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Original Articles: Gastroenterology

Meconium Ileus in Patients With Cystic Fibrosis Is Not a Risk Factor for Clinical Deterioration and Survival: The Israeli Multicenter Study

Efrati, Ori*; Nir, Judith*; Fraser, Drora; Cohen-Cymberknoh, Malena; Shoseyov, David; Vilozni, Daphna*; Modan-Moses, Dalit*; Levy, Ran*; Szeinberg, Amir*; Kerem, Eitan; Rivlin, Joseph§

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Journal of Pediatric Gastroenterology and Nutrition: February 2010 - Volume 50 - Issue 2 - p 173-178
doi: 10.1097/MPG.0b013e3181a3bfdd
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Cystic fibrosis (CF) is an inherited autosomal recessive disorder that may present with a large variety of clinical manifestations, in particular those of the gastrointestinal and respiratory tracts. Meconium ileus (MI) is a unique phenomenon in infants with CF and represents the earliest clinical abnormality with a prevalence of 10% to 21% (1–3). In these infants the meconium is highly viscid, desiccated, and inspissated, leading to intestinal obstruction (4,5). Clinical deterioration is an inevitable part of the natural history of CF. However, disease severity is influenced by multiple factors such as the type of genetic abnormality, mode and timing of diagnosis, and sex differences, with females having a lower survival rate than males (6). Several studies suggested that an early diagnosis of CF in infants may contribute to a more positive outcome, whereas delayed diagnosis leads to severe malnutrition, respiratory deterioration, and a higher mortality rate (7–9). In contrast, Assael et al (10) showed that the best prognostic factor in CF is the calendar date of birth, and that patients diagnosed in more recent years live longer than those diagnosed in past decades. Despite the fact that patients with CF presenting with MI are diagnosed soon after birth, some researchers noted poor growth in the first decade of life in these patients, particularly those who were treated surgically (11,12). Furthermore, the extensive and thorough longitudinal follow-up studies by the Wisconsin CF Neonatal Screening Project (11,12) demonstrated that children with MI had worse obstructive and restrictive lung function and worse nutritional status compared with patients without MI (3). Other studies, however, have shown similar long-term nutritional and respiratory outcomes in patients with CF with or without MI (2,4). MI is a unique and distinctive clinical entity possibly associated with a genetic factor or with a modifier gene other than the gene responsible for CF. Indeed, 30% siblings of children with MI are also affected by MI, instead of the expected 15%. (13,14).

The Israeli population with CF has unique genetic mutations. In addition, the follow-up studies reported to date covered 10 to 15 years of follow-up. Therefore, the aims of our study were 2-fold: to evaluate the clinical characteristics, risk factors, and survival rate among Israeli patients with CF with and without MI during and after prolonged surveillance (20–30 years); and to compare the long-term outcomes and survival between the MI groups treated surgically or conservatively.


Study Subjects

This study included patients from the 3 major accredited CF centers in Israel: Pediatric Pulmonology Unit, Safra Children's Hospital, Tel Hashomer, Ramat Gan; Department of Pediatrics, Carmel Medical Center, Haifa; and Department of Pediatrics and Cystic Fibrosis Center, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem. The medical records of 49 patients with CF who were born with MI between 1975 and 2006 were reviewed. We also selected a control group of 38 patients with CF without MI, matched to the cases by age, sex, and genetic mutation. There is no newborn screening for CF in Israel; therefore, all of the control patients were diagnosed because of their symptoms. The mean age of diagnosis was 9.9 ± 18.9 months (range prenatal diagnosis to 8 years). For technical reasons controls were selected for only 38 of the 49 patients. This study was approved by the institutional review boards. The diagnosis of CF was made by typical clinical manifestations and by abnormal sweat test or genetic mutations.

Nutritional Assessment

Height and weight measurements were performed every visit. Body mass index (BMI) z scores were calculated using reference values from the National Center for Health Statistics (15–17).

Pulmonary Function Tests

Pulmonary function tests were obtained every visit from age 5 years. Both absolute and predicted values of force expiratory volume in the first second (FEV1) and forced vital capacity were obtained. The severity of patients' pulmonary disease was evaluated by the number of pulmonary exacerbations, which necessitated hospitalization.

