Impact of Vitamin D Supplementation on Gross Motor Development of Healthy Term Infants: A Randomized Dose-Response Trial

In addition to benefits for bone health, vitamin D is implicated in muscle function in children and adults. Aims: To determine if vitamin D dosage positively correlated with gross motor development at 3 and 6 months of age. We hypothesized that higher doses would be associated with higher scores for gross motor skills. Methods: A consecutive sample of 55 healthy, term, and breastfed infants from Montreal, Canada were recruited from a randomized trial of vitamin D supplementation between 2009 and 2012. Infants were randomized to 400 International Units (IU) (n = 19), 800 IU (n = 18) or 1,200 IU (n = 18) vitamin D₃/day. Motor performance at 3 and 6 months was quantified by the Alberta Infant Motor Scale (AIMS). Plasma vitamin D₃ metabolites were measured by tandem mass spectrometry. Results: AIMS scores did not differ at 3 months. However, total AIMS scores and sitting subscores were significantly higher at 6 months in infants receiving 400 IU/day compared to 800 IU/day and 1,200 IU/day groups (p < .05). There were weak negative correlations with length and C-3 epimer of 25(OH)D. Conclusions: In contrast to our hypothesis, gross motor achievements were significantly higher in infants receiving 400 IU/day vitamin D. Our findings also support longer infants being slightly delayed.     

Absorption, dosage, and effect on mineral homeostasis of 25-hydroxycholecalciferol in premature infants: comparison with 400 and 800 IU vitamin D2 supplementation

Because the efficiency of vitamin D absorption or hepatic uptake and 25-hydroxylation appears decreased in very premature infants, the routine use of 25-hydroxycholecalciferol (25-OHD3) supplementation has been suggested. Absorption studies of a 3 micrograms/kg orally administered dose of 25-OHD3 showed peak serum 25-hydroxyvitamin D2 and -vitamin D3 (25-OHD) concentrations at 4 to 8 hours similar in timing but of lesser magnitude to those seen in adults. Administration of 1 microgram/kg birth weight/day of 25-OHD3 corrected moderately low, but not very low serum (25-OHD) concentrations, and 2 micrograms/kg BW/day resulted in rapid and sustained increase in serum 25-OHD. Administration of 800 IU ergocalciferol (D2) also produced significantly higher serum 25-OHD concentrations than those in infants given 400 IU vitamin D2, but increases in serum 25-OHD were more gradual than in infants given 25-OHD3. In treatment trials with infants weighing less than 1500 gm, those given 800 IU D2, compared with those given 400 IU D2, had higher serum calcium concentrations and less frequent moderate or severe hypomineralization. Infants given 2 micrograms/kg BW 25-OHD3 had a significant increase in serum phosphorus values, but a decrease in serum calcium and magnesium concentrations, and parathyroid hormone also was suppressed to low normal values. The frequency of moderate to severe hypomineralization remained the same as in infants given 400 IU D2. In a subgroup of infants, serum 1,25-dihydroxyvitamin D was elevated over adult values, both in infants given 25-OHD3 (68.5 +/- 8.4 pg/ml) and in infants given vitamin D2 (60 +/- 6.7 pg/ml). Serum vitamin D concentrations were undetectable in four of six infants receiving 25-OHD3, but were elevated (5 to 31 ng/ml) in four infants receiving vitamin D2. Although 800 to 1000 IU D2 can be recommended as routine vitamin D supplementation in very premature infants fed standard formula, the use of 25-OHD3 requires further study.     

Recommendations of prophylaxis of vitamin D deficiency in Poland (2009)

