[Explained by a Doctor] Is NIPT the Final Answer for Prenatal Diagnosis?

Revision date: April 27, 2026

NIPT is a highly accurate prenatal screening test, but it is not a definitive diagnosis. Due to false positives and the effects of CPM (confined placental mosaicism), even a "high risk" result requires a confirmatory test. A specialist explains the limits of the test and how to interpret it correctly.

What Is NIPT? — Defining a High-Accuracy Screening Test

NIPT (Non-Invasive Prenatal Testing) is a screening test that analyzes trace amounts of placenta-derived DNA fragments (cell-free fetal DNA, or cffDNA) present in maternal blood using next-generation sequencing and other technologies, in order to evaluate the risk of fetal chromosomal abnormalities. Because it can be performed with only a blood draw, the physical burden on the mother and fetus is extremely small, and it can be taken from around 10 weeks of pregnancy.(1)

NIPT was clinically introduced in the United States in 2011 and has since spread rapidly around the world. In Japan too, it began as clinical research in 2013 and is now widely offered, primarily at facilities certified by the Japanese Association of Medical Sciences. Compared with conventional screening tests (maternal serum marker tests and combined tests), its defining feature is extremely high sensitivity and specificity for the three major trisomies. However, no matter how high its accuracy, its fundamental position as a "screening test" does not change.

Main Conditions Targeted by NIPT

• Trisomy 21 (Down syndrome)
• Trisomy 18 (Edwards syndrome)
• Trisomy 13 (Patau syndrome)
• Sex chromosome abnormalities (Turner syndrome, Klinefelter syndrome, etc.) *depending on the facility
• Microdeletion syndromes (e.g., 22q11.2 deletion syndrome) *depending on the facility

Of these, the three conditions of trisomy 21, trisomy 18, and trisomy 13 are internationally recognized as the standard targets of testing. For sex chromosome abnormalities and microdeletion syndromes, coverage varies by facility and testing company, and sensitivity and PPV also tend to be lower than for the three major trisomies, so extra care is needed when interpreting results.

Accuracy Data for NIPT

The results from a large-scale study of over 280,000 cases (2018–2021) are as follows.(1)

Source: Heliyon, June 2024 (n=282,911)

As the data above make clear, sensitivity (the ability to correctly identify a positive result when the condition is present) is extremely high—98% or above—for all three conditions. However, PPV (positive predictive value) varies greatly by condition. While the PPV for Down syndrome is 86.81%, for Patau syndrome it is only 18.18%, meaning that even with a "high risk" result, the probability that no chromosomal abnormality is actually present is higher. This is the main basis for describing NIPT as a "risk assessment test" rather than a "diagnostic test."

Why NIPT Is Not a Definitive Diagnosis — False Positives and Positive Predictive Value (PPV)

The main reason NIPT is not a definitive diagnosis is the existence of "false positives." No screening test, of any kind, has 100% accuracy. NIPT is no exception, and there is a certain rate of cases in which a fetus with no actual chromosomal abnormality is judged "high risk."

What Are False Positives and Positive Predictive Value (PPV)?

● False positive: A case in which NIPT indicates "high risk (abnormality present)" even though the actual risk of chromosomal abnormality is low. False positives can cause unnecessary anxiety for the pregnant woman and her family.

● PPV (positive predictive value): The proportion of people judged "high risk" by the test who actually have the condition. A lower PPV means a higher proportion of false positives. PPV depends not only on the sensitivity and specificity of the test itself but also heavily on the prevalence (occurrence rate) of the target condition.

Understanding PPV is essential to correctly interpreting NIPT results. Even with a test whose specificity is as high as 99.97%, if the prevalence of the target condition is low, the proportion of people among those judged "high risk" who actually have the condition will be low. This is a phenomenon based on the fundamental statistical principle known as "Bayes' theorem," and it is a property common not just to NIPT but to all screening tests.