Genetics and Associated Diseases

The severe class I or II mutations, ΔF508 and W1282X (typical of the Jewish Ashkenazi patients) were examined. An associated disease index (AD index) was defined, which included the following 20 conditions: abdominal pain, distal intestinal obstruction syndrome (DIOS), rectal prolapse, gastritis, pancreatitis, pancreatic insufficiency, CF-related diabetes, cirrhosis, portal hypertension, percutaneous endoscopic gastrostomy (PEG) insertion, cholelithiasis, cholestasis, cholecystitis, arthritis, hepatitis, sinusitis, hemoptysis, nasal polyps, scoliosis, and organ transplantation (liver and lung). The total score could range from 0 to 20. For the purpose of examining the effect of age on the index it was dichotomized into low and high index score 0 to 1 (47.1% of the patients) and 2 or more associated conditions (52.3% of patients), respectively.

Statistical Methods

Categorical data such as prevalence of associated symptoms and conditions were analyzed using the Fisher exact test or the χ2 test as appropriate. Odds ratios and 95% confidence intervals were also computed. Continuous variables such as anthropometric measures, pulmonary function, and number of hospitalizations were compared between the study groups using the Student t test. Survival was compared between the patient groups using the Kaplan-Meyer method and the log-rank test. Multiple logistic regression analysis was used to examine the association between the case-control status and high AD index, controlling for the patients' age. Generalized linear model repeated measures procedure was used to examine changes of BMI and FEV1 with time and by case control status and to test for interactions between them. SPSS 15 (SPSS Inc, Chicago, IL) for Windows was used for the data analysis and a P < 0.05 was considered statistically significant.


Study Population

During the follow-up period, 355 patients with CF, about 70% of all registered Israeli patients with CF, were seen in our 3 centers. Of these, 49 patients were diagnosed in the first days of life because of MI (13.8% of CF population). The mean age of the case group was 17.4 ± 7.9 years, and 66% were male, whereas mean age of the control group was 19.3 ± 6.5 years, and 59% were male. Three control and 9 case patients were younger than 10 years old (7.9% and 18.4%, respectively), whereas another 7 (18.4%) and 9 (18.4%) of case and control patients were younger than 15 years old. Thus, the majority of the study population (31 [63.2%] cases and 28 [73.6%] controls) is composed of patients older than 15 years of age that have been continuously followed up for a prolonged period of time (mean age 24.9 ± 2.7 years).

Of our patients who were diagnosed with MI, 31 underwent surgery, whereas 18 were managed nonoperatively with Gastrografin enema. Operative procedures included ileostomy (n = 8), resection with primary anastamosis (n = 7), T tube ileostomy (n = 5), double-barrel ileostomy (n = 3), Bishop-Koop resection (n = 3), laparotomy with milking (n = 3), and end-to-end colostomy (n = 2). There were no significant differences in long-term complications (including DIOS) between the 2 groups except for CF-related diabetes, which was found in 12 (40%) of the surgical group and 2 (11.1%) of the medical group with odds ratio (and 95% confidence intervals) of 5.3 (1.03–27.5) and P = 0.033.

Genetic Analysis

Most of our patients had 2 severe CF transmembrane conductance regulator mutations. A similar prevalence of ΔF508 and W1282X mutations was observed in both groups. We found ΔF in 38.7% and 48% alleles in the study and control groups, respectively, and W1282X in 34.7% and 30.2%, respectively.

Survival and Lung Disease

During the study period, 8 patients died, 5 in the MI group—none of them with any direct association with the treatment or the primary MI event—and 3 of the control patients (P = NS) (Fig. 1). In addition, there were no statistically significant differences in pulmonary function tests between patients with MI and the non-MI controls (Fig. 2). Using generalized linear model with repeated measures, we showed the FEV1 changes over time (P < 0.001), but there was no statistically significant difference between cases and controls (P = 0.277) and no interaction between time and study group. Thus, even in long-term follow-up no differences between groups were found. The reduction in pulmonary function over time is demonstrated by the mean values for the total population, which were 86.0 ± 20.1, 75.9 ± 21.3, and 63.2 ± 21.4 at ages 7, 10, and 20 years, respectively. Within the MI group, we found that those treated surgically for MI did not differ from the patients who were treated medically at any age (data not presented). To further assess the severity of lung disease, we examined the number of hospitalizations and colonizations with Pseudomonas aeruginosa and Staphylococcus aureus. The number of hospitalization was higher in the patients with MI compared with control (13 ± 15.1 vs 6.9 ± 10.2 P = 0.037). However, bacterial colonization was similar in case and control groups, 85.7% and 94.7% (P = 0.288) for P aeruginosa and 46.9% versus 44.7% (P = 0.833) for the S aureus.

