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Vitamin D Deficiency in Children

Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Aug.22.2024

Vitamin D Deficiency in Children

Synopsis

Key Points

Threshold levels to define vitamin D deficiency vary by professional society but most set 20 ng/mL as cutoff for deficiency
95% of cases of vitamin D deficiency are due to deficient dietary intake of cholecalciferol (D₃)/ergocalciferol(D₂), or deficient cutaneous synthesis of cholecalciferol
Severe and long-standing deficiency can present with hypocalcemia or physical signs suggestive of rickets, such as:
- Short stature/delayed growth
- Thickened wrists and ankles
- Long bone bowing
- Rachitic rosary (beading of the ribs)
- Pectus carinatum (highly prominent sternum)
Serum 25-hydroxyvitamin D level test is the gold standard and definitive
Vitamin D replacement therapy on a daily or weekly regimen is appropriate for all cases of vitamin D deficiency
- When levels are back to within reference range, replacement dose may be lowered to a maintenance dose
Prognosis is favorable; most children treated for vitamin D deficiency achieve reference-range levels of 25-hydroxyvitamin D with standard therapy and do not develop complications

Urgent Action

Hypocalcemia due to reduced vitamin D–dependent calcium absorption can be life-threatening and requires prompt treatment, including calcium supplementation
- IV calcium is necessary for signs of severe neuromuscular irritability, such as hypocalcemic tetany

Pitfalls

Measuring the concentration of 1,25-dihydroxyvitamin D instead of 25-hydroxyvitamin D for assessment of vitamin D status can lead to erroneous conclusions because 1,25-dihydroxyvitamin D concentrations will be within reference range or even elevated in the face of vitamin D deficiency as a result of secondary hyperparathyroidism
Vitamin D requirements cannot ordinarily be met by human milk alone; infants should receive 400 international units/day of supplemental vitamin D, regardless of mode of feeding, but this is especially important for breastfed infants ^r1
- Despite long-standing recommendations to this effect, less than 40% of infants in the United States are receiving sufficient vitamin D ^r2

Terminology

Clinical Clarification

Vitamin D deficiency is a condition caused by low circulating levels of vitamin D ^r3
- Also called hypovitaminosis D
Serum concentration that constitutes vitamin D deficiency is controversial, especially in the pediatric population
- Threshold levels to define vitamin D deficiency vary by professional society, but most set 20 ng/mL as cutoff for deficiency ^r4
- According to the National Osteoporosis Society (now Royal Osteoporosis Society), levels greater than 20 ng/mL are sufficient for almost everyone; however, deficiency is defined as levels less than 10 ng/mL ^r5
Physiology
- Vitamin D is an essential steroid hormone that exists in the body as multiple forms
  - 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) are the main forms
- Vitamin D can be obtained from any of the following:
  - Dietary sources of vegetable origin (vitamin D₂ or ergocalciferol)
  - Dietary sources of animal origin (vitamin D₃ or cholecalciferol)
  - Through conversion of 7-dehydrocholesterol, synthesized in the skin, into cholecalciferol (vitamin D₃) by UV-B exposure
    - Vitamin D that comes from the skin or diet is biologically inert and requires 2 hydroxylation steps to become active
- In the liver, cholecalciferol is converted into 25-hydroxyvitamin D
  - 25-hydroxyvitamin D concentration depends on nutritional supply or synthesis in the skin after exposure to UV-B light
- In the kidney, 25-hydroxyvitamin D is converted to 1,25-dihydroxyvitamin D
- 1,25-dihydroxyvitamin D is considered to be the biologically active form, and its concentration is highly regulated
- Units for 25-hydroxyvitamin D levels are expressed as ng/mL or nmol/L; the conversion between them is [nmol/L] = 2.5 × [ng/mL]

Classification

Optimal vitamin D nutritional status is a subject of controversy, and threshold levels to define vitamin D deficiency vary by professional society

Vitamin D deficiency definitions.
	Institute of Medicine	Endocrine Society	American Academy of Pediatrics	Society for Adolescent Health and Medicine	Multinational Consensus Expert Panel on Rickets	Royal Osteoporosis Society
Vitamin D deficiency	Less than 20 ng/mL	Less than 20 ng/mL	Less than 15 ng/mL	Less than 20 ng/mL	Less than 12 ng/mL	Less than 10 ng/mL
Severe vitamin D deficiency			Less than 5 ng/mL
Mild to moderate vitamin D deficiency			5 to 15 ng/mL
Vitamin D insufficiency		21 to 29 ng/mL	16 to 20 ng/mL	20 to 29 ng/mL	12 to 20 ng/mL	10 to 20 ng/mL
Vitamin D sufficiency		30 ng/mL or greater	21 ng/mL or greater	30 ng/mL or greater	20 ng/mL or greater	21 ng/mL or greater

