Performance of Non-Invasive Prenatal Screening for Sex Chromosome Aneuploidies and Parental Decision-Making
Sex chromosome aneuploidies (SCAs), characterized by abnormal numbers of X or Y chromosomes, represent a significant category of chromosomal abnormalities with an estimated prenatal incidence of 1/435. These conditions, including monosomy X (45,X), trisomies (47,XXX, 47,XXY, 47,XYY), mosaicism, and other rare forms, are associated with diverse clinical outcomes ranging from subtle physical features to infertility or developmental delays. Historically, SCAs were diagnosed postnatally through karyotyping. However, advances in non-invasive prenatal testing (NIPT) have enabled earlier detection, raising critical questions about clinical utility, counseling challenges, and ethical considerations in reporting these findings. This study evaluates the performance of NIPT in detecting SCAs within a large cohort and examines parental decision-making following positive results.
Methodology and Cohort Characteristics
The retrospective analysis included 20,637 singleton pregnancies undergoing NIPT between January and December 2017 at a single center. After excluding cases with uninterpretable results, 20,601 pregnancies were stratified into six groups: advanced maternal age (≥35 years; 24.81%), high-risk serum screening (7.42%), intermediate-risk serum screening (13.74%), abnormal ultrasound findings (8.42%), in-vitro fertilization (4.37%), and low-risk pregnancies voluntarily opting for NIPT (37.27%). Ultrasound abnormalities included nuchal translucency (NT) thickening <3.5 mm, echogenic intracardiac foci, or other soft markers.
NIPT was performed using the BGISEQ-500 platform (Wuhan MGI Tech Co., Ltd.), which analyzes cell-free fetal DNA in maternal plasma. Positive SCA results were confirmed via invasive prenatal diagnosis (IPD) through amniocentesis or chorionic villus sampling followed by karyotyping. Statistical analysis utilized Chi-square tests, with a positive predictive value (PPV) calculated as the proportion of true positives among confirmed cases.
Detection Rates and Positive Predictive Value
Among the 20,601 cases, 64 (0.31%) screened positive for SCAs. The distribution of suspected abnormalities included 25 cases of monosomy X (39.06%), 15 cases of 47,XXX (23.44%), 16 cases of 47,XXY (25.00%), and 8 cases of 47,XYY (12.50%). Of these, 44 women (68.75%) underwent IPD, revealing 24 true positives and 20 false positives. The overall PPV for SCAs was 54.55%, with significant variation across subtypes:
- Monosomy X (45,X): PPV of 23.53% (4/17 confirmed cases), including one pure 45,X and three mosaic cases (45,X/46,XN).
- 47,XXX: PPV of 70.00% (7/10 confirmed).
- 47,XXY: PPV of 75.00% (9/12 confirmed).
- 47,XYY: PPV of 80.00% (4/5 confirmed).
Notably, no significant differences in PPV were observed between SCA subtypes (P >0.05). However, the high false-positive rate for monosomy X underscores technical challenges, potentially due to placental mosaicism or maternal biological factors.
Performance Across Risk Groups
PPV varied substantially based on maternal risk stratification:
- Advanced Maternal Age: Among seven cases undergoing IPD, six were confirmed (PPV 85.71%), including 100% PPV for 45,X and 47,XXX.
- High-Risk Serum Screening: Three of four cases were true positives (PPV 75.00%), with 100% accuracy for 47,XXX and 47,XXY but 0% for 45,X.
- Abnormal Ultrasound Findings: Two of five cases were confirmed (PPV 40.00%), with 25% PPV for 45,X and 100% for 47,XXY.
- Voluntary NIPT (Low-Risk): Ten of twenty cases were confirmed (PPV 50.00%), with lower accuracy for 45,X (20.00%) compared to trisomies (57.14–83.33%).
The intermediate-risk serum screening group had no positive SCA results, suggesting limited utility in this population.
Parental Decision-Making and Outcomes
Following genetic counseling, 24 cases with confirmed SCAs faced critical decisions:
- Pregnancy Continuation: Seven cases (29.17%) opted to continue, primarily involving 47,XXX or 47,XYY diagnoses.
- Termination: Thirteen cases (54.17%) elected termination, with 100% of monosomy X and 83.33% of 47,XXY cases choosing this outcome.
- Lost to Follow-Up: Four cases (16.67%) withdrew from further monitoring.
Among the 20 women declining IPD, 16 delivered infants with no reported abnormalities after ≥1 year of postnatal evaluation. One pregnancy resulted in stillbirth, and three cases were lost to follow-up.
Clinical and Ethical Implications
The study highlights the complexity of integrating NIPT-based SCA screening into routine prenatal care. While the overall PPV (54.55%) exceeds that of traditional first-trimester combined screening for common trisomies, the high false-positive rate for monosomy X (76.47%) raises concerns. Discordant results may stem from confined placental mosaicism, maternal copy number variations, or technical limitations in detecting sex chromosome imbalances.
Ethical debates center on whether to report SCA results given their variable phenotypes. For instance, 47,XYY males often exhibit normal development, whereas 45,X (Turner syndrome) and 47,XXY (Klinefelter syndrome) are linked to medical complications requiring early intervention. The high termination rate for 45,X (100%) and 47,XXY (83.33%) reflects parental anxiety about potential disabilities, influenced by counseling quality, cultural norms, and perceptions of future quality of life. Conversely, the decision to continue pregnancies with 47,XXX or 47,XYY may correlate with milder anticipated outcomes.
Limitations and Future Directions
The study’s retrospective design precluded calculation of sensitivity and specificity, as most parents declined postnatal confirmation. Additionally, the cohort’s termination rates exceeded prior reports, potentially reflecting regional biases or counseling practices. Longitudinal data on children with prenatally diagnosed SCAs are needed to clarify long-term outcomes and refine risk-benefit assessments.
Conclusion
NIPT demonstrates moderate accuracy in detecting fetal SCAs, with performance varying by subtype and maternal risk profile. While early diagnosis enables timely interventions, the ethical implications of reporting uncertain results necessitate rigorous pre-test counseling. Multidisciplinary teams must address parental education, psychological support, and individualized care plans to navigate the nuanced landscape of SCA management.
doi.org/10.1097/CM9.0000000000000868
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