Interpreting non-invasive prenatal test (NIPT) results
The non-invasive prenatal test (NIPT) is an accurate screening test for common trisomies, sex chromosome aneuploidies and other selected chromosome abnormalities.
NIPT differs from conventional prenatal screening methods in two important ways. First, conventional screening methods which use the concentration of serum proteins in maternal blood and on ultrasound have higher false-positive rates (incorrect “high risk” results in an unaffected pregnancy) and false negatives rates (incorrect “low risk” results in an affected pregnancy) than NIPT. Second, conventional screening methods report an individual risk score for a patient which takes into account ultrasound findings, the results of other screening tests and relevant family history. NIPT relies primarily on the relative concentrations of DNA fragments from different chromosomes in the mother’s blood.
NIPT results are reported as either ‘High Probability’ or ‘Low Probability’ for the chromosome abnormality being tested. The accuracy of this result can be viewed in two ways:
- The accuracy of the test in general i.e. the proportion of pregnancies in which the test correctly identifies the fetus as having (or not having) the disorder in question. This refers to the sensitivity and specificity (respectively) of the test for that disorder. These measures of test performance are based on the analysis of thousands of pregnancies. For example, the Table shows the sensitivity and specificity of Sonic’s NIPT for different autosomal trisomies:
- The accuracy of this test in a particular woman i.e. the chance that her own result correctly identifies whether the fetus has (or does not have) the disorder in question. This refers to the positive and negative predictive value (respectively) of the test for that woman. The answers depend both on the sensitivity and specificity (as above) and the chance that this particular woman could have an affected fetus.
For example, some general scenarios are considered below.
Woman who is at a very low prior risk, e.g. 1 in 5,000 (0.02%) of her fetus having trisomy 21.
This may apply to a young woman with normal fetal ultrasound, or a woman with a low probability result from conventional first trimester screen.
If the NIPT result is LOW PROBABILITY of trisomy 21
The negative predictive value of the test for this patient would be >99.99% i.e. it is almost certain that the result is correct, and that the fetus does not have trisomy 21. However, there is a very small chance (less than 1 in 10,000) that this normal test result is incorrect.
If the NIPT result is HIGH PROBABILITY of trisomy 21
The positive predictive value of the test for this patient would be approximately 20% i.e. it is possible but not definite that the result is correct, and that the fetus has trisomy 21. However, there is an 80% chance that this abnormal test result is incorrect.
A high probability NIPT result is more likely to be correct than a high probability conventional first trimester screen. Nonetheless, a high probability NIPT result must be confirmed by invasive testing by CVS or amniocentesis before making major medical decisions regarding the pregnancy.
Woman who is at low prior risk, e.g. 1 in 1,000 (0.1%) of her fetus having trisomy 21.
This may apply to a young woman with normal fetal ultrasound, or a woman with a low probability result from conventional first trimester screen.
If the NIPT result is LOW PROBABILITY of trisomy 21
The negative predictive value of the test for this patient would be approximately 99.99% i.e. it is almost certain that the result is correct, and that the fetus does not have trisomy 21. However, there is a very small chance (approximately 1 in 10,000) that this normal test result is incorrect.
If the NIPT result is HIGH PROBABILITY of trisomy 21
The positive predictive value of the test for this patient would be approximately 50% i.e. it is likely but not definite that the result is correct, and that the fetus has trisomy 21. However, there is a 50% chance that this abnormal test result is incorrect.
A high probability NIPT result is more likely to be correct than a high probability conventional first trimester screen. Nonetheless, a high probability NIPT result must be confirmed by invasive testing by CVS or amniocentesis before making major medical decisions regarding the pregnancy.
Woman who is at increased prior risk, e.g. 1 in 100 (1%) of her fetus having trisomy 21.
This may apply to an older woman, or a woman with a high probability result from conventional first trimester screen.
If the NIPT result is LOW PROBABILITY of trisomy 21
The negative predictive value of the test for this patient would be >99.9% i.e. it is highly likely that the result is correct, and that the fetus does not have trisomy 21. However, there is a very small chance (approximately 1 in 5,000) that this normal test result is incorrect.
If the NIPT result is HIGH PROBABILITY of trisomy 21
The positive predictive value of the test for this patient would be approximately 90% i.e. it is very likely that the result is correct, and that the fetus has trisomy 21. However, there is a 10% chance that this abnormal test result is incorrect.
A high probability NIPT result is more likely to be correct than a high probability conventional first trimester screen. Nonetheless, a high probability NIPT result must be confirmed by invasive testing by CVS or amniocentesis before making major medical decisions regarding the pregnancy
Woman who is at high probability, e.g. 1 in 10 (10%) of her fetus having trisomy 21.
This may apply to an older woman, or a woman with a very high probability result from conventional first trimester screen, or evidence of fetal malformations on ultrasound.
If the NIPT result is LOW PROBABILITY of trisomy 21
The negative predictive value of the test for this patient would be 99% i.e. it is likely that the result is correct, and that the fetus does not have trisomy 21. However, there is an approximately 1% chance that this result is incorrect for trisomy 21. In addition, this result does not preclude a chromosome disorder other than trisomy 21 being the underlying cause of her being identified as “high prior probability”. Invasive testing by CVS or amniocentesis with cytogenetic studies may still be warranted to check for a chromosome abnormality other than trisomy 21.
If the NIPT result is HIGH PROBABILITY of trisomy 21
The positive predictive value of the test for this patient would be approximately 99% i.e. it is very likely that the result is correct, and that the fetus has trisomy 21. Invasive testing by CVS or amniocentesis with cytogenetic studies would be warranted to confirm the diagnosis of trisomy 21.
Given that both a “low probability” result and a “high probability” result yield the same recommendation for invasive genetic testing, NIPT is not recommended as a screening test in women if there is a high prior probability of a chromosome abnormality.
Why is NIPT sometimes incorrect?
It is important to note the DNA fragments that are tested by NIPT are derived from the placenta and not the fetus. The placenta and fetus develop from the same cell i.e. the fertilised egg, and almost always have the same number of chromosomes. However, there are exceptions, and these can account for those uncommon situations in which the NIPT result does not match the fetal chromosomes.
For this reason, NIPT must be regarded as a screening test i.e. there is a small well-defined possibility that the NIPT will not reflect the actual chromosome status of the fetus. A “high probability” result should be confirmed by invasive genetic testing (CVS or amniocentesis) before taking irreversible steps in the management of the pregnancy. Conversely, a “low probability” result may still warrant invasive genetic testing if there are other indicators of a fetal chromosome disorder.
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