Vitamin D deficiency
- 25-hydroxyvitamin D less than 20 ng/mL: Institute of Medicine,^r6Endocrine Society,^r7 and Society for Adolescent Health and Medicine^r8
- 25-hydroxyvitamin D less than 15 ng/mL: American Academy of Pediatrics^r9
- 25-hydroxyvitamin D less than 12 ng/mL: Multinational Consensus Expert Panel on Rickets^r1
- 25-hydroxyvitamin D less than 10 ng/mL: UK's National Osteoporosis Society (now Royal Osteoporosis Society)^r5
Deficiency severity classifications
- Severe deficiency
  - 25-hydroxyvitamin D less than 5 ng/mL: American Academy of Pediatrics^r9^r10
- Mild to moderate deficiency
  - 25-hydroxyvitamin D of 5 to 15 ng/mL: American Academy of Pediatrics^r9^r10
Vitamin D insufficiency is a range of vitamin D levels between overt deficiency and the point at which parathyroid hormone levels approach or reach reference range; insufficiency classifications: ^r4
- 25-hydroxyvitamin D 12 to 20 ng/mL: Multinational Consensus Expert Panel on Rickets^r1
- 25-hydroxyvitamin D 16 to 20 ng/mL: American Academy of Pediatrics^r10
- 25-hydroxyvitamin D 21 to 29 ng/mL: Endocrine Society^r7
- 25-hydroxyvitamin D 10 to 20 ng/mL may be inadequate for some people: UK's National Osteoporosis Society (now Royal Osteoporosis Society)^r5

Diagnosis

Clinical Presentation

History

Mild to moderate vitamin D deficiency is asymptomatic ^c1
Severe and/or long-standing (months to years) vitamin D deficiency can produce the following: ^r11
- Symptomatic hypocalcemia, manifested by: ^c2
  - Irritability ^c3
  - Nervousness ^c4
  - Jitteriness ^c5
  - Malaise or lethargy ^c6^c7
  - Anorexia, poor feeding, and/or vomiting ^c8^c9^c10
  - Seizures (most common presentation in neonates) ^r12^c11
- Musculoskeletal complications, such as:
  - Current and/or history of myalgia or ostealgia ^r10^c12^c13
  - Bony deformities and stunted growth, characteristic of rickets ^r12^c14^c15
  - Nontraumatic or minimally traumatic fractures in rickets ^c16

Physical examination ^r1

Signs of hypocalcemia occur primarily with severe vitamin D deficiency
- Fasciculations and/or tremors ^c17^c18
- Carpopedal spasm ^c19
- Tetany ^c20
- Laryngeal stridor ^c21
- Seizure ^c22
Skeletal signs suggestive of rickets that can occur with severe vitamin D deficiency include:
- Slowing linear growth ^c23
- Metaphyseal swelling at long bone ends ^c24
- Genu varum: outward bowing of the lower legs (most common skeletal deformity in infants with untreated rickets) ^c25
- Genu valgum: knock knees (develops at later age than genu varum) ^c26
- Rachitic rosary (beading of the ribs) ^c27
- Pectus carinatum (highly prominent sternum) ^c28
- Delayed closure of the fontanelles ^c29
- Parietal and frontal bossing ^c30^c31
- Craniotabes ^c32
Nonskeletal signs suggestive of rickets, which can occur with severe vitamin D deficiency, include: ^r12
- Hypotonia ^c33
- Delayed motor milestones ^c34
- Enamel hypoplasia and delayed dentition ^c35^c36
- Failure to thrive ^c37
- Irritability in a young child ^c38

Causes and Risk Factors

Causes

Deficient dietary intake of cholecalciferol (D₃)/ergocalciferol(D₂) or deficient cutaneous synthesis of cholecalciferol (represents approximately 95% of cases^r13) ^c39
- Malnutrition ^c40
- Simple inadequate intake as a result of exclusive breastfeeding or insufficient consumption of vitamin D–fortified dairy products ^c41
- Deficient cutaneous synthesis of 25-hydroxyvitamin D is caused by inadequate sunlight (UV-B) exposure ^c42
Conditions affecting intestinal absorption^r14 (approximately 5% of cases^r13):
- Whipple disease ^c43
- Cystic fibrosis ^c44
- Celiac disease ^c45
- Parenchymal or cholestatic liver disease ^c46^c47
- Inflammatory bowel disease ^c48
Drugs that affect the absorption, metabolism, or activation of vitamin D (less than 1% of cases^r13):
- Glucocorticoids ^r14^c49
- Rifampin ^r14^c50
- Highly active antiretroviral therapy ^r14^c51
- Antiepileptic drugs ^r10^c52

Risk factors and/or associations

Genetics

Hereditary vitamin D–dependent rickets (rare inherited disorders) ^c53
- Vitamin D–dependent rickets type 1A (OMIM #264700)^r15 results from defects in the CYP27B1 gene, coding for 25-hydroxyvitamin D₃–1α-hydroxylase ^c54
- Vitamin D–dependent rickets type 1B (OMIM #600081)^r16 results from defects in the CYP2R1 gene, coding for 25-hydroxylase
- Vitamin D–dependent rickets type 2 (OMIM #277440)^r17 results from defects in the VDR gene, coding for the vitamin D receptor

Ethnicity/race

People with dark skin pigmentation are at higher risk ^r18^c55^c56
- Melanin absorbs UV-B radiation and reduces vitamin D₃ synthesis ^r19
- Require longer sun exposure than people with white skin to synthesize the same amount of vitamin D₃ ^r19