Adequate vitamin D intake and its status as well outdoor physical activity are important not only for normal bone development and Ca-P metabolism, but for optimal function of many organs and tissues throughout the body. Due to documented changes in dietary habits and physical activity level, both observed in growing children and adults, the prevalence of vitamin D insufficiency is continuously increasing. National Consultants and experts in this field established the Polish recommendations for prophylactic vitamin D supplementation in infants, toddlers, children and adolescents as well as in adults, including pregnant and lactating women based on current literature review. Taking into consideration pleyotropic vitamin D action and safety aspects serum 25-hydroxyvitamin D (25-OHD) level of 20-60 ng/ml (50-750 nmol/l) in children and 30-80 ng/ml (75-200 nmol/I) in adults is considered as optimal. Sunlight exposure inducing vitamin D production in the skin is main endogen source of vitamin D in the body but sunscreens may reduce skin synthesis by 90%. In Poland, skin synthesis is effective only from April to September so other sources of vitamin D such as diet and supplements play an important role. All newborns should be supplemented with 400 IU/d of vitamin D beginning from the first few days of life and continue during infancy. In formula fed infants vitamin D intake from the diet should be taken into account. In preterm infants higher total vitamin D intake (400-800 IU/day) is recommended till 40 weeks post conception. Total vitamin D intake in children and adolescents required from all sources (diet and/or supplements) should be 400 IU/d between October and March and throughout the whole year in case of inadequate vitamin D skin synthesis during the summer months. In overweight/obese children supplementation with higher dosage of vitamin D up to 800-1000 IU/d should be considered. Adults require 800-1000 IU/d of vitamin D. In pregnant and lactating women such supplementation is recommended in case of inadequate intake from diet and/or skin synthesis supplementation. Monitoring of serum 25-OHD level to define optimal dosage should be considered.     

Serum and red cell folates,and serum vitamin B12 in protein calorie malnutrition

In 22 cases of kwashiorkor, 19 cases of marasmus, and 16 normal controls, red cell folate, serum folate, and serum vitamin B₁₂ were estimated, and the bone marrow and peripheral blood examined. Erythrocyte folate deficiency was shown in 9 cases of kwashiorkor and 7 cases of marasmus. Serum folate deficiency was present in 14 cases of kwashiorkor and 7 cases of marasmus. Megaloblastosis was found in 45% of cases of kwashiorkor and 37% of cases of marasmus. Megaloblastosis and macrocytosis correlated more with erythrocyte than with serum folate deficiency. Serum vitamin B₁₂ levels in children with kwashiorkor or marasmus did not differ from those of normal controls. The role of folate deficiency in the pathogenesis of megaloblastosis in protein calorie malnutrition was confirmed.     

Plasma and urine carnitine levels and carnitine supplementation in children with malnutrition

The purpose of the present investigation was to determine serum and urinary carnitine levels in children suffering from protein-energy malnutrition (PEM) before and after dietary treatment and carnitine supplementation, and to compare them with those in healthy children. Plasma and urine carnitine levels were lower in patients with marasmus and kwashiorkor than in controls. There was no statistical difference between groups with and without carnitine supplementation on the first day. On the fifth day, in groups receiving carnitine supplementation, plasma and urine carnitine levels were significantly higher than in groups without supplementation (p < 0.01). On the 15th day there was no statistical significance between groups with PEM and controls.     

Maternal vitamin D deficiency and vitamin D supplementation in healthy infants

The objective of this study was to evaluate the common effects of maternal vitamin D deficiency, various doses of vitamin D given to newborns and the effects of these on vitamin D status in early childhood. Seventy-eight pregnant women and 65 infants who were followed up in various health centers were included in the sudy. 25-hydroxyvitamin-D (25-OHvitD), calcium (Ca), phosphorus (P) and alkaline phosphatase levels were measured in blood samples drawn from pregnant women in the last trimester. Infants born to these mothers were given 400 or 800 IU of vitamin D subsequently at the start of the second week. 25-OHvitD, Ca, P and alkaline phosphatase levels of the 65 infants who were brought in for controls (May-September 2000) were measured and hand-wrist X-rays were evaluated. We analyzed the relationship between vitamin D status of the mothers and infants and socio-economic status; mothers' dressing habits (covered vs uncovered), educational level, and number of pregnancies; and sunlight exposure of the house. Covered as a dressing habit meant covering the hair and sometimes part of the face and wearing dresses that completely cover the arms and legs. In 40 infants who were breast-fed and received the recommended doses of vitamin D on a regular basis, the relationship between serum vitamin D levels and supplementation doses given was analyzed. Serum 25-OHvitD level of the mothers was 17.50 +/- 10.30 and 94.8% of the mothers had a 25-OHvitD level below 40 nmol/L (below 25 nmol/L in 79.5%). The risk factors associated with low maternal 25-OHvitD were low educational level (p = 0.042), insufficient intake of vitamin D within diet (p = 0.020) and "covered" dressing habits (p = 0.012). 25-OHvitD level of the infants was 83.70 +/- 53.70 nmol/L, and 24.6% of the infants had 25-OHvitD levels lower than 40 nmol/L. Risk factors for low 25-OHvitD levels in infants were a) not receiving recommended doses of vitamin D regularly (p = 0.002) and b) insufficient sunlight exposure of the house (p = 0.033). There was a pour but significant correlation between maternal vitamin D levels and infants' 25-OHvitD levels at four months (r = 0.365, p < 0.05). No significant correlation was found between 25-OHvitD levels and supplementation doses of vitamin D (19 infants were supplemented with 400 IU/day and 21 with 800 IU/day of vitamin D) (p = 0.873). Severe maternal vitamin D deficiency remains a commonly seen problem in Turkey. However, vitamin D deficiency can be prevented by supplementation of vitamin D to newborns (at least 400 IU). Supplementation of 800 IU vitamin D in the areas of maternal vitamin D deficiency has no greater benefits for the infants.     

