Published online October 31, 2008
PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1014-1020 (doi:10.1542/peds.2007-2336)
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ARTICLE

Prevalence of Low Bone Mass and Deficiencies of Vitamins D and K in Pediatric Patients With Cystic Fibrosis From 3 Canadian Centers

Vijaylaxmi Grey, PhDa, Stephanie Atkinson, PhDa, Donna Drury, PDt, MScb, Linda Casey, MDc, Guylaine Ferland, PhDd, Caren Gundberg, PhDe and Larry C. Lands, MD, PhDb

a McMaster Children's Hospital, Hamilton, Ontario, Canada
b Montreal Children's Hospital, Montreal, Québec, Canada
c Stollery Children's Hospital, Edmonton, Alberta, Canada
d University of Montreal, Montreal, Québec, Canada
e Yale University, New Haven, Connecticut


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. In this cross-sectional observational study, we assessed both vitamins D and K status and bone health in pancreatic insufficient pediatric patients with cystic fibrosis from 3 Canadian cystic fibrosis centers.

METHODS. Eighty-one patients who had cystic fibrosis and were clinically stable for at least 3 months were enrolled. At the time of the clinic visit, anthropometric variables, lung function, pubertal status, intake of calcium and vitamins D and K, and physical activity were assessed. Blood was taken for analysis of biochemical biomarkers of bone turnover and status of vitamins D and K, and a urine sample was obtained for calcium, creatinine, sodium, and deoxypyridoline analyses. Whole-body bone mineral content and lumbar spine (L1–L4) bone mineral density were measured.

RESULTS. The children were relatively well nourished and had moderate to mild lung disease. Low bone mineral mass defined as a z score between –1.0 and –2.0, for gender and age was detected in 38% of the children for whole body and in 28% for lumbar spine. z score less than –2.0 was observed in 7 children for both bone measures. Suboptimal vitamin D status occurred in 95% of patients; suboptimal vitamin K status occurred in 82% of patients. Measures of plasma osteocalcin and carboxy-terminal propeptide type 1 procollagen and urinary deoxypyridoline compared with reference values for age, gender, and pubertal status reflected a state of suppressed bone formation and elevated bone resorption in a large proportion of the patients.

CONCLUSIONS. Bone mass of the whole body and spine was lower than expected for chronological age in approximately one third of pediatric patients with cystic fibrosis irrespective of gender or age. This may be explained by the observation of low bone turnover for developmental stage as indicated by bone biomarkers. Suboptimal status of vitamins D and K may be key causative factors of the low bone status for age.

Key Words: cystic fibrosis • nutrition • bone • vitamin D • vitamin K

Abbreviations: CF—cystic fibrosis • BMD—bone mineral density • 25-OHD—25-hydroxyvitamin D • FFQ—food frequency questionnaire • WBBMC—whole-body bone mineral content • LSBMD—lumbar spine bone mineral density • DXA—dual-energy radiograph absorptiometry • CRP—C-reactive protein • PTH—parathyroid hormone • PICP—carboxy-terminal propeptide type 1 procollagen • PIVKA-II—protein induced by vitamin K absence, factor II • GLU-OC—undercarboxylated osteocalcin • FEV1—forced expiratory volume in 1 second • INR—international normalized ratio

In the past 40 years, the median age of survival for patients with cystic fibrosis (CF) has increased from 10 years to the fourth decade of life.1 As a result, secondary morbidities, including osteopenia and osteoporosis, are emerging in both adults and children. In adults with CF in a Canadian tertiary care center, 36% had a diagnosis of osteopenia, 9% a diagnosis of osteoporosis, and 7% had vertebral fractures.2 Bone disease and high fracture rates have been reported elsewhere in late-stage CF, often in young adults.3,4 The temporal onset of bone deficit in patients with CF is unknown. Studies of children with CF are inconclusive, reporting both normal bone mineral density (BMD) without increased fracture risk in well-nourished children with mild lung disease5,6 and reduced BMD and increased fracture rates.7,8