Other risk factors/associations

Factors reducing exposure of skin to solar UV-B
- Overzealous use of sunscreen with sun protection factor 30 or higher: reduces biosynthesis of vitamin D₃ by more than 95% ^r7^c57
- Living in high-latitude areas (latitude higher than 40° north or south) ^r20^c58
- Cultural practices that encourage covering most or all skin ^r14^c59
Prolonged and exclusive breastfeeding ^r1^c60
- Breast milk is a poor source of vitamin D, and the amount contained is insufficient on its own to prevent deficiency in an infant unless the mother is taking high doses (4000 international units daily) of vitamin D supplements
- Infants breastfed from vitamin D–replete mothers will have vitamin D levels below reference range after 8 weeks of exclusive breastfeeding ^r21
Eating disorders (eg, bulimia nervosa, anorexia nervosa) ^c61^c62^c63
Picky eating in which children exclude milk and milk products, eggs, and other dietary sources of vitamin D ^c64
Lactose intolerance causing avoidance of milk ^c65^c66
- Not all milk substitutes (eg, soy milk, almond milk, rice milk) are fortified with vitamin D
Chronic kidney disease ^r10^c67

Diagnostic Procedures

Primary diagnostic tools

History (including sun exposure, vitamin D and calcium intake, and medication information) and presence of risk factors suggest vitamin D deficiency ^r1^c68
- Physical examination is generally only valuable in moderate to severe cases, when physical signs of hypocalcemia or skeletal abnormalities are found ^r1
Formal diagnosis is made by laboratory testing of vitamin D levels ^r7
- Obtain vitamin D levels in children with: ^r5^r9
  - Symptoms or signs of rickets, history of recurrent, low-trauma fractures, or other symptoms or conditions associated with vitamin D deficiency
  - Laboratory abnormalities associated with vitamin D (hypocalcemia, hypophosphatemia, or elevated alkaline phosphatase)
  - Radiographic evidence of osteopenia, rickets, or pathological fractures
  - Risk factors for vitamin D deficiency
    - Exclusively breastfed or premature infants
    - Dark-skinned infants and children
    - Children on medications that compromise vitamin D concentrations
      - Azole antifungals, corticosteroids, or cytochrome P450 3A4 inducers
      - Highly active antiretroviral therapy
      - Anticonvulsant drugs such as phenytoin, carbamazepine, oxcarbazepine, and phenobarbital
    - Chronic conditions such as chronic kidney disease, HIV/AIDS, Crohn disease, celiac disease, cystic fibrosis, and other diseases that affect vitamin D metabolism or nutrient absorption
    - Children who reside in areas with limited sun exposure (high latitude areas)
  - Earlier testing guidelines included children with obesity; however, this is no longer recommended in otherwise healthy children who are overweight or obese ^r7^r22
- Obtain vitamin D levels in children receiving treatment with bone-targeted drugs that require vitamin D sufficiency, such as bisphosphonates ^r5
- 25-hydroxyvitamin D level is the gold standard and definitive test for vitamin D deficiency
- Parathyroid hormone, serum calcium, serum phosphate, and alkaline phosphatase activity values are useful for differentiating simple deficiency of vitamin D intake or sunlight from vitamin D–resistant rickets
Diagnosis of nutritional rickets is suspected on the basis of history, physical examination, and biochemical testing, and is confirmed by radiographs ^r1
- Typical laboratory findings
  - Low 25-hydroxyvitamin D, serum phosphorus, and urinary calcium levels
  - Low or low–reference range serum calcium level
  - Elevated serum parathyroid hormone and alkaline phosphatase levels

Laboratory

Vitamin D levels
- Serum 25-hydroxyvitamin D (calcidiol) level ^c69
  - Most important test for vitamin D deficiency, reflecting long-term stores of the hormone ^r10
  - Threshold levels to define vitamin D deficiency
    - 25-hydroxyvitamin D level less than 15 ng/mL, per the American Academy of Pediatrics^r10
    - 25-hydroxyvitamin D level less than 20 ng/mL, per the Institute of Medicine^r6 and Endocrine Society^r7
    - 25-hydroxyvitamin D level less than 10 ng/mL, per the UK's National Osteoporosis Society (now Royal Osteoporosis Society)^r5
- Serum 1,25-dihydroxyvitamin D (calcitriol) level ^c70
  - Indicated only in cases evaluating for and monitoring certain conditions, such as inherited disorders of vitamin D metabolism ^r23
  - Elevated in hereditary vitamin D–resistant rickets ^r24
  - Low in vitamin D–dependent rickets type 1A (1α-hydroxylase deficiency) ^r24
  - Measuring the concentration of 1,25-dihydroxyvitamin D instead of 25-hydroxyvitamin D for assessment of vitamin D status can lead to erroneous conclusions because 1,25-dihydroxyvitamin D concentrations will be within reference range or even elevated in the presence of vitamin D deficiency as a result of secondary hyperparathyroidism
Serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase levels ^c71
- This set of tests can support a diagnosis of vitamin D deficiency or distinguish from other abnormalities of calcium and phosphorus metabolism ^r10
- Serum calcium level ^r10^c72
  - Most often at reference range in mild cases but can be slightly decreased
  - Notable decreases in calcium generally occur only in severe cases
- Serum phosphorus level ^c73
  - Test result serves as supporting information
  - Will be low with vitamin D deficiency
- Serum parathyroid hormone level ^r25^c74
  - Inverse association between calcium level and parathyroid hormone level: parathyroid hormone begins rising as 25-hydroxyvitamin D falls below 30 ng/mL (before calcium levels become below reference range)
  - High parathyroid hormone levels reflect secondary hyperparathyroidism, resulting from vitamin D deficiency
  - Low parathyroid hormone levels occur in phosphopenic causes of rickets
- Alkaline phosphatase level ^r26^c75
  - Result serves as supporting information
  - As serum 25-hydroxyvitamin D level decreases, alkaline phosphatase level increases, indicating bone resorption

