Evaluation of micronutrient status in pediatric palliative care clinic: a single-center cross-sectional study

Evaluation of micronutrient status in pediatric palliative care clinic: a single-center cross-sectional study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of micronutrient status in pediatric palliative care clinic: a single-center cross-sectional study Derşan Onur, Sunanur Çiftçi Sadıkoğlu, Nilgün Harputluoğlu, Behzat Özkan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4406044/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Sep, 2024 Read the published version in BMC Palliative Care → Version 1 posted 13 You are reading this latest preprint version Abstract Background Pediatric palliative care (PPC) patients are at an elevated risk of malnutrition. Nutritional inadequacy can also cause micronutrient deficiencies. These factors can lead to weight loss, stunted growth, and poor quality of life. Despite the prevalence of these issues, limited research exists in the micronutrient status of PPC patients. The purpose of this study was to determine the micronutrient levels of PPC patients to contribute to a better understanding of their micronutrient needs as well as the appropriate management of diet and treatment approaches. Methods This was a single-center observational cross-sectional retrospective study. This study evaluated the levels of vitamin B12, 25-hydroxyvitamin D, iron, ferritin, folate, calcium, phosphorus, and magnesium in PPC patients. The patients were classified according to the Chronic Complex Conditions (CCC) v2 and then compared. Results A total of 3,144 micronutrient data points were collected from 822 hospitalizations of 364 patients. At least one micronutrient deficiency was identified in 96.9% of the patients. The most prevalent deficiencies were observed for iron, calcium, and phosphate. In addition, 25-hydroxyvitamin D deficiency was observed in one-third of patients. Calcium, magnesium, phosphorus, folate, and 25-hydroxyvitamin D were negatively correlated with age. Conclusion The results of this study indicate that micronutrient deficiencies are highly prevalent in PPC patients. These findings have the potential to contribute to improvements in the nutritional and therapeutic management of patients. Palliative care pediatric diseases micronutrients deficiency malnutrition Figures Figure 1 Figure 2 Background Palliative care is a multidisciplinary health service that aims to improve the quality of life of children with chronic, complex, progressive, and life-threatening disorders while efficiently treating symptoms [ 1 ]. Children under this care are highly susceptible to malnutrition [ 2 ]. Nutritional deficiencies may result in weight loss, growth retardation, and reduced quality of life [ 3 – 6 ]. Micronutrients, which include nutritional elements such as vitamins and minerals, are essential for maintaining the normal functionality of the body. At least half of children under the age of five are affected by micronutrient deficiencies [ 7 ]. To the best of our knowledge, there is limited research on the micronutrient status of PPC patients. Malnutrition and micronutrient deficiencies have been reported in most children with cerebral palsy (CP) [ 8 , 9 ]. A study conducted on pediatric oncology patients revealed that micronutrient abnormalities were present in 74% of the patients. Selenium deficiency has been demonstrated to have a negative impact on clinical outcomes [ 10 ]. In contrast to the recommended nutritional intake and expert opinions for healthy children, there is a lack of evidence-based recommendations for micronutrient requirements in children with critical, chronic, and complex illnesses [ 11 ]. In the context of PPC, if nutritional history indicates inadequate nutritional intake and/or malnutrition, potential micronutrient deficiencies that may have systemic effects need to be investigated [ 3 ]. In addition to medical treatment, nutritional and micronutrient support may be important therapeutic approaches for improving the quality of life of patients monitored at PPC clinics. This approach may play an important role in the effects of chronic diseases and nutrition on metabolism, the course of acute disease, and the frequency of hospital admissions. The objective of this study was to contribute to a more comprehensive understanding of the micronutrient needs of PPC patients. Therefore, the study aimed to determine micronutrient levels and contribute to the development of more effective strategies for managing nutrition and treatment during hospitalization and follow-up. Methods Design This was an observational, cross-sectional, retrospective study performed at a single center in Türkiye. The levels of several micronutrients (vitamin B12, 25-hydroxyvitamin D, iron, ferritin, folate, calcium, phosphorus, and magnesium) were evaluated in patients aged between one month and 18 years who were admitted to the PPC clinic of Dr. Behçet Uz Children’s Hospital between November 2018 and September 2023. Settings and participants The main diagnoses were classified using the Chronic Complex Conditions (CCC) v2, which includes 11 categories (neurologic and neuromuscular, cardiovascular, respiratory, renal and urologic, gastrointestinal, hematologic or immunologic, metabolic, other congenital or genetic defect, prematurity/neonatal, malignancy, and miscellaneous not elsewhere classified) [ 12 ]. Patients hospitalized for off-label reasons without chronic, complex, progressive, or life-threatening diseases were excluded. Data other than the first value were excluded from values examined more than once during the same hospitalization of the same patient (seen more than once within a year or for posttreatment control purposes). Patients with conditions such as infection, intoxication, blood transfusion, or parenteral micronutrient intake that could change micronutrient levels were excluded. The reference values from our hospital laboratory were within2 the normal range of micronutrient levels [ 13 – 15 ]. The normal calcium (serum) level was determined to be 9–11 mg/dL for patients aged < 3 years, 8.8–10.8 mg/dL for patients aged 3–12 years, and 8.4–10.2 mg/dL for patients aged 13–18 years. The normal level of magnesium (serum) was determined to be 1.7–2.3 mg/dL. The normal levels of phosphorus (serum) were determined to be 4.8–8.4 mg/dL for patients aged < 1 year, 4.3–6.8 mg/dL for patients aged 1–5 years, 4.1–5.9 mg/dL for patients aged 6–12 years, 3.5–6.2 mg/dL for patients aged 13–16 years in boys and 3.2–5.5 mg/dL for patients aged 13–16 years in girls, and 2.9-5.0 mg/dL for patients aged 16 years and older. Vitamin B12 (serum) level 1576 pg/mL for patients aged 1613 pg/mL for patients aged 1–8 years, > 1125 pg/mL for patients aged 9–14 years and > 888 pg/mL for patients aged > 15 years. Folate (serum) levels were classified as deficiency for ≤ 3.9 ng/mL, indeterminate for 4.0-5.8 ng/mL, and normal for 5.9–26.8 ng/mL. The normal levels of ferritin (serum) were determined to be 50–200 ng/mL for the first 6 months, 7-140 ng/mL for patients aged 6 months to 5 years, 14–79 ng/mL for patients aged 6–14 years, 6–67 ng/mL for patients aged 15–18 years in girls, 13–83 ng/mL for patients aged 15–16 years in boys, and 11–172 ng/mL in boys aged > 16 years. The normal levels of iron (serum) were determined to be 65–175 µg/dL for patients aged < 6 months, 50–120 µg/dL for patients aged 6 months to 14 years, and 50–175 µg/dL for patients aged ≥ 15 years. The 25-hydroxyvitamin D (serum) level was classified as deficiency for 60 ng/mL. This study was reported in accordance with the STROBE statement [ 16 ] (see Appendix 1). The study was registered on ClinicalTrials.gov (Protocol ID: PPC Micronutrient, Clinical Trial Number: NCT06146452), Registration Date: 11/19/2023). Sample size To the best of our knowledge, our study was the first to evaluate micronutrient status in PPC patients, so there was no reference study. The sample size was calculated as 249 (hypothesized frequency: 50%, population size: 700, confidence limits: 5%, confidence level: 95%). The G * Power program was used to determine the sample size [ 17 ]. Statistical analysis The distribution of the data was checked using histograms, Q-Q plots, and the Kolmogorov-Smirnov test. To eliminate the effect of extreme outliers in the data, extreme outliers were removed using the “ 25th percentile – 3*Interquartile range (IQR) ” and “ 75th percentile + 3*IQR ”. Quantitative variables (age, micronutrient levels) were expressed as median and IQR (25th − 75th percentiles) in non-normal distribution, and mean and standard deviation (SD), and minimum-maximum (min-max) in normal distribution. Categorical variables (sex and diagnosis) were expressed as numbers and percentages and compared using the chi-square test or Fisher’s exact test. If a significant difference was identified between the groups following the comparison, the group or groups from which the difference originated were evaluated by post hoc analysis using the Tukey and Bonferroni tests. For numerical data comparisons between paired groups, the Student’s t-test or the Mann–Whitney U test was used. The relationship between two numerical variables was evaluated using Pearson or Spearman correlation tests. The data were analyzed, and data visualization was performed using Jamovi (Jamovi project 2023, Sydney, Australia, version 2.3) and the Statistical Package for Social Sciences (SPSS®, IBM, Chicago, USA, v.24.0). All analyses were conducted using two-tailed tests with a significance level of .05. Results A total of 400 patients were hospitalized in the PPC clinic, and 364 (91%) had at least one micronutrient evaluated in 822 different hospitalizations (mean: 2.25, SD: 2.11, min-max = 1–17). A total of 56.3% (n = 205) of the patients were male, with a median age of 44.9 (IQR: 15.5-112.4) months. The primary diagnoses of the patients were neurologic and neuromuscular in 59.6% (n = 217), metabolic in 11.3% (n = 41), other congenital or genetic defect in 9.3% (n = 34), and prematurity/neonatal in 9.3% (n = 34). In total, 24,866 micronutrients were included in the analysis. Following the exclusion of 35 extreme outliers (25-hydroxyvitamin D n = 3, iron n = 4, ferritin n = 10, vitamin B12 n = 12, and phosphate n = 6) and exclusions, 3144 micronutrient data were analyzed. At least one micronutrient deficiency was present in 96.9% of the patients (n = 353). The