A Concrete Example (Patau Syndrome, PPV 18.18%)

• Of 5 people judged "high risk" by NIPT, only about 1 actually has Patau syndrome
• The remaining approximately 4 people do not actually have a chromosomal abnormality (false positive)

The large difference in PPV between Down syndrome and Patau syndrome stems from differences in the occurrence rate (prevalence) of each chromosomal abnormality. Down syndrome occurs in about 1 in 700–800 births, whereas Patau syndrome is extremely rare, occurring in about 1 in 10,000–20,000 births. The lower the prevalence of a condition, the lower the PPV tends to be. For this reason, it is extremely risky to draw conclusions from a NIPT "high risk" result—especially for Patau syndrome or Edwards syndrome—without undergoing a confirmatory diagnostic test.(1)

The Main Cause of False Positives: What Is Confined Placental Mosaicism (CPM)?

The single largest cause of false positives in NIPT is "confined placental mosaicism (CPM)."(2)

What is CPM: A condition in which the chromosomal makeup of the placenta is abnormal even though the fetus's chromosomes are normal. Most of the cffDNA analyzed by NIPT is derived from the placenta's trophoblast cells. In other words, what NIPT strictly detects is not "fetal DNA" but "placental DNA." Therefore, in cases of CPM where the chromosomal abnormality is confined to the placenta alone, NIPT can mistakenly detect the placental abnormality as a "fetal abnormality."

CPM is estimated to occur in about 1–2% of all pregnancies, and is by no means a rare phenomenon. The mechanisms behind CPM are thought to include mitotic errors during the early stages of cell division after fertilization, and "trisomy rescue" (a phenomenon in which a fertilized egg that was originally trisomic is corrected to a normal chromosome number in some of its cells).(2)

Proportion of False Positives Attributable to CPM (by Chromosome)

Source: The Obstetrician & Gynaecologist, 2023 (Reference 2)

The data above show that the frequency of CPM occurrence differs greatly by chromosome type. It is particularly notable that the involvement of CPM is high for chromosome 13 and the sex chromosomes. For Turner syndrome (45,X), CPM is reported to be involved in up to 59% of false-positive cases, so special caution is needed when interpreting NIPT results related to sex chromosomes.(2)

Other Causes of False Positives Besides CPM

Besides CPM, several other factors are known to be able to cause false positives in NIPT.

• Vanishing twin: Cases where cffDNA released from a twin that was lost early in pregnancy affects the results
• Maternal chromosomal mosaicism: Cases where the mother herself has low-level chromosomal mosaicism
• Maternal malignancy: Rare cases where DNA fragments derived from a maternal tumor are detected as an abnormal signal
• Low fetal fraction: The risk of misjudgment arising from reduced test accuracy when the amount of cffDNA is insufficient

None of these factors occur as frequently as CPM, but they further support the reasons why NIPT results do not constitute a definitive diagnosis.

Abnormalities NIPT Cannot Detect: The Scope and Limits of the Test

NIPT is a test specialized in screening for numerical chromosomal abnormalities. In other words, its purpose is to detect whether a specific chromosome is present in more (trisomy) or fewer (monosomy) copies than the usual two. However, chromosomal numerical abnormalities are not the only congenital abnormalities that can occur in a fetus. In principle, the following are outside the scope of detection.

• Single-gene disorders (phenylketonuria, cystic fibrosis, sickle cell disease, muscular dystrophy, etc.): Conditions caused by mutations in a specific gene cannot be detected by NIPT
• Many structural chromosomal abnormalities (balanced translocations, some microdeletions/duplications): Even when the overall chromosome count is normal, structural abnormalities often fall outside the scope of NIPT detection
• Multifactorial genetic disorders (congenital heart disease, many neural tube defects): Conditions arising from a combination of genetic and environmental factors cannot be evaluated by chromosomal testing alone
• False negatives (cases where an abnormality is actually present but the result is "low risk") are also not completely zero, and can be caused by low fetal fraction or by CPM (in this case, where the placenta is normal but the fetus has an abnormality)

Chromosomal abnormalities account for only about 25–30% of all congenital abnormalities, and NIPT covers only a portion of that. Therefore, a "low risk" result does not mean that all congenital conditions have been ruled out. Even with a "low risk" NIPT result, it remains important to continue regular prenatal checkups and ultrasound examinations.

Tests Needed for a Definitive Diagnosis: Comparing Chorionic Villus Sampling and Amniocentesis

If NIPT indicates "high risk," or if a definitive diagnosis of a chromosomal abnormality is needed regardless of the NIPT result, an invasive test (chorionic villus sampling or amniocentesis) is required. Because these tests directly sample fetal cells or placental tissue and analyze the chromosomes, unlike a screening test they can provide a "definitive diagnosis."