Prevention of rickets and vitamin D deficiency in infants, children, and adolescents

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate sunshine exposure for the cutaneous synthesis of vitamin D is not easily determined for a given individual and may increase the risk of skin cancer, the recommendations to ensure adequate vitamin D status have been revised to include all infants, including those who are exclusively breastfed and older children and adolescents. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The current recommendation replaces the previous recommendation of a minimum daily intake of 200 IU/day of vitamin D supplementation beginning in the first 2 months after birth and continuing through adolescence. These revised guidelines for vitamin D intake for healthy infants, children, and adolescents are based on evidence from new clinical trials and the historical precedence of safely giving 400 IU of vitamin D per day in the pediatric and adolescent population. New evidence supports a potential role for vitamin D in maintaining innate immunity and preventing diseases such as diabetes and cancer. The new data may eventually refine what constitutes vitamin D sufficiency or deficiency.     

Maternal compared with infant vitamin D supplementation.

Vitamin D metabolites were studied in mother-infant pairs at delivery and eight and 15 weeks after that to evaluate the possibility of vitamin D supplementation of infant through the mother. Healthy mothers (n = 49) delivering in January received daily either 2000 IU (group 1), 1000 IU (group 2), or no (group 3) vitamin D. Their infants were exclusively breast fed, and those in group 3 received 400 IU of vitamin D a day. After eight weeks of lactation the infantile vitamin D concentrations were similar in groups 1 and 3 but significantly lower in group 2. The serum 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations were also lower in group 2. The mean mineral, parathyroid hormone, and alkaline phosphatase values showed no intergroup differences at any point. No infants showed any clinical or biochemical signs of rickets, and their growth was equal. In conclusion, a daily postpartum maternal supplementation with 2000 IU of vitamin D, but not with 1000 IU, seems to normalise the vitamin D metabolites of breast fed infants in winter. Maternal safety with such supplementation over prolonged periods, however, should be examined.     

Comparison between daily supplementation doses of 200 versus 400 IU of vitamin D in infants

The daily supplementation of vitamin D is mandatory for infants. However, there are still conflicting opinions about the exact daily dose. Thus, we aimed to evaluate a daily supplementation dose of 200 IU is sufficient and compared the supplementation doses of 200 and 400 IU per day. One hundred and sixty-nine infants were randomly assigned to two groups (group1, 200 IU/day; group 2, 400 IU/day) and there were 75 infants in group 1 and 64 were in group 2 with a total number of 139. The median levels of 25-hydroxyvitamin D3 were significantly increased in group 2 at the age of 4 months (group 1, 39.60 mcg/L; group 2, 56.55 mcg/L; p?<?0.0001). We clearly demonstrated that at the age of 4 months, none of the infants on the group 2 had a serum level of 25-hydroxyvitamin D3 less than 30 mcg/L. However, 21.3 % of the infants in group 1 had a level below 30 mcg/L. Thus, in order to avoid vitamin D deficiency and rickets, we recommend supplementation dose of vitamin D at 400 IU/day as a safe and effective dose.     

