PEDIATRICS Vol. 107 No. 1 January 2001, pp. 1-13
Early Diagnosis of Cystic Fibrosis Through Neonatal Screening Prevents Severe Malnutrition and Improves Long-Term Growth
Received Dec 13, 1999; accepted May 11, 2000.
,,
From the * University of Wisconsin Medical School, Madison,
Wisconsin; State Laboratory of Hygiene, Madison, Wisconsin; and the
§ Medical College of Wisconsin, Milwaukee, Wisconsin.
Objective. Despite its relative frequency among autosomal recessive diseases and the availability of the sweat test, cystic fibrosis (CF) has been difficult to diagnose in early childhood, and delays can lead to severe malnutrition, lung disease, or even death. The Wisconsin CF Neonatal Screening Project was designed as a randomized clinical trial to assess the benefits and risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed by comparing 16 demographic variables.
Methodology. Immunoreactive trypsinogen analysis was
applied to dried newborn blood specimens for recognition of CF risk
from 1985 to 1991 and was coupled to DNA-based detection of the 
F508
mutation from 1991 to 1994. Randomization of 650 341 newborns occurred
when their blood specimens reached the Wisconsin screening laboratory. This created 2 groups
an early diagnosis, screened cohort and a
standard diagnosis or control group. To avoid selection bias, we
devised a unique unblinding method with a surveillance program to
completely identify the control subjects. Because sequential analysis
of nutritional outcome measures revealed significantly better growth in
screened patients during 1996, we accelerated the unblinding and
completely identified the control group by April 1998. Having each
member of this cohort enrolled and evaluated for at least 1 year and
having completed a comprehensive surveillance program, we performed
another statistical analysis of anthropometric evaluated indices that
includes all CF patients without meconium ileus.
Results. The incidence of classical CF, ie, patients
diagnosed in this trial with a sweat chloride of 60 mEq/L greater, was
1:4189. By incorporating other CF patients born during the
randomization period, including 2 autopsy diagnosed patients and 8 probable patients, we calculate a maximum incidence of 1:3938 (95%
confidence interval: 3402-4611). Although there were group differences
in the proportion of patients with F508 genotypes and with
pancreatic insufficiency, validity of the randomization plan was
demonstrated by analyzing 16 demographic variables and finding no
significant difference after adjustment for multiple comparisons.
Focusing on patients without meconium ileus, we found a marked
difference in the mean ± standard deviation age of diagnosis for
screened patients (13 ± 37 weeks), compared with the standard
diagnosis group (100 ± 117). Anthropometric indices of
nutritional status were significantly higher at diagnosis in the
screened group, including length/height, weight, and head
circumference. During 13 years of study, despite similar nutritional
therapy and the inherently better pancreatic status of the control
group, analysis of nutritional outcomes revealed significantly greater
growth associated with early diagnosis. Most impressively, the screened group had a much lower proportion of patients with weight and height
data below the 10th percentile throughout childhood.
Conclusions. Although the screened group had a higher proportion of patients with pancreatic insufficiency, their growth indices were significantly better than those of the control group during the 13-year follow-up evaluation and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change when the height and weight data before 4 years of age for the controls detected by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the significant differences. Therefore, selection bias has been eliminated as a potential explanation. In addition, the results show that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible. We conclude that early diagnosis of CF through neonatal screening combined with aggressive nutritional therapy can result in significantly enhanced long-term nutritional status. Key words: cystic fibrosis, neonatal screening, malnutrition, long-term growth.
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