PEDIATRICS Vol. 105 No. 1 January 2000, pp. 53-61

Nutritional Status of Patients With Cystic Fibrosis With Meconium Ileus: A Comparison With Patients Without Meconium Ileus and Diagnosed Early Through Neonatal Screening

Hui-Chuan Lai, PhD, RD^*, Michael R. Kosorok, PhD^*, Anita Laxova, BS^*, Lisa A. Davis, MS, RD^*, Stacey C. FitzSimmon, PhD, and Philip M. Farrell, MD, PhD^*

From the ^* Departments of Pediatrics and Biostatistics, University of Wisconsin School of Medicine, Madison, Wisconsin; and the  Cystic Fibrosis Foundation, Bethesda, Maryland.

	ABSTRACT

Top Abstract Results Discussion Conclusion References

Objective.  This study was pursued as an extension of a randomized clinical investigation of neonatal screening for cystic fibrosis (CF). The objective was to determine if CF patients with meconium ileus (MI) were more likely to be malnourished compared with those without MI who were diagnosed during early infancy through neonatal screening.

Methodology.  Nutritional status was evaluated from early infancy to 13 years of age based on anthropometric, biochemical, and dietary assessments.

Results.  MI patients (n = 32) were smaller at birth (3117 g compared with 3413 g) and were shorter (22nd percentile compared with 48th percentile) and thinner (24th percentile compared with 49th percentile) compared with non-MI early diagnosed patients (n = 50) up to 13 years of age. Poor growth was particularly evident in 26 MI patients who required surgery for MI (height and weight at the 20th percentile), whereas those treated without surgery (n = 6) showed better height (45th percentile) and weight (37th percentile). Abnormal essential fatty acid profiles were significantly more prevalent in MI compared with non-MI early-diagnosed patients before 3 years of age. Daily intakes of calorie (130% compared with 111% recommended dietary allowances) and protein (339% compared with 279% recommended dietary allowances) were higher but the percentage of fat (37% compared with 38%) and linoleic acid (4.5% compared with 4.7%) in the diet were similar between the two groups.

Conclusions.  These results demonstrated a clear association of MI with malnutrition in CF. The observed poor growth among our MI patients was not because of poor dietary intakes, but was related to surgical treatment for MI and poor essential fatty acid status. These findings present new challenges regarding the optimal medical treatment and nutritional intervention for CF patients with MI.  Key words:  cystic fibrosis, meconium ileus, growth, height z-scores, weight z-scores, nutritional status, essential fatty acids, dietary intakes.

Meconium ileus (MI) is the earliest clinical manifestation of cystic fibrosis (CF). The prevalence of MI among CF patients was ~17% in the United States in 1995.¹ Before 1970, patients with MI had high operative mortality (50%-70%), and the long-term survival was lower than 20%.^2,3 With the improvement of surgical techniques and better neonatal postoperative care and nutrition, the survival and nutritional status of CF patients born with MI seem to be similar to CF patients without MI, as reported in several studies within the past decade.^4-9 However, our recent analysis using data from 1992 to 1995 CF Patient Registry showed that mean height and weight percentiles of patients with MI remain significantly lower compared with those of patients without MI.¹⁰

The majority of CF patients presenting with MI are diagnosed and treated for CF at the neonatal period. In contrast, CF patients without MI are usually diagnosed at older ages, depending on their symptoms and severity of the disease. For example, for CF patients with a new diagnosis of CF in 1995, mean ± SD and median age of diagnosis at positive sweat test for MI patients were 0.4 ± 1.9 years and 0.04 years, respectively, whereas those for patients without MI were 5.5 ± 9.3 years and 1.3 years, respectively.¹ The earlier age at diagnosis may be advantageous to CF patients with MI because it offers opportunities for early treatment, which may contribute to the diminishing differences in nutritional outcomes between MI and non-MI patients observed in recent reports.^4-8 Addressing this question is not only important in determining if MI has an intrinsic impact on CF disease outcomes, but is also important in view of our recent demonstration of significant nutritional benefits associated with early diagnosis by neonatal screening for CF among patients without MI.¹¹

In association with a controlled prospective study of CF neonatal screening in Wisconsin,^11,12 we were presented with an opportunity to compare nutritional outcomes between patients with MI and patients without MI who were diagnosed early through neonatal screening. Because these two patient groups were diagnosed with CF at similar ages by a positive sweat test and followed with a standardized treatment protocol after diagnosis, comparison between these two groups minimizes the influences of the variation in age at diagnosis and differences in disease treatment. We present here a comprehensive evaluation of the nutritional status including anthropometric, biochemical, and dietary assessments of patients with and without MI.

