Newborn screening (NBS) for cystic fibrosis (CF) is a standard public health measure implemented across the United States and many other nations. CF is a serious, inherited disorder caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. This gene disruption impairs the movement of salt and water in and out of cells, leading to the production of thick, sticky mucus. This mucus clogs pathways in the lungs and pancreas, causing severe health complications. Early detection through NBS allows for prompt intervention, which improves long-term health outcomes for affected children.
The Multi-Step Screening Process
The initial step in CF newborn screening uses a dried blood spot collected from a baby’s heel. This sample is analyzed for Immunoreactive Trypsinogen (IRT), a precursor to a pancreatic digestive enzyme. In infants with CF, pancreatic duct blockages cause IRT to leak into the bloodstream, resulting in high concentrations. Measuring IRT is a sensitive method for identifying babies at risk.
If the IRT level is elevated, the process moves to a second stage using the same sample. This involves screening for common mutations in the CFTR gene, which is the root cause of the disorder. Laboratories test for a panel of frequently occurring CFTR gene changes, aiming to identify one or two copies of a disease-causing variant. An abnormal screen result is defined by a high IRT level combined with the detection of at least one CFTR mutation. Because the screening is highly sensitive to avoid missing affected infants, follow-up diagnostic testing is always necessary.
Understanding False Results
Since the newborn screen is not diagnostic, inaccurate results are possible, commonly categorized as false positives and false negatives. A false positive occurs when the screen is abnormal, suggesting CF, but subsequent diagnostic testing proves the baby is unaffected. This is the most frequent screening error, accounting for approximately 90% of positive newborn screens.
False Positives
False positive results often occur because IRT levels are temporarily elevated for reasons unrelated to CF. For example, babies born prematurely or those who experienced a stressful or traumatic birth may have high IRT concentrations. The most common reason, however, is that the infant is a CF carrier, possessing only one mutated CFTR gene. The screening panel detects this single mutation, but the child’s second, healthy gene prevents them from developing CF symptoms.
False Negatives
A false negative result is much rarer, occurring when the newborn screen is reported as normal, yet the baby actually has CF. This can happen if the baby has a very rare CFTR mutation that is not included in the standard screening panel. A false negative can also occur if the baby’s IRT level is not high enough to trigger the second-tier genetic testing. This may happen in cases of meconium ileus or if a suboptimal cutoff value is used for IRT measurement. Although rare, a false negative is a serious concern because it delays diagnosis and subsequent treatment.
The Diagnostic Confirmation: The Sweat Test
Following an abnormal or inconclusive newborn screening result, the definitive step is the Sweat Chloride Test, considered the gold standard for confirming or ruling out CF. This test measures the concentration of chloride in the baby’s sweat. Individuals with CF have significantly higher amounts of salt in their sweat due to the malfunctioning CFTR protein. The procedure is non-invasive and painless, typically performed at a specialized center.
Sweat Test Procedure
The test begins by applying the chemical pilocarpine to a small patch of skin, usually on the arm or leg. A mild electrical current then safely stimulates the sweat glands to produce sweat, a process called iontophoresis. The sweat is collected on filter paper or gauze for approximately 30 minutes. The test is generally performed when the baby is between ten days and four weeks old, as a full-term infant produces enough sweat for a reliable sample by two weeks of age.
Interpreting Results
Results are measured in millimoles per liter (mmol/L) of chloride concentration. A result of 60 mmol/L or greater strongly indicates CF, while a result of 29 mmol/L or less makes CF unlikely. If the sweat test results are indeterminate, falling between 30 and 59 mmol/L, comprehensive CFTR gene sequencing is used as a secondary confirmatory step. This genetic analysis looks for a broader range of mutations than the initial newborn screen to clarify the diagnosis.