The causes of suboptimal bone health status may be multifactorial; the cause includes malabsorption of vitamins such as D and K and minerals such as calcium as a result of pancreatic insufficiency, generalized malnutrition, physical inactivity as a result of compromised lung function, corticosteroid use, and inflammation. Because 90% of peak bone mass is reached during the first 2 decades of life,9 perturbations in these modifiable factors may compromise achievement of a child's full genetic potential for adult bone mass.10,11

Although the roles of vitamins D12 and K13,14 in bone health are acknowledged and most patients with CF are prescribed supplements of these vitamins, uncertainty exists as to the specific requirement to support optimal bone health or which measures reflect adequate vitamin status. For vitamin D, optimal status measured by serum 25-hydroxyvitamin D (25-OHD) is now defined as >75 mmol/L.12 The authors of the consensus report on CF nutrition stated that their recommendations of 0.3 to 0.5 mg/day for vitamin K were possibly inadequate on the basis of the existing literature at that time.15 Until recently, assessment of vitamin K status used the relatively insensitive marker prothrombin time.16

This report represents a cross-sectional observational study of pancreatic-insufficient pediatric patients with CF from 3 Canadian CF centers in Canada with the objective to characterize their bone mineral status and to investigate the extent to which vitamin D and vitamin K status were associated with their bone mineral status. The contributions of clinical status, lung function, nutritional status, and habitual physical activity to bone health were also examined.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
Eighty-one patients with CF were enrolled. The diagnosis of CF was made by sweat test chloride value >60 mEq/L and a compatible clinical history. All participants were pancreatic insufficient, assessed by fecal fat measurements at the time of diagnosis, and were at least 8 years of age at the time of study. Patients who were admitted to the study were clinically stable for at least 3 months, and the majority had not taken systemic steroids. The patients were recruited from 3 Canadian pediatric CF centers: Hamilton McMaster Children's Hospital (n = 18), the Montreal Children's Hospital (n = 34), and Stollery Children's Hospital in Edmonton (n = 29). Overall, 60% of the patients in the clinics met the inclusion criteria, and the cohort studied represents a convenience sample chosen. Research ethics approval was granted from all 3 institutions, and informed consent and/or assent was obtained from the parents and/or from the patients of age, respectively.

Methods
Body weight, height, and pulmonary function were measured at the clinic visit.17 Weight, height, and calculated BMI expressed as a z score were obtained using the Centers for Disease Control and Prevention analysis software (EpiInfo 3.3 [Atlanta, GA]). Self-assessment of sexual maturity was done using the illustrations and descriptions of the 5 Tanner stages as published18,19 for breast size and pubic hair development for girls and genital size and pubic hair for boys. Each patient was asked to check the box over the picture that represented him or her for each component of the development. The Tanner stage variables were regrouped into 3 categories: prepubertal (stage 1), puberty (stages 2–4), and mature (late puberty/adult, stage 5). The validated habitual activity questionnaire, adapted from Hay and colleagues20–22 and used extensively in CF research, was administered to study participants. Total daily activity (hours/day) was calculated as the sum of moderate and vigorous activity. The patients were asked to complete a food frequency questionnaire (FFQ) for rapid assessment of calcium- and vitamins D–and K–rich foods. This FFQ was developed specifically for this study on the basis of a composite of published validated FFQs.23–25 It was composed of a list of foods for which an average serving size provided ≥30 mg of calcium, ≥10 IU of vitamin D, or ≥2 µg vitamin K. For each food item listed that was consumed by the child, the frequency of intake (times per day, week, or month) and the serving size (small, medium, or large) were indicated. The intakes of calcium and vitamins D and K were computed by multiplying the amount of calcium, vitamin D, and vitamin K, in each food item, by specified portion size, and frequency. Calcium and vitamin D and vitamin K intakes from supplements or other nutritional products were assessed and included in the intake computation.

