenge with non-specific ultrasound markers and limitations for diagnosis with non-invasive screening methods. Prenatal suspicion and early postnatal diagnosis are essential for promoting healthy growth and development, preventing complications, and providing healthcare professionals and families with the necessary support and resources for effective management. Presentation: We report two PWS cases caused by maternal uniparental disomy, who presented with IUGR, characterized by reduced fetal abdominal circumference (AC) in the second and early third trimesters, reduced fetal movements, normal Doppler indices and oligohydramnios. They were diagnosed in the early neonatal period with no prenatal suspicion but with similar ultrasound markers of the developing pregnancies, analyzed retrospectively. Aim: This study aims to emphasize the need to raise awareness among specialists about genetic syndromes such as Prader–Willi syndrome, to improve the information provided to couples regarding the limitations of current prenatal screening methods, as well as to ensure that, in cases of prenatal suspicion, appropriate genetic testing can be initiated. A confirmed diagnosis would allow timely and adequate measures to be taken, given the complications of the postnatal period in these patients and their need for specialized care and management. Conclusions: The presence of the aforementioned prenatal characteristics may raise suspicion for PWS. In such cases, invasive diagnostic procedures and methylation testing may be indicated, enabling earlier diagnosis and timely management, which can ultimately improve the quality of life of affected individuals and their families. Full article

Non invasive prenatal testing, NIPT, is widely used for fetal aneuploidy screening, but its clinical utility depends on gestational timing and maternal characteristics. Low fetal fraction can lead to unreportable tests and increased false negative risk, while GC-content-related sequencing bias may contribute to both false positive and false negative findings. We propose a Bayesian decision-theoretic optimization framework to recommend personalized NIPT timing across maternal body mass index (BMI) strata, explicitly incorporating test credibility and detection errors. We performed a retrospective analysis of de-identified NIPT records from a hospital in Guangdong Province, China, covering 1 January 2023 to 18 February 2024, including 1082 male fetus tests. Y chromosome concentration was used as a proxy for test reportability, with a 4 percent reporting threshold. Detection state proportions were empirically summarized from clinical reference information, with false positives at 10.35 percent and false negatives at 2.77 percent. A logistic regression model quantified the probability of obtaining a reportable result as a function of gestational week, maternal age, height, and weight, and the estimated probabilities were used to parameterize the Bayesian risk model. The optimized BMI-stratified schedule produced six BMI groups with recommended testing weeks ranging from 11 to 16, and the overall expected risk converged to 0.531. These results indicate a nonlinear BMI–timing relationship and suggest that a single universal testing week is suboptimal. The proposed framework provides quantitative decision support for BMI-stratified NIPT scheduling in clinical practice. Full article

Background/Objectives: X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare monogenic disorder characterized by hypohidrosis, hypotrichosis, and hypodontia, caused primarily by pathogenic variants in the EDA gene. XLHED predominantly affects males due to its X-linked recessive inheritance, while female carriers may exhibit variable phenotypes due to random X-inactivation. Early diagnosis is critical for timely counseling and emerging therapeutic interventions. We report a rare prenatal diagnosis of XLHED in dizygotic dichorionic male twins during a dichorionic diamniotic pregnancy. At 24 weeks’ gestation, ultrasonographic anomalies—facial dysmorphisms, oligodontia, and hypoechogenic skin—raised suspicion for ectodermal dysplasia. Methods: Non-invasive prenatal test and targeted next-generation sequencing (NGS) of Cell-free DNA identified an hemizygous EDA deletion (c.612_629del; p.Ile205_Gly210del) with 52% variant allele frequency. Results: This in-frame deletion affects a highly conserved region in the TNF homology domain of ectodysplasin-A1, likely compromising protein function. The variant was confirmed in both fetuses via genetic analysis on amniotic fluid and in the heterozygous state in the mother, consistent with X-linked recessive inheritance. Family history revealed a maternal uncle with XLHED. Additional heterozygous variants were also identified in CPT2, GBA1, GJB2, and SMN1 genes. Following comprehensive genetic counseling, the mother opted for abortion. Conclusions: This case underscores the value of applying advanced genomic technologies—cfDNA-based NGS—for prenatal diagnosis of rare genetic disorders. The identification of apathogenic EDA variant expands the mutational spectrum of XLHED and supports early diagnosis for informed reproductive decisions and potential access to emerging prenatal therapies. Broader application of such technologies may improve outcomes in future pregnancies at risk for monogenic disorders. Full article