	STUDY PARTICIPANTS AND METHODS

Study Participants

This study was part of the Wisconsin CF Neonatal Screening Project, which is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF using measurement of either immunotrypsinogen (IRT) from April 15, 1985 to June 1991 or the combination of IRT assays and DNA analyses for the F508 mutation from July 1, 1991 to June, 1994. The design and purpose of the Wisconsin CF Neonatal Screening Project has been described in detail elsewhere.^11,12 The Wisconsin CF Neonatal Screening Project was approved by the human subjects committee at the University of Wisconsin and the Research and Publications Committee/Human Rights Board at Children's Hospital of Wisconsin.

Two groups of patients enrolled in the Wisconsin CF Neonatal Screening Project, namely, patients with MI and patients without MI who were diagnosed early (ie, before 12 weeks of life) through neonatal screening were included in the present study. After the diagnosis of CF was confirmed by a positive sweat test and consent to participate in the study was obtained, patients were enrolled in the study and followed according to a protocol that focuses on the assessments of nutritional and pulmonary outcome variables. Data from the longitudinal follow-up assessments collected up to April 15, 1998 were included for analysis. In addition, to determine if MI patients enrolled in the Wisconsin CF Neonatal Screening Study are representative of the national CF patients with MI, 1986 to 1996 CF Patient Registry data were obtained. MI patients who were born during the same time period (April 15, 1985 to June 30, 1994) as Wisconsin patients were identified, and growth data collected between 1986 and 1996 were used to compare with those of the Wisconsin MI patients.

Nutritional Management

Once a diagnosis of CF was confirmed by a positive sweat test (sweat chloride concentration of 60 mmol/L or higher), the patient was followed every 6 weeks for the first year of life and every 3 months thereafter. The essential components of nutritional therapy include assessments of malabsorption and pancreatic enzyme replacement, recommendations of high fat and high calorie diets and supplementation of fat-soluble vitamins. In addition, plasma fatty acid profiles were monitored to evaluate the need for essential fatty acid (EFA) supplementation. When abnormal EFA profiles were observed, the patient was placed on oral supplementation of corn oil, corn oil-margarine, lipomul (Upjohn Company, Kalamazoo, MI), or microlipid (Mead Johnson & Company, Evansville, IN).

Methods for Nutritional Assessments

Nutritional assessments included anthropometric, biochemical, clinical, and dietary assessment. Methods for nutritional assessments were described in detail elsewhere.^11,13

Growth Measurements Standardized measurements of length, weight, and head circumference before 2 years of age, and height and weight after 2 years of age, were obtained every 3 months. Age- and sex-specific percentiles and z-scores for height and weight were computed by using the Epi Info program,¹⁴ which uses normalized growth reference curves from the National Center for Health Statistics (NCHS).^15-17 Percentage of ideal weight, as recommended by the CF Foundation Nutrition Consensus Report,¹⁸ was computed using our previously developed SAS program,⁹ which uses reference values (ie, mean weights of a given sex-age group and their corresponding standard deviation scores) derived from NCHS standards¹⁵ to compute ideal weight.

Biochemical Nutritional Indexes Blood samples were obtained every 6 months for the determination of biochemical markers reflective of nutritional status. Protein status was assessed by the serum concentrations of albumin, prealbumin, and retinol binding protein. Fat-soluble vitamin status was assessed by plasma concentrations of retinol (for vitamin A) and -tocopherol (for vitamin E). EFA status was assessed by analysis of plasma fatty acid profile. Analytical methods for these biochemical markers have been described in detail previously.^1319-23

Dietary Analysis Three-day dietary records were completed by the family every 6 months and analyzed by a registered dietitian. Computerized nutrient analysis programs, Nutritionist III and Nutritionist IV (N-Squared Computing, Silverton, OR), were used to calculate intakes of macronutrients (calorie, protein, carbohydrate, and fat) and selected micronutrients. The intakes of linoleic acid were calculated by using published values of human milk and formula composition, manufacturer's data where available, and food composition tables.²⁴ Nutrient intakes were evaluated as absolute quantities or in comparison with sex- and age-specific recommendations from the Recommended Dietary Allowances (RDA).²⁵

Pancreatic Status CF patients were classified according to their pancreatic function based on 3-day fat absorption studies, whenever possible, or a new classification method described and validated elsewhere,¹¹ that is based on the plasma concentrations of vitamins A and E and the blood IRT concentrations during the interval from the neonatal period to the age of 4 years.