Whole-body bone mineral content (WBBMC), lean and fat mass, and lumbar spine (L1–L4) BMD (LSBMD) were measured by dual-energy radiograph absorptiometry (DXA) using QDR Hologic Discovery machine at McMaster Children's Hospital and Montreal Children's Hospital. The Lunar Prodigy was used at Stollery Children's Hospital. Age- and gender-specific z scores were generated from a specialized Web-based pediatric software (www.bcm.tmc.edu/bodycomlab).26 This software allowed for comparison of data collected on both Hologic and Lunar DXA machines. Z scores for the WBBMC and LSBMD values generated on Hologic machines were also computed using the recently published reference data based on a large number of healthy American children from 6 to 16 years,27 because it represents the most up-to-date reference database for bone mass measurements based on a large sample size of children scanned on the same DXA device as used for 2 sites in our study. Z scores between –1.0 and –2.0 and less than –2.0 were used to define low and very low bone mass for age and gender, respectively, as suggested in a recent guide to bone mass measurements in growing patients.28

Laboratory Tests
Fasting blood samples were drawn on the morning of the clinic visit and processed immediately. Biochemical measures were missing from 3 to 10 patients, as a result of insufficient blood volume or technical difficulties associated with the analyses. Whole-blood samples were analyzed for prothrombin time in the local hospital laboratory. Serum samples were separated and sent to the local hospital laboratory immediately for analysis of calcium and alkaline phosphatase. The remaining serum was aliquotted and frozen at –70°C for analysis of C-reactive protein (CRP), 25-OHD, parathyroid hormone (PTH), vitamin K, osteocalcin (total and undercarboxylated), and carboxy-terminal propeptide type 1 procollagen (PICP), a marker of bone formation. Citrated plasma was frozen for protein induced by vitamin K absence, factor II (PIVKA-II) analyses. The patients also provided a midstream urine sample (first morning void). Urine calcium, creatinine, and sodium were done in the local hospital laboratory, and an aliquot was frozen at –70°C for deoxypyridoline analysis. CRP was analyzed by nephelometry (Dade Behring, Mississauga, Ontario, Canada), and 25-OHD was analyzed by Nichols Advantage. When Nichols could no longer provide reagents, the Diasorin RIA (ESBE Scientific, Markham, Ontario, Canada) was used and all values were adjusted to Diasorin values on the basis of method comparison provided by the laboratory. PTH was analyzed using the Roche modular E-module (Roche Diagnostics, Laval, Quebec, Canada). Vitamin K was analyzed by high-performance liquid chromatography in Dr Ferland's laboratory29,30; osteocalcin, both total and undercarboxylated (GLU-OC), by radioimmunoassay in Dr Gundberg's laboratory31; and PICP, urinary deoxypyridoline (Quidel [ESBE Scientific]), and PIVKA-II (Asserachrom [Abbott Laboratories, Mississauga, Ontario, Canada]) by ELISA using the indicated commercial kits. Unless otherwise stated, all analyses were done in the laboratory in Hamilton.

Statistical Analysis
Study statistics were performed using SPSS 10.0 (SPSS Inc, Chicago, IL). The prevalence of vitamin D and vitamin K deficiency using the cutoff of 75 nmol/L for 25-OHD12 and 0.29 mmol/L for vitamin K16 was expressed as a percentage, as was the prevalence of low bone mineral content using 2 different definitions: WBBMC z score less than–1.0 and LSBMD z score less than –1.0. To explore what proportion of patients were deficient for vitamin D and vitamin K using functional markers, GLU-OC >20% (Dr Gundberg, verbal communication, April 2005) and PIVKA-II >2 ng/mL (package insert), cross-tabulations were used.

To explore differences in vitamin D status between seasons and for the bone markers and WBBMC between Tanner stages (prepuberty, puberty, and postpuberty), we compared the group means by using analysis of variance. Two-tailed tests of significance were used in all statistical analyses. A multiple regression was undertaken to assess the effect on bone status (WBBMC z score, LSBMD z score, and biochemical bone markers as dependent variables) of the following risk factors (independent variables): age, gender, HTz (Height z score), BMI, calcium intake, serum vitamin K, %GLU-OC and 25-OHD levels, forced expiratory volume in 1 second (FEV1), inhaled steroids, and physical activity. The "enter" method in SPSS was used in the analysis. All tests were conducted to a 5% level of significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Clinical Characteristics
The clinical characteristics of the patients recruited are shown in Table 1. There was no significant difference in age between boys and girls. Twenty-one children were prepubertal (Tanner stage 1 and mean age 9.6 ± 1.04 years), 42 were pubertal (Tanner stages 2–4 and mean age 12.7 ± 1.38 years), and 13 were late puberty (Tanner 5 and mean age 16.5 ± 1.4 years). Five children did not complete the Tanner self-report. Of the 78 patients for whom we had FEV1 results, 59 had relatively mild lung disease (FEV1 >70%), 16 moderate (FEV1 40%–70%), and 3 severe (FEV1 <40%). The children were relatively well nourished with only 2 of 81 having a BMI z score less than –2.0 and 14 of 81 with a BMI z score between –1 and –2. Nine children had height and weight z scores below –2.0.