Chorionic Villus Sampling (CVS)

This test, performed around 11–13 weeks of pregnancy, involves inserting a fine needle through the abdomen (transabdominal approach) or through the cervix (transcervical approach) to collect chorionic villi (mainly placental tissue) and directly analyze the chromosomes. Because results are available early, it may be chosen when a woman wants to know the results early in pregnancy. However, since the tissue sampled is placental, it should be noted that the influence of CPM cannot be completely ruled out. If CPM is suspected, amniocentesis may also be performed as a follow-up.

Amniocentesis

This test, performed from 16 weeks of pregnancy onward, involves inserting a fine needle into the abdomen under ultrasound guidance to collect and culture fetal-derived cells in the amniotic fluid, then analyzing the chromosomes. The cells in the amniotic fluid are shed from the fetus's skin, urinary tract, digestive tract, and so on, and since they differ from placental tissue, a major advantage is that they are less susceptible to false positives caused by CPM. For a high-risk NIPT result not accompanied by abnormal ultrasound findings, amniocentesis is increasingly recommended internationally.(2)

The Process for Undergoing a Definitive Diagnostic Test

1. Receive a "high risk" result from NIPT
2. Confirm the meaning of the result and the available options in a consultation with your physician or genetic counselor
3. Undergo a detailed ultrasound evaluation of fetal morphology
4. Undergo chorionic villus sampling (11–13 weeks) or amniocentesis (16 weeks onward)
5. Discuss the path forward with your physician and genetic counselor based on the chromosomal analysis results

Comparing Miscarriage Risk

Source: Ultrasound in Obstetrics & Gynecology, January 2015 (Reference 3)

There was once a time when the miscarriage risk of invasive testing was reported to be around 1–2%, but thanks to recent improvements in ultrasound technology and standardized procedures, the figures above—extremely low—are now typical when performed by an experienced physician. Since the risk is still not zero, it is important to make the decision after thorough consultation with your physician. It is recommended that you weigh the risks of the test against the benefits of the information gained, and decide whether to undergo the test only after you and your family are satisfied with that decision.(3)

Differences Between NIPT and Definitive Diagnosis: Comparison Table

The main differences between NIPT and definitive diagnostic tests are summarized below.

• Type of test — NIPT: Screening (risk assessment) / Chorionic villus sampling, amniocentesis: Definitive diagnosis
• Timing — NIPT: from 10 weeks / Chorionic villus sampling: 11–13 weeks / Amniocentesis: from 16 weeks
• Invasiveness — NIPT: None (blood draw only) / Chorionic villus sampling, amniocentesis: Present (abdominal puncture)
• Miscarriage risk — NIPT: None / Chorionic villus sampling: About 0.22% / Amniocentesis: About 0.11%
• CPM influence — NIPT: Present (cause of false positives) / Chorionic villus sampling: Present (possible) / Amniocentesis: Less susceptible
• Detection scope — NIPT: Numerical chromosomal abnormalities (limited) / Chorionic villus sampling, amniocentesis: Chromosomes in general
• Certainty of result — NIPT: Risk value (probability) / Chorionic villus sampling, amniocentesis: Definitive diagnosis

As this shows, the very purpose of testing differs fundamentally between NIPT and definitive diagnostic tests. NIPT is a screening tool for "efficiently identifying a population at high risk of chromosomal abnormality," while a definitive diagnosis is a test for "conclusively determining whether that risk is actually present." Correctly understanding this two-stage process leads to the appropriate use of prenatal testing.

Steps to Take After Receiving Your NIPT Result

After receiving your NIPT result, whether it is "low risk" or "high risk," it is important to take the appropriate next steps. Below, we explain the recommended course of action for each type of result.

If the Result Is "Low Risk"

A "low risk" result indicates that the likelihood of the chromosomal abnormalities targeted by the test is very low. However, as noted above, NIPT cannot detect conditions outside its scope, and there remains a small possibility of a false negative. For this reason, even with a low-risk NIPT result, it is important to continue regular prenatal checkups (including ultrasound examinations). Also, if any abnormal findings are detected on ultrasound, additional testing may be needed regardless of the NIPT result.