FIG. 1
FIG. 1:
The survival between the patient groups using the Kaplan-Meyer method and the log-rank test.
FIG. 2
FIG. 2:
Left, longitudinal changes in FEV1 in relation to age in MI and the control group. Right, The relation between BMI and age in MI and the control group.

Nutritional Assessment

We examined the values of BMI in the 2 patient groups at ages 1, 5, 10, and 20 years (Fig. 2, Table 1), whereas mean z score for BMI at ages 5, 10, and 20 years are shown in Table 1. The mean z scores for BMI and mean BMI did not differ at any time point as shown in the table. Generalized linear model with repeated measures showed that changes in mean BMI and z scores of BMI values occurred over time (P < 0.001) but that there were no statistically significant differences between the study groups (P = 0.277) nor was there interaction between changes over time with case or control status. The change in z score in BMI over time is seen in the mean values for the whole population, which were −0.28 ± 1.17, −0.75 ± 0.89, and −2.23 ± 2.00 at ages 5, 10, and 20 years, respectively. PEG insertion was studied as another marker for nutritional status. Although we found a trend toward a higher rate of PEG insertion in the MI group (16.3% vs 7.9%), this did not reach statistical significance (P = 0.335). In regard to pancreatic insufficiency, all of our case patients and all except 4 from the control group were pancreatic insufficient.

Selected characteristics and clinical measures in patients with CF with and without MI

Associated Clinical Disease

To evaluate the overall disease severity, we computed an AD index, comprising multiple parameters as detailed in Patients and Methods (Table 2). The mean value for the MI CF group was 2.63 ± 2.36 and for the CF group alone 1.71 ± 1.87 with near statistical significance P = 0.052. Because the AD index is associated with age, we examined the high index (2 plus associated conditions) using multiple logistic regression analysis including age (Table 2). We found that in the presence of age the case or control difference was reduced (P = 0.067) in the whole population. In patients younger than 20 years of age, only age was associated with AD index (P = 0.004), whereas neither age not case control status were associated with AD index in patients 20 years and older. Distal intestinal obstruction syndrome was the only clinical phenomenon that showed statistical difference between the groups (49% vs 18.4%, P = 0.003). Abdominal pain and organ transplantation resulted in a higher trend in the study group (10 patients vs 2 patients and 9 patients vs 2 patients); however, these differences did not reach statistical significance.

Logistic regression models describing the association between high AD index (2+ associated diseases), case-control status (0 or 1) and age of patient in years, by patients' age


Long-term follow-up studies of patients with MI are scarce, particularly those with extended assessment such as the present study (20–30 years). We demonstrated favorable and similar survival rates, pulmonary function, and nutritional status among our patients with CF with MI compared with patients without MI. This is in agreement with previous studies, which have shown that morbidity and mortality in these patients are related to their lung disease and not to the initial MI manifestation during infancy (2,4).

In the past decade studies have shown improvement in the survival of patients with CF diagnosed in infancy. Patients with MI are diagnosed during their first days of life and may, therefore, be at an advantage because early multidisciplinary intervention and treatment may be initiated (10,18,3,19), preventing irreversible lung insult. In contrast, several publications by the Wisconsin CF Neonatal Screening Project (6,11,12) suggested that MI represents a specific phenotype, predisposing patients to malnutrition, severe pulmonary deterioration, and reduced survival. In addition, the group emphasized the term mode and type of diagnosis as opposed to only age at diagnosis(6) and showed that the combination of respiratory symptoms and gastrointestinal abnormalities in the neonatal period was associated with the greatest risk for lung disease and mortality.

In contrast to previous longitudinal studies covering periods of 10 to 15 years, our results represent a longer follow-up (20–30 years, mean 24.9). As the follow-up period increases, the influence of MI itself in patients with CF diminishes and the morbidity becomes unrelated to the immediate effects of the MI in early life. Thus, differences between studies may be related in part to the duration of follow-up. This hypothesis is supported by our logistic regression analysis, which showed that younger patients with CF with MI (younger than 20 years) have a 3-fold risk for high AD index, controlling for age. Although this finding was not significant, it may indicate higher morbidity in cases compared with controls. The higher AD index associated with MI in the study population, especially in younger patients, may be attributed in part to short-term complications. In accordance with these findings, the number of hospitalizations of patients with MI was significantly higher compared with the control group. However, this difference in the number of hospitalizations was apparent only during the first 5 years of life. Similarly, mean FEV1 was lower in the MI group patients, but this difference diminished with age, so that by 15 years of age FEV1 of both groups was similar (Fig. 2). We hypothesize that this reflects short-term morbidity related to intestinal obstruction, surgery, feeding difficulties, total parenteral nutrition therapy, and stoma-related complications.

