Several investigators have reported an increased frequency of CF among infants with jejunoileal atresia (JIA) [deLorimier et al., 1969; Nixon et al., 1971; Zerella et al., 1976; Rescorla et al., 1985]. However, the figures vary widely, and no population-based data exist. The purpose of this study was to quantitate the magnitude of the association between JIA and CF in Atlanta using population-based data from 1968-1995.

Materials and Methods

During the study period, MACDP ascertained 67 isolated jejunal atresia cases and 27 isolated ileal atresia cases, for an overall isolated JIA prevalence of 1.8/10,000 live births listed in Table I. Among the JIA cases, 38 were caucasian, 52 were African-American, and 4 were Asian or hispanic. As indicated in Table II, 4 of the 38 (11%) caucasian infants with JIA also had CF. Two of the four infants with CF were male, and two were female. Two were diagnosed by positive sweat tests, and two were diagnosed by molecular analysis. Both of the infants diagnosed by DNA were homozygous for the most common mutation which is a 3 base pair deletion resulting in the loss of phenylalanine at amino acid position 508 in the gene product.

We used the observed to expected (O/E) ratio analysis to compare the risk for CF among caucasian JIA cases with caucasian infants in the general population of Atlanta based on: 1) data collected for MACDP during the study period, 2) the relatively high estimated population incidence of 1/2000 for CF, and 3) a total of 526,000 caucasian live births during the study period. The expected number of caucasian JIA cases with CF is 0.019 as listed in Table III, and the O/E ratio is greater than 210 (P <0.0001). The O/E ratio and the Poisson distribution were derived using a statistical analysis package (Statistical Analysis Battery for Epidemiologic Research) available at the Centers for Disease Control and Prevention. The O/E ratio increases if a lower CF incidence is used in the calculations. From the reverse perspective, the estimated risk for JIA among caucasian infants with CF is 4/263 or 1.5%, based on the 1/2000 population incidence for CF. This risk increases to almost 3% if a 1/3800 incidence is used in the calculations.

Discussion

An increased frequency of CF among infants with JIA, ranging from 9% to 14%, has been reported in the surgical literature [deLorimier et al., 1969; Nixon et al., 1971; Zerella et al., 1976; Rescorla et al., 1985]. This study provides the first data from a population-based surveillance system evaluating the magnitude of the association between JIA and CF. In Atlanta, 11% of the caucasian JIA cases also had CF. The O/E ratio of caucasian JIA cases with CF is greater than 210, indicating that caucasian infants with JIA are at greater than 210 times the risk for CF compared with the caucasian infants in the general population.

Among the JIA cases in this study, 38 were caucasian, and 52 were African-American, which is consistent with the higher rate of isolated jejunal atresia in African-American infants based on MACDP data reported by Cragan et al. [1993]. The reason for this increase is unclear. However, we are presuming that it is not due to CF since the incidence of CF in the African-American population is much lower, with an estimated incidence of 1/17,000 [Kulczycki et al., 1974]. It is possible that race is not an actual risk factor for JIA but may serve as a marker for one or more other unmeasured factors. It is presumed that most cases of JIA in humans are the result of a late intrauterine vascular disruption. JIA has been produced experimentally by ligating branches of the superior mesenteric artery in several types of experimental animals [Louw et al., 1955; Santulli et al., 1961; Abrams, 1968]. The pathogenesis of JIA in fetuses with CF include several possible mechanisms which are all consequences of meconium ileus (Fig. 1) [Lloyd, 1986]. Meconium ileus may lead to a localized area of ischemia resulting in stenosis or atresia. In addition, the heavy, meconium-filled bowel may twist as a result of hyperperistalsis producing a volvulus. Ischemic bowel at the base of the volvulus may also lead to an atresia. Ischemic necrosis of the entire volvulus may produce a pseudocyst which will ultimately form an atresia with calcifications.

Most of the duodenum and both the jejunum and the ileum are supplied by the superior mesenteric artery [Moore et al., 1993]. However, the jejunum and ileum are predisposed to volvulus, unlike the duodenum which lies retroperitoneally and becomes fixed to the posterior abdominal wall. In this study, volvulus was documented in two of the four JIA cases that also had CF. Meconium ileus was present in all four cases.

Our study has two limitations. First, the CF registry at Emory University includes only 85% of the children with CF who live in Atlanta. Therefore, it is possible that the diagnosis of CF was underascertained in our JIA cases. However, if underascertainment for CF does exist, the O/E ratio would be even higher than 210. Similarly, we do not have data on the number of fetuses that were prenatally diagnosed with CF and terminated which could lead to underascertainment for CF, but again, the potential underascertainment would increase the O/E ratio.

Despite these limitations, our study has two important strengths. It is the first population-based study that has quantitated the magnitude of the association between JIA and CF. Previous reports are based on surgical case series. Second, multiple sources of case ascertainment were used in the study, and these provide the best potential for complete case finding.

In summary, this study shows that caucasian infants with JIA have greater than 210 times the risk for CF compared with caucasian infants in the general population. This association is also biologically plausible and is a consequence of meconium ileus. The results of this study also have implications for management of infants born with JIA and genetic counseling for families with affected infants. CF would already be in the differential diagnosis for any newborn presenting with meconium ileus, and all infants with JIA and meconium ileus should be tested for CF. In addition, if a family presents for counseling for the recurrence risk of JIA and the child has died, the presence or absence of meconium ileus is an essential piece of information. If this information is not available, carrier testing of the parents for CF should be considered before providing recurrence risk counseling to the family.

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TABLE 1. Anatomic Location of Isolated Jejunoileal Atresia, Atlanta, 1968-1995

^aJIA indicates jejunoileal atresia.

TABLE 2. Numbers and Percentages of Caucasian Jejunoileal Atresia Cases that are Positive and Negative for Cystic Fibrosis, Atlanta, 1968-1995