1. Among infants randomized to undergo either newborn screen with cystic fibrosis (CF) testing included or undergo normal pediatric surveillance, those who underwent newborn screen were diagnosed significantly earlier.
2. Infants diagnosed based on surveillance were significantly more likely to be severely malnourished compared to those diagnosed by newborn screen.
Original Date of Publication: January 2001
Study Rundown: Cystic fibrosis (CF) is an autosomal recessive disease responsible for multi-system organ involvement most commonly secondary to impaired chloride channel transport. Patients with CF often experience pulmonary, sinus, endocrine, and nutrition complications. At the time of this study’s publication, many patients were diagnosed through sweat testing following recognition of signs/symptoms linked to the disease. In 1996, the average age of diagnosis was 5 years and this delay in diagnosis was associated with worse nutritional status and lung disease. In order to provide support for a recommendation for CF diagnosis via newborn screening, this clinical trial investigated the potential benefits of neonatal screening on nutrition outcomes. Infants were diagnosed using testing for elevated immunoreactive trypsinogen (IRT), which was later modified to include both IRT and DNA testing. A total incidence rate of 1:3938 was seen in the cohort, with those who underwent newborn screening diagnosed significantly earlier than those diagnosed by surveillance. In addition, those who were diagnosed on newborn screening were at significantly lower risk of being severely malnourished (having height and weight values below the 10th percentile) when compared to those diagnosed by surveillance. The randomized and blinded nature of this study strengthened the value of its results; however, it was limited in the change of diagnostic technique partway through the study resulting in a potential decrease in the number of cases identified on newborn screen. This study aided in establishing the value of early diagnosis and early intervention in the care of children with CF. Since the introduction of newborn screening, every state in the United States has adopted use of either IRT or combined IRT-DNA testing. Now, nearly 60% of cases of CF are diagnosed by newborn screen, up from under 10% in 2001, with the average age of diagnosis under 2 years.
In-Depth [blinded, randomized control trial]: From April 1985 to 1998, 2 cystic fibrosis centers along with a newborn screening program in Wisconsin began a randomized clinical trial examining the effects of early screening for CF on nutritional and pulmonary outcomes. Children were randomized to either undergo newborn screening or traditional pediatric follow-up which included being monitored for signs or symptoms of CF during acute and health maintenance visits. Initial newborn screening included the use of IRT analysis, with testing later modified in June 1991 to add DNA testing for ∆F508, the most common CF-related genetic mutation. All children were screened and then randomized such that the control group’s lab results were blinded. These results were eventually unblinded. Positive testing on either the IRT or DNA testing in the screening group resulted in pediatrician-parental contact with the recommendation for a follow-up sweat test when the child was 4 to 6 weeks of age. Children with sweat chloride tests of > 60 mEq/L were diagnosed with CF; those with 40-60 mEq/L were considered to have an indeterminate diagnosis. and those with sweat tests < 40 mEq/L were not diagnosed with CF. Patients presenting with meconium ileus were also put into the “other CF group.” Children diagnosed with CF (both through newborn screening and at a later age) were given the option to enroll for study inclusion. Children with CF underwent standardized nutritional and pulmonary assessments along with therapeutic disease management starting at the time of diagnosis. Surveillance of patient outcomes was performed through healthcare provider-completed surveys and review of birth and death certificates.
A total of 650 341 babies born during the study period were randomized to either undergo newborn CF screening or be in the control group. In total, 325 121 infants were included in the screening group and 325 120 were included in the control group. Among those in the screening group, 220 862 underwent IRT and 104 308 underwent both IRT and DNA testing. Overall, 157 patients were identified with CF. Additional diagnoses on autopsy and from sweat chloride testing in the 40-60 mEq/L range, resulted in a total incidence of CF in this cohort was 1:3938. In removing patients who presented with meconium ileus at birth and those found to have initial false negatives, children who underwent initial newborn screen (n = 56) were diagnosed significantly earlier than those in the control group (n = 107; 13 + 37 wks in screening group v. 107 + 117 in control group, p < 0.001). At the time of diagnosis, those screened had significantly higher length (p < 0.001), weight (p < 0.05), and head circumference (p < 0.01) than those in the control group. Throughout the study, significantly greater odds of being severely malnourished, as determined by having a weight and height below the 10th percentile, was observed in the control group when compared to the screening group (odds ratio for weight = 4.12, 95% CI: 1.64-10.38; odds ratio for height = 4.62, 95% CI: 1.70-12.61). Odds of being below the 10th percentile for height disappeared by 9 years of age for those who were screened early on.
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