Cystic Fibrosis Screening for Newborns

In the case of most diseases screening is an important preventative step within diagnostics, and due to the genetic basis of cystic fibrosis (CF), the screening of infants is gaining attention and supplemental research. For example, according to a report in the journal Pediatrics, the state of California has recently developed a three-step newborn screening model for CF which has shown signs of high efficiency, sensitivity, positive predictive value and low false positives in the first five years.1

“This is very important as many of the newborns born with CF are born to parents who never new CF was part of their family history, probably because only carriers of mutations existed in the family,” explained Gregory J. Tsongalis, PhD, HCLD, CC, professor of pathology and director of the Laboratory for Clinical Genomics and Advanced Technology (CGAT) at the Dartmouth Hitchcock Medical Center and the Audrey and Theodor Geisel School of Medicine at Dartmouth in Lebanon, N.H.

Caused by mutations of the cystic fibrosis transmembrane (CFTR) gene, CF currently has no cure and its consequential mutations are known to cause a build-up of thick mucus which can clog the gastrointestinal tract or airways. These mutations result from the malfunction of cell proteins that, when functioning normally, channel chloride ions and water out of cells. This malfunction disrupts the body’s natural balance of salt and water needed to maintain a normal, thin coating of fluid and mucus inside the lungs and in the passageways of other organs.

Infant CF

According to the Cystic Fibrosis Foundation, newborn screening for CF is done in the first 2 or 3 days after birth ( This early diagnosis can lead to the possibility of early treatment and thus may help prevent serious, lifelong problems in those with this disease. Furthermore, by diagnosing CF early, CF healthcare providers can work with parents to inform them of ways to help keep their child as healthy as possible and to delay or prevent many future health problems related to the disease.

“Newborn screening is accepted everywhere as a state-of-the-art standard of care. There have been studies which go back over a decade now finding that the earlier you pick up CF the better the patients do in the long run,” explained Stanley Fiel, MD, regional chair of medicine and director of adult cystic fibrosis program at Morristown Medical Center in Morristown, N.J.

SEE ALSO: Promising Treatments for Cystic Fibrosis

Additionally, research has shown that children who receive treatment and care for CF early in life have better nutritional and overall health results than those diagnosed later, also as reported by the CFF. By monitoring CF from birth, patients can have years added to their lives, reduced hospital stays, healthier weights and heights, improved growth and lung function.

Assisting in the maintenance of health growth patterns in children with the disease, CF centers now pay particular attention to changes in growth measurements as useful markers of nutrition and disease activity through the implementation of standardized growth charts. This can also help initiate more rigorous evaluations and interventions aimed at providing optimal care to these young patients, as stated in the November 2015 article, “Charting the course of young children with cystic fibrosis,” in Pediatrics.2

The Standard Process

Typically, days after a child is born a healthcare provider in a hospital setting will acquire a few drops of blood from a heel prick of the child. They will then place this blood sample on a special pre-printed collection card, known as a Guthrie card.

Along with a baby’s information, this card is then mailed to a state laboratory which tests the sample for CF. A second test a few weeks later is often conducted as well to check the levels of immunoreactive trypsinogent (IRT), a chemical made by the pancreas.

“The disease is very variable. There’s a large group of patients who are more similar in the way that they respond as infants, but there’s also a group, more of a minority, who have milder phenotypes,” further explained Fiel. “However, when the disease is diagnosed in infants they can immediately start receiving the proper medications to avoid loss of lung function and the possibility of later being mistakenly treated for allergy or asthma.

IRT is normally found in small levels in the body, but in people who have CF, IRT levels tend to be elevated. Based on a newborn baby’s screening results, guardians may be asked to bring him or her to a CF Foundation-accredited care center for sweat testing to determine the child’s possession of a gene mutation. It is important to note that there is no correlation with the sweat value and worsened effects of the disease.

After the sweat test, molecular analyses are also conducted to show with categorization the CFTR defect, where the gene causes an abnormality in the production of the protein. This is critical because knowing what category a mutation falls into will help determine what the proper therapies are.

California’s New Process

The California program was developed after more than five years of research to identify the ideal Immunoreactive trypsinogen (IRT) cut point and CF mutation panel to maximize CF detection, while minimizing detection of false positives. According to the report, the three steps consist of measuring immunoreactive trypsinogen in all dried blood spot specimens, testing from 28 to 40 selected CF transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values of at least 62 ng/mL (top 1.6%), and performing DNA sequencing on specimens found to have only one mutation in step 2.

Next, Infants with two or more mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with one mutation were considered carriers and their parents offered telephone genetic counseling. From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened using this process.

In total, the program identified 345 CF cases, 533 CFTR-related metabolic syndrome (CRMS) cases, and 1,617 carriers; 28 cases of CF were missed. Of the 345 patients with CF, 20 (5.8%) infants were initially assessed as having CRMS; their CF diagnosis occurred after age 6 months.

“Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births,” Martin Kharrazi, PhD, MPH, from the California Department of Public Health, Richmond, and colleagues wrote, according to Medscape3. “A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days.”

These findings came from a large group of more than 2.5 million newborns and the screened group was also highly diverse. Genotyping, as part of screening, was comprehensive in terms of mutations and Intron 8 Poly (T) Tract status before referral to CF specialty care centers.

“The California program is exceeding its goal of 90% detection in California’s three main subgroups (Hispanics, Whites and African-Americans),” stated the California Department of Public Health. “The comprehensive CF mutation testing conducted in California most accurately identifies babies who are true non-disease “carriers” from those who carry a second CF mutation, some of whom may convert to CF or a more mild single-organ disease in the future and benefit from the specialized care provided at a CF center.”

In a statement to ADVANCE, the California Department of Public Health explained that this three-step approach is different from two-step processes used in other programs for three major reasons. First, the IRT cut point is higher than other programs in the U.S., but lower than that in many other parts of the world (98.4% in California vs. 95-96% in other states vs. 99-99.5% in other countries).

Second, the mutation panel is tailored to the diverse California population and is restricted to CF-causing mutations, compared to other states that use commercially available products that include common mutations of varying clinical consequence and other mutations that are predominantly found in White populations. Finally, California’s approach is unique in using comprehensive DNA sequence testing of the CF gene for those found to have only one panel mutation and only refers babies with two or more mutations identified for diagnostic testing. Other states refer babies with one or more mutations after panel testing.

Utilizing this method, newborn screening for cystic fibrosis can progress as a vital tool to help slow the progression of the fatal genetic disease. Without the screening of newborns, irreversible damage to the lungs and digestive system may occur, and families could spend years of anguish trying to understand their child’s health condition before a CF diagnosis is reached.

Lindsey Nolen is a staff writer. Contact:

1. Pediatrics. Newborn Screening for Cystic Fibrosis in California. Available at:
2. The Journal of Pediatrics. Charting the course of young children with cystic fibrosis. Available at:
3. Medscape. Chronic fatigue syndrome: A toolkit for providers. Available at:

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