Data and Statistical Analysis

SAS (version 6.12, SAS Institute, Inc, Cary NC, 1996) and S-Plus statistical software (StatSci: A Division of MathSoft, Inc, Seattle, WA) were used for data processing, compiling descriptive tables, summary statistics, and graphical analyses. All statistical analyses were performed separately for each gender and/or stratified by gender because of the well-documented gender difference in survival and clinical course between male and female CF patients.^26,27

Wilcoxon rank sum test for continuous outcomes and ² test for categorical outcomes were used to assess group differences for variables with single observation per patient. Repeated measures analysis using generalized estimating equations (GEE) with a working assumption of independence among observations²⁸ was used to assess group differences for variables with longitudinal, multiple observations per patient. The identity link was used for continuous outcomes and the logit link combined with the binomial variance function was used for dichotomous outcomes in the GEE models. All analyses were performed by using the PROC GENMOD procedure in SAS and adjusted for sex, age, genotype, and pancreatic status. Because birth weight was significantly lower in the MI compared with the non-MI group and a significant interaction between birth weight and age was observed, birth weight and its interactions with age were included as covariates in the GEE models. The validity of GEE models were verified by examining normal quantile-quantile plots of residuals for continuous outcomes and plots of residuals versus fitted values for both continuous and dichotomous outcomes. All values were expressed as mean ± SEM.

	RESULTS

Top Abstract Results Discussion Conclusion References

Patient Population and Characteristics

Between April 15, 1985 and June 30, 1994, a total of 56 patients were diagnosed with CF without MI through neonatal screening and enrolled in the early diagnosis group, as described elsewhere.¹¹ Of the 56 CF patients, 6 did not have valid sweat tests established before 12 weeks of life. The reasons for delayed positive sweat tests included false-negative screening tests, one false-negative initial sweat test and late response to scheduled clinic visits for sweat tests. Because these 6 patients were diagnosed later than anticipated in the screening program and treatment was not initiated within the first 12 weeks of life, they were excluded from the present study. The remaining 50 patients are referred to as the non-MI early diagnosis group. A total of 32 CF patients born with MI were identified between April 15, 1985 and June 30, 1994. Twenty-six of those were treated surgically and the other 6 were treated medically for MI. Of the 26 patients treated surgically for MI, 17 patients had intestinal resection and 7 patients did not have any bowel removed during MI surgery to relieve obstruction. For the remaining 2 MI patients treated surgically, information on intestinal resection was not documented. For the national CF population, a total of 8271 patients who were born during the same birth cohort as the Wisconsin patients were identified from the 1986 to 1996 CF Patient Registry. Of these, 1763 patients had MI. The percentage of CF patients with MI seems to be comparable between the national CF population (21.3%) and our Wisconsin CF population (22.1%).

Table 1 summarizes the baseline characteristics of the study populations. As expected, age at positive sweat test did not differ significantly between the Wisconsin MI and the non-MI early diagnosis groups. Although gender distribution seems to be somewhat different between the Wisconsin MI and the non-MI early diagnosis groups, this difference was not statistically significant (P = .11). Birth weight and birth weight percentile were significantly lower in the Wisconsin MI compared with the non-MI early diagnosis group (P = .014). Proportionately fewer patients with F508 homozygous mutations but more patients with non-F508 mutations were observed in the Wisconsin MI group compared with the non-MI early diagnosis group (P = .034). No significant differences were found in pancreatic status and use of pancreatic enzyme supplementation between the Wisconsin MI and the non-MI early diagnosis groups.

The demographic and CF diagnostic profiles of MI patients in Wisconsin were similar to those of national MI patients (Table 1). No significant differences in gender, age at positive sweat test, genotype, and use of pancreatic enzyme supplementation were found between these two groups.

Growth Indexes of Nutritional Status

At the time of CF diagnosis, MI patients showed significantly lower length percentile (mean ± SEM, 33 ± 6 vs 48 ± 4; P = .02) and weight percentile (21 ± 4 vs 39 ± 4, P < .001) compared with those of the non-MI early diagnosed patients in Wisconsin. These differences remained significant after adjusting for gender, genotype, and pancreatic status. However, the difference in length percentile between the MI and the non-MI early diagnosis groups became insignificant, whereas the difference in weight percentile remained significant (P = .005), after additional adjustment for birth weight. Percent ideal weight was somewhat, but not significantly, higher in the non-MI early diagnosis group (97 ± 1) compared with that of the MI group (93 ± 2) at the time of diagnosis.

The poorer growth indexes noted in MI patients at diagnosis persisted throughout the entire 13-year follow-up period (Fig 1). It is noteworthy that height and weight z-scores declined from birth to ~6 months of age in the MI group, whereas those of non-MI early diagnosis group did not show such decline. In addition, mean height and weight z-scores of the non-MI early diagnosis group approached normal (mean across all ages, 0.06 SD or 48th percentile for height and 0.02 SD or 50th percentile for weight), whereas those of MI patients were much lower (mean across all ages, 0.78 SD or 30th for height and 0.71 SD or 30th percentile for weight). The differences in height and weight z-scores between the MI and non-MI early diagnosis groups were significant at all ages as assessed by GEE analysis, which adjusted for age, sex, genotype, pancreatic status, and birth weight.