Biochemical findings in various disorders of vitamin D and calcium.
	Calcium level	Phosphorus level	Parathyroid hormone level	25-hydroxyvitamin D level	1,25-dihydroxyvitamin D level
Vitamin D deficiency	Mild hypocalcemia to calcium within reference range; moderate hypocalcemia, or severe hypocalcemia	Low	High	Low	Normal or high
Vitamin D–dependent rickets type 1A (1α-hydroxylase deficiency)	Low	Low	High	Normal or high	Very low
Vitamin D–dependent rickets type 1B (25-hydroxylase deficiency)	Low	Low	High	Very low	Variable
Vitamin D–dependent rickets type 2 (vitamin D receptor defects)	Low	Low	High	Normal or high	High
Hypophosphatemic rickets (X-linked)	Normal	Very low	Normal or slightly high	Normal or low	Low
Hypophosphatemic rickets with hypercalciuria	Normal	Low	Normal or low	Normal	High

Imaging

Plain film radiography ^r1^c76
- Used to assess skeletal complications of severe vitamin D deficiency and required to document skeletal abnormalities to assign a formal diagnosis of rickets
- Imaging areas should include long bones with views at the knee and wrist (distal ulna), which are the sites where rickets initially manifests
  - Widening of the epiphyseal plate and loss of definition of the zone of calcification at the epiphyseal/metaphyseal interface are the earliest radiographic signs of rickets
- Skeletal features characteristic of advanced rickets
  - Minimal-trauma fractures
  - Pelvic deformities including outlet narrowing (indicates risk of obstructed labor and death)
  - Rachitic rosary on anterior rib ends
  - Angular deformities in arm and leg bones
  - Splaying, fraying, cupping, and coarse trabecular pattern of metaphyses

Differential Diagnosis

Most common

Calcium deficiency (without vitamin D deficiency) due to inadequate dietary calcium ^r27^c77^d1
- Typical scenario for this is a child who avoids milk products but gets plenty of sunlight exposure and/or eats egg yolks, fish, or liver
- Similarities with vitamin D deficiency
  - Severe cases can also present with features of rickets ^r28
- Distinguished from vitamin D deficiency on the basis of laboratory testing
  - 25-hydroxyvitamin D level is at reference range if it is an isolated calcium deficiency without deficiency of vitamin D
- Definitive diagnosis is established by serum calcium and 25-hydroxyvitamin D levels
Hereditary resistance to vitamin D (OMIM #277440)^r17^c78
- Rare autosomal recessive condition of vitamin D resistance that results from abnormalities in the VDR gene, which encodes the vitamin D receptor
- Presents with rickets and alopecia within the first 2 years of life
- Distinguished from vitamin D deficiency by 25-hydroxyvitamin D level being within reference range or high, and by the massive doses of calcitriol and calcium required to normalize serum calcium
- Definitive diagnosis is made by genetic testing
Hypophosphatemic rickets (2 forms) ^r12^c79
- Inherited disorders that present with rickets due to renal phosphate wasting
- Can have a similar phenotype to severe vitamin D deficiency (bowed legs)
- Distinguished from vitamin D deficiency–associated rickets on the basis of biochemical findings, which show 25-hydroxyvitamin D levels within reference range to low, low serum phosphorus level, and increased urinary phosphate excretion
- X-linked hypophosphatemic rickets ^r29
  - Caused by mutations in PHEX gene
  - Presents with short stature, leg bowing, and dental abnormalities
  - Serum fibroblast growth factor 23 (FGF23) level is high and urine phosphate level is very high
- Hypophosphatemic rickets with hypercalciuria ^r29
  - Rare autosomal recessive disorder due to loss of function mutations in a renal sodium phosphate transporter
  - Presents with bone pain and muscular weakness
  - Serum 1,25 dihydroxyvitamin D level is elevated and FGF23 level is within reference range

Treatment

Goals

Restore serum 25-hydroxyvitamin D to level greater than 30 ng/mL ^r10
Treat symptoms of severe hypocalcemia (eg, seizure, tetany) if present ^r10
Prevent complications, such as osteopenia, osteoporosis, and rickets ^r30

Disposition

Admission criteria

Admission is warranted in patients with symptomatic hypocalcemia manifesting with tetany ^r31