Introduction: The scope and accessibility of prenatal testing have significantly expanded in recent years, reaching a broader population of pregnant women. Advances in non-invasive diagnostic methods support informed decision-making and help reduce the need for invasive procedures. Objective: The objective was to evaluate pregnant women’s knowledge regarding prenatal testing and assess the quality of information provided by healthcare professionals, including the frequency of screening and invasive procedures. Materials and Methods: A total of 310 obstetric patients from maternity wards in two hospitals in northern Poland completed a survey addressing prenatal tests, sources of information, and the quality of guidance received from medical staff. Results: Nearly 75% of respondents demonstrated adequate knowledge of the purpose, indications, and scope of prenatal testing. Physicians were identified as the primary source of information. Approximately 50% correctly indicated the recommended number of ultrasound examinations during pregnancy. No correlation was observed between knowledge of prenatal testing and a history of delivering a child with health complications. The combined first-trimester test was performed in 48.6% of cases, NIPT in 11.6%, and invasive testing in 1.8% of the study group. Conclusions: Public awareness of prenatal testing in Poland remains insufficient. With the introduction of partially reimbursed tests in 2024, we recommend strengthening educational efforts through social campaigns and targeted training for healthcare professionals. Full article

Objective: To evaluate the association between low and high fetal fraction (FF) of cell-free fetal DNA on non-invasive prenatal screening (NIPS) and placental pathology. Methods: We undertook a prospective cohort study of patients undergoing NIPS between July 2022 and July 2023 through Natera Inc. Based on the FF percentile, the study cohort was divided into three groups: high FF (≥95th%), low FF (≤5th%), and a control group (FF 6th–94th%). Our primary study outcome was a composite of high-risk placental lesions. We compared the occurrence of the primary study outcome across the study groups using the chi² test. Multivariable regression analyses were performed to predict the likelihood of the primary outcome based on the FF percentile. Selected obstetric and neonatal outcomes were assessed as secondary outcomes. Results: The primary outcome was present in 11 (50.0%), 19 (48.7%), and 11 (35.5%) of participants in the low FF, high FF, and control cohorts, respectively (p = 0.46). In an adjusted model, the FF percentile was not associated with the primary outcome (aOR 2.41 (0.72–8.42) for low FF, aOR 1.55 (0.51–4.82) for high FF). Chorangiosis (p = 0.02) and fetal inflammatory response (p = 0.002) were seen more commonly in the low and high FF groups. Spontaneous preterm birth was more common in the low FF group (p = 0.04). Conclusions: Our study did not identify a correlation between high-risk histopathological patterns and extremely low or high FF when compared to a control cohort. Chorangiosis and fetal inflammatory response were found more commonly in the low and high FF groups. Full article

Background: Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA (cfDNA) in maternal blood has revolutionized prenatal screening for trisomies 21, 18, and 13. This approach, based on next-generation sequencing (NGS), usually allows the detection of other chromosomal abnormalities; however, their clinical value in routine practice requires further evidence. Objectives: This study aimed to assess the experience and clinical utility of genome-wide NIPT in pregnant women at intermediate risk in the autonomous communities of Aragón and Valencia, Spain. Methods: For this purpose, a retrospective cohort study was conducted between 2020 and 2024 across two public hospitals. Pregnant women at intermediate risk for trisomies 21, 18, or 13, were included, as well as those meeting specific clinical criteria. Participants were offered either basic or expanded NIPT, and positive results were confirmed by invasive prenatal testing or placental analysis. Results: Among 9,059 expanded NIPT tests, 132 (1.45%) indicated a high-risk result for less common chromosomal anomalies, comprising 60 rare autosomal aneuploidies (RAAs), 39 copy number variants (CNVs), 23 sex chromosome aneuploidies (SCAs), and 10 multiple abnormalities. The positive predictive value (PPV) was 5.5% for RAAs in the fetus, 12.8% for CNVs (31% for deletions), and 58% for SCAs. Conclusions: Several confirmed anomalies were clinically significant and would not have been detected through conventional screening. Opportunistic use of expanded NIPT enables the detection of additional clinically relevant abnormalities, potentially improving obstetric management without substantially increasing invasive testing. Full article

Background: The second-to-fourth digit ratio (2D:4D) serves as a non-invasive proxy for prenatal androgen exposure. While its relationship with adult athletic ability is well documented, evidence for its association with childhood physical fitness remains inconsistent, and links between 2D:4D and objective fitness measures in prepubertal children are unclear. Methods: In this cross-sectional study, 338 prepubertal children (181 girls, 157 boys; aged 5–12 years) underwent precise measurement of right- and left-hand 2D:4D ratios (intra-class correlation coefficient = 0.94). Physical fitness was evaluated using standardized tests: the Illinois agility run, bent-arm hang, and standing long jump. Results: Among boys, higher 2D:4D ratios were modestly associated with prolonged bent-arm hang performance (β = 0.19, q = 0.04) and shorter Illinois agility times (β = −0.19, q = 0.04). No significant associations were observed in girls. All effect sizes were small, suggesting subtle, sex-dependent influences rather than robust predictors of performance. Conclusions: These findings indicate that prenatal hormonal environment may exert a limited, sex-specific influence on early physical fitness characteristics. Although biologically informative, the observed associations are insufficient for direct application in talent identification in sports. Longitudinal research incorporating direct hormonal measurements and broader populations is recommended to clarify developmental mechanisms and causal pathways. Full article