If the Result Is "High Risk"

1. First, upon receiving the result, contact your physician or genetic counselor to receive a detailed explanation
2. Do not decide whether to continue or end the pregnancy based on the NIPT result alone — always undergo a definitive diagnostic test
3. Confirm the presence or absence of fetal morphological abnormalities through a detailed ultrasound examination
4. Undergo chorionic villus sampling or amniocentesis depending on gestational age
5. Discuss the path forward with your physician and genetic counselor based on the results of the definitive diagnosis

The most important thing when a NIPT result is "high risk" is not to make major decisions based on the NIPT result alone. In particular, since the PPV for Patau syndrome and Edwards syndrome falls below 50%, many people who receive a "high risk" judgment may fall into the category where no chromosomal abnormality is found on definitive diagnosis. Although this is a psychologically difficult situation, a calm judgment based on accurate information is required.

＼Find out your risk for Down syndrome and sex chromosome conditions during pregnancy／

Frequently Asked Questions

Q1. If NIPT shows "low risk," can I assume my baby is healthy?

A. NIPT's "low risk" result only indicates a low risk for the chromosomal abnormalities targeted by the test (mainly trisomy 21, 18, and 13). Single-gene disorders, many structural chromosomal abnormalities, and morphological abnormalities are outside the scope of NIPT detection. There is also a nonzero possibility of a false negative (an abnormality actually being present despite a low-risk result). It is recommended that you continue regular prenatal checkups and ultrasound examinations even after a low-risk result.

Q2. If NIPT shows "high risk," do I need to immediately consider termination?

A. "High risk" simply indicates a higher likelihood, not a certainty. First, it is recommended that you undergo a definitive diagnosis via chorionic villus sampling or amniocentesis. Depending on the condition, PPV can fall below 50%, meaning many "high risk" results may in fact be false positives. It is important to make a decision only after fully hearing the results of the definitive diagnosis and the explanations of your physician and genetic counselor.

Q3. Why is the PPV for Patau syndrome so low?

A. PPV is influenced not only by the accuracy of the test but also greatly by the prevalence (actual occurrence rate) of the condition. Because Patau syndrome occurs less frequently than Down syndrome (about 1 in 10,000–20,000 births), the proportion of cases with no actual abnormality is higher even when the result is "high risk." In addition, the proportion of false positives attributable to CPM is also high for Patau syndrome, at about 22%, further raising the false-positive rate.(1)(2)

Q4. Should I choose amniocentesis or chorionic villus sampling?

A. When a NIPT high-risk result is obtained but no abnormality is found on ultrasound, amniocentesis is often recommended. This is because it is less susceptible to the effects of CPM. Chorionic villus sampling, on the other hand, has the advantage of being performed early in pregnancy (11–13 weeks) and is chosen when a woman wants to know the results early. The miscarriage risk for both tests is very low, though not zero, so please consult thoroughly with your physician.(2)(3)

Q5. What is the most important thing to know before undergoing NIPT?

A. The most important point is that NIPT is a screening test, not a definitive diagnosis. A "high risk" result is not a certainty, and a "low risk" result does not rule out all abnormalities. It is recommended that you receive counseling from a physician or genetic counselor before testing, and understand how to interpret the results and what the next steps are before undergoing the test.

Q6. How long does it take to get NIPT results?

A. Generally, NIPT results are available about 1–2 weeks after the blood draw. However, this may vary somewhat depending on how busy the testing facility or laboratory is. After receiving your result, it is important to have your physician or genetic counselor explain it to you.

Q7. Can NIPT result in a "result withheld" or "retest recommended" outcome?

A. Yes, in rare cases, the result may come back as "result withheld" or "retest recommended." The main cause is an insufficient amount of fetal fraction (cffDNA). This is more likely to occur when the mother's BMI is high or when the pregnancy is too early. A retest with a fresh blood draw often resolves this, but if the retest still cannot produce a result, a definitive diagnostic test should be considered.

[References]

(1) Japan Association of Obstetricians and Gynecologists, July 2018
(2) Diagn Cytopathol, February 2016
(3) Kodansha, April 2024