Recommendations for specialist referral

Gastroenterologist ^r7
- Indicated for work-up for malabsorption (such as in Crohn disease, celiac disease, or cystic fibrosis with a gastrointestinal component) for a patient who is vitamin D deficient despite plentiful dietary vitamin D and calcium and sunlight exposure
Endocrinologist
- Indicated in any of the following settings:
  - Deficiency is established with absence of known risk factors
  - Atypical biochemistry, such as persistent hypophosphatemia or elevated creatinine level
  - Family history of rickets
  - Infants younger than 1 month with hypocalcemia (owing to seizure risk)
    - In this situation, mothers should be referred to internists for determination of vitamin D status
  - Failure to normalize vitamin D levels after 8 to 12 weeks of initial treatment

Treatment Options

Vitamin D replacement therapy on a daily or weekly regimen is appropriate for all cases of vitamin D deficiency ^r7

There are 2 forms: plant-based D₂ (ergocalciferol) and animal-derived D₃ (cholecalciferol); either may be used to prevent or treat vitamin D deficiency
- Most professional society (eg, Endocrine Society) guidelines do not state a preference between vitamin D₂ and vitamin D₃ ^r7
- Vitamin D₃ is considered the treatment of choice for vitamin D deficiency according to the National Osteoporosis Society (now Royal Osteoporosis Society) ^r5
  - Vitamin D₃ is cleared less rapidly and is more bioavailable than vitamin D₂
  - Evidence suggests vitamin D₃ may be more effective in raising serum levels to the desired threshold
Calcitriol (1,25-dihydroxyvitamin D) is reserved for special cases, such as: ^r10
- 1α-hydroxylase deficiency (inability to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D) or chronic kidney disease
- Severe symptomatic hypocalcemia, presenting with seizure and/or tetany (requires rapid increase of 1,25-dihydroxyvitamin D activity to boost serum calcium level)
Obtaining vitamin D from dietary sources alone is not currently recommended as a reliable means of vitamin D supplementation
For simple vitamin D deficiency, treatment doses should be continued until 25-hydroxyvitamin D levels normalize; thereafter, use maintenance doses ^r1
- Duration of the treatment varies between 4 weeks and 3 months ^r32
For vitamin D deficiency accompanied by nutritional rickets, treatment doses should continue for a minimum of 3 months or until vitamin D levels normalize and radiographic changes are evident; some children may require longer treatment duration ^r1
- If parathyroid hormone levels are elevated, add elemental calcium
Children requiring greater doses of vitamin D to correct vitamin D deficiency include: ^r7
- Children who are obese
- Children taking medications that reduce vitamin D levels (eg, anticonvulsants, glucocorticoids)
- Children with conditions that cause vitamin D malabsorption (eg, inflammatory bowel disease, celiac disease, cystic fibrosis)

Drug therapy

Dosing is described as vitamin D₃ (cholecalciferol); vitamin D₂ (ergocalciferol) is similarly dosed
Vitamin D₃ (cholecalciferol) ^r7^c80
- For vitamin D deficiency
  - General population
    - Vitamin D (Cholecalciferol) Oral drops, solution; Neonates: 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once weekly for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 10 to 25 mcg (400 to 1,000 International Units) PO once daily.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Infants: 25 to 125 mcg (1,000 to 5,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once weekly for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 10 to 25 mcg (400 to 1,000 International Units) PO once daily.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children and Adolescents: 50 to 150 mcg (2,000 to 6,000 International Units) PO once daily or 350 to 1,250 mcg (14,000 to 50,000 International Units) PO once weekly for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 15 to 25 mcg (600 to 1,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once monthly.
  - Chronic kidney disease
    - Vitamin D (Cholecalciferol) Oral drops, solution; Infants: 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 10 to 25 mcg (400 to 1,000 International Units) PO once daily.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children and Adolescents with vitamin D concentration less than 5 ng/mL: 200 mcg (8,000 International Units) PO once daily for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children and Adolescents with vitamin D concentration 5 to 15 ng/mL: 100 mcg (4,000 International Units) PO once daily for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children and Adolescents with vitamin D concentration 16 to 30 ng/mL: 50 mcg (2,000 International Units) PO once daily for at least 6 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily.
- For routine supplementation
  - General population (recommended daily allowance)
    - Vitamin D (Cholecalciferol) Oral drops, solution; Premature Neonates weighing less than 1.5 kg: 5 to 10 mcg/day (200 to 400 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Premature Neonates weighing 1.5 kg or more: 10 mcg/day (400 International Units/day) PO; doses up to 20 mcg/day (800 International Units/day) PO have been used.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Neonates: 10 mcg/day (400 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Infants: 10 mcg/day (400 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children: 10 to 15 mcg/day (400 to 600 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Adolescents: 10 to 15 mcg/day (400 to 600 International Units/day) PO.
  - Cystic fibrosis
    - Vitamin D (Cholecalciferol) Oral drops, solution; Neonates: 10 to 12.5 mcg (400 to 500 International Units) PO once daily. Adjust dosage to maintain serum 25-hydroxyvitamin D concentrations of 30 ng/mL or more. Max: 50 mcg/day (2,000 International Units/day).
    - Vitamin D (Cholecalciferol) Oral drops, solution; Infants: 10 to 12.5 mcg (400 to 500 International Units) PO once daily. Adjust dosage to maintain serum 25-hydroxyvitamin D concentrations of 30 ng/mL or more. Max: 50 mcg/day (2,000 International Units/day).
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children 1 to 10 years: 20 to 25 mcg (800 to 1,000 International Units) PO once daily. Adjust dosage to maintain serum 25-hydroxyvitamin D concentrations of 30 ng/mL or more. Max: 100 mcg/day (4,000 International Units/day).
    - Vitamin D (Cholecalciferol) Oral capsule; Children and Adolescents 11 to 17 years: 20 to 50 mcg (800 to 2,000 International Units) PO once daily. Adjust dosage to maintain serum 25-hydroxyvitamin D concentrations of 30 ng/mL or more. Max: 250 mcg/day (10,000 International Units/day).
Calcitriol (1,25-dihydroxyvitamin D) ^c81
- Calcitriol Oral solution; Infants, Children, and Adolescents: 0.05 mcg/kg/day PO (Max: 0.5 mcg/day) until calcium concentrations normalize; give with calcium.