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional CMA and exome sequencing through its ability to detect both sequence and structural variants in a single assay. Emerging tools such as optical genome mapping, RNA sequencing, and long-read sequencing further enhance diagnostic yield and variant interpretation. This review summarizes major technological advancements, assesses their clinical utility and limitations, and outlines future directions in prenatal genomics. Full article

Introduction: For pregnant women with a history of fetal and neonatal alloimmune thrombocytopenia (FNAIT) or hemolytic disease of the fetus and newborn (HDFN), prenatal intervention in subsequent pregnancies may be necessary to prevent complications for the fetus. A non-invasive prenatal diagnostic procedure (NIPD) is recommended for fetal blood group genotyping. RT-PCR is used for fetal RHD determination as a reliable screening method with high sensitivity and specificity. For other antigens with variants involving single-base substitutions, droplet digital PCR (ddPCR) and next-generation sequencing (NGS) are recommended to reduce the risk of false-negative results. Only NGS offers the possibility of determining the cell-free fetal DNA (cffDNA) fraction in maternal plasma by sequencing additional gene fragments in parallel, but no standard exists for assay validation. Material and Methods: A custom-made primer panel was designed to target the common platelet and red cell antigens involved in fetal red cell and platelet incompatibilities, as well as additional anonymous single-nucleotide polymorphism (SNP) targets for use as an internal control. Amplicon-based NGS was carried out using semiconductor sequencing. For HPA-1a (HPA*1A, ITGB3) and K (KEL*01.01, KEL) assay validation, the limit of detection (LOD) and limit of quantification (LOQ) were estimated, as were false-positive antithetic alleles, linearity, and inter-assay variation, using cell-free DNA (cfDNA) extracted from the blood samples of healthy blood donors. An additional analysis was performed using 23 diagnostic samples from 21 pregnant women. Results: Regression analysis of dilution series using HPA-1a- and K-positive cell-free plasma samples in antigen-negative donor plasma showed that recovery is definitely feasible up to an HPA*1A and KEL*01.01 allele frequency of 1%. Base calls of false-positive antithetic alleles were detected with a maximum of 0.25% using 21 healthy blood donors. The LOD was estimated to be 0.2057% (mean + 3 SD) for HPA*1A with a LOQ of 0.6298% (mean + 10 SD). For KEL*01.01, the LOD was 0.1706% (mean + 3 SD) and the LOQ was 0.5314% (mean + 10 SD). The analysis of 15 of 21 cases with diagnostic samples from pregnant women with neonatal blood available for confirmatory testing resulted in 100% concordant results. The fetal fraction of these samples was calculated with a median of 11.03% (95% CI: 8.89, 13.20). Conclusions: NGS for non-invasive fetal blood group genotyping is an accurate and reliable method. In-house validation of the used assays can be performed using healthy donors to determine the LOD, LOQ and sensitivity. The threshold for paternally inherited fetal HPA*1A and KEL*01.01 alleles could be set at 1% (i.e., 2% fetal fraction) to obtain reliable test results. Internal controls for assessing the fetal fraction are essential to avoid false-negative test results. Full article

Background: Family health history (FHH) is essential for genomic medicine and risk assessment, but its completeness in Japanese prenatal settings is poorly understood. Prior studies show that details such as cause of death (COD) and age at onset are often missing. To address this gap, we conducted a pilot observational exploratory study evaluating FHH completeness in a Japanese prenatal genetic counseling setting. Methods: We analyzed data from 24 participants (12 couples) who underwent prenatal genetic counseling at a university hospital, most of whom were of advanced maternal age and had undergone non-invasive prenatal testing (NIPT). FHH was collected using a structured form at the first visit and revised at the second visit. Completeness was assessed for four items: medical history, age at death, COD, and age at disease onset. Associations with participant characteristics were also explored. Results: Disease history was most complete, while COD and age at onset were frequently missing. Age at death was more complete than COD, indicating that information on deceased relatives or timelines was harder to obtain. Participants with personal or family medical conditions tended to provide more complete FHH. The structured form and opportunity for revision likely enhanced completeness. Conclusions: This pilot study shows that COD and age at onset are the least complete components of FHH in Japanese prenatal counseling. The small sample size and single-hospital setting limit the generalizability of the findings, but they suggest that structured prompts and preparation before visits may improve FHH completeness and enhance risk assessment in clinical practice. Full article