Integrative Neuromuscular Training in Adolescents and Children Treated for Cancer (INTERACT): Study Protocol for a Multicenter, Two-Arm Parallel-Group Randomized Controlled Superiority Trial.

Background: Improved survival rates for children and adolescents diagnosed with cancer call for novel strategies for reducing short- and long-term treatment-related side effects. These include the physical and metabolic sequelae that are exacerbated by sedentary behavior and treatment-induced toxicities. We aim to investigate the effect of an integrative neuromuscular training intervention during the first 6 months of anti-cancer treatment primarily on muscle strength, and secondarily on exercise capacity, physical function, markers of metabolic syndrome, dysmetabolism, and health-related quality of life during and after ended treatment. Methods: One hundred and twenty-seven children and adolescents, newly diagnosed with malignant and benign neoplasia, aged 6-17 years, and treated with chemotherapy or radiation will be randomized to either the intervention or the control arm of the study. The intervention group will, in addition to usual care, be offered a combination of 6 months of supervised physical exercise (integrative neuromuscular training) and home-based exercise. The active control group will, in addition to usual care, receive information along an unsupervised written home-based training program. All participants, including parents, will receive information about the importance of physical exercise during the course of cancer treatment, at the start of treatment, and in 5 monthly sessions. The primary outcome is measured in terms of isometric quadriceps muscle strength. Secondary outcomes include muscle strength and endurance, markers of metabolic syndrome and dysmetabolism, exercise capacity, physical function and activity, days of hospitalization, and health-related quality of life. Assessment will be conducted at treatment initiation (baseline), at 3 and 6 months after inclusion, and 1 month and 1 year after ended treatment. The primary endpoint for lower-body muscle strength is at 6 months after treatment initiation. The effects of the intervention will be evaluated through a constrained linear mixed model. Discussion: This national randomized controlled study has the potential to provide new knowledge concerning the short- and long-term effects of a novel, inclusive approach for youth exercise programming (integrative neuromuscular exercise) in children and adolescents during anti-cancer treatment. Using a pragmatic, low-cost, and time-efficient training design, this intervention can be easily adapted to both hospital and home settings. Clinical Trial Registration: ClinicalTrials.gov (NCT04706676), first released January 5, 2021.

Pregnancy or cord 25-hydroxyvitamin D is not associated with measures of body fat or adiposity in children from three months to three years of age. An Odense Child Cohort study.

BACKGROUND & AIMS: The susceptibility to overweight in adults born during winter season may suggest foetal programming of prenatal vitamin D levels on adiposity. We investigated whether cord or pregnancy serum 25-hydroxyvitamin D (s-25OHD) was associated with infant and child body fat measures in a Danish population-based prospective cohort. METHODS: In the Odense Child Cohort, 1905 singletons had cord s-25OHD and data on waist circumference (WC), weight, body mass index (BMI), and sum of skin folds (SSF) at median 3.7 months, 18.9 months and three years' age. Early and late pregnancy samples of s-25OHD (mean gestational age 12 and 29 weeks) were chosen as secondary exposures. Multiple linear and logistic regression as well as linear mixed models was applied testing the relation between cord and pregnancy s-25OHD and body fat outcomes and their Z-scores by use of updated national reference populations. Models were adjusted for maternal educational level, maternal ethnicity, pre-gestational BMI and season of birth, a priori stratified by sex. RESULTS: The median [IQR] cord s-25OHD was 45.5 [31.1; 60.9] nmol/L. Cord s-25OHD <50 nmol/L was found in 57.5%; values < 25 nmol/L in 16.3%. The mean Z-scores of body fat measures at all ages were in the range of -0.32 to +0.42. No consistent associations were found between s-25OHD in cord, early pregnancy or late pregnancy and WC, weight, BMI, SSF, or their Z-scores at ages 3.7 months, 18.9 months, or 3 years. Neither did a computed composite outcome (WC, SSF, BMI, or weight >90th vs. ≤90 percentile) associate with cord or pregnancy s-25OHD. CONCLUSION: Cord or pregnancy s-25OHD was not associated with measures of body fat or adiposity in children up to three years of age. Our data suggested no programming effect of maternal s-25OHD on offspring obesity in a relatively lean and healthy population of mothers.

Prediction of birth weight small for gestational age with and without preeclampsia by angiogenic markers: an Odense Child Cohort study.