micronutrient levels according to the CCC groups are presented in the Table. Table. Micronutrient levels according to CCC v2 CCC Calcium , Median (IQR) (mg/dL) Magnesium , Median (IQR) (mg/dL) Phosphate , Median (IQR) (mg/dL) 25(OH)D , Median (IQR) (pg/mL) Neurologic and Neuromuscular 9.2 (8.7-9.7) 2.11 (1.92-2.29) 4.2 (3.5-4.9) 25.86 (17.11-34.12) Cardiovascular 9.4 (9-10.1) 2.25 (2.09-2.4) 4.7 (4.4-5.2) 49.7 (42.8-54.35) Respiratory 10.0 (9.5-10.3) 2.25 (2.04-2.34) 5.07 (4.2-5.95) 22.15 (12.45-33.35) Renal and Urologic 7.7 (6.3-7.9) 1.87 (1.52-2.12) 5.7 (5.21-7.38) 49.35 (26.4-72.3) Gastrointestinal 9.6 (9.2-9.8) 2.12 (1.96-2.23) 5.07 (4.73-6.22) 21.4 (21.3-59.94) Hematologic or immunologic 9.6 (9.3-10.5) 2.3 (2.24-2.39) 5.5 (5.19-5.62) 49.36 (-) Metabolic 9.4 (8.9-9.7) 2.16 (1.96-2.32) 4.33 (3.75-4.93) 23.8 (17-32.8) Other CGD 9.2 (8.4-9.9) 2.11 (1.97-2.37) 4.44 (3.69-5.12) 20.62 (13.5-35.06) Malignancy 8.7 (8.0-9.6) 1.8 (1.55-2.02) 4.15 (2.65-5.65) - Premature and Neonatal 9.5 (9.0-10.1) 2.22 (2.03-2.34) 4.64 (4.0-5.5) 30.38 (21.9-39.7) Mis., not elsewhere classified 9.9 (9.0-10.3) 1.83 (1.68-2.3) 5.18 (4.3-6.15) 20.11 (-) Total 9.3 (8.8-9.8) 2.14 (1.95-2.31) 4.38 (3.6-5.06) 26.35 (18.09-35.08) CCC Ferritin , Median (IQR) (mg/dL) Iron , Median (IQR) (mg/dL) Folate , Median (IQR) (mg/dL) Vitamin B12 , Median (IQR) (pg/mL) Neurologic and neuromuscular 76.9 (36.4-158.2) 54.2 (34.2-74.4) 9.4 (6.2-13.97) 719 (515-980) Cardiovascular 213.7 (-) 77.6 (-) 16.1 (14.7-17.6) 694 (467-1227) Respiratory 171.3 (51.3-291.4) 41.6 (33.3-87.2) 12.7 (10.5-14) 614.5 (525-858.5) Renal and urologic - - 3.3 (-) 920.5 (852-989) Gastrointestinal 185.1 (139.4-652.5) 37.6 (31.2-44.0) 20.9 (16.6-25.3) 1111.5 (1052-1171) Hematologic or immunologic 38.2 (23.8-52.6) 41.8 (40.5-43.2) 19.9 (16.3-23.6) 521 (475-1067) Metabolic 190.6 (42.4-331.2) 62.2 (37.65-94.4) 9.3 (5.5-13.0) 737 (575-1022) Other CGD 188.7 (56.7-344.4) 52 (33.4-83.0) 9.6 (4.9-13.8) 871.5 (625.5-1143.5) Malignancy - - - - Premature and neonatal 241.0 (83.7-477.5) 69.6 (49.2-101.5) 16.2 (12.8-17.7) 879 (687-1342) Mis., not elsewhere classified 49.2 (-) - - 628 (-) Total 85.0 (40.9-252.9) 52.3 (34.5-81.5) 10.9 (6.4-15.0) 739 (545-1066) CCC v2: Chronic Complex Conditions version 2 (Feudtner et al., 2014), IQR: Interquartile range, Mis: Miscellaneous, CGD: Congenital or Genetic Defect, 25(OH)D: 25-Hydroxyvitamin D. Calcium The calcium levels of 364 patients were evaluated on average 2.23 times (SD: 2.08; min-max: 1–17). The median calcium level was 9.3 mg/dL (IQR: 8.8–9.8). There were 187 patients (23.0%) with hypocalcemia and twenty-one patients (2.6%) with hypercalcemia. A significant difference was observed between the calcium levels and the diagnosis groups (χ 2 (10) = 46.0, p < 0.001). Post hoc analysis revealed that hypercalcemia was more prevalent in the malignancy group than in the normocalcemia group (p = 0.001). In addition, hypercalcemia was more common in the prematurity/neonatal group than in the hypocalcemia and normocalcemia groups (p < 0.001 and p = 0.034, respectively). Hypocalcemia was observed in all tests in the renal and urological groups (100.0%, n = 7) and in 50.0% (n = 2) of the patients in the malignancy group. There was no significant difference between the calcium levels and sex (p = 0.227). A negative correlation was observed between age and the calcium level (r s (1) = -0.344, p < 0.001) (Fig. 1). Magnesium A total of 360 patients underwent magnesium level evaluation on average 2.18 times (SD: 2.03; min-max: 1–16). The median magnesium level was 2.14 (IQR: 1.95–2.31) mg/dL. A total of fifty-three patients (6.7%) exhibited hypomagnesemia, while 204 patients (25.6%) exhibited hypermagnesemia. There was a significant difference in the magnesium levels between the diagnosis groups (χ 2 (10) = 26.8, p = 0.003). According to the post hoc analysis, hypomagnesemia was more frequent than normomagnesemia and hypermagnesemia in the renal & urological group (p = 0.001 and p = 0.020, respectively), and hypomagnesemia was more frequent than normomagnesemia in the malignancy group (p = 0.004). Hypomagnesemia was present in 50.0% (n = 2) of patients in the malignancy group and 42.9% (n = 3) of those in the renal and urological group. There was no significant difference between magnesium levels and sex (p = 0.942). A negative correlation was observed between age and magnesium levels (r s (1) = -0.301, p < 0.001) (Fig. 1). Phosphate A mean of 2.19 (SD: 2.05; min-max: 1–17) levels were evaluated in 360 patients. The median phosphate level was 4.38 (IQR: 3.6–5.06) mg/dL. There were 146 (18.3%) patients with hypophosphatemia and 70 (8.8%) patients with hyperphosphatemia. There was no significant difference between the phosphate levels and sex (p = 0.077). However, there was a significant difference between the phosphate levels and diagnosis groups (χ 2 (10) = 48.8, p < 0.001). Post hoc analysis revealed that the frequency of hypophosphatemia was greater than that of hyperphosphatemia in the neurological group (p = 0.02). In contrast, hyperphosphatemia was more frequent than hypophosphatemia and normophosphatemia in the respiratory group (p = 0.001 and p < 0.001, respectively). Furthermore, hyperphosphatemia was more frequent than normophosphatemia in the hematological and immunological groups (p = 0.039). Hypophosphatemia was present in 25.0% (n = 1) of those in the malignancy diagnosis group and 20.8% (n = 100) of those in neurological and neuromuscular diagnosis group. There was a negative correlation between age and phosphorus level (r s (1) = − 0.371, p < 0.001) (Fig. 2). Vitamin B12 A total of 157 patients underwent evaluation of vitamin B12 levels, with an average of 1.17 assessments (SD: 0.53; min-max: 1–4). The median vitamin B12 level was 739 (IQR: 545–1066) pg/mL. Two tests (1.1%) demonstrated deficiency, six tests (3.2%) indicated insufficiency, and forty-five tests (24.3%) exhibited elevation. There was no significant difference between B12 levels and diagnosis groups or sexes (χ 2 (10) = 10.1, p = 0.337 and p = 0.778, respectively). Vitamin B12 deficiency and insufficiency were present only in the neurologic and neuromuscular groups (n = 2, 1.7%; n = 6, 5.0%, respectively). There was no significant correlation between age and vitamin B12 levels (r s (1) = -0.120, p = 0.103). Folate A total of 108 patients underwent evaluation of their folate levels, with an average of 1.09 assessments (SD: 0.32; min-max: 1–4) per patient. The median folate level was 10.9 (IQR: 6.4–15.0) ng/mL. Six (5.1%) tests yielded results indicating deficiency, while 19 (16.1%) tests yielded indeterminate results. There was no significant difference between folate levels and sex (p = 0.409). However, there was a significant difference between the folate levels and diagnosis groups (χ 2 (10) = 21.0, p = 0.007). Folate deficiency was present in the only evaluated patient in the renal and urological group (100%, n = 1), 6.3% (n = 1) in the metabolic group, and 5.4% (n = 4) in the neurological and neuromuscular group. Indeterminate folate levels were present in 33.3% (n = 2) of patients in the other congenital or genetic defects group and in 18.9% (n = 14) of patients in the neurologic and neuromuscular group. There was a significant correlation between age and folate levels (r s (1) = -0.361, p < 0.001) (Fig. 2). Ferritin A total of 105 patients underwent evaluation of their ferritin levels, with an average of 1.15 assessments (SD: 0.41, min-max: 1–3) per patient. The median ferritin level was 85.0 (IQR: 40.9-252.9) ng/mL. Of the tests, 7.4% (n = 9) were low and 54.1% (n = 66) were high. There was no significant difference between ferritin levels and the diagnosis groups or sex (χ 2 (10) = 12.7, p = 0.112 and p = 0.091, respectively). Low ferritin levels were present in 14.3% (n = 2) of the metabolic diagnosis group and 8.9% (n = 7) of the neurologic and neuromuscular group. There was no significant correlation between age and ferritin levels (r s (1) = -0.004, p = 0.968). Iron A total of 109 patients underwent iron level evaluation on average 1.12 times (SD: 0.36, min-max = 1–3) per patient. The median iron level was 52.3 (IQR: 34.5–81.5) µg/dL. Iron levels were found to be low in 58 (47.2%) and high in 4 (3.3%) tests. There were no significant differences between the iron levels and diagnosis groups and sex (χ 2 (10) = 3.7, p = 0.816 and p = 0.050, respectively). Low iron was present in 100% (n = 2 each) of the gastrointestinal and hematologic/immunologic diagnosis groups, 66.7% (n = 2) of the respiratory group, and 46.8% (n = 37) of the neurologic and neuromuscular group. There was no significant correlation between age and iron level (r s (1) = -0.152, p = 0.094). 25-Hydroxyvitamin D A total of 154 patients underwent evaluation of their 25-hydroxyvitamin D levels, with an average of 1.22 assessments per patient (SD: 0.52, min-max: 1–4). The median 25-hydroxyvitamin D level was 26.35 (IQR: 18.09–35.08) ng/mL. In total, 23 tests (12.2%) revealed a deficiency, 37 tests (19.6%) indicated insufficiency, and 15 tests (8%) showed an elevation. There was no significant difference between 25-hydroxyvitamin D levels and sex or diagnosis groups (p = 0.975 and χ 2 (10) = 13.7, p = 0.132, respectively). 25-Hydroxyvitamin D deficiency was present in 25.0% (n = 1) of the patients in the respiratory group and 16.7% (n = 3) of those in the other congenital or genetic defects group. 