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Introduction
NIPT (Non-Invasive Prenatal Testing), now widely recognized as an option in prenatal diagnosis, has gained attention as a non-invasive and highly accurate screening for chromosomal abnormalities such as Down syndrome.
However, even when NIPT results are “negative (low risk),” some cases may still require further testing such as amniocentesis, depending on pregnancy progress or fetal findings.
This article focuses on “NIPT retesting”, discussing the reliability of negative results, situations requiring further testing, and medical decision-making criteria based on the latest research and guidelines.
What Is NIPT? Overview and Accuracy
NIPT analyzes fragments of cell-free fetal DNA (cfDNA) in maternal blood to assess the risk of chromosomal abnormalities. It mainly screens for:
- Trisomy 21 (Down syndrome)
- Trisomy 18 (Edwards syndrome)
- Trisomy 13 (Patau syndrome)
Detection rates are very high — sensitivity for trisomy 21 is around 99%. However, it is important to note that NIPT is a screening test, not a diagnostic test.
What Does a Negative (Low Risk) Result Mean?
A “negative” or “low risk” NIPT result indicates a very low probability of the tested abnormalities, but it does not guarantee the fetus is free of abnormalities.
Possible causes of false negatives include:
- Low fetal cfDNA fraction (<4%)
- Chromosomal mosaicism
- Placental mosaicism (discordance between placenta and fetus)
- Abnormalities outside NIPT’s testing scope
Indeed, studies report rare cases where chromosomal abnormalities were detected after birth despite a negative NIPT.
When Retesting (Amniocentesis) May Be Recommended
- Abnormal Ultrasound Findings
If mid-pregnancy ultrasound shows signs such as edema, congenital heart defects, or skeletal anomalies, amniocentesis may be advised even after a negative NIPT. - High-Risk Factors (Age or Family History)
Women over 35 or with a family history of chromosomal disorders may require additional testing despite negative results. - Low Fetal cfDNA Fraction
Some reports indicate the fetal DNA fraction; if below threshold (e.g., 3.5%), detection reliability decreases and retesting is recommended. - For Reassurance
Some families opt for diagnostic confirmation via amniocentesis to reduce anxiety and obtain certainty.
Amniocentesis: Benefits and Risks
Benefits
- Nearly 100% accuracy for diagnosing chromosomal abnormalities
- Detects microdeletion syndromes (e.g., 22q11.2 deletion) and structural anomalies
Risks
- Miscarriage risk of 0.1–0.3%
- Possible complications such as infection or bleeding
Key Points for Consulting Physicians
Decisions on retesting should consider:
- NIPT coverage and results
- Ultrasound findings
- Fetal cfDNA fraction
- Family history or genetic background
- Psychological needs of the parents
Doctors typically follow guidelines from the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Society of Human Genetics.
Expert Perspective: Negative ≠ Absolute Reassurance
A 2022 study from Nippon Medical School reported chromosomal abnormalities confirmed after birth in some NIPT-negative cases, underscoring the need for cautious interpretation and multifactorial decision-making.
Importance of Genetic Counseling
Genetic counseling ensures accurate understanding of:
- The real meaning of negative results (not equal to “no abnormalities”)
- False negative risks
- Options for future pregnancy management
- Ethical considerations and family decision-making
This process supports informed choice, which is central to prenatal care.
Misconceptions and Clarifications
- Myth 1: Negative = absolutely healthy fetus
→ False. NIPT only screens for major trisomies, not sex chromosome disorders, microdeletions, or structural anomalies. - Myth 2: Retesting is only for positive results
→ False. If ultrasound shows abnormalities, retesting (amniocentesis) may be advised even after a negative NIPT.
International Guidelines
- ACOG (American College of Obstetricians and Gynecologists): Recommends considering diagnostic testing regardless of NIPT results if ultrasound abnormalities or maternal risk factors exist.
- NICE (UK National Institute for Health and Care Excellence): States that additional testing should be offered if ultrasound anomalies are present, even with negative NIPT.
Clinical Case Example
At a Japanese university hospital, a woman with negative NIPT was later found at 20 weeks ultrasound to have a fetus with severe congenital heart defect. Amniocentesis confirmed 22q11.2 deletion syndrome, which NIPT does not cover.
This case highlights the importance of combining ultrasound findings with diagnostic testing for accurate outcomes.
Cost and Psychological Considerations
- Cost: Amniocentesis is usually not covered by insurance, costing ¥80,000–150,000 ($600–1,200).
- Psychological impact: While more testing can increase anxiety, definitive results may provide reassurance and allow better preparation for delivery and care.
FAQs
Q1: NIPT was negative, but ultrasound showed abnormalities. What should I do?
→ Consult your doctor or genetic counselor about options, including amniocentesis.
Q2: Is retesting (amniocentesis) covered by insurance?
→ Most are self-paid, but specific conditions may be partially covered if deemed medically necessary.
Conclusion: Negative NIPT Does Not Eliminate the Need for Retesting
While a negative NIPT result is highly reliable, it is not absolute. Depending on pregnancy progression and additional findings, diagnostic testing such as amniocentesis may be necessary.
A comprehensive approach combining NIPT + ultrasound + genetic counseling offers the safest and most reliable pregnancy care.
