Newborn Screening Clinical Care Guidelines

Newborn screening for cystic fibrosis has been implemented nationwide since 2010, but differences in state screening algorithms and follow-up practices have led to variation in equity, sensitivity, and timeliness of diagnosis. This evidence based consensus guideline provides recommendations to improve consistency and optimize CF newborn screening across the United States.

7 min read

Cystic Fibrosis Newborn Screening: A Systematic Review-Driven Consensus Guideline from the United States Cystic Fibrosis Foundation

McGarry ME, Raraigh KS, Farrell P, et al. Cystic Fibrosis Newborn Screening: A Systematic Review-Driven Consensus Guideline from the United States Cystic Fibrosis Foundation. International Journal of Neonatal Screening. 2025, 11(2); 24. https://doi.org/10.3390/ijns11020024.

Purpose and Background

Newborn screening for cystic fibrosis has been performed in all U.S. states since 2010, but variations in screening and follow-up practices among states can lead to differences in equity, sensitivity, and timeliness of intervention. These variations prompted the development of this evidence-based consensus guideline on CF newborn screening.

As of 2025, all CF newborn screening algorithms in the United States include an initial biochemical screen for immunoreactive trypsinogen (IRT). If IRT levels are elevated, targeted molecular analysis is performed using a cystic fibrosis transmembrane conductance regulator gene (CFTR) variant panel. Some programs also include CFTR gene sequencing for infants with only one variant found using the CFTR panel. Newborn screening is not meant to be diagnostic; infants who screen positive are referred for diagnostic sweat chloride testing.

Newborn screening programs develop and validate screening algorithms and practices. Programs aim to maximize the proportion of infants with CF identified by screening and to minimize the number of false positive screens by optimizing IRT cutoffs and implementing variant panels and referral algorithms tailored to the ancestral groups present in their state’s population.

Methodology

The Cystic Fibrosis Foundation convened a multidisciplinary committee comprised of clinicians and researchers with expertise in CF, primary care, genetic counseling and newborn screening, parents of children with CF, and CF Foundation staff. Recommendation statements were voted on after systematic reviews related to newborn screening processes affecting equity, sensitivity, and timeliness of diagnosis had been performed using a population, intervention, comparison, and outcome (PICO) framework.

Key Recommendations

For details, please refer to published guidelines. All recommendations reached 100% consensus.

Type	Recommendations	Evaluation of the Evidence
IRT	1. The Cystic Fibrosis Foundation recommends the use of a floating IRT cutoff over a fixed immunoreactive trypsinogen cutoff.	100% Consensus
	2. The Cystic Fibrosis Foundation recommends using a very high IRT referral strategy in CF newborn screening programs whose variant panel does not include all CF-causing variants in CFTR2 or does not have a variant panel that achieves at least 95% sensitivity in all ancestral groups within the state.	100% Consensus
CFTR Variant Testing	3. The Cystic Fibrosis Foundation recommends that CF newborn screening algorithms should not limit CFTR variant detection to the F508del variant or variants included in the ACMG-23 panel.	100% Consensus
	4. The Cystic Fibrosis Foundation recommends that CF newborn screening programs screen for all CF-causing CFTR variants as identified by CFTR2.	100% Consensus
	5. The Cystic Fibrosis Foundation recommends conducting CFTR variant screening twice weekly or more frequently as resources allow.	100% Consensus
CFTR Sequencing	6. The Cystic Fibrosis Foundation recommends the inclusion of a CFTR sequencing tier following IRT and CFTR variant panel testing to improve the specificity and positive predictive value of CF newborn screening.	100% Consensus
Communication	7. The Cystic Fibrosis Foundation recommends that both the primary care provider and the CF specialist be notified of abnormal newborn screening results.	100% Consensus

CFTR=Cystic fibrosis transmembrane conductance regulator gene; CFTR2=Clinical and Functional Translation of CFTR database; ACMG=American College of Medical Genetics and Genomics; ACMG-23=23 variants recommended for population-based CF carrier screening by the ACMG in 2004.

Unanswered Questions

How should newborn screening programs address cost-effectiveness, resource allocation, and implementation strategies when making changes to their algorithms?
Is there an ideal IRT percentile cutoff, and how should cutoffs be calculated? For example, should there be considerations based on population size and composition, specimen collection parameters, or other factors?
How can newborn screening programs overcome the lack of commercially available kits that target all CF-causing variants recommended for CFTR genotyping?
The Cystic Fibrosis Foundation has published a guideline for management of CFTR-related metabolic syndrome (CRMS)/cystic fibrosis screen-positive, inconclusive diagnosis (CFSPID), but how should newborn screening programs tailor algorithms to minimize the detection of infants with CRMS/CFSPID, while still achieving high sensitivity of screening for CF?
Despite CF affecting people of all races, ethnicities, and ancestries, there are numerous barriers to equity in CF newborn screening.
- How can culturally aware communication with families improve timeliness and follow-up?
- How can the detection of CFTR variants be improved in ancestral populations with rare and/or understudied CFTR variants (e.g., Asian and African populations)?
- How can we raise awareness in the medical field that CF can occur in all races, ethnicities, and ancestries despite the traditional teaching that it primarily affects the non-Hispanic white population?
What are the best practices to improve communication among the newborn screening program, primary care provider, and CF specialist?
What are best practices to screen and diagnose infants for whom the typical CF newborn screening process may not occur as intended, such as infants in remote rural areas, infants born in other countries due to parental military deployment or other employment, infants using tribal health services, infants previously exposed to CFTR modulators in utero, and infants in the neonatal intensive care unit?
How would regionalization of CF newborn screening (i.e., one newborn screening lab providing services for multiple states) impact sensitivity, equity, cost, and timeliness?

Use of This Guideline Executive Summary

The CF Foundation intends for this executive summary of its guideline to summarize the published guideline. The published guideline summarizes evidence, and provides reasonable clinical recommendations based on that evidence, to clinicians, patients, and other stakeholders. Care decisions regarding individual patients should be made using a combination of these recommendations, the associated benefit-risk assessment of treatment options from the clinical team, the patient’s individual and unique circumstances, as well as the goals and preferences of the patients and families that the team serves, as a part of shared decision-making between the patient and clinician. The guideline is intended to be location agnostic and is applicable to individuals with CF in all settings including but not limited to outpatient clinics, hospitals, in-home, psychiatric facilities, long-term care facilities, incarceration, detention, and foster care settings.

This executive summary was prepared by:

Denise M. Kay, PhD (New York State Department of Health)

Meghan E. McGarry, MD MAS (University of Washington)

The guidelines were published in April 2025.

Share this article

Topics

Clinical Care Guidelines | Clinician Resources