Practice Guidelines

CDC Releases Recommendations for State Newborn Screening Programs for Cystic Fibrosis

matthew j. neff

The Centers for Disease Control and Prevention (CDC) released recommendations on the screening of newborns for cystic fibrosis. The report includes an evaluation of the benefits and risks of this type of screening. It also provides recommendations on how to effectively implement screening programs for states that choose to routinely screen newborns for cystic fibrosis. The recommendations were published in the October 15, 2004, recommendations and reports series of Morbidity and Mortality Weekly Report. The full report is available online at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5313a1.htm. An editorial discussing these guidelines also appears in this issue of American Family Physician on page 1482.

In November 2003, the CDC and the Cystic Fibrosis Foundation (CFF) cosponsored a workshop to examine the benefits and risks of newborn screening for cystic fibrosis. The three objectives of the workshop were: (1) to review and evaluate the scientific evidence on the benefits and risks of newborn screening for cystic fibrosis; (2) to review screening, diagnostics, and follow-up concerns when making decisions about newborn screening for cystic fibrosis; and (3) to disseminate information about models and best practices for states that choose to adopt newborn screening for cystic fibrosis.

Evidence presented at the workshop supported the clinical utility of this type of screening. Demonstrated benefits include improved growth and cognitive development, reduced hospitalizations, and improved survival. Risks include psychosocial effects for carrier children and their families, and exposure of children to infectious agents through person-to-person transmission in clinical settings.

Background

Cystic fibrosis is the second most common life-shortening, childhood-onset inherited disorder in the United States, behind sickle cell disease. Annually, about 1,000 persons in the United States are diagnosed with cystic fibrosis. In 1979, a test to measure the levels of immunoreactive trypsinogen (which is substantially elevated in newborns with cystic fibrosis) in dried blood spots was introduced and made universal newborn screening for cystic fibrosis possible. This test is now the basis for newborn screening protocols.

In 15 to 20 percent of children with cystic fibrosis, the first symptom is meconium ileus; adverse outcomes include malnutrition, lung disease, and mortality. Because meconium ileus is diagnostic for cystic fibrosis, screening does not increase early detection for these children.

Early recognition of cystic fibrosis based on symptoms often is difficult because the majority of symptoms are not specific to the condition. Therefore, affected children are often diagnosed with celiac disease, food allergies, asthma, or bronchitis. The consequences of misdiagnosis include unnecessary diagnostic tests and hospitalizations, multiple office visits, cost to the health care system, and anxiety for parents.

The median age at diagnosis for all persons with cystic fibrosis in the United States is 5.3 months. The overall median age at diagnosis includes infants diagnosed soon after birth based on newborn screening, prenatal screening, family history, or the presence of meconium ileus. The median age at diagnosis based on signs and symptoms other than meconium ileus is 14.5 months, compared with 0.2 months in those with meconium ileus and 0.5 months for those receiving newborn screening. A diagnosis based on symptoms is associated with a more than twofold greater risk of medical complications before diagnosis than a diagnosis resulting from screening. Adverse psychosocial effects for the child's family also may result during the delay between the appearance of cystic fibrosis-related symptoms and diagnosis.

In 1999, a CFF consensus panel developed a new case definition for cystic fibrosis based on the following criteria: the presence of at least one characteristic phenotypic feature or a history of cystic fibrosis in a sibling or a positive newborn screening test, together with laboratory evidence of an abnormality in the gene that regulates expression of the cystic fibrosis transmembrane conductance regulator protein as documented by (1) elevated sweat chloride concentrations, (2) identification of two mutations associated with cystic fibrosis, or (3) in vivo demonstration of characteristic abnormalities in ion transport across the nasal epithelium. Sweat testing can be performed accurately on most infants at two to three weeks of age, but not all infants have sufficient quantities of sweat for reliable testing. Although a sweat chloride level of 60 mEq per L is diagnostic of cystic fibrosis, infants with cystic fibrosis often have initial sweat values of 30 to 59 mEq per L.

In 2000, approximately 400,000 children (10 percent) born in the United States were screened for cystic fibrosis, and this number was expected to increase to 800,000 in 2004. Screening protocols for cystic fibrosis are listed in the accompanying table.