As we know CF-related complications tend to manifest later in life, in the second or third decade. To evaluate this assumption, we examined the association between case or control status and high AD index, in the older age group with a follow-up of more than 20 years. We found that indeed, in this age group there was no increased prevalence of associated conditions in our patients with MI compared with the control group, suggesting equal morbidity and survival in patients with CF with and without MI as they mature beyond 20 years of age. Therefore, we stress the importance of analyzing results for patients with CF from their first few years after they undergo surgical procedures but also, perhaps more significantly, after 2 to 3 decades.

There is a lack of consensus regarding whether patients with CF presenting with MI have more frequent long-term gastrointestinal (GI) manifestations. Dray et al (20) found no significant association between DIOS and a history of meconium ileus. However, in the present study, the only parameter that differed between the groups was DIOS with an odds ratio of 4.25 in cases versus controls (P = 0.003). This difference may be explained by abdominal surgery during the neonatal period, which predisposes the patients with MI to abdominal adhesions, irregular motility, intestinal blinded loop, and abnormal secretion of mucus in the intestine.

The correlation between the genotype and phenotype in patients with CF with MI is uncertain. However, a positive correlation between severe mutations, such as ΔF508 and G542X has been found (21,22). A strong link between ΔF508 genotype and pancreatic insufficiency has been reported. Indeed, 38.9% of our study population carried at least 1 allele of ΔF508 that might explain the high prevalence of pancreatic insufficiency in our patients (100% in cases and 95% in the control group). The specific and unique mutant CF gene found in our patient population, W1282X, which was responsible for 35% of our mutant alleles, as compared with 1% in the world population (23) may in part explain the disagreement between our results and those of previous reports (6,11,12). It should be noted that the morbidity and mortality associated with this gene have not been extensively studied. The comparatively mild presentation of MI in our patients with CF is of particular interest because W1282X, which is almost exclusively manifested in Israeli Ashkenazi Jews (23) is a type of severe stop mutation. It is highly unlikely that W1282X has a protective effect that may contribute to the better results seen in our patients. It is possible, however, that the Israeli patients with MI constitute a diverse clinical entity; many of whom are under the influence of this specific gene, or the presence of this particular mutation may allow a specific modifier gene that alters the clinical manifestations of MI in our patient population.

Despite the fact that we did not investigate the presence or character of a modifier gene, we believe that it is a realistic possibility. Indeed, different haplotypic variability was found in patients with CF who presented with MI (13). In contrast, Zielenski et al (24) did not find any alleles associated with MI and suggested the existence of multiple variance or other modifier genes.

Neither the patients treated surgically nor patients treated medically by Gastrografin enema experienced severe complications during the newborn period. Similarly, after the 1970s many studies showed a high success rate, up to 100%, for the various surgical techniques mentioned (25,26). Accordingly, advances in surgical techniques, total parenteral nutrition, vitamins and elemental diet, and perioperative care have contributed to the general improvement in the short-term survival of these patients.

There are several limitations to our study. First, data were taken from 3 CF centers, possibly with different modes of treatment and follow-up. However, our results show similarity and homogeneity, when analyzing the data from each medical center separately. Second, data regarding the age at diagnosis in the control group as well as information on surgery and medical treatments in the newborn period were incomplete. Imaging findings, postoperation follow-up, and immediate minor complications such as fever, vomiting, pain, and suture dehiscence were not included in our data. For long-term follow-up, such as in the present study, we think that these data possess minor relevance. Taken together, we do not believe that these limitations would influence our ability to generalize these results to the general population with CF.

Our study shows, for the first time, the results regarding patients with CF suffering from MI with a unique genetic mutation. In addition, these patients were studied for a long period. These data may be helpful and can serve the families and the clinicians for better understanding and prediction of the prognosis and problems in patients with CF presenting with MI.

In conclusion, children and adults with CF with MI as neonates show similar nutritional and respiratory status and survival rates as their control patients with CF without MI. The distinct genetic mutation and the prolonged follow-up may contribute to the favorable results as compared with other studies. Additional factors may have contributed to the improved outcome: advances in perinatal diagnosis and care, surgical and anesthetic management, as well as better postoperative nutrition. The early diagnosis of patients with MI in our population may be of benefit, with lower morbidity and increased survival.


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Cystic fibrosis; Meconium ileus; Nutritional status; Pulmonary function; Survival

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