25-hydroxyvitamin D insufficiency was present in 31.6% (n = 6) of the metabolic group, 27.8% (n = 6) of those in the other congenital or genetic defects group, and 25.0% (n = 1) of the respiratory group. A negative correlation was observed between 25-hydroxyvitamin D levels and age (r s (1) = -0.361, p < 0.001) (Fig. 2). Discussion A retrospective evaluation of the levels of micronutrients in PPC patients was conducted. The results of this study demonstrated that 96.9% of PPC patients exhibited at least one micronutrient deficiency. In addition, one in three patients exhibited vitamin D deficiency, while the most prevalent micronutrient deficiencies were iron, calcium, and phosphate. No significant correlation was detected between micronutrient levels and sex. Conversely, calcium, magnesium, phosphorus, folate, and vitamin D levels negatively correlated with age. In our study, we found hypocalcemia in 23% of test. Hypocalcemia has been the subject of studies in children who are critically ill [ 18 , 19 ]. Only Escobedo-Monge et al. reported the occurrence of hypocalcemia in pediatric patients with a history of chronic disease, while Chidomere et al. reported the occurrence of hypocalcemia in children with CP [ 20 , 21 ]. However, in a study by Carman et al., no significant differences were observed in calcium levels between patients with CP and a control group [ 22 ]. Although the study populations were defined as having chronic diseases (malnutrition, syndromes, encephalopathies, kidney disease, or disorders), it is not possible to compare them with chronic complex diseases and PPC patients since the diagnostic distribution of their patients was not mentioned in these studies. Nevertheless, hypocalcemia observed in our study may have been due to vitamin D deficiency. The fact that our patient profile was composed of bedridden and palliative care patients with low exposure to the sun and living indoors at all times may explain the observed vitamin D deficiency and associated hypocalcemia. In the same study, Carman et al. reported that children with CP exhibited low levels of zinc, vitamin A, phosphorus, and manganese [ 22 ]. In another study conducted on patients with CP, 14.5% of patients exhibited phosphorus deficiency [ 23 ]. In accordance with the findings of previous studies, our investigation revealed hypophosphatemia in 18.3% of patients. In our PPC clinic, 59.6% of patients had neurologic and neuromuscular diagnoses. In studies conducted in children with chronic neurologic diseases similar to our study group, vitamin D deficiency was 12.6–76.9%, while vitamin D insufficiency was 15.7–61.0% [ 8 , 21 , 24 – 28 ]. A study of pediatric cancer patients revealed that vitamin D deficiency was prevalent both at baseline (64%) and during treatment (33–50%) [ 29 ]. One-third of the patients had low vitamin D levels. In addition, our study revealed a negative correlation between vitamin D levels and age, which is in contrast with the findings of Le Roy et al. [ 28 ]. Several factors contribute to the risk of vitamin D deficiency in PPC patients. These include low exposure to sunlight, nutritional difficulties, and polypharmacy, particularly for antiepileptics, which are commonly found in children with CP [ 30 ]. It may be posited that the low levels of 25-hydroxyvitamin D observed were due to a combination of facilitating factors. While this may appear to be a simple observation, it serves as a valuable reminder for clinicians working in this field regarding vitamin D supplementation. Concurrently, vitamin D is important for PPC patients because of its capacity to prevent a multitude of complications commonly observed in these patients, including fractures and susceptibility to infection. In studies conducted on children with CP, magnesium levels were lower than those in the control group [ 23 , 31 ]. Hypomagnesemia was reported in 45% and hypermagnesemia in 12% of patients with a history of chronic disease [ 20 ]. In their study, Carman et al. there was no significant difference between the magnesium levels of patients with CP and those of the control group [ 22 ]. Contrary to our initial expectations, our study revealed a greater rate of hypermagnesemia than hypomagnesemia in PPC patients. However, further research is required to substantiate these findings, which represent the highest rates reported in the literature. The vitamin B12 deficiency observed in our patient was lower than that observed in other studies (1.1%) [ 8 , 23 , 32 ]. In addition, along with iron parameters, vitamin B12 was the only vitamin that did not correlate with age. In a study conducted in pediatric patients with malignancy, vitamin B12 deficiency was observed in 6% of patients at diagnosis and in 5% of patients at 18 months [ 10 ]. Due to the limited number of patients with malignant diseases included in our study, vitamin B12 levels were not evaluated. In a separate study, elevated vitamin B12 levels were observed in 32% of the patients with CP [ 23 ]. Elevated vitamin B12 levels were found to be 4.1 times greater in individuals aged 2–50 years with neurodevelopmental disorders than in controls [ 33 ]. Although low vitamin B12 levels may cause neurological problems, the mechanism of high vitamin B12 levels in patients with neurological problems (CP, muscular dystrophy etc.) is not fully understood [ 33 ]. However, it has been reported that high oxidative stress and hypoxia may cause high vitamin B12 levels [ 34 , 35 ]. A previous study revealed that 67.5% of children with CP had inadequate daily dietary folate intake [ 36 ]. Folic acid deficiency has also been reported in 32% of patients with CP [ 23 ]. İspiroğlu et al. reported a folate deficiency of 10% in their study of patients who could not feed themselves due to neurological disease [ 32 ]. In contrast to the limited number of studies, we found folic acid deficiency in 5.1% and indeterminate in 16.1% of our patients. The reason for this phenomenon remains unknown due to the limitations of the study methodology. It has been hypothesized that nutritional status and micronutrient supplementation may be contributing factors. Further research is needed to confirm these findings. In this study, iron levels were low in almost half of the patients. However, ferritin levels were low in only 7.4% of the patients. Previous studies have indicated that iron and ferritin levels are lower in children with CP [ 23 , 28 , 31 , 37 , 38 ]. Furthermore, Le Roy et al. observed a decline in ferritin levels with increasing age, consistent with the results of our study [ 28 ]. İspiroğlu et al. reported an iron deficiency rate of 8% [ 32 ]. One study reported that iron deficiency was present in 19% of children receiving long-term enteral nutrition [ 39 ]. During our study, we did not assess the nutritional status or anemia status of the patients. Strengths and limitations To the best of our knowledge, this study is the first to examine micronutrient levels in PPC patients. Importantly, micronutrient levels may be misleading in cases of infection or inflammation [ 40 ]. Furthermore, antiepileptic drugs may induce micronutrient deficiencies owing to their impact on bone and mineral metabolism [ 41 ]. One of the limitations of our study was that all possible confounding factors for micronutrient levels (nutrition, micronutrient usage and metabolic, endocrinological, and infectious conditions) were not evaluated. Although tests performed for infectious conditions were excluded, it would have been beneficial to match them with laboratory and clinical findings and to evaluate and exclude bias and false negatives. Since our study was retrospective, we were unable to evaluate laboratory problems (appropriate blood collection or transfer methods) that could affect micronutrient levels. Additionally, the inability to evaluate the status of other micronutrients (zinc, vitamin B1, etc.) that could not be studied at our hospital represents another limitation of our study. Conclusions In PPC patients, it is important to evaluate micronutrient abnormalities that may accompany nutritional status. This evaluation process may vary according to the diagnoses, nutritional status, and acute disease. By preventing patients with multiple chronic complex problems from becoming more complicated, their quality of life can be improved. Further research is needed to determine the micronutrient status of patients with PPC and to develop appropriate interventions. Abbreviations CCC: Chronic Complex Conditions CP: cerebral palsy IQR: Interquartile range Min-max: minimum-maximum PPC: Pediatric Palliative Care SD: Standard deviation Declarations Availability of data and materials The datasets utilized in this study are not publicly available due to considerations pertaining to the protection of individual privacy. Consent for data set sharing was not obtained during the ethics committee approval. However, it is available (fully anonymized) from the corresponding author (DO) upon reasonable request. Acknowledgements We would like to extend our heartfelt thanks to all the patients and their families. Funding None Contributions D.O. conceived of the presented idea. D.O. and S.Ç.S. devised the project, the main conceptual ideas and proof outline. D.O., N.H. and B.Ö. developed the theory and performed the computations. S.Ç.S. collected and processed the data. D.O and S.Ç.S. analyzed the data. All authors discussed the results and contributed to the final manuscript. Ethics declarations Ethics approval and consent to participate Approval was obtained from the University of Health Sciences İzmir Dr. Behçet Uz Pediatrics and Surgery Training and Research Hospital Ethics Committee (09.28.2023/882). Informed consent was obtained from all participants and/or their legal guardians. All methods were conducted in accordance with the ethical standards set forth in the 1964 Declaration of Helsinki and its subsequent amendments. Consent for publication Not applicable. Competing interests The authors declare no potential conflicts of interest. References Splinter W. Pediatric Palliative Care. Curr Anesthesiol Rep. 2017;7:164–7. Kurilina T, Marushko T, Pysariev A, Loboda R, Shurygina I, Mashurenko K. NUTRITIONAL SUPPORT OF PALLIATIVE CHILDREN WITH SERIOUS NUTRIRION DEFICIT. Inter Collegas. 2018;5:27–31. Fraser L, Connor S, Marston J. History and epidemiology. In: Hain R, Goldman A, Rapoport A, Meiring M, editors. Oxford Textbook of Palliative Care for Children. Oxford University Press; 2021. pp. 3–16. Siden H, Soon G, Cox K, Straatman L. 374 NUTRITIONAL FAILURE AND CACHEXIA IN A PEDIATRIC PALLIATIVE CARE POPULATION. J Investig Med. 2006;54:S144. Bıçak Ayık D, Büyükbayram Z, Can G. Determination of malnutrition status in palliative care patients. 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Micronutrient status influences clinical outcomes of paediatric cancer patients during treatment: A prospective cohort study. Clin Nutr. 2021;40:2923–35. Marino LV, Valla FV, Beattie RM, Verbruggen SCAT. Micronutrient status during paediatric critical illness: A scoping review. Clin Nutr. 2020;39:3571–93. Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: Updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatr. 2014;14:1–7. Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative on pediatric reference intervals: A CALIPER white paper. Crit Rev Clin Lab Sci. 2017;54:358–413. Pagana KD, Pagana TJ, Pagana TN. (2021) Mosby’s® Diagnostic and Laboratory Test Reference, 15th Edition. Elsevier, Inc., St. Louis, MO. Wong ECC, Brugnara C, Straseski JA, Kellogg MD, Adeli K. Chemistry tests. In: Wong ECC, Brugnara C, Straseski JA, Kellogg MD, Adeli K, editors. 