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  		TABLE 1 Age, Anthropometry, and Clinical Characteristics of Pediatric Patients With CF

 
Three patients had been on oral steroids previously but not within the past 6 months, and 2 reported recent use. Thirty-four patients reported inhaled steroid use, 20 of whom were taking >400 µg/day beclamethasone dipropionate equivalents. Only 2 patients had CRP levels >10 mg/L, and 75% had levels <1 mg/L. Daily activity computed from the habitual activity questionnaire provides an estimate of the time spent in moderate and vigorous activity. The mean time spent was 6.7 ± 3.3 hours for boys and 5.9 ± 3.0 for girls, similar to that reported by others.22 Healthy boys aged 6 to 13 years have an average activity level of 7.35 ± 2.06 hours/day and girls 6.94 ± 1.73 hours/day.21 Twenty-four patients reported an activity of <4 hours/day.

Calcium and Vitamin Status
The mean and range of values for each of the measured biomarkers of vitamin status indicated that suboptimal status occurred (Table 2). For vitamin D status, 95% of the patients had suboptimal levels of 25-OHD defined as <75 nmol/L. There was no difference (P = .37) in the mean values for serum 25-OHD in patients studied in summer 48 ± 22 nmol/L (n = 39; May to October) or winter 36 ± 17 nmol/L (n = 36, November to April), and the mean values were consistent across all centers. Vitamin K values were <0.29 nmol/L in 65% of the patients, with 30% having undetectable levels (<0.03 nmol/L). By using GLU-OC <20% and PIVKA-II <2 ng/mL as the indicator of adequate vitamin K status, 82% of the patients had suboptimal vitamin K. International normalized ratio (INR) levels were normal for all but 9 patients. Serum calcium levels were within reference range for all the patients, and only 5 patients had higher than normal urine calcium excretion (urine calcium/creatinine ratio >0.6). PTH levels were high in 10% of the patients (>40 pg/mL), and there was no significant correlation between PTH and vitamin D levels. Dietary intakes of calcium, vitamin D, and vitamin K based on an FFQ met or exceeded the recommended values for age of the dietary reference intakes for most children (Table 3).


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  		TABLE 2 Markers of Vitamin D and K Status and Calcium in Pediatric Patients With CF

 

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  		TABLE 3 Intakes of Calcium, Vitamin D, and Vitamin K From Food and Supplements in Comparison With Recommended Intakes for Age (IOM), and Recommended Vitamin Supplementation for Children With CF

 
Bone Mineral Content and Bone Biomarkers
Analysis of DXA scans was obtained from 77 patients for whole body and 76 for lumbar spine (Table 4). Missing data resulted from patients who were not available for DXA scans within an acceptable time frame (1 month) or because of movement during the scan. Low bone mineral content for gender and chronological age was detected in 29 (38%) of patients (WBBMC z score < –1.0), and 20 (28%) of the patients had LSBMD z scores < –1.0 using the reference data from Ellis et al.26 Seven patients had a markedly reduced LSBMD and WBBMC for age (z score less than–2.0). Table 4 shows that WBBMC z score and LSBMD z scores were low in all stages of puberty for both boys and girls. For the girls, the prepubertal group had the lowest z scores for both WBBMC and LSBMD. Lumbar spine BMD z scores computed by using the new North American reference data using Hologic QDR4500 machine27 for patients from 2 of our study centers that did measures on a Hologic machine (n = 48 out of total patients with DXA data available) were not significantly different from the z scores originally computed using the Ellis et al26 reference data (–0.35 ± –1.38 vs –0.32 ± 1.32), but for WBBMC, the new North American reference data27 yielded a significantly lower z score value (–0.720 ± 1.530 vs –0.545 ± 0.997).