Screening Protocols for Cystic Fibrosis
Protocol	Action after elevated IRT on first specimen	Result of DNA assay on first specimen	Action	Result of repeat DNA assay on first specimen	Action	Result of IRT assay on second specimen	Action
IRT-repeat IRT	Test second specimen for IRT					Exceeds cutoff	Refer to sweat test
IRT-DNA (F508)	DNA assay for F508 alleles	One to two mutations detected	Refer to sweat test
		No mutation detected				Exceeds cutoff	Refer to sweat test
IRT-DNA (multiple mutations)	DNA assay for multiple mutations	One to two mutations detected	Refer to sweat test
IRT-DNA (F508, multiple mutations)	DNA assay for F508 alleles	Two mutations detected	Refer to sweat test or treatment	Two mutations detected	Refer to sweat test or treatment
		One mutation detected	DNA assay for multiple mutations	One mutation detected	Inconclusive result reported
IRT = immunoreactive trypsinogen. Adapted from Grosse SD, Boyle CA, Botkin JR, Comeau AM, Kharrazi M, Rosenfeld M, et al. Newborn screening for cystic fibrosis: evaluation of benefits and risks and recommendations for state newborn screening programs. MMWR Recomm Rep 2004;53(RR-13):7.

Scientific Evidence

The CDC performed a search of the MEDLINE database for articles on newborn screening for cystic fibrosis published since 1997. Relevant articles had to measure patient-oriented outcomes (either health outcomes or psychosocial outcomes) in groups of children identified with cystic fibrosis through newborn screening compared with children identified through other means. The group also included findings from previously published studies that were identified in reference lists. The report summarizes current knowledge concerning the strength of evidence for health benefits of newborn screening for cystic fibrosis, including assessments of the strengths and limitations of study designs and the consistency and magnitude of reported benefits.

Benefits

growth and nutrition

The most clearly defined benefit of newborn screening for cystic fibrosis is improved growth in affected children. One study found long-term improvements in height-for-age measures and reductions in chronic malnutrition. Results of another study demonstrated that the height advantage in children who were screened persisted through at least 10 years of age.

cognitive development

Newborn screening has been shown to positively influence neurodevelopment in a subset of children with cystic fibrosis. A study of school-age children and adolescents found moderate, clinically significant improvements in general cognitive ability in those with vitamin E deficiency at the time of diagnosis.

hospitalization

Studies have shown a substantial benefit of newborn screening in reducing the days of hospitalization for children with cystic fibrosis. However, the authors state that a preliminary analysis of retrospectively collected data from a randomized controlled trial did not show this to be the case. Studies also have shown that newborn screening can reduce costs to the health care system with regard to hospitalizations and reduced ordering of sweat tests.

survival

Several studies have reported proportional reductions of at least 50 percent in mortality rates among children with cystic fibrosis who are diagnosed by newborn screening. However, the authors point out that child mortality as a result of cystic fibrosis is low in absolute terms and the majority of findings from individual studies lack statistical significance.

pulmonary status

The effect of newborn screening on pulmonary status among patients with cystic fibrosis as measured by chest radiography and lung function is uncertain. Three studies have shown evidence of less severe lung damage among children identified by newborn screening; no difference in lung function was demonstrated in two of those studies. One Australian study reported evidence of better lung function and less lung damage among children with cystic fibrosis who were born after screening was implemented.

health-related quality of life

Evidence is lacking for improved health-related quality of life as a patient-oriented outcome measure for the efficacy of newborn screening for cystic fibrosis. Differences in health-related quality of life may be related directly to the frequency of pulmonary exacerbations and treatment interventions, including hospitalization, and not to nutritional status or lung function.

distribution of benefits

The benefits of screening are more significant for certain children. For example, greater growth is primarily of benefit to children who would have been below the normal range in the absence of screening. The cognitive benefits from screening are greater among children who are at risk for micronutrient deficiency. Newborn screening for cystic fibrosis is most likely to be helpful for children who do not receive a prompt diagnosis despite severe disease manifestations. Although child mortality from cystic fibrosis is low, early detection may save an infant from a life-threatening event, such as hyponatremic dehydration. However, persons with pancreatic sufficiency may not benefit from newborn screening. Also, the 20 percent of patients with meconium ileus do not appear to benefit from newborn screening for cystic fibrosis because they generally receive a diagnosis at birth.

benefits to families

In addition to the health benefits for the children, the families may benefit from the elimination of diagnostic concerns, the value of the genetic risk information gained, and the potential for identifying older siblings who are symptomatic but have not received a diagnosis of cystic fibrosis.

Risks

The potential for harm from person-to-person transmission can be avoided through involvement of newborn screening programs with cystic fibrosis care centers and adoption of infection control practices. Other potential negative outcomes from screening include the psychological and social effects of carrier identification for parents and children and the effects of false-positive results. Screening programs should focus on ways to minimize parental anxiety and misunderstanding through better communication of screening results and provision of information about newborn screening.

Recommendations

From the preponderance of evidence, the authors conclude that the health benefits of screening newborns for cystic fibrosis outweigh the risk of harm. They recommend that states consider routine newborn screening for cystic fibrosis in conjunction with systems to ensure access to high-quality care. The following is a list of the specific recommendations from the report:

• When deciding whether to add newborn screening for cystic fibrosis, states should consider available state resources and priorities as well as available national guidelines regarding cystic fibrosis screening, diagnosis, and treatment.