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Chidomere RI, Ukpabi IK, Chukwudi N, Ojinnaka N. (2020) Micronutrient Levels in Children with Cerebral Palsy in Abia State, Nigeria. West Afr J Med 812–8. Carman KB, Aydın K, Kilic Aydin B, et al. Evaluation of micronutrient levels in children with cerebral palsy. Pediatr Int. 2022;64:e15005. Rakhmaeva RF, Kamalova AA. Laboratory indicators of nutritional status in children with cerebral palsy. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bull Perinatol Pediatrics). 2022;67:170–6. Isik G, Ustundag B, Dogan Y. Vitamin D Insufficiency in Children with Chronic Neurological Diseases: Frequency and Causative Factors. Iran J Child Neurol. 2023;17:31. Akpınar P. Vitamin D status of children with cerebral palsy: Should vitamin D levels be checked in children with cerebral palsy? North Clin Istanb. 2018;5:341–7. Manohar S, Gangadaran RP. Vitamin D status in children with cerebral palsy. Int J Contemp Pediatr. 2017;4:615–9. Alenazi KA, Alanezi AA. Prevalence of vitamin D deficiency in children with cerebral palsy: a meta-analysis. Pediatr Neurol. 2024. https://doi.org/10.1016/J.PEDIATRNEUROL.2024.03.021 . Le Roy C, Barja S, Sepúlveda C, Guzmán ML, Olivarez M, Figueroa MJ, Alvarez M. Vitamin D and iron deficiencies in children and adolescents with cerebral palsy. Neurologia. 2021;36:112–8. Iniesta RR, Paciarotti I, Davidson I, McKenzie JM, Brand C, Chin RFM, Brougham MFH, Wilson DC. 5-Hydroxyvitamin D concentration in paediatric cancer patients from Scotland: a prospective cohort study. Br J Nutr. 2016;116:1926–34. Alenazi KA. Vitamin D deficiency in children with cerebral palsy: A narrative review of epidemiology, contributing factors, clinical consequences and interventions. Saudi J Biol Sci. 2022;29:2007–13. Kalra S, Aggarwal A, Chillar N, Faridi MMA. Comparison of Micronutrient Levels in Children with Cerebral Palsy and Neurologically Normal Controls. Indian J Pediatr. 2015;82:140–4. Hope S, Nærland T, Høiland AL, et al. Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia. FASEB J. 2020;34:8114–24. Arendt JFB, Nexo E. Cobalamin Related Parameters and Disease Patterns in Patients with Increased Serum Cobalamin Levels. PLoS ONE. 2012;7:e45979. Veasey SC, Lear J, Zhu Y, Grinspan JB, Hare DJ, Wang S, Bunch D, Doble PA, Robinson SR. Long-Term Intermittent Hypoxia Elevates Cobalt Levels in the Brain and Injures White Matter in Adult Mice. Sleep. 2013;36:1471–81. Kangalgil M, Özfer Özçelik A. Determination of Nutritional Status in Children with Cerebral Palsy. Güncel Pediatri. 2018;16:69–84. Zhu H, Mao S, Li W. (2023) Association between Cu/Zn/Iron/Ca/Mg levels and cerebral palsy: a pooled-analysis. Scientific Reports 2023 13:1 13:1–12. EL-ASHEER OSAMAM, GAAAMD; MD, Sc. MASOUDM MH. Nutritional Assessment and Intervention in Children with Cerebral Palsy (Clinical Audit). Med J Cairo Univ. 2018;86:1811–6. Gottrand M, Muyshont L, Couttenier F, Beghin L, Martigne L, Coopman S, Turck D, Michaud L, Guimber D, Gottrand F. Micronutrient Status of Children Receiving Prolonged Enteral Nutrition. Ann Nutr Metab. 2013;63:152–8. Dao DT, Anez-Bustillos L, Cho BS, Li Z, Puder M, Gura KM. Assessment of Micronutrient Status in Critically Ill Children: Challenges and Opportunities. Nutrients. 2017;9:1185. Verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F. Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg. 2010;112:1–10. Additional Declarations No competing interests reported. Supplementary Files Appendix2CCCMicronutrientstatustable.xlsx Appendix3Micronutrientgraphicalabstract.png Cite Share Download PDF Status: Published Journal Publication published 04 Sep, 2024 Read the published version in BMC Palliative Care → Version 1 posted Editorial decision: Revision requested 23 Jul, 2024 Reviews received at journal 22 Jul, 2024 Reviews received at journal 14 Jul, 2024 Reviews received at journal 10 Jul, 2024 Reviewers agreed at journal 02 Jul, 2024 Reviewers agreed at journal 01 Jul, 2024 Reviewers agreed at journal 29 Jun, 2024 Reviewers agreed at journal 21 Jun, 2024 Reviewers invited by journal 27 May, 2024 Editor invited by journal 27 May, 2024 Editor assigned by journal 27 May, 2024 Submission checks completed at journal 20 May, 2024 First submitted to journal 11 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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21:53:06","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22604,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix2CCCMicronutrientstatustable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4406044/v1/7ab85608709643371904898b.xlsx"},{"id":57729444,"identity":"d31a43eb-638b-40f0-a10b-313ef365c7ff","added_by":"auto","created_at":"2024-06-04 21:53:06","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1129542,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix3Micronutrientgraphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4406044/v1/4d9069bce26c5821a76f26a8.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of micronutrient status in pediatric palliative care clinic: a single-center cross-sectional study","fulltext":[{"header":"Background","content":"\u003cp\u003ePalliative care is a multidisciplinary health service that aims to improve the quality of life of children with chronic, complex, progressive, and life-threatening disorders while efficiently treating symptoms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Children under this care are highly susceptible to malnutrition [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nutritional deficiencies may result in weight loss, growth retardation, and reduced quality of life [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMicronutrients, which include nutritional elements such as vitamins and minerals, are essential for maintaining the normal functionality of the body. At least half of children under the age of five are affected by micronutrient deficiencies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To the best of our knowledge, there is limited research on the micronutrient status of PPC patients. Malnutrition and micronutrient deficiencies have been reported in most children with cerebral palsy (CP) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A study conducted on pediatric oncology patients revealed that micronutrient abnormalities were present in 74% of the patients. Selenium deficiency has been demonstrated to have a negative impact on clinical outcomes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast to the recommended nutritional intake and expert opinions for healthy children, there is a lack of evidence-based recommendations for micronutrient requirements in children with critical, chronic, and complex illnesses [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the context of PPC, if nutritional history indicates inadequate nutritional intake and/or malnutrition, potential micronutrient deficiencies that may have systemic effects need to be investigated [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to medical treatment, nutritional and micronutrient support may be important therapeutic approaches for improving the quality of life of patients monitored at PPC clinics. This approach may play an important role in the effects of chronic diseases and nutrition on metabolism, the course of acute disease, and the frequency of hospital admissions.\u003c/p\u003e \u003cp\u003eThe objective of this study was to contribute to a more comprehensive understanding of the micronutrient needs of PPC patients. Therefore, the study aimed to determine micronutrient levels and contribute to the development of more effective strategies for managing nutrition and treatment during hospitalization and follow-up.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003eThis was an observational, cross-sectional, retrospective study performed at a single center in T\u0026uuml;rkiye. The levels of several micronutrients (vitamin B12, 25-hydroxyvitamin D, iron, ferritin, folate, calcium, phosphorus, and magnesium) were evaluated in patients aged between one month and 18 years who were admitted to the PPC clinic of Dr. Beh\u0026ccedil;et Uz Children\u0026rsquo;s Hospital between November 2018 and September 2023.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSettings and participants\u003c/h2\u003e \u003cp\u003eThe main diagnoses were classified using the Chronic Complex Conditions (CCC) v2, which includes 11 categories (neurologic and neuromuscular, cardiovascular, respiratory, renal and urologic, gastrointestinal, hematologic or immunologic, metabolic, other congenital or genetic defect, prematurity/neonatal, malignancy, and miscellaneous not elsewhere classified) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patients hospitalized for off-label reasons without chronic, complex, progressive, or life-threatening diseases were excluded. Data other than the first value were excluded from values examined more than once during the same hospitalization of the same patient (seen more than once within a year or for posttreatment control purposes). Patients with conditions such as infection, intoxication, blood transfusion, or parenteral micronutrient intake that could change micronutrient levels were excluded.