An inconclusive result from a Non-Invasive Prenatal Test (NIPT) can cause anxiety, but it is important to understand what this result means. The NIPT is a screening tool that analyzes cell-free DNA (cfDNA) fragments from the placenta circulating in the mother’s bloodstream to assess the risk for certain chromosomal conditions. When the test is inconclusive, often called a “no call,” the laboratory could not gather sufficient genetic information to provide a reliable risk assessment. This outcome is a technical limitation and does not automatically indicate a problem with the developing baby.
Understanding the Technical Basis of an Inconclusive Result
An inconclusive NIPT result means the laboratory was unable to obtain enough data for a confident risk determination. The central technical concept is the Fetal Fraction (FF), which is the percentage of cell-free DNA in the maternal blood sample that originates from the placenta. Laboratories require a minimum FF, typically ranging from 2% to 4%, for the test to be reliable. If the FF falls below this threshold, the small amount of placental DNA is masked by the larger volume of maternal DNA. This prevents the accurate distinction between normal and abnormal chromosomal patterns, resulting in a “no call.”
Primary Factors Contributing to Insufficient Fetal DNA
The most frequent reason for a low Fetal Fraction is related to the timing of the test. The amount of fetal DNA naturally increases as the pregnancy progresses, so testing too early is a common cause of an inconclusive result. While NIPT is often available starting at 10 weeks of gestation, testing precisely at the minimum gestational age may mean the FF is at the lower end of the detectable range.
Maternal Body Mass Index (BMI) is another major factor that can dilute the concentration of fetal DNA. A higher BMI is associated with a larger maternal blood volume, which effectively lowers the proportion of placental DNA in the sample. Studies show that NIPT failure rates increase significantly with higher maternal weight.
In some cases, the problem lies with the placenta itself, known as confined placental mosaicism. This occurs when the placenta’s genetic material differs from the fetus, which can lead to a lower than expected Fetal Fraction. Low FF has also been statistically associated with certain fetal conditions, particularly Trisomy 13 and Trisomy 18, though this is a less common cause than maternal factors.
Maternal Biological Conditions and Sample Constraints
Factors beyond Fetal Fraction can also interfere with the test’s ability to analyze the DNA. The presence of extraneous DNA from the mother can confound the analysis, such as a recent blood transfusion. A transfusion introduces donor DNA fragments into the bloodstream, disrupting the test’s ability to isolate and quantify the cell-free DNA specific to the pregnancy.
Certain underlying maternal health conditions can also complicate the analysis. Undiagnosed maternal malignancy or specific autoimmune disorders can release abnormal amounts of cell-free DNA into the mother’s blood. This excess maternal DNA can overwhelm the sample, making it difficult to differentiate between maternal and placental DNA signals.
Technical issues related to the sample itself, while less common, can also lead to an inconclusive outcome. If the blood sample is not properly handled (e.g., delayed processing or exposure to excessive heat), white blood cells may break down. This process releases a surge of maternal DNA, which rapidly dilutes the Fetal Fraction and prevents a clear reading.
Clinical Management and Next Diagnostic Steps
The most common first step after an inconclusive NIPT result is a retest, ideally performed after a waiting period of a few weeks. The natural progression of pregnancy allows the Fetal Fraction to increase, making a successful result more likely on the second attempt.
If the repeat NIPT is also inconclusive, or if the gestational age is advanced, the healthcare provider will discuss alternative screening and diagnostic options. Non-invasive alternatives include the enhanced First-Trimester Screening or the Second-Trimester Quad Screen. These tests combine blood markers and ultrasound measurements to estimate risk and can provide valuable information, though they are generally less sensitive than NIPT.
For a definitive diagnosis, invasive procedures like Chorionic Villus Sampling (CVS) or Amniocentesis are available. CVS is typically performed between 10 and 13 weeks and samples placental tissue. Amniocentesis is done after 15 weeks and samples amniotic fluid. These diagnostic tests provide a direct analysis of the fetal chromosomes, offering a clear answer despite carrying a small, procedure-related risk of miscarriage.
Interpreting Risk Following an Unsuccessful NIPT Attempt
Receiving an inconclusive result can be unsettling, but in the majority of cases, it does not signal a problem with the fetus. The technical failure is most often attributed to common maternal factors like high BMI or the timing of the blood draw.
However, a persistently low Fetal Fraction, especially after a second inconclusive attempt, can be statistically correlated with a slightly increased chance of certain rare conditions. This correlation exists because some chromosomal abnormalities (such as Trisomy 13 and Trisomy 18) are sometimes associated with placental dysfunction that results in lower fetal DNA release. Follow-up testing is always required to confirm or rule out any underlying concern, as the inconclusive NIPT alone is not a diagnosis.