Vitamin D consensus for Italian children, 30 ng needed, up to 4,000 IU if over age 10 – May 2018

Vitamin D in pediatric age: consensus of the Italian Pediatric Society and the Italian Society of Preventive and Social Pediatrics, jointly with the Italian Federation of Pediatricians.

Ital J Pediatr. 2018 May 8;44(1):51. doi: 10.1186/s13052-018-0488-7.
Saggese G1, Vierucci F2, Prodam F3, Cardinale F4, Cetin I5, Chiappini E6, De' Angelis GL7, Massari M5, Miraglia Del Giudice E8, Miraglia Del Giudice M8, Peroni D1, Terracciano L9, Agostiniani R10, Careddu D11, Ghiglioni DG12, Bona G13, Di Mauro G14, Corsello G15.

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Vitamin D plays a pivotal role in the regulation of calcium-phosphorus metabolism, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur.Besides its historical skeletal functions, in the last years it has been demonstrated that vitamin D directly or indirectly regulates up to 1250 genes, playing so-called extraskeletal actions. Indeed, recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious, allergic and autoimmune diseases. Thus, vitamin D deficiency may affect not only musculoskeletal health but also a potentially wide range of acute and chronic conditions. At present, the prevalence of vitamin D deficiency is high in Italian children and adolescents, and national recommendations on vitamin D supplementation during pediatric age are lacking. An expert panel of the Italian Society of Preventive and Social Pediatrics reviewed available literature focusing on randomized controlled trials of vitamin D supplementation to provide a practical approach to vitamin D supplementation for infants, children and adolescents.

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Table 6 Risk factors for vitamin D deficiency in the first year of life
• Non-Caucasian ethnicity with dark skin pigmentation
• Inadequate diets (i.e. vegan diet)
• Chronic kidney disease
• Hepatic failure and/or cholestasis
• Malabsorption syndromes (i.e. cystic fibrosis, inflammatory bowel diseases, celiac disease at diagnosis, etc.)
• Chronic therapies: anticonvulsants, systemic glucocorticoids, antiretroviral therapy, systemic antifungals (i.e. ketoconazole)
• Infants born from mothers with multiple risk factors for vitamin D deficiency, particularly in absence of vitamin D supplementation during pregnancy
Table 7 Risk factors for vitamin D deficiency between 1 and 18 years of age
• Non-Caucasian ethnicity with dark skin pigmentation
• Reduced sunlight exposure (due to lifestyle factors, chronic illness or hospitalization, complex disability, institutionalization, covering clothing for religious or cultural reasons) and/or constant use of sunscreens
• International adoption
• Obesity
• Inadequate diets (i.e. vegan diet)
• Chronic kidney disease
• Hepatic failure and/or cholestasis
• Malabsorption syndromes (i.e. cystic fibrosis, inflammatory bowel diseases, celiac disease at diagnosis, etc.)
• Chronic therapies: anticonvulsants, systemic glucocorticoids, antiretroviral therapy, systemic antifungals (i.e. ketoconazole)

Summary of recommendations

Definition of vitamin D status

Individual vitamin D status can be assessed evaluating serum circulating 25(OH)D levels.
Depending on 25(OH)D levels, vitamin D status can be defined as follows:
Sufficiency >30 ng/ml Insufficiency 20-29 ng/ml Deficiency < 20 ng/ml Severe deficiency < 10 ng/ml
The term hypovitaminosis D refers to serum 25(OH)D levels < 30 ng/ml.

Evaluation of vitamin D status

The isotope dilution- LC-MS/MS is considered the preferred method for measuring serum 25(OH)D levels, especially in the neonatal period. However, considering the reduced availability on the Italian territory of this method, other reliable immunoassay methods can be used if performed in certified laboratories, with the exclusion of neonates.

Prevalence of hypovitaminosis D in Italy in pediatric age

Available epidemiological studies show a high prevalence of hypovitaminosis D (above 50%) throughout Italy. Adolescents are particularly at risk of hypovitaminosis D.
Vitamin D status of newborns is influenced by ethnicity, season of birth, and maternal vitamin D status during pregnancy.
Vitamin D status of children and adolescents is influenced by sun exposure, seasonality, ethnicity, and body mass index.

Vitamin D supplementation

0-12 months

We recommend vitamin D supplementation in the first year of life to ensure an adequate vitamin D status and to prevent nutritional rickets.
We recommend vitamin D supplementation in all newborns independently of the type of feeding.
Vitamin D supplementation should be started within the first days of life and continued throughout the first year.
Infants born at term without risk factors for vitamin D deficiency should receive 400 IU/day of vitamin D.
In the presence of risk factors for vitamin D deficiency (Table 6) up to 1000 IU/day of vitamin D can be given.
In the first year of life we recommend daily administration of vitamin D.
We recommend against using vitamin D metabolites and their analogs (calcifediol, alfacalcidol, calcitriol, and dihydrotachysterol) for the routine vitamin D supplementation.
The administration of these compounds increases the risk of hypercalcemia and is not able to maintain and/or restore vitamin D stores.
We recommend against routine 25(OH)D testing in infants in the first year of life. We suggest to measure serum 25(OH)D levels in infants with multiple risk factors for vitamin D deficiency (Table 6).