• States that implement newborn screening for cystic fibrosis should collect follow-up data in collaboration with cystic fibrosis care centers and should analyze this information to monitor and improve the quality of cystic fibrosis newborn screening. In particular, states should collect, share, and analyze data by using standard protocols to evaluate and optimize laboratory algorithms used to screen for cystic fibrosis and refer for diagnosis. States seeking guidance on optimal laboratory protocols might wish to consult with states that have more experience in screening for cystic fibrosis in newborns.

• Newborn screening for cystic fibrosis should be accompanied by rigorous infection control practices to minimize the risk to children with cystic fibrosis detected at an early age of acquiring infectious organisms associated with lung disease from older patients. Further research is needed to evaluate and optimize these practices.

• Newborn screening systems should ensure education of parents and health care professionals and communication of screening results to primary care physicians in a manner that will ensure prompt referral to diagnostic centers. For cystic fibrosis, these should be centers skilled in providing sweat tests to young, presymptomatic children with cystic fibrosis and accurate and effective counseling to families, including those with infants identified as carriers. States are encouraged to work with each other and with professional organizations and federal agencies to develop approaches to provide newborn screening information to parents during the prenatal and perinatal periods on all conditions, including cystic fibrosis, to facilitate informed choices and appropriate responses to positive screening results.

Practice Guideline Briefs

Matthew J. Neff

Improving the Quality of Care for Adults with Type 2 Diabetes Mellitus

The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services has released a technical review on improving the quality of health care for adult patients with type 2 diabetes mellitus. "Closing the Quality Gap: A Critical Analysis of Quality Improvement Strategies. Volume 2-Diabetes Mellitus Care” was released in September 2004 as AHRQ Publication No. 04-0051-2 and is available online at http://www.ahrq.gov/clinic/evrptpdfs.htm#qualgap2.

Diabetes affects more than 17 million people in the United States, and, factoring in undiagnosed cases of diabetes and impaired glucose tolerance, one in seven Americans either has diabetes or is at high risk for developing it. According to the authors, the quality of care for patients with diabetes is less than optimal because many of these patients are not receiving established processes of care (e.g., eye and foot screening) or achieving optimal outcomes (e.g., controlled hemoglobin A1C levels).

The researchers searched the MEDLINE database, the Cochrane Collaboration's Effective Practice and Organisation of Care registry, article bibliographies, and relevant journals for experimental evaluation of quality-improvement interventions in the outpatient care of adults with type 2 diabetes mellitus.

Quality-improvement targets included measures of disease control (e.g., serum A1C levels, blood pressure) and physician adherence (e.g., serial monitoring of A1C levels, control of hypertension, management of cardiovascular risk factors). The researchers found 58 articles reporting a total of 66 trials that met the established inclusion criteria. The most common quality-improvement interventions tested in these studies were organizational change (40 trials), patient education (28 trials), and physician education (24 trials). Fifty-two trials involved interventions that used more than one quality-improvement strategy.

The researchers did not find any strategy to be unambiguously beneficial in the care of patients with diabetes. The physician-education strategy produced large median effects for glycemic control and physician adherence, but the findings were of only borderline significance. Interventions that used case- or disease-management strategies resulted in significantly greater median reductions in serum A1C levels compared with interventions that lacked a component of disease management; however, this trend did not reach statistical significance. All of the other quality-improvement strategies that were evaluated failed to improve serum A1C levels or physician adherence to an appreciable extent. In the larger randomized trials, employing more than one quality-improvement strategy appeared to be more beneficial than single-faceted interventions; however, the small number of studies limits the reliability of this finding.

Overall, the review found that multifaceted interventions may be more likely than single-faceted interventions to have positive effects on glycemic control and physician adherence. However, the conclusions are limited by probable publication bias favoring smaller trials and nonrandomized trials, and the presence of multiple quality-improvement strategies in a given intervention.

ACS Releases 2005 Edition of Cancer Facts & Figures

The American Cancer Society (ACS) released the 2005 edition of its annual publication, Cancer Facts & Figures, which provides a concise summary of the most frequently used cancer statistics, estimates of new cancer diagnoses and deaths for the current year, and national and state data on incidence, mortality, survival, and cancer risk factors. The report is available on the American Cancer Society Web site at http://www.cancer.org.

This year's edition also features a special section on cancers caused by infectious disease. The report estimates that in 2005, 17 percent of new cancer diagnoses worldwide will be attributable to infection. These figures include 5 million diagnoses (26 percent of new cases) in developing countries and 360,000 diagnoses (7.3 percent of new cases) in developed countries.

Other statistics include:

Answers to This Issue's Clinical Quiz Q1. C Q2. B Q3. A Q4. C Q5. C Q6. B Q7. B Q8. A, B, C Q9. C, D Q10. B, D Q11. A, B, C Q12. B, D

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