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  		TABLE 4 Bone Mineral Content Parameters in Relation to Puberty from DXA

 
The values for bone biomarkers for boys and girls in relation to pubertal stage are shown in Table 5. Mean values for the bone formation marker osteocalcin were lower than reference values (Dr Gundberg, written communication, March 2003) for all female patients and almost all but 1 male patient during puberty. Sixty percent of prepubertal and late pubertal girls had osteocalcin values that were lower than reference values, whereas for the boys, 60% of prepubertal and 30% of late pubertal patients had values below normal reference values. The bone formation marker PICP was also below normal in all stages of puberty in both girls and boys.33,34 The mean values for the bone resorption marker deoxypyridoline were higher than reference values33 during prepuberty and puberty.


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  		TABLE 5 Serum Bone Biomarkers in Relation to Puberty in Pediatric Patients With CF

 
Correlates of Bone Status
Table 6 shows the results of the multiple regression analysis for the outcome variables along with the covariates that had a statistically significant effect on each outcome. The independent variables that were omitted from the list did not have a significant association with the outcome variables. The variable BMI z score was deleted from the regression models because of multicollinearity. The covariates age, Tanner stage, height z score, BMI, and 25-OHD were predictors of WBBMC z scores, whereas age, height z score, and BMI were predictors of LSBMD z scores. Calcium intake had an effect on the bone formation marker osteocalcin, whereas GLU-OC had an effect on the formation markers PICP and osteocalcin and the resorption marker deoxypyridoline-creatinine ratio.


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  		TABLE 6 Multiple Regression Analysis of the Relationship Between Bone Status and Risk Factors

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This cross-sectional survey demonstrated that moderately low WBBMC (z score less than –1.0) for age was prevalent in 38% of patients and moderately low LSBMD (z score less than –1.0) for age in 28% of patients in the 3 Canadian tertiary care centers studied. A markedly reduced LSBMD and WBBMC for age (z score less than –2.0) were noted for 7 patients. In the subset of patients for whom we compared their DXA values with the new North American data,27 the prevalence was 48% for WBBMC z score less than –1 and 29.5% for LSBMD z score less than –1. Perturbations in bone turnover were substantiated by indication of elevated bone resorption and suppressed bone formation when values for key bone biomarkers of patients with CF were compared with reference values. Thus, despite relatively good health as indicated by mild to moderate lung function, lack of inflammation, reasonable physical activity, and BMI status, subclinical indication of less than optimal bone health status was present; the widespread deficiencies in both 25-OHD and serum vitamin K status as assessed by plasma levels or GLU-OC may be the underlying causative factors.

Low WBBMC for age was observed previously in children and adolescents with CF from Denmark,35 United Kingdom,36 France,37 and Italy,8 although, in some studies,8,37 the extent of bone mineral deficit was greater than we observed. Although low bone mineral content for age may be a function of short stature or delayed puberty,35 our results of Tanner self-assessment suggest that pubertal progression was normal. Height z score was a significant predictor in the multivariate analysis (Table 6) and thus may explain some of the observed low bone mass.

The measures of bone biomarkers support the thesis that bone turnover was disturbed in this population of children and youth with CF. Mean serum levels of the biomarkers of bone formation (osteocalcin and PICP), were ~50% and 30% lower than reference values for age in both boys and girls, which is considered clinically significant.38 Reduced bone formation has been noted by others.39,40 Bone resorption as indicated by urine deoxypyridinoline-creatinine ratio was 25% to 50% higher in girls and 25% higher in boys than reference values. Also, urinary deoxypyridinoline-creatinine ratio was inversely correlated to both WBBMC and LSBMD (r = –0.46, P < .001), but this may be attributable to the age-related decrease in resorption during late puberty.