Preterm infants

We suggest for VLBW infants a vitamin D intake of 200-400 IU/day (including the amount administered through parenteral nutrition, fortified breast milk, or preterm infant formula).
When VLBW infants reach a weight > 1500 g and full enteral nutrition we suggest vitamin D supplementation at 400-800 IU/day.
We recommend vitamin D supplementation at 400-800 IU/day for preterm infants with birth weight > 1500 g.
After a post-conceptional age of 40 weeks, recommendations for vitamin D supplementation are equal to those for healthy term infants.
We recommend against routine 25(OH)D testing in preterm newborns.

1-18 years

We recommend vitamin D supplementation in children and adolescents with risk factors for vitamin D deficiency (Table 7). Moreover, we recommend to evaluate modifiable life-style risk factors for deficiency, particularly a reduced sun exposure. Ensuring an adequate vitamin D intake is particularly important during adolescence.
We recommend daily vitamin D supplementation ranging from 600 IU/day (i.e. in presence of reduced sun exposure) up to 1000 IU/day (i.e. in presence of multiple risk factors for vitamin D deficiency).
In cases of poor compliance, supplementation with intermittent dosing (weekly or monthly doses for a cumulative monthly dose of 18000-30000 IU of vitamin D) can be considered, starting from children aged 5-6 years and particularly during adolescence.
We suggest vitamin D supplementation from the end of fall to the beginning of spring (November- April) in children and adolescents with reduced sun exposure during summer. We suggest continuous vitamin D supplementation in cases of permanent risk factors for vitamin D deficiency.
Individuals on anticonvulsants, oral corticosteroids, antimicotics and antiretroviral drugs should receive at least 2-3 times more vitamin D than the daily requirement recommended for age.
We endorsed as Tolerable Upper Intake Levels of vitamin D those proposed by EFSA in 2012 (1000 IU/day for infants; 2000 IU/day for children ages 1 to 10 years; 4000 IU/day for children and adolescents ages 11 to 17 years).
We recommend against using vitamin D metabolites and their analogs (calcifediol, alfacalcidol, calcitriol, and dihydrotachysterol) for the routine vitamin D supplementation.
The administration of these compounds increases the risk of hypercalcemia and is not able to maintain and/or restore vitamin D stores.
We recommend against routine 25(OH)D testing in children and adolescents. We suggest to measure serum 25(OH)D levels in presence of multiple risk factors for vitamin D deficiency. Vitamin D status should be monitored at least yearly in subjects that require supplementation during the whole year because affected from pathological conditions or receiving drugs affecting vitamin D metabolism (Table 7).

Skeletal actions of vitamin D Nutritional rickets

Children of immigrants living in industrialized countries are at increased risk of nutritional rickets because they usually present several risk factors for vitamin D deficiency such as prolonged breastfeeding without vitamin D supplementation, increased skin pigmentation, reduced sun exposure due to cultural habits (i.e. veiling), and reduced intestinal calcium uptake due to an excessive intake of high-phytates foods.
In suspicion of nutritional rickets we recommend the assessment of serum 25(OH)D, parathyroid hormone, alkaline phosphatase, calcium, and phosphorus levels and an X-rays evaluation of metaphyseal sites (wrists and ankles) to confirm the diagnosis.
Treatment of nutritional rickets is based on the administration of vitamin D (2000 IU/day in patients aged less than 1 year, 3000-6000 IU/day in patients aged 1 to 12 years and 6000 IU/day in patients older than 12 years for a minimum of 3 months) and calcium (30-75 mg/kg/day of elemental calcium in 3 divided doses, starting at a higher dose and weaning down to the lower end of the range over 2-4 weeks).
Vitamin D metabolites and their analogs (calcifediol, alfacalcidol, calcitriol, and dihydrotachysterol) are not recommended for routine treatment of nutritional rickets.
Daily administration of vitamin D is preferred in infants. Intermittent administration of vitamin D may be considered in children and adolescents with poor compliance with daily treatment (i.e. 50000 IU weekly for 6-8 consecutive weeks or 100000 IU monthly for 3-4 consecutive months).
We recommend against the administration of a single large dose of vitamin D > 300000 IU.
After rickets healing, we recommend to continue vitamin D supplementation according to age (400-1000 IU/day in the first year of life and 600-1000 IU/day from 1 to 18 years).