Purpose: To investigate the predictive performance of placental growth factor (PlGF) and soluble FMS-like kinase 1 (sFlt-1) on birth weight and small for gestational age (SGA), in a large, population-based cohort.Methods: Women enrolled in the population-based, prospective Odense Child Cohort Study with early (GA < 20 weeks) and/or late (≥20 weeks) pregnancy blood samples (n = 1937) were included. The association between log-transformed values of the biomarkers and birth weight Z-score was studied using multivariate regression models. The prediction of SGA overall, and in women developing preeclampsia, by biomarkers was evaluated using receiver operating characteristic analyses.Results: No substantial associations between early pregnancy biomarkers and SGA were seen. PlGF measured in late pregnancy demonstrated the strongest association with birth weight Z-score (adjusted ß-coefficient = 0.43 [95%CI = 0.35; 0.50]). The area under curve (AUC) for predicting SGA was higher for sFlt-1/PlGF compared to sFlt-1 (0.74 versus 0.63, p = .006) and reached excellent prediction for SGA after preeclampsia (AUC 0.94). Optimal sFlt-1/PlGF ratio cut-offs had higher negative predictive value (NPV) and positive predictive value (PPV) for SGA (cut-off > 5.0; NPV = 99.1%, PPV = 5.4%) compared to each marker individually.Conclusion: The sFlt-1/PlGF ratio is a potential predictor of SGA in population-based screening, particularly when preeclampsia is also present.

Blood pressure in 3-year-old girls associates inversely with umbilical cord serum 25-hydroxyvitamin D: an Odense Child Cohort study.

Background Low foetal vitamin D status may be associated with higher blood pressure (BP) in later life. Objective To examine whether serum 25-hydroxyvitamin D2+3 (s-25OHD) in cord and pregnancy associates with systolic and diastolic BP (SBP; DBP) in children up to 3 years of age. Design Prospective, population-based cohort study. Methods We included 1594 singletons from the Odense Child Cohort with available cord s-25OHD and BP data at median age 3.7 months (48% girls), 18.9 months (44% girls) or 3 years (48% girls). Maternal s-25OHD was also assessed at gestational ages 12 and 29 weeks. Multiple regression models were stratified by sex a priori and adjusted for maternal educational level, season of birth and child height, weight and age. Results In 3-year-old girls, SBP decreased with -0.7 mmHg (95% CI -1.1; -0.3, P = 0.001) and DBP with -0.4 mmHg (95% CI -0.7; -0.1, P = 0.016) for every 10 nmol/L increase in cord s-25OHD in adjusted analyses. Moreover, the adjusted odds of having SBP >90th percentile were reduced by 30% for every 10 nmol/L increase in cord s-25OHD (P = 0.004) and by 64% for cord s-25OHD above the median 45.1 nmol/L (P = 0.02). Similar findings were observed between pregnancy s-25OHD and 3-year SBP, cord s-25OHD and SBP at 18.9 months, and cord s-25OHD and DBP at 3 years. No consistent associations were observed between s-25OHD and BP in boys. Conclusion Cord s-25OHD was inversely associated with SBP and DBP in young girls, but not in boys. Higher vitamin D status in foetal life may modulate BP in young girls. The sex difference remains unexplained.

A novel inverse association between cord 25-hydroxyvitamin D and leg length in boys up to three years. An Odense Child Cohort study.