\u003c/p\u003e \u003cp\u003eThe reference values from our hospital laboratory were within2 the normal range of micronutrient levels [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The normal calcium (serum) level was determined to be 9\u0026ndash;11 mg/dL for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;3 years, 8.8\u0026ndash;10.8 mg/dL for patients aged 3\u0026ndash;12 years, and 8.4\u0026ndash;10.2 mg/dL for patients aged 13\u0026ndash;18 years. The normal level of magnesium (serum) was determined to be 1.7\u0026ndash;2.3 mg/dL. The normal levels of phosphorus (serum) were determined to be 4.8\u0026ndash;8.4 mg/dL for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;1 year, 4.3\u0026ndash;6.8 mg/dL for patients aged 1\u0026ndash;5 years, 4.1\u0026ndash;5.9 mg/dL for patients aged 6\u0026ndash;12 years, 3.5\u0026ndash;6.2 mg/dL for patients aged 13\u0026ndash;16 years in boys and 3.2\u0026ndash;5.5 mg/dL for patients aged 13\u0026ndash;16 years in girls, and 2.9-5.0 mg/dL for patients aged 16 years and older. Vitamin B12 (serum) level\u0026thinsp;\u0026lt;\u0026thinsp;200 pg/mL was determined as deficiency and 200\u0026ndash;300 pg/mL was determined as insufficiency. High vitamin B12 levels were determined to be \u0026gt;\u0026thinsp;1576 pg/mL for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;1 year, \u0026gt;\u0026thinsp;1613 pg/mL for patients aged 1\u0026ndash;8 years, \u0026gt;\u0026thinsp;1125 pg/mL for patients aged 9\u0026ndash;14 years and \u0026gt;\u0026thinsp;888 pg/mL for patients aged\u0026thinsp;\u0026gt;\u0026thinsp;15 years. Folate (serum) levels were classified as deficiency for \u0026le;\u0026thinsp;3.9 ng/mL, indeterminate for 4.0-5.8 ng/mL, and normal for 5.9\u0026ndash;26.8 ng/mL. The normal levels of ferritin (serum) were determined to be 50\u0026ndash;200 ng/mL for the first 6 months, 7-140 ng/mL for patients aged 6 months to 5 years, 14\u0026ndash;79 ng/mL for patients aged 6\u0026ndash;14 years, 6\u0026ndash;67 ng/mL for patients aged 15\u0026ndash;18 years in girls, 13\u0026ndash;83 ng/mL for patients aged 15\u0026ndash;16 years in boys, and 11\u0026ndash;172 ng/mL in boys aged\u0026thinsp;\u0026gt;\u0026thinsp;16 years. The normal levels of iron (serum) were determined to be 65\u0026ndash;175 \u0026micro;g/dL for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;6 months, 50\u0026ndash;120 \u0026micro;g/dL for patients aged 6 months to 14 years, and 50\u0026ndash;175 \u0026micro;g/dL for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;15 years. The 25-hydroxyvitamin D (serum) level was classified as deficiency for \u0026lt;\u0026thinsp;12 ng/mL, insufficiency for 12\u0026ndash;20 ng/mL, normal for 20\u0026ndash;60 ng/mL, and elevated for \u0026gt;\u0026thinsp;60 ng/mL.\u003c/p\u003e \u003cp\u003eThis study was reported in accordance with the STROBE statement [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] (see Appendix 1). The study was registered on ClinicalTrials.gov (Protocol ID: PPC Micronutrient, Clinical Trial Number: NCT06146452), Registration Date: 11/19/2023).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eTo the best of our knowledge, our study was the first to evaluate micronutrient status in PPC patients, so there was no reference study. The sample size was calculated as 249 (hypothesized frequency: 50%, population size: 700, confidence limits: 5%, confidence level: 95%). The G\u003csup\u003e*\u003c/sup\u003ePower program was used to determine the sample size [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe distribution of the data was checked using histograms, Q-Q plots, and the Kolmogorov-Smirnov test. To eliminate the effect of extreme outliers in the data, extreme outliers were removed using the \u0026ldquo;\u003cem\u003e25th percentile \u0026ndash; 3*Interquartile range (IQR)\u003c/em\u003e\u0026rdquo; and \u0026ldquo;\u003cem\u003e75th percentile\u0026thinsp;+\u0026thinsp;3*IQR\u003c/em\u003e\u0026rdquo;.\u003c/p\u003e \u003cp\u003eQuantitative variables (age, micronutrient levels) were expressed as median and IQR (25th \u0026minus;\u0026thinsp;75th percentiles) in non-normal distribution, and mean and standard deviation (SD), and minimum-maximum (min-max) in normal distribution. Categorical variables (sex and diagnosis) were expressed as numbers and percentages and compared using the chi-square test or Fisher\u0026rsquo;s exact test. If a significant difference was identified between the groups following the comparison, the group or groups from which the difference originated were evaluated by post hoc analysis using the Tukey and Bonferroni tests. For numerical data comparisons between paired groups, the Student\u0026rsquo;s t-test or the Mann\u0026ndash;Whitney U test was used. The relationship between two numerical variables was evaluated using Pearson or Spearman correlation tests.\u003c/p\u003e \u003cp\u003eThe data were analyzed, and data visualization was performed using Jamovi (Jamovi project 2023, Sydney, Australia, version 2.3) and the Statistical Package for Social Sciences (SPSS\u0026reg;, IBM, Chicago, USA, v.24.0).\u003c/p\u003e \u003cp\u003eAll analyses were conducted using two-tailed tests with a significance level of .05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 400 patients were hospitalized in the PPC clinic, and 364 (91%) had at least one micronutrient evaluated in 822 different hospitalizations (mean: 2.25, SD: 2.11, min-max\u0026thinsp;=\u0026thinsp;1\u0026ndash;17). A total of 56.3% (n\u0026thinsp;=\u0026thinsp;205) of the patients were male, with a median age of 44.9 (IQR: 15.5-112.4) months. The primary diagnoses of the patients were \u003cem\u003eneurologic and neuromuscular\u003c/em\u003e in 59.6% (n\u0026thinsp;=\u0026thinsp;217), \u003cem\u003emetabolic\u003c/em\u003e in 11.3% (n\u0026thinsp;=\u0026thinsp;41), \u003cem\u003eother congenital or genetic defect\u003c/em\u003e in 9.3% (n\u0026thinsp;=\u0026thinsp;34), and \u003cem\u003eprematurity/neonatal\u003c/em\u003e in 9.3% (n\u0026thinsp;=\u0026thinsp;34).\u003c/p\u003e\n\u003cp\u003eIn total, 24,866 micronutrients were included in the analysis. Following the exclusion of 35 extreme outliers (25-hydroxyvitamin D n\u0026thinsp;=\u0026thinsp;3, iron n\u0026thinsp;=\u0026thinsp;4, ferritin n\u0026thinsp;=\u0026thinsp;10, vitamin B12 n\u0026thinsp;=\u0026thinsp;12, and phosphate n\u0026thinsp;=\u0026thinsp;6) and exclusions, 3144 micronutrient data were analyzed.\u003c/p\u003e\n\u003cp\u003eAt least one micronutrient deficiency was present in 96.9% of the patients (n\u0026thinsp;=\u0026thinsp;353). The micronutrient levels according to the CCC groups are presented in the Table.\u003c/p\u003e\n\u003ch4\u003eTable.\u0026nbsp;Micronutrient levels according to CCC v2\u003c/h4\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"708\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCalcium\u003c/strong\u003e, Median (IQR) (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMagnesium\u003c/strong\u003e, Median (IQR) (mg/dL)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhosphate\u003c/strong\u003e, Median (IQR) (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e25(OH)D\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003eMedian (IQR) (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eNeurologic and Neuromuscular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.2 (8.7-9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.11 (1.92-2.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.2 (3.5-4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e25.86 (17.11-34.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eCardiovascular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.4 (9-10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.25 (2.09-2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.7 (4.4-5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e49.7 (42.8-54.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e10.0 (9.5-10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.25 (2.04-2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e5.07 (4.2-5.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e22.15 (12.45-33.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eRenal and Urologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e7.7 (6.3-7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e1.87 (1.52-2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e5.7 (5.21-7.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e49.35 (26.4-72.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.6 (9.2-9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.12 (1.96-2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e5.07 (4.73-6.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e21.4 (21.3-59.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eHematologic or immunologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.6 (9.3-10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.3 (2.24-2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e5.5 (5.19-5.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e49.36 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eMetabolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.4 (8.9-9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.16 (1.96-2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.33 (3.75-4.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e23.8 (17-32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eOther CGD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.2 (8.4-9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.11 (1.97-2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.44 (3.69-5.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e20.62 (13.5-35.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eMalignancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e8.7 (8.0-9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e1.8 (1.55-2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.15 (2.65-5.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003ePremature and Neonatal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.5 (9.0-10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.22 (2.03-2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.64 (4.0-5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e30.38 (21.9-39.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eMis., not elsewhere classified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.9 (9.0-10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e1.83 (1.68-2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e5.18 (4.3-6.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e20.11 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.463276836158194%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548022598870057%\" valign=\"top\"\u003e\n \u003cp\u003e9.3 (8.8-9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.3954802259887%\" valign=\"top\"\u003e\n \u003cp\u003e2.14 (1.95-2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.254237288135593%\" valign=\"top\"\u003e\n \u003cp\u003e4.38 (3.6-5.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.338983050847457%\" valign=\"top\"\u003e\n \u003cp\u003e26.35 (18.09-35.