Bone health

Vitamin D directly influences bone mass acquisition contributing to the regulation of calcium-phosphorus metabolism, and indirectly stimulating the development of muscle tissue.
Available evidence suggests a positive effect of vitamin D supplementation on bone mass acquisition in children and adolescents with vitamin D deficiency.
Recent studies suggest a relationship between maternal vitamin D status during pregnancy and bone mass of the fetus and the newborn. Uncertain evidence exists on the relationship with bone mass later in life until the acquisition of bone mass.

Extraskeletal actions of vitamin D

Respiratory infections

Recent studies suggest an association between vitamin D deficiency and the severity or the incidence of respiratory infections in children. However, because current evidence is weak, we suggest against vitamin D administration as a therapy for respiratory infections, beyond the correction of a documented vitamin D deficiency.
No definitive evidence exists to recommend vitamin D supplementation for prevention of respiratory infections (non-associated with wheezing) or recurrent respiratory infections. However, some studies suggested that serum 25(OH)D higher than those needed for the prevention of nutritional rickets may be necessary to exert a regulatory effect on the immune system.
We recommend against routine 25(OH)D testing in children with respiratory infections.
A single RCT suggested that vitamin D supplementation may help in preventing non complicated acute otitis media. However, considering this limited evidence, evaluation of serum 25(OH)D levels may be reasonable before starting supplementation in these children.

Other infections

Reduced serum 25(OH)D levels are found in children with different types of infectious diseases (tuberculosis, HIV, viral hepatitis, acute diarrhea).
However, available evidence does not support a causal relationship between hypovitaminosis D and infections.
We suggest the evaluation of vitamin D status only in patients affected by tuberculosis or HIV infection, as they may benefit from vitamin D supplementation, in particular due to concomitant treatments that influence vitamin D metabolism.
We recommend against vitamin D supplementation to reduce incidence or severity of non-respiratory infections in children. However, as few studies showed that vitamin D supplementation improves clinical parameters in patients with active tuberculosis or HIV infection, more rigorous and extensive studies are needed to evaluate the role of vitamin D supplementation in infectious diseases, considering also the setting of care, children's age and nutritional status, potential co-infections and compliance with anti-infective therapy.

Asthma

Recent meta-analyses did not find an association between 25(OH)D levels in cord blood or during pregnancy and the development of asthma later in life.
Several studies showed a relationship between latitude, prevalence of hypovitaminosis D and increase in allergic asthma prevalence in the pediatric population.
Low serum 25(OH)D levels are associated with increased asthma severity and increased risk of asthma exacerbations requiring hospitalization or medical treatment. Recent meta-analyses suggest that supplementation with vitamin D (500-2000 IU/day) may reduce the risk of asthma exacerbation.
We recommend against routine 25(OH)D testing in children with asthma.

Atopic dermatitis and allergic diseases

Low serum 25(OH)D levels are associated with increased incidence and/or severity of AD in children in most but not all studies. Indeed, a pathogenetic role of vitamin D in AD has yet to be demonstrated.
We recommend against routine 25(OH)D testing in children with AD. Serum 25(OH)D evaluation may be considered in children with severe AD unresponsive to common therapy and multiple risk factors for vitamin D deficiency.
In pediatric population there is limited evidence regarding a possible favourable effect of vitamin D supplementation on several aspects of AD.
A short trial of vitamin D supplementation can be considered in patients with severe AD unresponsive to common therapy, especially in the late winter-early spring period. In presence of documented vitamin D deficiency, we recommended adequate treatment to restore vitamin D status, followed by supplementation at doses recommended for age.
Vitamin D supplementation for primary prevention of allergic diseases, including food allergies, remains an attractive area of study, but actual evidence does not allow to make any recommendation.

Type 1 diabetes mellitus

Children and adolescents with T1DM are at risk for vitamin D deficiency.
Recommended vitamin D intakes in patients with T1DM are the same as those for the healthy pediatric population.
Recommendations for vitamin D treatment in subjects with T1DM and vitamin D deficiency are the same as those for the healthy pediatric population.
At present, there is no evidence that vitamin D supplementation may delay the development of T1DM or may ameliorate its clinical features. However, we recommend to maintain vitamin D intake for age and to treat vitamin D deficiency if found.
We recommend against routine 25(OH)D testing in children with T1DM.

Inflammatory bowel diseases

In patients with IBDs (Crohn's disease or ulcerative colitis) we suggest to evaluate serum 25(OH)D levels at diagnosis and at least yearly, preferably in the late winter-early spring period.
We recommend continuous vitamin D supplementation at higher doses than those recommended for age (at least 1000-1500 IU/day).
We recommend to treat vitamin D deficiency with daily vitamin D at higher doses than those recommended for otherwise healthy pediatric population (at least 2000-4000 IU/day), for a minimum of 6-8 weeks.
Intermittent bolus doses of vitamin D for a cumulative dose of at least 400000 IU should be reserved for IBDs patients with vitamin D deficiency and poor compliance with daily treatment.
After achieving vitamin D sufficiency, we recommend to continue with vitamin D supplementation at higher doses than those recommended for age (at least 1000-1500 IU/day).