Computerized cry analysis in infants affected by severe protein energy malnutrition

A new method of computerized cry analysis has been utilized to evaluate the cries of infants affected by severe protein energy malnutrition. We studied 17 Kenian babies affected by severe malnutrition for more than four months (9 cases of marasmus and 8 of kwashiorkor) and a control group of 17 well-nourished babies. The cries of the malnourished children showed lower inter-utterance variability, formants' frequencies and cry score. assigned by the Infant Cry Modulation Assessment Scale. The melodic pattern was more often flat, rising or falling-rising, when compared to the cries of the well-nourished babies. We hypothesize that these differences reflect the state of brain damage associated with protein energy malnutrition. No differences were found between the cries of infants affected by marasmus and those affected by kwashiorkor, between the cries recorded before and after nutritional therapy and between the first cries of malnourished children who subsequently died during hospitalization and those of infants who survived.     

Cry analysis in infants with severe malnutrition

Sound spectrographic investigations of the cries of 5 infants, age 7 m to 2y, with severe malnutrition (one with kwashiorkor and four with marasmus) were compared with the cries of 15 healthy children of corre-sponding ages. The cry of the child with kwashiorkor resembled those of the normal infants. The cries of the marasmic children showed a significant increase in the minimum and maximum pitch, and in the occurrence of biphonation and flat melody types. These features have also been found in the cries of children with brain damage. We therefore believe that cry analysis can be an additional means of investigating to what degree the brain is affected in children with malnutrition.     

Effect of different doses of vitamin D on osteocalcin and deoxypyridinoline in preterm infants

Background: Metabolic bone disease of prematurity is a common problem in preterm infants. The aim of the present paper was to measure the effect of vitamin D, in order to see the relation between vitamin D and urinary excretion of deoxypyridinoline (DPD), serum osteocalcin (OC), calcium (Ca), inorganic phosphorus (P), and alkaline phosphatase (ALP). Methods: Three different doses of vitamin D, 200 IU/kg (group 1, 11 infants), 400 IU/kg (group 2, 15 infants) and 800 IU/kg bodyweight/day (group 3, 11 infants), were administered to a total of 37 preterm infants between 15th day of birth until the 30th day of birth. Results: There were no significant differences in levels of serum Ca and P before and after vitamin D supplementation in all groups. Serum ALP levels were increased in all but significantly only in groups 1 and 3. Serum OC levels were also increased in each group by the treatment. Urinary DPD excretion was increased gradually by the increase in vitamin D intake, but it was significant only in group 3. Conclusion: High dose of vitamin D supplementation might accelerate bone turnover and increased urinary DPD levels might reflect increased bone resorption. To the best of the authors’ knowledge this is the first study comparing the effects of different vitamin D dose, by the means of urinary collagen cross‐links, on bone turnover in preterm infants.     

MALNUTRITION AND SIZE OF THE CEREBRAL VENTRICLES1

Examination of the size of the cerebral ventricles by means of echoencephalography in Ethiopian infants and young children with severe malnutrition showed a moderate but significant increase in children with kwashiorkor, examined up to 3–4 weeks after admission, whereas children with marasmus showed no deviation from the normal. Further studies will show whether or not this abnormality in the kwashiorkor children is a transient phenomenon. The observation gives one more reason for caution in using head circumference as a measure of brain size.     

How much vitamin D for neonates?

To assess the adequacy of different dosages of neonatal vitamin D, 25-hydroxyvitamin D serum concentrations were longitudinally monitored in 27 low-birth-weight and 25 full-term well infants from birth to 16 weeks after delivery. The infants were randomly assigned to receive either 10 micrograms/d (400 IU/d) or 20 micrograms/d (800 IU/d) of vitamin D or 0.85 or 1.5 micrograms/d of 25-hydroxyvitamin D3. In each infant who received 10 or 20 micrograms/d of vitamin D 25-hydroxyvitamin D, serum concentrations greater than 20 ng/mL were maintained, with some low-birth-weight infants reaching 60-ng/mL concentrations. Similarly, in the low-birth-weight infants receiving 1.5 and 0.85 micrograms/d of 25-hydroxyvitamin D3, serum 25-hydroxyvitamin D levels greater than 12 ng/mL were maintained. In the full-term infants who received 1.5 micrograms/d of 25-hydroxyvitamin D3, serum 25-hydroxyvitamin D concentrations of greater than 12 ng/mL were maintained, but in those who received 0.85 micrograms/d, serum 25-hydroxyvitamin D concentrations of 10 ng/mL could not be maintained. These vitamin D status data document that 10 micrograms (400 IU) of vitamin D represents a sufficient daily intake for both premature and full-term well infants. These data also indicate that while as little as 0.85 micrograms/d of 25-hydroxyvitamin D3 may facilitate vitamin D sufficiency in low-birth-weight neonates, it does not do so in full-term infants.     

Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants

AIMS: To test the hypothesis that a vitamin D dose of 200 IU/kg, maximum 400 IU/day, given to preterm infants will maintain normal vitamin D status and will result in as high a bone mineral density as that attained with the recommended dose of 960 IU/day. METHODS: Thirty nine infants of fewer than 33 weeks of gestational age were randomly allocated to receive vitamin D 200 IU/kg of body weight/day up to a maximum of 400 IU/day or 960 IU/day until 3 months old. Vitamin D metabolites, bone mineral content and density were determined by dual energy x-ray absorptiometry, and plasma ionised calcium, plasma alkaline phosphatase, and intact parahormone measurements were used to evaluate outcomes. RESULTS: The 25 hydroxy vitamin D concentrations tended to be higher in infants receiving 960 IU/day, but the differences did not reach significance at any age. There was no difference between the infants receiving low or high vitamin D dose in bone mineral content nor in bone mineral density at 3 and 6 months corrected age, even after taking potential risk factors into account. CONCLUSIONS: A vitamin D dose of 200 IU/kg of body weight/day up to a maximum of 400 IU/day maintains normal vitamin D status and as good a bone mineral accretion as the previously recommended higher dose of 960 IU/day. Vitamin D is a potent hormone which affects organs other than bone and should not be given in excess to preterm infants.     

A comparison of fasting plasma insulin and growth hormone concentrations in marasmic, kwashiorkor, marasmic-kwashiorkor and underweight children.

Fasting plasma insulin and growth hormone concentrations were measured in 24 marasmic, 11 kwashiorkor, 16 marasmic-kwashiorkor, and 4 underweight children. Hormone measurements were made by a special modification of the Hales and Randle double antibody immunoassay with increased sensitivity in the concentration range 0-25 micronU/ml. Fasting plasma insulin was low in marasmus, kwashiorkor, and marasmic-kwashiorkor children, and increased to normal levels after recovery. Fasting plasma growth hormone was elevated in all groups during malnutrition and was significantly decreased to normal levels after recovery. There were no significant differences in plasma insulin or growth hormone levels between the different clinical types of severe protein energy malnutrition. These hormonal changes in severe protein energy malnutrition are of complex and not fully understood etiology. However, recovered children appear to have a hormonal pattern similar to that described in normal control infants and children.     

Interleukin-1 in malnutrition.

The effect of malnutrition on the in vitro production of interleukin-1 by lipopolysaccharide stimulated circulating monocytes has been investigated in children suffering from kwashiorkor and marasmus. The interleukin-1 activity was significantly lower in children with severe malnutrition. Furthermore, macrophages from children with kwashiorkor produced factors that suppressed mouse thymocyte proliferation. These observations show a significant impairment of macrophage function and provide a mechanism for the suppression of cellular immunity in malnutrition.     

The quality of the diet in Malawian children with kwashiorkor and marasmus

Nutritionists have suggested that kwashiorkor is related to low dietary protein and/or antioxidant intake. This study explored the hypothesis that among Malawian children with severe malnutrition, those with kwashiorkor consume a diet with less micronutrient- and antioxidant-rich foods, such as fish, eggs, tomatoes and orange fruits (mango, pumpkin and papaya), than those with marasmus. A case-control method with a food frequency questionnaire was used to assess the habitual diet. Children with severe childhood malnutrition presenting to the central hospital in Blantyre, Malawi during a 3-month period in 2001 were eligible to participate. The food frequency questionnaire collected data about foods consumed by siblings <60 months of age in the home. It was assumed that the habitual diet of all siblings 1-5 years old in the same home was similar. Dietary diversity was assessed using a validated method, with scores that ranged from 0 to 7. Regression modelling was used to control for demographic and disease covariates. A total of 145 children with kwashiorkor and 46 with marasmus were enrolled. Children with kwashiorkor consumed less egg and tomato than those with marasmus: 17 (15) vs. 24 (31) servings per month for egg, mean (SD), P < 0.01 and 27 (17) vs. 32 (19) servings per month for tomato, P < 0.05. Children with kwashiorkor had a similar dietary diversity score as those with marasmus, 5.06 (0.99) vs. 5.02 (1.10), mean (SD). Further research is needed to determine what role consumption of egg and tomato may play in the development of kwashiorkor.     