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"714\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFerritin\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e(mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIron\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003eMedian (IQR) (mg/dL)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFolate\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003eMedian (IQR) (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVitamin B12\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003eMedian (IQR) (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eNeurologic and neuromuscular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e76.9 (36.4-158.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e54.2 (34.2-74.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e9.4 (6.2-13.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e719 (515-980)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eCardiovascular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e213.7 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e77.6 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e16.1 (14.7-17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e694 (467-1227)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e171.3 (51.3-291.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e41.6 (33.3-87.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e12.7 (10.5-14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e614.5 (525-858.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eRenal and urologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e3.3 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e920.5 (852-989)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e185.1 (139.4-652.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e37.6 (31.2-44.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e20.9 (16.6-25.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e1111.5 (1052-1171)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eHematologic or immunologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e38.2 (23.8-52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e41.8 (40.5-43.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e19.9 (16.3-23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e521 (475-1067)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eMetabolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e190.6 (42.4-331.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e62.2 (37.65-94.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e9.3 (5.5-13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e737 (575-1022)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eOther CGD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e188.7 (56.7-344.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e52 (33.4-83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e9.6 (4.9-13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e871.5 (625.5-1143.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eMalignancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003ePremature and neonatal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e241.0 (83.7-477.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e69.6 (49.2-101.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e16.2 (12.8-17.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e879 (687-1342)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eMis., not elsewhere classified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e49.2 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e628 (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e85.0 (40.9-252.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.80672268907563%\" valign=\"top\"\u003e\n \u003cp\u003e52.3 (34.5-81.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.647058823529413%\" valign=\"top\"\u003e\n \u003cp\u003e10.9 (6.4-15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.48739495798319%\" valign=\"top\"\u003e\n \u003cp\u003e739 (545-1066)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCCC v2: Chronic Complex Conditions version 2\u0026nbsp;(Feudtner et al., 2014), IQR: Interquartile range, Mis: Miscellaneous,\u0026nbsp;CGD: Congenital or Genetic Defect,\u0026nbsp;25(OH)D: 25-Hydroxyvitamin D.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eCalcium\u003c/h2\u003e\n \u003cp\u003eThe calcium levels of 364 patients were evaluated on average 2.23 times (SD: 2.08; min-max: 1\u0026ndash;17). The median calcium level was 9.3 mg/dL (IQR: 8.8\u0026ndash;9.8). There were 187 patients (23.0%) with hypocalcemia and twenty-one patients (2.6%) with hypercalcemia. A significant difference was observed between the calcium levels and the diagnosis groups (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;46.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Post hoc analysis revealed that hypercalcemia was more prevalent in the malignancy group than in the normocalcemia group (p\u0026thinsp;=\u0026thinsp;0.001). In addition, hypercalcemia was more common in the prematurity/neonatal group than in the hypocalcemia and normocalcemia groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.034, respectively). Hypocalcemia was observed in all tests in the renal and urological groups (100.0%, n\u0026thinsp;=\u0026thinsp;7) and in 50.0% (n\u0026thinsp;=\u0026thinsp;2) of the patients in the malignancy group. There was no significant difference between the calcium levels and sex (p\u0026thinsp;=\u0026thinsp;0.227). A negative correlation was observed between age and the calcium level (r\u003csub\u003es\u003c/sub\u003e (1) = -0.344, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig. 1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eMagnesium\u003c/h2\u003e\n \u003cp\u003eA total of 360 patients underwent magnesium level evaluation on average 2.18 times (SD: 2.03; min-max: 1\u0026ndash;16). The median magnesium level was 2.14 (IQR: 1.95\u0026ndash;2.31) mg/dL. A total of fifty-three patients (6.7%) exhibited hypomagnesemia, while 204 patients (25.6%) exhibited hypermagnesemia. There was a significant difference in the magnesium levels between the diagnosis groups (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;26.8, p\u0026thinsp;=\u0026thinsp;0.003). According to the post hoc analysis, hypomagnesemia was more frequent than normomagnesemia and hypermagnesemia in the renal \u0026amp; urological group (p\u0026thinsp;=\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.020, respectively), and hypomagnesemia was more frequent than normomagnesemia in the malignancy group (p\u0026thinsp;=\u0026thinsp;0.004). Hypomagnesemia was present in 50.0% (n\u0026thinsp;=\u0026thinsp;2) of patients in the malignancy group and 42.9% (n\u0026thinsp;=\u0026thinsp;3) of those in the renal and urological group. There was no significant difference between magnesium levels and sex (p\u0026thinsp;=\u0026thinsp;0.942). A negative correlation was observed between age and magnesium levels (r\u003csub\u003es\u003c/sub\u003e (1) = -0.301, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003ePhosphate\u003c/h2\u003e\n \u003cp\u003eA mean of 2.19 (SD: 2.05; min-max: 1\u0026ndash;17) levels were evaluated in 360 patients. The median phosphate level was 4.38 (IQR: 3.6\u0026ndash;5.06) mg/dL. There were 146 (18.3%) patients with hypophosphatemia and 70 (8.8%) patients with hyperphosphatemia. There was no significant difference between the phosphate levels and sex (p\u0026thinsp;=\u0026thinsp;0.077). However, there was a significant difference between the phosphate levels and diagnosis groups (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;48.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Post hoc analysis revealed that the frequency of hypophosphatemia was greater than that of hyperphosphatemia in the neurological group (p\u0026thinsp;=\u0026thinsp;0.02). In contrast, hyperphosphatemia was more frequent than hypophosphatemia and normophosphatemia in the respiratory group (p\u0026thinsp;=\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Furthermore, hyperphosphatemia was more frequent than normophosphatemia in the hematological and immunological groups (p\u0026thinsp;=\u0026thinsp;0.039). Hypophosphatemia was present in 25.0% (n\u0026thinsp;=\u0026thinsp;1) of those in the malignancy diagnosis group and 20.8% (n\u0026thinsp;=\u0026thinsp;100) of those in neurological and neuromuscular diagnosis group. There was a negative correlation between age and phosphorus level (r\u003csub\u003es\u003c/sub\u003e (1)\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.371, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eVitamin B12\u003c/h2\u003e\n \u003cp\u003eA total of 157 patients underwent evaluation of vitamin B12 levels, with an average of 1.17 assessments (SD: 0.53; min-max: 1\u0026ndash;4). The median vitamin B12 level was 739 (IQR: 545\u0026ndash;1066) pg/mL. Two tests (1.1%) demonstrated deficiency, six tests (3.2%) indicated insufficiency, and forty-five tests (24.3%) exhibited elevation. There was no significant difference between B12 levels and diagnosis groups or sexes (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;10.1, p\u0026thinsp;=\u0026thinsp;0.337 and p\u0026thinsp;=\u0026thinsp;0.778, respectively). Vitamin B12 deficiency and insufficiency were present only in the neurologic and neuromuscular groups (n\u0026thinsp;=\u0026thinsp;2, 1.7%; n\u0026thinsp;=\u0026thinsp;6, 5.0%, respectively). There was no significant correlation between age and vitamin B12 levels (r\u003csub\u003es\u003c/sub\u003e (1) = -0.120, p\u0026thinsp;=\u0026thinsp;0.103).