BACKGROUND AND AIM: Long standing vitamin D deficiency in children causes rickets with growth impairment. We investigated whether sub-ischial leg length (SLL) is shorter, and cephalo-caudal length:length (CCL:L) ratio and sitting height:height (SH:H) ratio larger, with lower cord s-25-hydroxyvitamin D (25OHD) in the population-based prospective Odense Child Cohort, Denmark. METHODS: We included healthy singletons born to term with available measures of cord 25OHD and anthropometrics up to three years' age. Linear regression was stratified by sex a priori and adjusted for maternal ethnicity, pre-pregnancy body mass index and smoking during pregnancy, season of blood sampling and child age. RESULTS: Median (IQR) cord 25OHD was 48.0 (34.0-62.4) nmol/L. At mean age 19.1 months, n = 504, mean (SD) SLL was 31.7 (1.7) cm; CCL:L-ratio 0.62 (0.01). At 36.3 months, n = 956, mean SLL was 42.9 (2.0) cm; SH:H-ratio 0.56 (0.01). No participants had rickets. In adjusted analyses, 19-months-old boys had 0.1 cm shorter SLL (p = 0.009) and 0.1% higher CCL:L-ratio (p = 0.04) with every 10 nmol/L increase in cord 25OHD. Similar findings were seen for late pregnancy 25OHD. In the highest cord 25OHD quartile (>60.7 nmol/L), SLL was 0.8 cm shorter (95% C.I.: 1.36;-0.29, linear trend, p = 0.004), and CCL:L-ratio 0.8% higher (95% C.I. 8.0x10-05;0.01, linear trend, p = 0.01), compared to lowest quartile (<30.7 nmol/L). Similar associations with cord 25OHD were observed in 3-year-old boys. No consistent associations between 25OHD and anthropometrics were seen in girls at either age. CONCLUSION: No leg shortening was found with decreasing cord s-25OHD in a healthy population of infants. A small, yet significant inverse association between cord 25OHD and SLL in boys 1½-3 years warrants further investigations.

Cord serum 25-hydroxyvitamin D is not associated with cranial anthropometrics in infants up to 6 months of age. An Odense Child Cohort study.

Skull changes are poorly described in vitamin D insufficiency [serum 25-hydroxyvitamin D (s-25(OH)D) 25-50 nmol/L]. We aimed to investigate factors associated with cranial anthropometrics in infants, especially s-25(OH)D. In infants 2.5-6 months old from the Odense Child Cohort, associations between cord and pregnancy s-25(OH)D and anterior fontanel area (n = 765), head circumference (HC, n = 1776) and head shape (n = 1527) were investigated along with other factors. Age was corrected for preterm birth. The mean (SD) s-25(OH)D in early pregnancy was 65.97 (21.33) nmol/L; late pregnancy 78.61 (27.18) nmol/L; and cord 47.1 (21.7) nmol/L. At median (IQR) age 3.7 (2.5-5.9) months, the fontanel area was 225 (0-1690) mm2, and mean (SD) HC was 41.5 (1.5) cm. Asymmetric/flat head shape was present in 846 infants (55.3%). No associations were found between cord, early or late pregnancy s-25(OH)D and any cranial measure by univariate or adjusted analysis. Among significant, independent associations in multivariate analysis, fontanel area was associated inversely with gestational age (GA); HC was associated directly with GA, maternal pre-pregnancy overweight and caesarean section and inversely with smoking; and asymmetrical head shape showed a novel association with male sex: adjusted OR = 1.54 (95% CI 1.25; 1.89), p < 0.001. Other associations with asymmetrical head shape included parity 3+, gestational age and maternal age 30+ years (all protective). In conclusion, neither pregnancy nor cord s-25(OH)D was associated with fontanel size, HC or asymmetrical head shape despite a high prevalence of cord s-25(OH)D < 50 nmol/L. Lower GA was associated with larger fontanel size, lower HC and asymmetrical head shape, and boys more frequently had asymmetrical head shape, probably due to heavier heads.

S-25-hydroxyvitamin D and C3-epimers in pregnancy and infancy: An Odense Child Cohort study.

BACKGROUND: Analysis of serum 25-hydroxyvitamin D (s-25(OH)D) may be complicated by the less active or in-active vitamin D metabolite C3-epi-25(OH)D3 (C3-epimer). We aimed to explore the relationship between s-C3-epimer and s-25(OH)D and other determinants and describe the longitudinal course of the C3-epimer fraction in paired mother-child samples. METHOD: S-25(OH)D and s-C3-epimer were estimated by liquid chromatography mass spectrometry in 290 mother-infant pairs from the population-based Odense Child Cohort. Longitudinal analyses were feasible in two subcohorts; B) early and late pregnancy, cord, three and 18months (n=132); and C) early and late pregnancy, delivery and cord (n=105). RESULTS: Mean s-25(OH)D was 50.6-110.4nmol/L at the six time points. The mean C3-epimer fraction was 10.1% at three months, 1.1%-3.0% at the other time points. In multivariate analyses, the s-C3-epimer correlated with s-25(OH)D (all time points, p<0.001), and season, maternal and infant age and maternal vitamin D supplementation at some time points. The C3-epimer fraction fluctuated between adjacent time points. By cosinor analyses, a season-dependent sinusoidal pattern for s-25(OH)D and C3-epimer fraction was found and changes between adjacent time points depended on season (p<0.007 or trend). In early infancy, subtraction of the C3-epi-25(OH)D3 from total s-25(OH)D resulted in reclassification of 8% of the children by use of the 75nmol/L cut off for s-25(OH)D. CONLCUSION: The s-C3-epimer was independently correlated to s-25(OH)D, season, maternal vitamin D supplementation, maternal and infant age. The C3-epimer fraction was only of clinical importance in early infancy, where it could lead to misclassification of the vitamin D status.