Nondrug and supportive care

Nutritional counseling ^c82
- The recommended daily allowance for vitamin D represents a daily intake that is sufficient to maintain bone health and normal calcium metabolism in healthy people, including those who are pregnant or lactating ^r33
  - Upper tolerable intake varies depending on the child's age and is available through the National Institutes of Health - Office of Dietary Supplements. ^r32^r33
- Vitamin D requirements in infants cannot ordinarily be met by human breast milk alone
  - Breastfed infants should receive vitamin D supplementation beginning in the first 3 to 5 days of life ^r34
  - Vitamin D supplementation is also recommended for non-breastfeeding infants who are consuming less than 1L of formula per day ^r35
- In the United States, most dietary vitamin D comes from fortified foods ^r33
  - Milk and infant formula are fortified with either vitamin D₂ or D₃, as are some brands of breakfast cereals, orange juice, yogurt, margarine, and plant milk alternatives ^r33^r36
  - Natural dietary sources of vitamin D₃ include:
    - Fatty fish, such as salmon, mackerel, and tuna
    - Beef liver, cheese, and egg yolks
  - Natural dietary sources of vitamin D₂ include:
    - Mushrooms
    - Phytoplankton

Comorbidities

Vitamin D deficiency is often accompanied by other micronutrient deficiencies, especially other fat-soluble vitamins (particularly vitamins A and K) and calcium ^r37^c83^c84^c85^c86
Vitamin D deficiency is associated with autoimmune diseases, such as: ^r38
- Type 1 diabetes mellitus ^c87
- Multiple sclerosis ^c88
- Rheumatoid arthritis ^c89
- Juvenile systemic lupus erythematosus ^c90

Special populations

Chronic kidney disease ^r10
- Vitamin D supplementation is standard care, but those with 25-hydroxyvitamin D level less than 30 ng/mL should receive vitamin D replacement therapy
- Measure 25-hydroxyvitamin D levels after the first 3 months of therapy to assess the need for further treatment; when it is adequate, check annually
- Assess serum corrected calcium concentrations and phosphorus level at 1 month and then every 3 months
- If total serum corrected calcium level exceeds 10.2 mg/dL, or if serum phosphate level exceeds the upper limit for age and 25-hydroxyvitamin D levels are within reference range, vitamin D may be discontinued
- Calcitriol has utility in children with chronic kidney disease stages 2 through 5 for the treatment of secondary hyperparathyroidism
  - As kidney function continues to decline, the enzyme activity of 1α-hydroxylase decreases; therefore, calcitriol preparations may be needed rather than vitamin D₂ or D₃ preparations
Cystic fibrosis
- Maintaining optimal vitamin D stores in this population is especially important because severe bone disease may exclude these individuals from being qualified for lung transplant
- Vitamin D₃ supplements should be given to maintain 25-hydroxyvitamin D concentrations; 30 ng/mL or greater^r39 is standard (Cystic Fibrosis Foundation Consensus Conference on Bone Health Guidelines), but 35 ng/mL can be used as cutoff level when parathyroid hormone is less than 50 pg/mL^r40
- Treatment doses vary depending upon child's age and degree of vitamin D deficiency (based on the existing vitamin D level)^r39 and are available through the Cystic Fibrosis Foundation website^r41

Treatment and prevention of vitamin D deficiency.
Age	Calcium recommended dietary allowance (mg/day)	Vitamin D recommended dietary allowance for prevention (international units/day)	Prevention if risk factors for deficiency are present (international units/day)	Daily treatment doses for vitamin D deficiency (international units/day)	Alternate weekly treatment doses for vitamin D deficiency (international units/week)
Neonates	200	400	400 to 1000	1000	50,000
1 to 6 months	200	400	400 to 1000	1000 to 2000	50,000
6 to 12 months	260	400	400 to 1000	2000	50,000
1 to 3 years	700	600	600 to 1000	2000	50,000
4 to 8 years	1000	600	600 to 1000	2000	50,000
9 to 13 years	1300	600	600 to 1000	2000	50,000
14 to 18 years	1300	600	600 to 1000	2000	50,000

