Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth

Objective. Despite its relative frequency among autosomal recessive disease s and the availability of the sweat test, cystic fibrosis (CF) has been dif ficult to diagnose in early childhood, and delays can lead to severe malnut rition, lung disease, or even death. The Wisconsin CF Neonatal Screening Pr oject was designed as a randomized clinical trial to assess the benefits an d risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed b y comparing 16 demographic variables. Methodology. Immunoreactive trypsinogen analysis was applied to dried newbo rn blood specimens for recognition of CF risk from 1985 to 1991 and was cou pled to DNA-based detection of the Delta F508 mutation from 1991 to 1994. R andomization of 650 341 newborns occurred when their blood specimens reache d the Wisconsin screening laboratory. This created 2 groups-an early diagno sis, screened cohort and a standard diagnosis or control group. To avoid se lection bias, we devised a unique unblinding method with a surveillance pro gram to completely identify the control subjects. Because sequential analys is 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 coh ort enrolled and evaluated for at least 1 year and having completed a compr ehensive surveillance program, we performed another statistical analysis of anthropometric evaluated indices that includes all CF patients without mec onium ileus. Results. The incidence of classical CF, ie, patients diagnosed in this tria l 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 inciden ce of 1:3938 (95% confidence interval: 3402-4611). Although there were grou p differences in the proportion of patients with DF508 genotypes and with p ancreatic insufficiency, validity of the randomization plan was demonstrate d by analyzing 16 demographic variables and finding no significant differen ce after adjustment for multiple comparisons. Focusing on patients without meconium ileus, we found a marked difference in the mean +/- standard devia tion age of diagnosis for screened patients (13 +- 37 weeks), compared with the standard diagnosis group (100 +/- 117). Anthropometric indices of nutr itional 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 pan creatic status of the control group, analysis of nutritional outcomes revea led significantly greater growth associated with early diagnosis. Most impr essively, the screened group had a much lower proportion of patients with w eight and height data below the 10th percentile throughout childhood. Conclusions. Although the screened group had a higher proportion of patient s with pancreatic insufficiency, their growth indices were significantly be tter than those of the control group during the 13-year follow-up evaluatio n and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change w hen the height and weight data before 4 years of age for the controls detec ted by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the si gnificant differences. Therefore, selection bias has been eliminated as a p otential explanation. In addition, the results show that severe malnutritio n persists after delayed diagnosis of CF and that catch-up may not be possi ble. We conclude that early diagnosis of CF through neonatal screening comb ined with aggressive nutritional therapy can result in significantly enhanc ed long-term nutritional status.