Inverse associations between cord vitamin D and attention deficit hyperactivity disorder symptoms: A child cohort study.

OBJECTIVE: To examine the association between cord 25-hydroxyvitamin D2+3 (25(OH)D) and attention deficit hyperactivity disorder symptoms in toddlers, using Child Behaviour Checklist for ages 1.5-5. METHOD: In a population-based birth cohort, a Child Behaviour Checklist for ages 1.5-5 questionnaire was returned from parents of 1233 infants with mean age 2.7 (standard deviation 0.6) years. Adjusted associations between cord 25(OH)D and Child Behaviour Checklist-based attention deficit hyperactivity disorder problems were analysed by multiple regression. Results The median cord 25(OH)D was 44.1 (range: 1.5-127.1) nmol/L. Mean attention deficit hyperactivity disorder problem score was 2.7 (standard deviation 2.1). In adjusted analyses, cord 25(OH)D levels >25 nmol/L and >30 nmol/L were associated with lower attention deficit hyperactivity disorder scores compared to levels ⩽25 nmol/L ( p = 0.035) and ⩽30 nmol/L ( p = 0.043), respectively. The adjusted odds of scoring above the 90th percentile on the Child Behaviour Checklist-based attention deficit hyperactivity disorder problem scale decreased by 11% per 10 nmol/L increase in cord 25(OH)D. CONCLUSION: An inverse association between cord 25(OH)D and attention deficit hyperactivity disorder symptoms in toddlers was found, suggesting a protective effect of prenatal vitamin D.

Vitamin D supplementation, cord 25-hydroxyvitamin D and birth weight: Findings from the Odense Child Cohort.

BACKGROUND & AIMS: Hypovitaminosis D, defined as serum 25-hydroxyvitamin D (s-25(OH)D) <50 nmol/L, is frequent in pregnant women and neonates worldwide and has been associated with both low birth weight (BW) and placental weight (PW) as well as reduced placental development. We aimed to assess the prevalence and the risk factors of cord vitamin D deficiency (s-25(OH)D <25 nmol/L) and insufficiency (s-25(OH)D 25-50 nmol/L) and to evaluate the association between cord s-25(OH)D levels and neonatal outcomes (BW, PW and PW/BW ratio). METHODS: Women enrolled in Odense Child Cohort, a Danish observational prospective population-based cohort, who gave birth to singletons and donated a blood sample for s-25(OH)D measurements were included (n = 2082). RESULTS: The prevalence of cord vitamin D deficiency was 16.7% and 41.0% for insufficiency. White skin, winter season at birth, maternal supplementation dose of <15 µg/day, non-western ethnicity and high body mass index (BMI) were identified as independent risk factors of both vitamin D deficiency and insufficiency. Adherence to the recommended vitamin D supplementation dose (10 µg/day) was reported by 87% (primipara 91% vs. multipara 81%, p < 0.0001). An U-shaped relationship between cord s-25(OH)D and BW was visualized by spline regression (p = 0.003). After adjustment, cord s-25(OH)D was positively associated with BW (ß = 1.522, p = 0.026), PW (ß = 0.927, p < 0.001) and PW/BW ratio (ß = 0.018, p < 0.001), largely driven by positive associations for cord s-25(OH)D >60 nmol/L. CONCLUSION: Cord hypovitaminosis D was present in 57.7%. Multipara was identified as a novel risk factor of non-adherence to vitamin D supplementation recommendations; and a maternal supplementation dose <15 µg/day as a novel, independent risk factor of cord hypovitaminosis D. Higher BW, PW, and PW/BW ratio were associated to higher cord s-25(OH)D levels with a suggested cut-off at 60 nmol/L. More studies are encouraged to elucidate the impact of cord s-25(OH)D levels on offspring health and to establish optimal cut-offs for these outcomes.