View larger version (32K): [in this window] [in a new window]   Fig. 1.   Comparison of growth indexes (mean ± SEM) and the prevalence of malnutrition among Wisconsin cystic fibrosis (CF) patients with meconium ileus (MI), Wisconsin CF patients without MI who were diagnosed during early infancy through neonatal screening, and national CF patients with MI who were born during the same birth cohort as Wisconsin patients. The corresponding number of observations is indicated for each age group for Wisconsin patients. P values indicate statistical significance between the two Wisconsin patient groups as assessed by generalized estimating equations and adjusted for gender, age, pancreatic status, genotype, and birth weight. Data for national MI patients were obtained from the 1986 to 1996 CF Patient Registry.

Examination within the MI population indicated that those treated surgically for MI were more stunted (P = .002) and wasted (P < .001) compared with the non-MI early diagnosis group, whereas MI patients treated medically were slightly more wasted (P = .045) but not stunted (P = .9) compared with the non-MI early diagnosis group. Similarly, the prevalence of height Z score <10th percentile, weight z-score <10th percentile, and percent ideal weight <90% were significantly higher among MI patients, particularly in the subgroup of MI patients treated surgically. When we compared the subgroup of MI patients who were treated surgically and had intestinal resections as part of the MI surgery (n = 17) with those who were treated surgically but had no intestinal resections (n = 7) or with all other MI patients (n = 15), no significant differences in height and weight z-scores were found (P > .09 for all comparisons). This suggests that surgical treatment, but not intestinal resection, may be associated with the poor growth outcomes of MI patients, although our sample size may be too small to detect a difference between the groups with or without intestinal resection. Lastly, growth patterns of the Wisconsin MI patients were similar to those of national MI patients, which were also significantly poorer than the Wisconsin non-MI early diagnosis group.

Biochemical Markers of Nutritional Status

Biochemical markers of nutritional status including serum albumin, prealbumin, retinol binding protein, and plasma retinol and -tocopherol concentrations were significantly higher in the MI group compared with the non-MI early diagnosis group at the time of CF diagnosis (Table 2). However, these differences were no longer present at 6 months of age, and GEE analysis indicated no significant differences in the longitudinal patterns of these biochemical markers between the MI and the non-MI early diagnosis groups. Nevertheless, it is noteworthy that the biochemical markers of nutritional status were low for both MI and non-MI patients compared with normal values at all ages. For example, 35% of the patients had serum albumin concentrations <3 g/dL, 27% of the patients had plasma vitamin A concentrations <20 µg/dL, and 41% of the patients had plasma -tocopherol concentrations <500 µg/dL at the time of CF diagnosis.

Differences in plasma EFA profiles were noted between the MI and the non-MI early diagnosis groups (Fig 2). MI patients showed significantly lower plasma linoleic acid levels (P = .001) with concurrent increases in 20:39 levels (P = .001) and triene/tetraene ratios (P = .06) before 2 years of age. Consistently, a significantly higher prevalence of EFA deficiency was observed in the MI group (60%-80% had plasma linoleic acid <26% and 20%-40% had triene-tetraene ratio >.2) compared with that of the non-MI early diagnosis group (40%-50% had plasma linoleic acid <26% and 5%-20% had triene-tetraene ratio >.2) before 3 years of age. Similar to results from growth indexes, the significantly poorer EFA status noted in the MI group was primarily attributable to patients treated surgically (P = .002 for linoleic acid levels, P = .005 for 20:39 fatty acid levels and P = .036 for triene/tetraene ratio). MI patients treated medically showed similar EFA status (P > .7 for all 3 indexes) compared with the non-MI early diagnosis group.

View larger version (33K): [in this window] [in a new window]   Fig. 2.   Comparison of plasma essential fatty acid profiles (mean ± SEM) and the prevalence of abnormal plasma essential fatty acid profiles between cystic fibrosis patients with meconium ileus and cystic fibrosis patients without meconium ileus who were diagnosed during early infancy through neonatal screening. The corresponding number of observations is indicated for each age group. P values indicate statistical significance between the two patient groups before 3 years of age as assessed by generalized estimating equations and adjusted for gender, age, pancreatic status, genotype, and birth weight.

Dietary Intakes and Fat Absorption

Figure 3 shows the longitudinal patterns of macronutrient intakes. Mean energy (kcal/kg/d) and protein (g/kg/d) intakes were >100% of RDA at all ages and were significantly higher in the MI compared with the non-MI early diagnosis groups, P < .05. Fat intakes consisted of ~45% of total calorie at the neonatal period, declined rapidly to ~35% by 6 months of age, and maintained at 35% to 38% between 1 and 10 years of age. Linoleic acid intakes were relatively high at 7% to 8% of total calorie during the first 6 months of life but declined rapidly to ~4% after 1 year of age. No significant differences in the intakes of fat and linoleic acid were observed between the MI and the non-MI early diagnosis groups.