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eFolate\u003c/h2\u003e\n \u003cp\u003eA total of 108 patients underwent evaluation of their folate levels, with an average of 1.09 assessments (SD: 0.32; min-max: 1\u0026ndash;4) per patient. The median folate level was 10.9 (IQR: 6.4\u0026ndash;15.0) ng/mL. Six (5.1%) tests yielded results indicating deficiency, while 19 (16.1%) tests yielded indeterminate results. There was no significant difference between folate levels and sex (p\u0026thinsp;=\u0026thinsp;0.409). However, there was a significant difference between the folate levels and diagnosis groups (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;21.0, p\u0026thinsp;=\u0026thinsp;0.007). Folate deficiency was present in the only evaluated patient in the renal and urological group (100%, n\u0026thinsp;=\u0026thinsp;1), 6.3% (n\u0026thinsp;=\u0026thinsp;1) in the metabolic group, and 5.4% (n\u0026thinsp;=\u0026thinsp;4) in the neurological and neuromuscular group. Indeterminate folate levels were present in 33.3% (n\u0026thinsp;=\u0026thinsp;2) of patients in the other congenital or genetic defects group and in 18.9% (n\u0026thinsp;=\u0026thinsp;14) of patients in the neurologic and neuromuscular group. There was a significant correlation between age and folate levels (r\u003csub\u003es\u003c/sub\u003e (1) = -0.361, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eFerritin\u003c/h2\u003e\n \u003cp\u003eA total of 105 patients underwent evaluation of their ferritin levels, with an average of 1.15 assessments (SD: 0.41, min-max: 1\u0026ndash;3) per patient. The median ferritin level was 85.0 (IQR: 40.9-252.9) ng/mL. Of the tests, 7.4% (n\u0026thinsp;=\u0026thinsp;9) were low and 54.1% (n\u0026thinsp;=\u0026thinsp;66) were high. There was no significant difference between ferritin levels and the diagnosis groups or sex (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;12.7, p\u0026thinsp;=\u0026thinsp;0.112 and p\u0026thinsp;=\u0026thinsp;0.091, respectively). Low ferritin levels were present in 14.3% (n\u0026thinsp;=\u0026thinsp;2) of the metabolic diagnosis group and 8.9% (n\u0026thinsp;=\u0026thinsp;7) of the neurologic and neuromuscular group. There was no significant correlation between age and ferritin levels (r\u003csub\u003es\u003c/sub\u003e (1) = -0.004, p\u0026thinsp;=\u0026thinsp;0.968).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eIron\u003c/h2\u003e\n \u003cp\u003eA total of 109 patients underwent iron level evaluation on average 1.12 times (SD: 0.36, min-max\u0026thinsp;=\u0026thinsp;1\u0026ndash;3) per patient. The median iron level was 52.3 (IQR: 34.5\u0026ndash;81.5) \u0026micro;g/dL. Iron levels were found to be low in 58 (47.2%) and high in 4 (3.3%) tests. There were no significant differences between the iron levels and diagnosis groups and sex (\u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;3.7, p\u0026thinsp;=\u0026thinsp;0.816 and p\u0026thinsp;=\u0026thinsp;0.050, respectively). Low iron was present in 100% (n\u0026thinsp;=\u0026thinsp;2 each) of the gastrointestinal and hematologic/immunologic diagnosis groups, 66.7% (n\u0026thinsp;=\u0026thinsp;2) of the respiratory group, and 46.8% (n\u0026thinsp;=\u0026thinsp;37) of the neurologic and neuromuscular group. There was no significant correlation between age and iron level (r\u003csub\u003es\u003c/sub\u003e (1) = -0.152, p\u0026thinsp;=\u0026thinsp;0.094).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e25-Hydroxyvitamin D\u003c/h2\u003e\n \u003cp\u003eA total of 154 patients underwent evaluation of their 25-hydroxyvitamin D levels, with an average of 1.22 assessments per patient (SD: 0.52, min-max: 1\u0026ndash;4). The median 25-hydroxyvitamin D level was 26.35 (IQR: 18.09\u0026ndash;35.08) ng/mL. In total, 23 tests (12.2%) revealed a deficiency, 37 tests (19.6%) indicated insufficiency, and 15 tests (8%) showed an elevation. There was no significant difference between 25-hydroxyvitamin D levels and sex or diagnosis groups (p\u0026thinsp;=\u0026thinsp;0.975 and \u0026chi;\u003csup\u003e2\u003c/sup\u003e(10)\u0026thinsp;=\u0026thinsp;13.7, p\u0026thinsp;=\u0026thinsp;0.132, respectively). 25-Hydroxyvitamin D deficiency was present in 25.0% (n\u0026thinsp;=\u0026thinsp;1) of the patients in the respiratory group and 16.7% (n\u0026thinsp;=\u0026thinsp;3) of those in the other congenital or genetic defects group. 25-hydroxyvitamin D insufficiency was present in 31.6% (n\u0026thinsp;=\u0026thinsp;6) of the metabolic group, 27.8% (n\u0026thinsp;=\u0026thinsp;6) of those in the other congenital or genetic defects group, and 25.0% (n\u0026thinsp;=\u0026thinsp;1) of the respiratory group. A negative correlation was observed between 25-hydroxyvitamin D levels and age (r\u003csub\u003es\u003c/sub\u003e (1) = -0.361, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA retrospective evaluation of the levels of micronutrients in PPC patients was conducted. The results of this study demonstrated that 96.9% of PPC patients exhibited at least one micronutrient deficiency. In addition, one in three patients exhibited vitamin D deficiency, while the most prevalent micronutrient deficiencies were iron, calcium, and phosphate. No significant correlation was detected between micronutrient levels and sex. Conversely, calcium, magnesium, phosphorus, folate, and vitamin D levels negatively correlated with age.\u003c/p\u003e \u003cp\u003eIn our study, we found hypocalcemia in 23% of test. Hypocalcemia has been the subject of studies in children who are critically ill [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Only Escobedo-Monge et al. reported the occurrence of hypocalcemia in pediatric patients with a history of chronic disease, while Chidomere et al. reported the occurrence of hypocalcemia in children with CP [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, in a study by Carman et al., no significant differences were observed in calcium levels between patients with CP and a control group [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Although the study populations were defined as having chronic diseases (malnutrition, syndromes, encephalopathies, kidney disease, or disorders), it is not possible to compare them with chronic complex diseases and PPC patients since the diagnostic distribution of their patients was not mentioned in these studies. Nevertheless, hypocalcemia observed in our study may have been due to vitamin D deficiency. The fact that our patient profile was composed of bedridden and palliative care patients with low exposure to the sun and living indoors at all times may explain the observed vitamin D deficiency and associated hypocalcemia.\u003c/p\u003e \u003cp\u003eIn the same study, Carman et al. reported that children with CP exhibited low levels of zinc, vitamin A, phosphorus, and manganese [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In another study conducted on patients with CP, 14.5% of patients exhibited phosphorus deficiency [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In accordance with the findings of previous studies, our investigation revealed hypophosphatemia in 18.3% of patients.\u003c/p\u003e \u003cp\u003eIn our PPC clinic, 59.6% of patients had neurologic and neuromuscular diagnoses. In studies conducted in children with chronic neurologic diseases similar to our study group, vitamin D deficiency was 12.6\u0026ndash;76.9%, while vitamin D insufficiency was 15.7\u0026ndash;61.0% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. A study of pediatric cancer patients revealed that vitamin D deficiency was prevalent both at baseline (64%) and during treatment (33\u0026ndash;50%) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. One-third of the patients had low vitamin D levels. In addition, our study revealed a negative correlation between vitamin D levels and age, which is in contrast with the findings of Le Roy et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Several factors contribute to the risk of vitamin D deficiency in PPC patients. These include low exposure to sunlight, nutritional difficulties, and polypharmacy, particularly for antiepileptics, which are commonly found in children with CP [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It may be posited that the low levels of 25-hydroxyvitamin D observed were due to a combination of facilitating factors. While this may appear to be a simple observation, it serves as a valuable reminder for clinicians working in this field regarding vitamin D supplementation. Concurrently, vitamin D is important for PPC patients because of its capacity to prevent a multitude of complications commonly observed in these patients, including fractures and susceptibility to infection.\u003c/p\u003e \u003cp\u003eIn studies conducted on children with CP, magnesium levels were lower than those in the control group [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Hypomagnesemia was reported in 45% and hypermagnesemia in 12% of patients with a history of chronic disease [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In their study, Carman et al. there was no significant difference between the magnesium levels of patients with CP and those of the control group [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Contrary to our initial expectations, our study revealed a greater rate of hypermagnesemia than hypomagnesemia in PPC patients. However, further research is required to substantiate these findings, which represent the highest rates reported in the literature.\u003c/p\u003e \u003cp\u003eThe vitamin B12 deficiency observed in our patient was lower than that observed in other studies (1.1%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In addition, along with iron parameters, vitamin B12 was the only vitamin that did not correlate with age. In a study conducted in pediatric patients with malignancy, vitamin B12 deficiency was observed in 6% of patients at diagnosis and in 5% of patients at 18 months [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Due to the limited number of patients with malignant diseases included in our study, vitamin B12 levels were not evaluated. In a separate study, elevated vitamin B12 levels were observed in 32% of the patients with CP [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Elevated vitamin B12 levels were found to be 4.1 times greater in individuals aged 2\u0026ndash;50 years with neurodevelopmental disorders than in controls [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Although low vitamin B12 levels may cause neurological problems, the mechanism of high vitamin B12 levels in patients with neurological problems (CP, muscular dystrophy etc.) is not fully understood [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, it has been reported that high oxidative stress and hypoxia may cause high vitamin B12 levels [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA previous study revealed that 67.5% of children with CP had inadequate daily dietary folate intake [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Folic acid deficiency has also been reported in 32% of patients with CP [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. İspiroğlu et al. reported a folate deficiency of 10% in their study of patients who could not feed themselves due to neurological disease [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In contrast to the limited number of studies, we found folic acid deficiency in 5.1% and indeterminate in 16.1% of our patients. The reason for this phenomenon remains unknown due to the limitations of the study methodology. It has been hypothesized that nutritional status and micronutrient supplementation may be contributing factors. Further research is needed to confirm these findings.