Monitoring

For simple vitamin D deficiency, measure 25-hydroxyvitamin D level 1 and 3 months after beginning therapy ^c91
For rickets due to vitamin D deficiency
- Monitor serum calcium and phosphorus levels weekly ^c92^c93
- Measure 25-hydroxyvitamin D level after 2 to 3 months
- Repeat skeletal radiography to assess healing response after 2 to 3 months ^c94
In patients with chronic kidney disease treated for vitamin D deficiency ^r10
- Measure 25-hydroxyvitamin D level after first 3 months of therapy to assess the need for further treatment; once adequate, measure annually
- Serum corrected calcium concentrations and phosphorous concentrations should be assessed at 1 month and every 3 months

Complications and Prognosis

Complications

Nutritional rickets, caused by vitamin D deficiency ^c95
- Phosphaturia caused by secondary hyperparathyroidism results in a low–reference range or low serum phosphorus level
- Consequently, an inadequate calcium-phosphorus product causes abnormal chondrocyte differentiation, defective mineralization of the growth plate, and defective osteoid mineralization ^r42
- In young children who have little mineral in their skeleton, this defect results in a variety of skeletal deformities classically known as rickets ^r10
  - Skeletal deformities include: ^r20
    - Scoliosis
    - Long bone bowing
    - Rachitic rosary (beading of the ribs)
    - Pectus carinatum
    - Thickened wrists and ankles
- Can lead to any of the following:
  - Respiratory complications:
    - Obstruction and lower respiratory infections due to weakened thoracic wall ^r7
    - Pneumonia in infants ^r24
  - Risk of fracture
    - Children with radiographically confirmed rickets have an increased risk of fracture ^r1
- Infants and children with 25-hydroxyvitamin D levels lower than 10 ng/mL are at risk, particularly if calcium intake is insufficient (300-500 mg/day) or deficient (less than 300 mg/day) ^r1
Other skeletal defects
- Untreated subclinical vitamin D deficiency affects bone acquisition, beginning in utero and extending into adolescence ^r43
  - Osteopenia and osteoporosis ^r44^c96^c97
    - Decrease in the efficiency of intestinal calcium and phosphorus absorption of dietary calcium and phosphorus, resulting in increase of parathyroid hormone levels
    - Secondary hyperparathyroidism maintains serum calcium within reference range at the expense of mobilizing calcium from the skeleton and increasing phosphorus wasting in the kidneys
    - Parathyroid hormone–mediated increase in osteoclastic activity creates local foci of bone weakness and causes a generalized decrease in bone mineral density
  - Fractures ^r30^c98
    - Risk of fracture is elevated in older children and adolescents with vitamin D deficiency
    - Risk of fracture is not elevated in infants and younger children with simple vitamin D deficiency (eg, no radiographic evidence of rickets) ^r1
  - Osteomalacia ^c99
    - Decreased mineralization and increased action of parathyroid hormone ^r10
  - Dental caries
    - Persistent vitamin D deficiency may pose in increased risk for dental caries ^r45^r46
Complications of treatment
- Vitamin D toxicity ^c100
  - In children, defined as hypercalcemia and serum 25-hydroxyvitamin D level greater than 100 ng/mL, with hypercalciuria and suppressed parathyroid hormone ^r47
  - Extremely rare ^r47
  - Recommended to check serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level of intake ^r48
  - Manifests as any or all of the following: ^r10
    - Hypercalcemia
    - Serum 25-hydroxyvitamin D level greater than 150 ng/mL
    - Suppressed parathyroid hormone
    - Nephrolithiasis, when vitamin D is combined with calcium
  - IV calcium is necessary for signs of severe neuromuscular irritability, such as hypocalcemic tetany

Prognosis

Prognosis is favorable for treated vitamin D deficiency; most children treated achieve reference-range levels of 25-hydroxyvitamin D with no complications ^r7

Screening and Prevention

Screening

Routine screening for vitamin D deficiency is not recommended in healthy children ^r22^r49

Some recommend screening children at risk of vitamin D deficiency; however, the American Academy of Pediatrics report on Optimizing Bone Health in Children and Adolescents advises screening for vitamin D deficiency only in patients with disorders associated with low bone mass such as rickets and/or a history of recurrent, low-trauma fractures ^r7^r30

UK's National Osteoporosis Society (now Royal Osteoporosis Society) recommends routine vitamin D supplementation in children at risk for vitamin D deficiency rather than screening with 25-hydroxyvitamin D measurements ^r5^c101

At-risk populations ^r7

Exclusively breastfed or premature infants
Dark-skinned infants and children
Children on medications that compromise vitamin D concentrations
- Azole antifungals, corticosteroids, or cytochrome P450 3A4 inducers
- Highly active antiretroviral therapy
- Anticonvulsant drugs such as phenytoin, carbamazepine, oxcarbazepine, and phenobarbital
Children with chronic conditions such as chronic kidney disease, HIV/AIDS, celiac disease, Crohn disease, cystic fibrosis, and other diseases that affect vitamin D metabolism or nutrient absorption
Children who reside in areas with limited sun exposure (high latitude areas) ^c102
Children who are obese
Infants whose mothers have established vitamin D deficiency ^r50
Siblings of children with established vitamin D deficiency ^r50