Prevention and treatment of vitamin D and calcium deficiency in children and adolescents: Indian Academy of Pediatrics (IAP) guidelines

Justification

Vitamin D deficiency (VDD) is being increasingly reported from India from all age-groups. Reports suggest that VDD affects all age groups, from neonates to adolescents. Further, habitually low calcium intakes are also reported in Indian children. Given the multiple guidelines, peculiarities of Indian circumstances, changing lifestyles, and lack of fortification, the Indian Academy of Pediatrics (IAP) felt the need for a Practice Guideline for Pediatricians for the prevention and treatment of vitamin D and calcium deficiency in children and adolescents.

Process

The ‘Guideline for Vitamin D and Calcium in Children’ committee was formed by the IAP in September 2016. A consultative committee meeting was held in November 2016 in Mumbai. Evidence from Indian and international studies and other previous published recommendations, which were pertinent to the Indian circumstances, were collated for the preparation of these guidelines.

Objectives

To present a practice guideline for pediatricians for the prevention and treatment of deficiency of vitamin D and calcium in the Indian context.

Recommendations

For the prevention of rickets in premature infants, 400 IU of vitamin D and 150-220 mg/kg of calcium, and in neonates, 400 IU of vitamin D and 200 mg of calcium are recommended daily. For prevention of rickets and hypocalcemia in infants (after neonatal period) upto 1 year of age, and from 1-18 years, 400 IU and 600 IU vitamin D/day and 250-500 mg/day and 600-800 mg/day of calcium, respectively, are recommended. For treatment of rickets in premature neonates, infants upto 1 year and from 1-18 years, 1000 IU, 2000 IU and 3000-6000 IU of vitamin D daily, respectively, and elemental calcium of 70-80 mg/kg/day in premature neonates and 500-800 mg daily for all children over that age are recommended. Larger doses of vitamin D may be given from 3 months to 18 years of age as 60,000 IU/week for 6 weeks.

     

Association of vitamin D supplementation with respiratory tract infection in infants

Vitamin D deficiency has been reported to be associated with respiratory tract infection (RTI). However, evidence regarding the effects of vitamin D supplementation on susceptibility of infants to RTI is limited. In this prospective birth cohort study, we examined whether vitamin D supplementation reduced RTI risk in 2,244 infants completing the follow‐up from birth to 6 months of age. The outcome endpoint was the first episode of paediatrician‐diagnosed RTI or 6 months of age when no RTI event occurred. Infants receiving vitamin D supplements at a daily dose of 400–600 IU from birth to the outcome endpoint were defined as vitamin D supplementation and divided into four groups according to the average frequency of supplementation: 0, 1–2, 3–4, and 5–7 days/week. We evaluated the relationship between vitamin D supplementation and time to the first episode of RTI with Kaplan–Meier plots. The associations of vitamin D supplementation with infant RTI, lower RTI (LRTI), and RTI‐related hospitalization were assessed using modified Poisson regression. The median time to first RTI episode was 60 days after birth (95% CI [60, 90]) for infants without supplementation and longer than 6 months of age for infants with supplementation (p < .001). We observed inverse trends between supplementation frequency and risk of RTI, LRTI, and RTI‐related hospitalization (p for trend < .001), with the risk ratios in the 5–7 days/week supplementation group of 0.46 (95% CI [0.41, 0.50]), 0.17 (95% CI [0.13, 0.24]), and 0.18 (95% CI [0.12, 0.27]), respectively. These associations were significant and consistent in a subgroup analysis stratified by infant feeding.