View larger version (30K): [in this window] [in a new window]   Fig. 3.   Comparison of dietary intakes (mean ± SEM) between cystic fibrosis patients with meconium ileus and cystic fibrosis patients without meconium ileus who were diagnosed during early infancy through neonatal screening. The corresponding number of observations are indicated for each age group. P values indicate statistical significance between the two patient groups before 3 years of age as assessed by generalized estimating equations and adjusted for gender, age, pancreatic status, genotype, and birth weight.

For patients taking pancreatic enzyme supplementation, the dose of pancreatic enzymes per kg of weight per day increased with age from ~6000 units at 1 year of age to 9000 units at 3 years of age with no differences between the MI and the non-MI early diagnosis group. Between 4 and 11 years of age, the dose of pancreatic enzymes also increased with age and was an average of 2300 units higher in the MI group (11 000 units at age 4 and 15 500 units at age 11) compared with that of the non-MI early diagnosis group (9500 units at age 4 and 12 500 units at age 11), P = .05. For patients who completed fecal fat absorption studies (on or off enzymes), fat absorption coefficients did not differ significantly between the MI group (81.7 ± 2.6%; n = 27) and the non-MI early diagnosed group (85.5 ± 1.4%; n = 38), P = .38.

Other Clinical Indexes Associated With Growth

Several clinical indexes that may influence growth of CF patients were compared between MI and non-MI early diagnosed groups. Consistent with findings from comparisons of growth indexes, the growth and nutrition component of the Schwachman-Kulczycki score²⁹ was significantly better in the non-MI early diagnosis (23.3 ± 0.3) compared with the MI group (21.7 ± 0.2), P = .007. No significant differences in the other components of the Schwachman-Kulczycki scores were observed between the two groups.

Indicators of respiratory infection were similar between the MI and the non-MI early diagnosis groups. For example, no significant differences in the incidence (non-MI, 0.2 ± 0.03; MI, 0.16 ± 0.04 per person year), the prevalence (non-MI, 70%; MI, 63%) or the age of initial acquisition of Pseudomonas aeruginosa in respiratory secretions (non-MI, 3.0 ± 0.4; MI, 2.7 ± 2.3 years) were observed between the two groups. In addition, frequencies of the presence of respiratory symptoms at time of study visits, such as cough (33 ± 3% for the MI and 32 ± 3% for the non-MI early diagnosis groups, respectively) and wheezing (7 ± 1% for the MI and 6 ± 2% for the non-MI early diagnosis groups, respectively) were similar between the two groups.

MI treated surgically, plasma EFA status (linoleic acid concentration), and Schwachman-Kulczycki scores for activity and physical examination were positively and significantly correlated with height and weight z-scores in multiple regression analyses using GEE models that adjusted for gender, age, pancreatic insufficiency, genotype, and birth weight (Table 3). In contrast, P aeruginosa infection and the frequency of respiratory symptoms were not significantly associated with height and weight z-scores.

	DISCUSSION

Top Abstract Results Discussion Conclusion References

Findings from the present study indicated that CF patients without MI, when diagnosed during early infancy through neonatal screening and followed with comprehensive nutritional therapy, were able to achieve normal growth with overall height and weight at ~48th NCHS percentiles from birth to 12 years of life. In contrast, CF patients presenting with MI had significant stunting and wasting, with height and weight across all ages at ~23rd NCHS percentiles, despite early diagnosis and treatment. The observed differences in growth between these two patient groups in our study were quite dramatic and remained highly significant after adjusting for gender, age, pancreatic status, genotype, and birth weight. These findings differ from previous studies, which reported similar growth outcomes between CF patients with and without MI.^4,6

One important factor that may explain the discrepancy between the present and previous studies^4,6 is the difference in age of diagnosis between patients with and without MI. Patients presenting with MI often have a presumptive diagnosis of CF at birth and begin receiving therapy before diagnosis of CF is confirmed by a positive sweat test. In contrast, non-MI patients are not treated for CF until after diagnosis is made by a positive sweat test. This difference in treatment initiation is reflected in our observation of higher levels of biochemical nutritional indicators in MI compared with non-MI patients at the time of positive sweat test (Table 2). Because age of diagnosis was shown to be an important determinant of nutritional status,^8,11 our study comparing MI patients with non-MI patients who were diagnosed early with screening may produce different results than those reported previously,^4,6 which compared MI patients to non-MI patients diagnosed at variable ages. Another strength of the present study is that our study population represents a completely identified and prospectively followed patient cohort in Wisconsin throughout the past decade. Therefore, the impact of selection bias resulted from unstandardized treatment and incomplete patient inclusion, as may occur in previous retrospective studies,^4,6 would be minimal in the present study.