Concern for bone health in CF has led to the recent recommendation that plasma 25-OHD should be maintained at ≥75 nmol/L.12 Despite supplementation with vitamin D and mean intakes above recommended amounts (93% took >400 IU/day and 66% >400 IU/day), 95% of our patients had plasma 25-OHD levels lower than this cutoff value, and 50% had values <40 nmol/L, which is considered the deficient range. Low vitamin D levels were noted previously,41–43 but it is difficult to compare prevalence because different assay methods for serum 25-OHD and cutoff values complicate between-study comparisons. The lack of difference between summer (April to October) and winter (November to April) levels of 25-OHD or geographic locations, Edmonton being farther north, may reflect the reported use of sunscreen in approximately half of the patients and the consistent use of supplements.

Vitamin K has a role in bone formation through osteoblastogenesis,44 or by maintaining the full biological activity of osteocalcin.45 As well, it may play a role in calcium balance.46 Carboxylated osteocalcin is synthesized and secreted by osteoblasts, and elevated GLU-OC reflects vitamin K deficiency47 and is inversely correlated with measures of bone quality and quantity in animal models48,49 and fracture risk in postmenopausal women.50 Moreover, vitamin K supplementation improved bone strength in postmenopausal women,51,52 and better vitamin K status in young girls was associated with lower bone turnover.53 Suboptimal vitamin K status was widespread among our study patients. Serum vitamin K was low in 65% of the patients, with 30% having undetectable levels of serum vitamin K. When the vitamin K status was assessed by either of the biomarkers GLU-OC or PIVKA-11, 82% had abnormal levels. Only 12% of the patients had an INR value >1.2, confirming the insensitivity of INR as a measure of vitamin K sufficiency. A significant negative correlation was seen between serum vitamin K and GLU-OC levels (r = –0.46, P < .01). The majority of patients had intakes of vitamin K in excess of dietary reference intake recommendations,54 94% had >75 µg/day, and 40% had more than the recommended intake for the CF population of 300 µg/day. This may in part be attributable to the lack of availability of an adequate oral vitamin K supplement. Very few multivitamin supplements, except those targeted for patients with CF, have added vitamin K, and there is currently no single-entity, commercially available, oral vitamin K supplement in Canada.

As for vitamins D and K, calcium intakes seemed generous in our patients, with only 10 patients consuming less than the recommended 1300 mg/day. Calcium intake was positively associated with the bone formation marker osteocalcin. Adequate calcium intakes in the face of reduced bone status were also observed by Buntain et al.6 Calcium homeostasis was normal, and only 5 patients had higher than normal urinary calcium excretion.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Low bone mineral mass occurred in up to 38% of this representative sample of Canadian children and youth with CF despite relatively normal lung function, physical activity, and dietary intakes of key vitamins and calcium essential to bone health. Despite widespread supplementation with vitamins D and K, suboptimal biochemical status was observed. These results point to the importance of monitoring vitamin status and bone health even in relatively healthy children with CF. Greater intakes of vitamins that are essential for bone health are also required to maintain optimal status. This can be determined only by designing randomized clinical intervention trials with graded dosages of the vitamins.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from the Canadian Cystic Fibrosis Foundation.

We are grateful to all of the patients with CF who participated in this study. We thank Ruth Milner for advice on study design and Adefowope Odueyungbo for assistance with the statistical analysis and are also grateful to Dr Linda Pedder (Hamilton) and Dr Peter Zuberbuhler (Stollery) for cooperation.


   FOOTNOTES
 
Accepted Feb 13, 2008.

Address correspondence to Vijaylaxmi Grey, PhD, Department of Pathology and Molecular Medicine, McMaster University Medical Centre, Room 2N17, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada. E-mail: grey{at}hhsc.ca

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Bone disease has emerged as a common complication in patients with CF as they live longer. Bone mass accrual occurs during puberty, but reports on the incidence of low bone mass in children/adolescents with CF vary with the population studied.

 

What This Study Adds

We report on the prevalence of low bone mass and the deficiency of vitamins D and K, 2 nutrients associated with bone health, in clinically stable patients with CF from 3 Canadian pediatric CF centers.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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