\u003c/p\u003e \u003cp\u003eIn this study, iron levels were low in almost half of the patients. However, ferritin levels were low in only 7.4% of the patients. Previous studies have indicated that iron and ferritin levels are lower in children with CP [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Furthermore, Le Roy et al. observed a decline in ferritin levels with increasing age, consistent with the results of our study [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. İspiroğlu et al. reported an iron deficiency rate of 8% [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. One study reported that iron deficiency was present in 19% of children receiving long-term enteral nutrition [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. During our study, we did not assess the nutritional status or anemia status of the patients.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eTo the best of our knowledge, this study is the first to examine micronutrient levels in PPC patients.\u003c/p\u003e \u003cp\u003eImportantly, micronutrient levels may be misleading in cases of infection or inflammation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Furthermore, antiepileptic drugs may induce micronutrient deficiencies owing to their impact on bone and mineral metabolism [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. One of the limitations of our study was that all possible confounding factors for micronutrient levels (nutrition, micronutrient usage and metabolic, endocrinological, and infectious conditions) were not evaluated. Although tests performed for infectious conditions were excluded, it would have been beneficial to match them with laboratory and clinical findings and to evaluate and exclude bias and false negatives. Since our study was retrospective, we were unable to evaluate laboratory problems (appropriate blood collection or transfer methods) that could affect micronutrient levels. Additionally, the inability to evaluate the status of other micronutrients (zinc, vitamin B1, etc.) that could not be studied at our hospital represents another limitation of our study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn PPC patients, it is important to evaluate micronutrient abnormalities that may accompany nutritional status. This evaluation process may vary according to the diagnoses, nutritional status, and acute disease. By preventing patients with multiple chronic complex problems from becoming more complicated, their quality of life can be improved. Further research is needed to determine the micronutrient status of patients with PPC and to develop appropriate interventions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCCC: Chronic Complex Conditions\u003c/p\u003e\n\u003cp\u003eCP: cerebral palsy\u003c/p\u003e\n\u003cp\u003eIQR: Interquartile range\u003c/p\u003e\n\u003cp\u003eMin-max: minimum-maximum\u003c/p\u003e\n\u003cp\u003ePPC: Pediatric Palliative Care\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets utilized in this study are not publicly available due to considerations pertaining to the protection of individual privacy. Consent for data set sharing was not obtained during the ethics committee approval. However, it is available (fully anonymized) from the corresponding author (DO) upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to extend our heartfelt thanks to all the patients and their families.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.O. conceived of the presented idea. D.O. and S.\u0026Ccedil;.S. devised the project, the main conceptual ideas and proof outline. D.O., N.H. and B.\u0026Ouml;. developed the theory and performed the computations. S.\u0026Ccedil;.S. collected and processed the data. D.O and S.\u0026Ccedil;.S. analyzed the data. All authors discussed the results and contributed to the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval was obtained from the University of Health Sciences İzmir Dr. Beh\u0026ccedil;et Uz Pediatrics and Surgery Training and Research Hospital Ethics Committee (09.28.2023/882).\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all participants and/or their legal guardians. All methods were conducted in accordance with the ethical standards set forth in the 1964 Declaration of Helsinki and its subsequent amendments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no potential conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSplinter W. Pediatric Palliative Care. Curr Anesthesiol Rep. 2017;7:164\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurilina T, Marushko T, Pysariev A, Loboda R, Shurygina I, Mashurenko K. NUTRITIONAL SUPPORT OF PALLIATIVE CHILDREN WITH SERIOUS NUTRIRION DEFICIT. Inter Collegas. 2018;5:27\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraser L, Connor S, Marston J. History and epidemiology. 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Med J Cairo Univ. 2018;86:1811\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGottrand M, Muyshont L, Couttenier F, Beghin L, Martigne L, Coopman S, Turck D, Michaud L, Guimber D, Gottrand F. Micronutrient Status of Children Receiving Prolonged Enteral Nutrition. Ann Nutr Metab. 2013;63:152\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDao DT, Anez-Bustillos L, Cho BS, Li Z, Puder M, Gura KM. Assessment of Micronutrient Status in Critically Ill Children: Challenges and Opportunities. Nutrients. 2017;9:1185.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F. Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg. 2010;112:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-palliative-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pcar","sideBox":"Learn more about [BMC Palliative Care](http://bmcpalliatcare.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pcar/default.aspx","title":"BMC Palliative Care","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Palliative care, pediatric diseases, micronutrients, deficiency, malnutrition","lastPublishedDoi":"10.21203/rs.3.rs-4406044/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4406044/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePediatric palliative care (PPC) patients are at an elevated risk of malnutrition. Nutritional inadequacy can also cause micronutrient deficiencies. These factors can lead to weight loss, stunted growth, and poor quality of life. Despite the prevalence of these issues, limited research exists in the micronutrient status of PPC patients. The purpose of this study was to determine the micronutrient levels of PPC patients to contribute to a better understanding of their micronutrient needs as well as the appropriate management of diet and treatment approaches.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a single-center observational cross-sectional retrospective study. This study evaluated the levels of vitamin B12, 25-hydroxyvitamin D, iron, ferritin, folate, calcium, phosphorus, and magnesium in PPC patients. The patients were classified according to the Chronic Complex Conditions (CCC) v2 and then compared.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 3,144 micronutrient data points were collected from 822 hospitalizations of 364 patients. At least one micronutrient deficiency was identified in 96.9% of the patients. The most prevalent deficiencies were observed for iron, calcium, and phosphate. In addition, 25-hydroxyvitamin D deficiency was observed in one-third of patients. Calcium, magnesium, phosphorus, folate, and 25-hydroxyvitamin D were negatively correlated with age.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe results of this study indicate that micronutrient deficiencies are highly prevalent in PPC patients. These findings have the potential to contribute to improvements in the nutritional and therapeutic management of patients.\u003c/p\u003e","manuscriptTitle":"Evaluation of micronutrient status in pediatric palliative care clinic: a single-center cross-sectional study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 21:52:58","doi":"10.21203/rs.3.rs-4406044/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-23T18:33:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-22T17:16:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-14T20:05:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-10T15:56:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277127370769022720512473361932040388684","date":"2024-07-02T14:05:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52954818236009192676462901257916148722","date":"2024-07-01T09:53:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175838468454621734824797001951764673208","date":"2024-06-29T19:47:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308051050688484632868460722305547731317","date":"2024-06-21T14:00:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-27T12:20:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-27T07:34:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-27T07:22:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-20T13:33:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Palliative Care","date":"2024-05-11T15:51:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-palliative-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pcar","sideBox":"Learn more about [BMC Palliative Care](http://bmcpalliatcare.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pcar/default.aspx","title":"BMC Palliative Care","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b154d3c-bec2-4253-a095-bcb9eba706d6","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-09T16:12:32+00:00","versionOfRecord":{"articleIdentity":"rs-4406044","link":"https://doi.org/10.1186/s12904-024-01546-9","journal":{"identity":"bmc-palliative-care","isVorOnly":false,"title":"BMC Palliative Care"},"publishedOn":"2024-09-04 16:05:27","publishedOnDateReadable":"September 4th, 2024"},"versionCreatedAt":"2024-06-04 21:52:58","video":"","vorDoi":"10.1186/s12904-024-01546-9","vorDoiUrl":"https://doi.org/10.1186/s12904-024-01546-9","workflowStages":[]},"version":"v1","identity":"rs-4406044","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4406044","identity":"rs-4406044","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}