Vitamin D Depletion in Pregnancy Decreases Survival Time, Oxygen Saturation, Lung Weight and Body Weight in Preterm Rat Offspring.

Animal studies suggest a role of vitamin D in fetal lung development although not studied in preterm animals. We tested the hypothesis that vitamin D depletion aggravates respiratory insufficiency in preterm rat offspring. Furthermore, the effects of vitamin D depletion on growth and lung surfactant were investigated. Female Sprague-Dawley rats were randomly assigned low vitamin D (VDL) or control diet before mating and followed with serum 25-hydroxyvitamin D (s-25(OH)D) determinations. After cesarean section at gestational day 19 (E19) or day 22 (E22), placental weight, birth weight, crown-rump-length (CRL), oxygenation (SaO2) at 30 min and survival time were recorded. The pup lungs were analyzed for phospholipid levels, surfactant protein A-D mRNA and the expression of the vitamin D receptor (VDR). S-25(OH)D was significantly lower in the VDL group at cesarean section (12 vs. 30nmol/L, p<0.0001). Compared to the controls, E19 VDL pups had lower birth weight (2.13 vs. 2.29g, p<0.001), lung weight (0.09 vs. 0.10g, p = 0.002), SaO2 (54% vs. 69%, p = 0.002) as well as reduced survival time (0.50 vs. 1.25h, p<0.0001). At E22, the VDL-induced pulmonary differences were leveled out, but VDL pups had lower CRL (4.0 vs. 4.5cm, p<0.0001). The phospholipid levels and the surfactant protein mRNA expression did not differ between the dietary groups. In conclusion, Vitamin D depletion led to lower oxygenation and reduced survival time in the preterm offspring, associated with reduced lung weight and birth weight. Further studies of vitamin D depletion in respiratory insufficiency in preterm neonates are warranted.

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review.

Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are major complications to preterm birth. Hypovitaminosis D is prevalent in pregnancy. We systematically reviewed the evidence of the impact of vitamin D on lung development, surfactant synthesis, RDS, and BPD searching PubMed, Embase, and Cochrane databases with the terms vitamin D AND (surfactant OR lung maturation OR lung development OR respiratory distress syndrome OR fetal lung OR prematurity OR bronchopulmonary dysplasia). Three human studies, ten animal studies, two laboratory studies, and one combined animal and laboratory study were included. Human evidence was sparse, allowing no conclusions. BPD was not associated with vitamin D receptor polymorphism in a fully adjusted analysis. Animal and laboratory studies showed substantial positive effects of vitamin D on the alveolar type II cell, fibroblast proliferation, surfactant synthesis, and alveolarization. These data support the hypothesis of hypovitaminosis D as a frequent, modifiable risk factor of RDS and BPD, which should be tested in randomized controlled trials on pregnant women, those with threatening preterm delivery, or in the preterm neonates. Future experimental and human studies should aim to identify optimal time windows, vitamin D doses, and cut-off levels for 25-hydroxyvitamin D in interventions against RDS, BPD, and later adverse respiratory outcomes.

Diagnosis of preeclampsia with soluble Fms-like tyrosine kinase 1/placental growth factor ratio: an inter-assay comparison.

The angiogenic factor ratio soluble Fms-kinase 1 (sFlt-1)/placental growth factor (PlGF) is a novel diagnostic tool for preeclampsia. We compared the efficacy of the KRYPTOR (BRAHMS) automated assays for sFlt-1 and PlGF with the Elecsys (Roche) assays in a routine clinical setting. Preeclamptic women (n = 39) were included shortly after the time of diagnosis. Normotensive control pregnancies were matched by gestational age (n = 76). The KRYPTOR assays performed comparably or superior to Elecsys (sFlt-1/PlGF area under the curve 0.746 versus 0.735; P = .09; for non-obese 0.820 versus 0.805, P = .047). For early-onset preeclampsia, KRYPTOR area under the curve increased to 0.929 with a 100% specificity for preeclampsia at cut-off 85 and an 88.9% sensitivity for preeclampsia at cut-off 33. For women with preeclampsia and preterm delivery or Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome, the KRYPTOR sFlt-1/PlGF ratio was manifold increased (P < .01). The sFlt-1/PlGF ratio proved especially useful in early-onset preeclampsia, preeclampsia with preterm delivery or HELLP, and among non-obese women.