Celiac disease

We recommend to evaluate serum 25(OH)D levels in patients with CD at diagnosis and 6-12 months after the beginning of gluten-free diet if deficiency
has been found. We suggest against further 25(OH)D evaluations in case of sufficient 25(OH)D levels or documented normalization of vitamin D status and strict adherence to the gluten-free diet.
Recommendations for treatment of vitamin D deficiency in patients with newly diagnosed CD are equivalent to those for IBDs patients, as both these conditions are associated with intestinal malabsorption.
As gluten-free diet restores normal intestinal absorption, after treatment of deficiency we recommend vitamin D supplementation according to the modalities and requirements for otherwise healthy children and adolescents.

Obesity and metabolic syndrome

Epidemiological studies showed that obese children and adolescents are at high risk for vitamin D deficiency.
Obesity is the cause and not the effect of this association because of the deposition of vitamin D in adipose tissue with consequent reduction in serum 25(OH)D levels.
It is uncertain if vitamin D deficiency may worsen metabolic profile of obese children and adolescents.
We suggest against vitamin D administration to improve obesity-related complications, given inconsistent results and the small number of studies.
We suggest vitamin D supplementation at higher doses than those recommended for age (10001500 IU/day) from the end of fall to the beginning of spring (November-April) in obese children and adolescents to ensure an adequate vitamin D status. Obese subjects with reduced sun exposure during summer should receive vitamin D supplementation throughout the year. Finally, sensible sunlight exposure and outdoor physical exercise should be encouraged in obese children and adolescents.
We recommend against routine evaluation of 25(OH)D levels in obese subjects. If an obese individual does not receive vitamin D supplementation and has a sedentary indoor lifestyle with consequent reduced sun exposure, serum 25(OH)D evaluation may be considered to confirm vitamin D deficiency and start adequate treatment.
In obese subjects with vitamin D deficiency we recommend vitamin D treatment at higher doses than those recommended for otherwise healthy pediatric population (at least 2000-4000 IU/day), for a minimum of 6-8 weeks.

Autism

Autistic individuals frequently develop nutritional deficiencies, especially in presence of food selectivity;
causal relationship with vitamin D deficiency is uncertain.
We recommend against routine evaluation of 25(OH)D levels in children with autism.
We recommend against vitamin D treatment to improve patient's performance considering the limited and conflicting available evidence.

Depression

Epidemiological studies that evaluated an association between vitamin D deficiency and depression are lacking at present.
We recommend against routine evaluation of 25(OH)D levels in children with depression.
We recommend against vitamin D administration to improve mood.

Pregnancy and breastfeeding

We suggest against routine screening of serum 25(OH)D levels in all pregnant and breastfeeding women. We suggest to consider serum 25(OH)D testing in women with multiple risk factors for vitamin D deficiency, particularly if not receiving vitamin D supplementation, and/or with specific conditions possibly affecting pregnancy course (Table 9).
We recommend vitamin D supplementation in all pregnant and breastfeeding women at a dose of 600 IU/day. Women with risk factors for vitamin D deficiency should receive higher dosages (1000-2000 IU/day).
We suggest to start vitamin D supplementation at the beginning of pregnancy and continue for the entire duration of pregnancy and lactation.

Appendix. Management of asymptomatic vitamin D deficiency and insufficiency

In children and adolescents with asymptomatic vitamin D deficiency [25(OH)D < 20 ng/ml] we recommend the administration of 2000 IU/day or 50000 IU/week of vitamin D2 or D3 for 6-8 weeks (8 weeks in adolescents) in order to obtain a sufficient vitamin D status [25(OH)D > 30 ng/ml].
After completion of treatment, serum 25(OH)D concentrations should be revaluated.
In presence of adequate vitamin D status [25(OH)D > 30 ng/ml], we recommend to continue vitamin D supplementation as recommended for age.
In subjects with asymptomatic vitamin D deficiency assuming drugs interfering with vitamin D metabolism (anticonvulsants, oral corticosteroids, antifungals like ketoconazole, anti-retroviral drugs) we recommend vitamin D treatment at higher doses than those recommended for otherwise healthy pediatric population (at least 2000-4000 IU/day), for a minimum of 6-8 weeks.
Considering available evidence, particularly the lack of Italian studies, at present we do not recommend other modalities different from daily or weekly administration of vitamin D to treat asymptomatic vitamin D deficiency.
In case of detection of asymptomatic vitamin D insufficiency [25(OH)D between 20 and 29 ng/ml], particularly in subjects at risk for vitamin D deficiency, we recommended to start vitamin D supplementation according to the modalities and requirements recommended for age.