Findings from our study demonstrated an independent association of MI to poor growth after accounting for other clinical factors including EFA status, Schwachman-Kulczycki clinical score and respiratory infection status. These findings suggest a possibility that MI may represent a distinct phenotype of CF, as proposed by several reports.^4,8,30 However, MI also presents with a variable degree of severity. Milder cases of MI, as represented by those treated without surgical intervention, may have a better outlook for growth, as observed in our study. On the other hand, MI requiring surgery may be an indicator of a more severe disease, which is the underlying cause for malnutrition.

In our study population, the poorer growth in MI patients treated surgically could not be explained by intestinal resection resultant from MI repair. This finding implies a possibility that gastrointestinal surgery itself may be a potential risk factor for poor growth outcomes in MI patients. It is possible that postoperative treatment of MI patients treated surgically may compromise optimal nutritional management during the neonatal period, when maximal weight gain is to be achieved. Our observation of a decline in height and weight z-scores during the first 6 months of life in the MI group compared with the opposite trend observed in the non-MI early diagnosis group is supportive of this possibility.

The observation of a relatively low birth weight among MI patients noted in our study is consistent with that reported previously.^4,31 Because birth weight is highly associated with childhood growth,^32-34 one may wonder how much of the differences in height and weight z-scores between the MI and the non-MI groups observed in the present study is because of birth weight differences. In our multiple regression analyses, we included birth weight and its interactions with age as covariates for adjustment because we noted an age by birth weight interaction of the associations between birth weight and height z-scores and weight z-scores. After these adjustments, MI remains a significant predictor for low height and weight z-scores. In addition to the aforementioned adjustments for birth weight, we also performed a subgroup analysis in which only patients with birth weight >2800 g in the MI group (n = 22) were compared with the non-MI early diagnosed patients, whose birth weights were all >2800 g. The associations of MI to poor height and weight z-scores remain significant (P < .01) under these subgroup analyses.

A third factor associated with growth outcomes is EFA status. In our study, MI patients had significantly greater intakes for calorie and protein. Intakes of calorie, protein, fat, and linoleic acid for both MI and non-MI groups were greater than normal compared with RDA levels²⁵ and met the guidelines recommended by the CF Foundation Nutrition Consensus Report.¹⁸ In addition, the efficiency of fat absorption were not different between MI and non-MI groups based on our fecal fat data. Nevertheless, abnormal plasma EFA status was more prevalent in MI compared with non-MI patients. The latter observation was consistent with the report by Lloyd-Still et al,³⁵ who demonstrated a much greater difficulty achieving for correction of EFAs in MI compared with non-MI patients. Our findings of a relatively normal dietary intake and fat absorption, yet poor EFA status, support the hypothesis that the EFA abnormalities in CF patients may occur on a primary basis rather than secondary to malabsorption.^36-39 Abnormal EFA status is frequently present in CF patients^39-42 and has been shown to be correlated with growth rate in children.⁴³ In our study, plasma linoleic acid concentrations were positively correlated with height percentiles, and to a lesser extent, with weight percentiles. These results suggest that the poor growth outcomes observed in MI patients may be partially attributable to abnormal EFA status.

Lastly, the overall clinical status as indicated by Schwachman-Kulczycki scores in physical examination and activity components were also significantly correlated with growth outcomes in our multiple regression analyses. On the other hand, we did not observe significant associations of Pseudomonas aeruginosa infection or respiratory symptoms to growth outcomes. One possible explanation is that our study population is relatively young and most patients have relatively mild respiratory diseases, which may not affect growth adversely.

	CONCLUSION

Top Abstract Results Discussion Conclusion References

In summary, our results demonstrated a definitive association of MI with malnutrition in a cohort of CF patients who were identified and followed prospectively with a standardized treatment protocol for 13 years. The observed poor growth among MI patients was not a consequence of poor dietary intakes, but was related to surgical treatment for MI and poor EFA status. The predisposition of MI to abnormal EFA status warrants the consideration for more effective supplementation of EFAs in CF patients with MI. The relationship between surgery and poor growth, attributable to either the surgical treatment directly, or to an underlying process indicative of CF disease severity, may have important implications for treatment. Further research is needed to determine if the impact of MI on poor growth is associated with a worse prognosis of CF.

	ACKNOWLEDGMENTS

This work was supported by National Institutes of Health Grant 2R01 DK34108 and by a Postdoctoral Research Fellowship from the Cystic Fibrosis Foundation.