Screening tests

Serum 25-hydroxyvitamin D measurement ^c103

Prevention

All children
- Adequate dietary intake of 400 international units/day or greater for neonates to infants aged 1 year; 600 international units/day or greater for children and adolescents aged 1 to 18 years ^r1^r6^r7^c104
  - May be obtained via natural sources of vitamin D, fortified foods, and/or supplementation
  - Vitamin D–rich foods include oily fish (such as sardines), eggs, meat, and milk. Foods that are fortified with vitamin D include some breakfast cereals, orange juices, yogurts, and infant formula ^r5
  - Guidelines recommend empiric supplementation to prevent nutritional rickets ^r51
    - May lower risk of respiratory infections
- Exposure to sunlight ^r14^c105
  - Sensible exposure to sunlight may help meet some vitamin D requirements in infants and children older than 6 months; however, most organizations do not advocate encouraging sun exposure to prevent vitamin D deficiency owing to the risk of skin cancer and cumulative UV-related skin damage ^r14
    - In light-skinned children, the amount of vitamin D produced in response to sun exposure (enough to reach a slight pinkness over the full body while wearing a swimsuit) is equivalent to ingesting 10,000 to 25,000 international units ^r19
    - Sun exposure (without sunscreen) to uncovered forearms and legs for 10 to 15 minutes around midday during summer months is sufficient to meet vitamin D requirements in light-skinned children ^r9^r52
  - Infants younger than 6 months should remain out of direct sunlight ^r53^c106
Supplementation for infants and children at risk of vitamin D deficiency ^r1^r2^c107
- Neonates to infants aged 12 months ^r48
  - Recommended daily intake:
    - Vitamin D (Cholecalciferol) Oral drops, solution; Neonates: 10 mcg/day (400 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral drops, solution; Infants: 10 mcg/day (400 International Units/day) PO.
    - Supplement breastfed and partially breastfed infants with vitamin D beginning in first 3 to 5 days of life ^r35
    - Vitamin D supplementation is also recommended for non-breastfeeding infants who are consuming less than 1 L of formula per day ^r2
    - Continue supplementation unless the infant is weaned to at least 1 L/day or 1 quart/day of vitamin D–fortified formula or whole milk ^r35
      - Some organizations recommend supplementation for all newborns for the first year of life, regardless of the type of feeding ^r54
    - Preterm infants require higher doses ^r54
      - Vitamin D (Cholecalciferol) Oral drops, solution; Premature Neonates weighing less than 1.5 kg: 5 to 10 mcg/day (200 to 400 International Units/day) PO.
      - Vitamin D (Cholecalciferol) Oral drops, solution; Premature Neonates weighing 1.5 kg or more: 10 mcg/day (400 International Units/day) PO; doses up to 20 mcg/day (800 International Units/day) PO have been used.
    - Despite long-standing recommendations to this effect, less than 40% of infants in the United States are receiving sufficient vitamin D ^r2
- Children older than 12 months
  - Recommended daily intake:
    - Vitamin D (Cholecalciferol) Oral drops, solution; Children: 10 to 15 mcg/day (400 to 600 International Units/day) PO.
    - Vitamin D (Cholecalciferol) Oral capsule; Adolescents: 10 to 15 mcg/day (400 to 600 International Units/day) PO.
  - Some groups recommend supplementation with vitamin D only over periods of reduced sun exposure (eg, winter in the northern latitudes or summer in hot climates) ^r54
  - Continuous vitamin D supplementation in children with permanent risk factors for vitamin D deficiency ^r54
  - Children who are obese and children on anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and HIV/AIDS medications may require 2 to 3 times the recommended amount of vitamin D
Supplementation during pregnancy and lactation
- Supplementation in pregnant individuals can ensure infant has adequate vitamin D levels and prevent: ^r51
  - Congenital vitamin D–deficiency rickets
  - Intrauterine mortality
  - Preterm birth
  - Small for gestational age birth
  - Neonatal mortality
  - Elevated alkaline phosphatase level
  - Neonatal hypocalcemia
  - Increased fontanelle size
- In pregnant and lactating individuals, especially those with darker skin or those who wear veils and other body covering, screening for and treatment of maternal vitamin D deficiency is recommended by some but not all organizations ^c108
- 600 international units/day or greater is the recommended daily allowance in pregnant individuals; higher intake may increase amount of vitamin D in breast milk ^r55^r56
- Breastfed infants should receive vitamin D supplements for the first 12 months of life, beginning within the first 5 days of life ^c109
- Begin vitamin D supplementation in infants whose mothers have established vitamin D deficiency or are at high risk of vitamin D deficiency ^r56^r57
In all children, adequate dietary calcium should be maintained, since negative calcium balance depletes vitamin D stores: ^r1
- Daily calcium requirements based on age: ^r6
  - Neonates to infants aged 6 months: 200 mg
  - Infants aged 7 to 12 months: 260 mg
  - Children aged 1 to 3 years: 700 mg
  - Children aged 4 to 8 years: 1000 mg
  - Children aged 9 years and older: 1300 mg

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Vitamin D Deficiency in Children

Synopsis

Key Points

Urgent Action

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination r1

Causes and Risk Factors

Causes

Risk factors and/or associations

Genetics

Ethnicity/race

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Admission criteria

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Comorbidities

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations r7

Screening tests

Prevention

Physical examination ^r1

At-risk populations ^r7