Understanding Positive Scores and Retesting Criteria for Down Syndrome

In recent years, non-invasive prenatal testing (NIPT) has become increasingly common in prenatal care. This testing allows for the assessment of fetal chromosomal abnormalities early in pregnancy. Among these, Down syndrome (Trisomy 21) receives the most attention. This article provides a detailed explanation of what a positive NIPT score means, how to determine the need for retesting, the accuracy of the test, and its clinical applications, based on the latest research and guidelines.

1. What is NIPT?

NIPT is a non-invasive screening method that analyzes cell-free fetal DNA (cfDNA) present in maternal blood to assess the risk of chromosomal abnormalities in the fetus. Unlike traditional invasive procedures such as chorionic villus sampling (CVS) or amniocentesis, NIPT only requires a blood sample, significantly reducing the risk of miscarriage.

Chromosomal abnormalities assessed by NIPT include:

• Trisomy 21 (Down syndrome)
• Trisomy 18 (Edwards syndrome)
• Trisomy 13 (Patau syndrome)
• Sex chromosome abnormalities (e.g., Turner syndrome)

Down syndrome is particularly prioritized in NIPT due to its higher birth prevalence and the strong interest among pregnant women and their families.

(Reference: Gil MM, Quezada MS, Bregant B, et al. Analysis of cfDNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2015)

2. What is a Positive Score for Down Syndrome?

NIPT results are typically reported as a “risk ratio” or “positive probability (positive score).” This is a statistically calculated probability of the fetus having Down syndrome, based on the proportion of cfDNA derived from chromosome 21 in the sample.

Interpreting Positive Scores:

• Low Risk (Negative): The score is below the threshold; the likelihood of Trisomy 21 is extremely low.
• High Risk (Positive): The score exceeds the threshold; the likelihood of Trisomy 21 is higher.
• Uncertain (Borderline / Gray Zone): The score does not clearly reach the threshold; retesting or additional testing is recommended.

Although specific thresholds vary by testing provider, a risk lower than 1:100 is generally considered low, and 1:100 or higher is considered high.

3. Criteria for Retesting

A positive NIPT score does not guarantee that the fetus has Down syndrome. NIPT is a screening test—not a diagnostic one. Thus, further assessment is essential in positive cases.

3‑1. Retesting for High-Risk Scores

• Repeat NIPT through blood draw
  False positives may occur due to low cfDNA concentrations or sample quality, so a second NIPT may be performed on the same individual.
• Invasive diagnostic testing (CVS or amniocentesis)
  For high-risk scores, confirmatory diagnosis is recommended, acknowledging the associated miscarriage risk.

3‑2. Managing Borderline Scores

• When scores are near the cutoff, repeat testing is used to verify score consistency.
• Women with low cfDNA fractions (e.g., those with high BMI) may be at increased risk for false negatives, necessitating personalized evaluation by a physician.

(Reference: Benn P, Borrell A, Cuckle H, et al. Review of NIPT performance for Down syndrome using maternal blood cfDNA. Prenat Diagn. 2013)

4. Factors Affecting Positive Scores

Understanding what affects the score helps improve decision-making about retesting.

Maternal Factors:

• High BMI: Dilution of cfDNA may lower scores
• Pregnancy complications (e.g., preeclampsia): Can contribute to false positives

Fetal Factors:

• Mosaicism (partial chromosomal abnormalities)
• Twin pregnancy: Interpreting scores is complex if only one fetus is affected

Technical Factors:

• cfDNA extraction quality and library preparation accuracy
• NGS (next-generation sequencing) analysis algorithms

5. Clinical Use and Considerations

NIPT reduces the psychological burden and invasive testing risks for pregnant women. However, the following points must be observed:

• A positive score is not a diagnosis → confirm with invasive testing
• A negative score does not mean zero risk → rare false negatives exist
• Genetic counseling is crucial → results must be explained clearly by a physician or counselor
• Example retesting flow:
   NIPT performed → Positive score → High risk → Consider invasive test
   Borderline → Repeat NIPT or additional test
   Low risk → Continue with routine pregnancy care

6. Summary So Far

• NIPT is an innovative test that reduces maternal burden and enables early risk identification for Down syndrome
• A positive score is a screening result, not a definitive diagnosis
• Accurate understanding of retesting criteria and close collaboration with healthcare providers ensures safe and effective pregnancy management

7. Important Notes for Pregnant Women and Families

When undergoing NIPT, do not rely solely on the positive or negative score. Consider the following:

• Timing of testing
   After 10 weeks of gestation, fetal cfDNA becomes sufficient for accurate analysis
• Differences among testing companies
   Each has different algorithms and score thresholds → Always confirm with your provider
• Twin pregnancy or previous pregnancy history
   Twin pregnancies may show intermediate scores if only one fetus is affected.
   A history of chromosomal abnormality warrants more intensive genetic counseling
• Psychological support
   A positive score can cause stress → Counseling provides both accurate information and emotional support

8. Future Outlook

NIPT technology is evolving rapidly. Future developments may allow earlier and broader detection of chromosomal and genetic disorders. Machine learning and AI-based analysis are also expected to further reduce false positives and negatives.

This advancement will enable families to better understand fetal health and contribute to more accurate prenatal diagnostics and reduced emotional stress.

9. Conclusion

• NIPT is a screening test; a positive score is a probability indicator
• Determining the need for retesting or diagnosis requires consultation with a doctor or genetic counselor
• Factors affecting the positive score include maternal, fetal, and technical elements
• Psychological support for the pregnant woman and family is an essential part of care
• Future improvements in analysis accuracy and target conditions are anticipated

Proper understanding of this information allows families to make informed decisions and safely use NIPT in assessing risks like Down syndrome.

References

Benn P, et al. Prenatal detection of aneuploidy using maternal plasma DNA sequencing. Prenat Diagn. 2013

ACOG Committee Opinion No. 682. Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2016