In addition to the authors, we would like to thank the following investigators who participated in the Wisconsin Cystic Fibrosis Neonatal Screening Study Group: University of Wisconsin, Madison, Medical School, MadisonC. Green, M. Palta, M. J. Rock, A. Tluczek, M. Block, L. Feenan, M. Harrison, L. Makholm, L. J. Wei, and BS Wilfond; the Medical College of Wisconsin, MilwaukeeW. T. Bruns, M. Splaingard, E. Mischler, H. Colby, W. Gershan, C. McCarthy, L. Rusakow, and M. E. Freeman; and Wisconsin State Laboratory of Hygiene, MadisonG. Hoffman, D. J. Hassemer, and R. H. Laessig.

	FOOTNOTES

Received for publication Feb 8, 1999; accepted Apr 29, 1999.

Reprint requests to (H.-C.L.) Departments of Pediatrics and Biostatistics, University of Wisconsin-Madison, K6/428 Clinical Sciences Center, Madison, WI 53792. E-mail: lai{at}biostat.wisc.edu

	ABBREVIATIONS

MI, meconium ileus; CF, cystic fibrosis; IRT, immunotrypsinogen; EFA, essential fatty acids; NCHS, National Center for Health Statistics; RDA, recommended dietary allowances; GEE, generalized estimating equations.

	REFERENCES

Top Abstract Results Discussion Conclusion References

1. Cystic Fibrosis Foundation. Patient Registry 1995 Annual Data Report. Bethesda, MD: Cystic Fibrosis Foundation; August 1996
2. Robinson MJ, Norman AP Life tables for cystic fibrosis. Arch Dis Child. 1975; 50:962-967 [Abstract]
3. McLantlin JF, Dickson AS, Swain AJ Meconium ileus: immediate and long-term survival. Arch Dis Child. 1972; 47:207-210
4. Kerem E, Corey M, Kerem B, Durie P, Tsui L-C, Levison H Clinical and genetic comparisons of patients with cystic fibrosis, with or without meconium ileus. J Pediatr. 1989; 114:767-773 [CrossRef][Medline]
5. Rescorla FJ, Grosfeld JL, West KJ, Vane DW Changing patterns of treatment and survival in neonates with meconium ileus. Arch Surg. 1989; 142:837-840
6. Del Pin CA, Czyrko C, Ziegler MM, Scanlin TF, Bishop HC Management and survival of meconium ileus. A 30-year review. Ann Surg. 1992; 215:179-185 [Medline]
7. Coutts JAP, Docherty JG, Carachi R, Evans TJ Clinical course of patients with cystic fibrosis presenting with meconium ileus. Br J Surg. 1997; 84:555 [CrossRef][Medline]
8. Hudson I, Phelan PD Are sex, age at diagnosis, or mode of presentation prognostic factors for cystic fibrosis? Pediatr Pulmonol 1987; 3:288-297 [Medline]
9. FitzSimmons SC The changing epidemiology of cystic fibrosis. J Pediatr. 1993; 122:1-9 [Medline]
10. Lai HC, Corey M, FitzSimmons SC, Kosorok MR, Farrell PM Comparison of growth status in patients with cystic fibrosis between the United States and Canada. Am J Clin Nutr. 1999; 69:531-538 [Abstract/Free Full Text]
11. Farrell PM, Kosorok MR, Laxova A, Nutritional benefits of neonatal screening for cystic fibrosis. N Engl J Med. 1997; 337:963-969 [Abstract/Free Full Text]
12. Fost NC, Farrell PM A prospective randomized trial of early diagnosis and treatment of cystic fibrosis: a unique ethical dilemma. Clin Res 1989; 37:495-500 [Medline]
13. Marcus MS, Sondel SA, Farrell PM, Nutritional status of infants with cystic fibrosis associated with early diagnosis and intervention. Am J Clin Nutr 1991; 54:578-585 [Abstract/Free Full Text]
14. Dean AG, Dean JA, Coulombier D, et al. Epi Info, Version 6: A Word Processing, Database and Statistical Program for Epidemiology on Microcomputers. Atlanta, GA: Centers for Disease Control and Prevention; 1994
15. Hamill PVV, Drizd TA, Johnson CL, Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr. 1992; 55:108-116 [Abstract/Free Full Text]
16. Dibley MJ, Goldsby JB, Staehling NW, Development of normalized curves for the international growth reference: historical and technical considerations. Am J Clin Nutr. 1987; 46:736-748 [Abstract/Free Full Text]
17. Dibley MJ, Staehling NW, Nieburg P, Interpretation of Z-score anthropometric indicators derived from the international growth references. Am J Clin Nutr. 1987; 46:749-762 [Abstract/Free Full Text]
18. Ramsey BW, Farrell PM, Pencharz, et al Nutritional assessment and management in cystic fibrosis: a consensus report. Am J Clin Nutr. 1992; 55:108-116
19. Hicks JM, Boeckx RL. Pediatric Clinical Chemistry. Philadelphia, PA: WB Saunders; 1984
20. Shetty PS, Watrasiewwicz KE, Jung RT, James WPT Rapid-turnover transport proteins: an index of subclinical protein-energy malnutrition. Lancet. 1979; 2:230-232 [Medline]
21. Farrell PM, Mischler EH, Engle MJ, Brown DJ, Lau SM Fatty acids abnormalities in cystic fibrosis. Pediatr Res. 1985; 19:104-109 [Medline]
22. Bieri JG, Tolliver TJ, Catignani GL Simultaneous determination of -tocopherol and retinol in plasma or red cells by high-pressure liquid chromatography. Am J Clin Nutr. 1979; 32:2143-2149 [Abstract/Free Full Text]
23. Farrell PM, Bieri JG, Fratantoni JF, Wood RE, di Sant'Agnese PA The occurrence and effects of human vitamin E deficiency: study in patients with cystic fibrosis. J Clin Invest. 1977; 60:233-241
24. Pennington JAT, Church HN. Bowes and Church's Food Values of Portions Commonly Used. 14th-17th ed. New York, NY: Harper & Row; 1985, 1989, 1994, 1998
25. National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press, 1989
26. Britton J Effects of social class, sex and region of residence on age at death from cystic fibrosis. Br Med J. 1989; 298:483-487
27. Rosenfeld M, Davis R, FitzSimmons S, Pepe M, Ramsey B Gender gap in cystic fibrosis mortality. Am J Epidemiol. 1997; 145:794-803 [Abstract/Free Full Text]
28. Liang KY, Zeger SL Longitudinal data analysis using generalized linear models. Biometrika. 1986; 73:13-22 [Abstract/Free Full Text]
29. Schwachman H, Kulczycki LL Long-term study of 105 patients with cystic fibrosis. Am J Dis Child 1958; 96:6-15
30. Mornet E, Simon-Bouy B, Seree JL, Genetic differences between cystic fibrosis with and without meconium ileus. Lancet. 1988; 1:376-388 [Medline]
31. Hsia DYV Birth weight in cystic fibrosis of the pancreas. Ann Hum Genet. 1959; 23:289-299 [Medline]
32. Ounsted M, Taylor MF The postnatal growth of children who were small-for-dates or large-for-dates at birth. Dev Med Child Neurol. 1971; 13:421-434 [Medline]
33. Babson SG, Philips DS Growth and development of twins dissimilar in size at birth. N Engl J Med. 1973; 289:937-940
34. Strauss RS, Dietz WH Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr. 1998; 133:67-72 [CrossRef][Medline]
35. Lloyd-Still JD, Bibus DM, Power CA, Johnson SB, Holman RT Essential fatty acid deficiency and predisposition to lung disease in cystic fibrosis. Acta Paediatr. 1996; 85:1426-1432 [Medline]
36. Hubbard VS, Dunn DG, di Sant Agnese PA Abnormal fatty acid composition of plasma lipids in cystic fibrosis: a primary or secondary defect? Lancet. 1977; 2:1302-1304 [Medline]
37. Lloyd-Still JD, Johnson SB, Holman RT Essential fatty acid status and fluidity of plasma phospholipids in cystic fibrosis infants. Am J Clin Nutr. 1991; 54:1029-1035 [Abstract/Free Full Text]
38. Strandvik B, Svensson E, Seyberth HW Prostaglandin biosynthesis in patients with cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids. 1996; 55:419-425 [CrossRef][Medline]
39. Farrell PM, Mischler EH, Engle MJ, Brown DJ, Lau S-M Fatty acid abnormalities in cystic fibrosis. Pediatr Res. 1985; 19:104-109
40. Roulet M, Frascarolo P, Rappaz I, Pilet M Essential fatty acid deficiency in well nourished young cystic fibrosis patients. Eur J Pediatr. 1997; 156:952-956 [CrossRef][Medline]
41. Robberecht ACE Current knowledge on fatty acids in cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids. 1996; 55:129-138 [CrossRef][Medline]
42. van Egmond AWA, Kosorok MR, Koscik R, Laxova A, Farrell PM Effect of linoleic acid intake on growth of infants with cystic fibrosis. Am J Clin Nutr. 1996; 63:746-752 [Abstract/Free Full Text]
43. Bohles H, Heid H, Stehr K, Fekl W Deficiencies of essential fatty acids and Vit E in cystic fibrosis. Z Ernar Wissensch. 1979; 18:81-87