Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

1.1. Definition and diagnosis of nutritional rickets

• Nutritional rickets, a disorder of defective chondrocyte differentiation and mineralization of the growth plate and defective osteoid mineralization, is caused by vitamin D deficiency and/or low calcium intake in children. (1⊕⊕⊕)

• The diagnosis of nutritional rickets is made on the basis of history, physical examination, and biochemical testing, and is confirmed by radiographs. (1⊕⊕⊕)

1.2. Vitamin D status

• The panel recommends the following classification of vitamin D status, based on serum 25-hydroxyvitamin D (25OHD) levels. (1⊕⊕⊕)

  • ■ Sufficiency, >50 nmol/L
  • ■ Insufficiency, 30–50 nmol/L
  • ■ Deficiency, <30 nmol/L

1.3. Vitamin D toxicity

• Toxicity is defined as hypercalcemia and serum 25OHD > 250 nmol/L, with hypercalciuria and suppressed PTH. (1⊕⊕⊕)

1.4. Dietary calcium intake to prevent rickets

• For infants 0–6 and 6–12 months of age, the adequate calcium intake is 200 and 260 mg/d, respectively. (1⊕⊕⊕)

• For children over 12 months of age, dietary calcium intake of <300 mg/d increases the risk of rickets independent of serum 25OHD levels. (1⊕⊕○)

• For children over 12 months of age, the panel recommends the following classification of dietary calcium intake. (1⊕⊕○)

  • ■ Sufficiency, >500 mg/d
  • ■ Insufficiency, 300–500 mg/d
  • ■ Deficiency, <300 mg/d

1.5. Vitamin D deficiency and fractures

• Children with radiographically confirmed rickets have an increased risk of fracture. (1⊕⊕○)

• Children with simple vitamin D deficiency are not at increased risk of fracture. (1⊕⊕○)

2.1. Vitamin D supplementation for the prevention of rickets and osteomalacia

• 400 IU/d (10 μg) is adequate to prevent rickets and is recommended for all infants from birth to 12 months of age, independent of their mode of feeding. (1⊕⊕⊕)

• Beyond 12 months of age, all children and adults need to meet their nutritional requirement for vitamin D through diet and/or supplementation, which is at least 600 IU/d (15 μg), as recommended by the Institute of Medicine (IOM). (1⊕⊕⊕)

2.2. Target for vitamin D supplementation

• In healthy children, routine 25OHD screening is not recommended, and consequently, no specific 25OHD threshold for vitamin D supplementation is targeted in this population. (1⊕⊕⊕)

2.3. Candidates for preventative vitamin D supplementation beyond 12 months of age

In the absence of food fortification, vitamin D supplementation should be given to:

• Children with a history of symptomatic vitamin D deficiency requiring treatment. (1⊕⊕⊕)

• Children and adults at high risk of vitamin D deficiency, with factors or conditions that reduce synthesis or intake of vitamin D. (1⊕⊕⊕)

• Pregnant women (see Section 3.1).

2.4. Dose of vitamin D and calcium for the treatment of nutritional rickets

• For treatment of nutritional rickets, the minimal recommended dose of vitamin D is 2000 IU/d (50 μg) for a minimum of 3 months. (1⊕⊕⊕)

• Oral calcium, 500 mg/d, either as dietary intake or supplement should be routinely used in conjunction with vitamin D in the treatment regardless of age or weight. (1⊕⊕⊕)

2.5. Appropriate route of administration and duration of therapy

• We recommend oral treatment, which more rapidly restores 25OHD levels than IM treatment. (1⊕⊕⊕)

• For daily treatment, both D₂ and D₃ are equally effective. (1⊕⊕⊕)

• When single large doses are used, D₃ appears to be preferable compared to D₂ because the former has a longer half-life. (1⊕⊕⊕)

• Vitamin D treatment is recommended for a minimum of 12 weeks, recognizing that some children may require longer treatment duration. (1⊕⊕⊕)

3.1. Dietary practices and nutrient intakes among mothers associated with nutritional rickets in infants

• Maternal vitamin D deficiency should be avoided by ensuring that women of childbearing age meet intakes of 600 IU/d recommended by the IOM. (1⊕⊕⊕)

• Pregnant women should receive 600 IU/d of vitamin D, preferably as a combined preparation with other recommended micronutrients such as iron and folic acid. (2⊕⊕○)

3.2. Early feeding, supplementation, complementary feeding, and nutrient intake associated with rickets in infants

• In addition to an intake of 400 IU/d of vitamin D, complementary foods introduced no later than 26 weeks should include sources rich in calcium. (1⊕⊕⊕)

• An intake of at least 500 mg/d of elemental calcium must be ensured during childhood and adolescence. (1⊕⊕⊕)

3.3. Association of sunlight exposure to nutritional rickets

• Because UVB rays trigger epidermal synthesis of pre-vitamin D₃, restricted exposure to sun increases the risk of vitamin D deficiency and nutritional rickets. (1⊕⊕⊕)

• Environmental factors, such as latitude, season, time of day, cloud cover, and pollution affect availability of UVB, whereas personal factors, such as time spent outdoors, skin pigmentation, skin coverage, age, body composition, and genetics affect the dose-response of UVB exposure and circulating 25OHD. (2⊕⊕○)

• No safe threshold of UV exposure allows for sufficient vitamin D synthesis across the population without increasing skin cancer risk. (2⊕⊕○)

4.1. The relationship between vitamin D during pregnancy and infant growth and bone mass

• Pregnant women should receive 600 IU/d of supplemental vitamin D. This will ensure adequacy of maternal 25OHD, especially in women at risk of deficiency, to prevent elevated cord blood alkaline phosphatase (ALP), increased fontanelle size, neonatal hypocalcemia and congenital rickets, and to improve dental enamel formation. (2⊕⊕○)

• There is little evidence that maternal supplementation with vitamin D will protect or improve birth anthropometry (2⊕○○) and no evidence that supplementation with vitamin D will protect or improve short- or long-term growth or bone mass accretion. (2⊕⊕○)

4.2. The effect of calcium supplementation during pregnancy on infant bone mass

• Pregnant women do not need calcium intakes above recommended non-pregnant intakes to improve neonatal bone. (1⊕⊕⊕)

4.3. Influence of calcium or vitamin D supplementation in pregnancy or lactation on breast milk calcium or vitamin D

• Lactating women should ensure they meet the dietary recommendations for vitamin D (600 IU/d) for their own needs, but not for the needs of their infant. (1⊕⊕⊕)

• Lactating women should not take high amounts of vitamin D as a means of supplementing their infant. (2⊕⊕○)

• Pregnant and lactating women should meet the recommended intakes of calcium. Maternal calcium intake during pregnancy or lactation is not associated with breast milk calcium concentrations. (1⊕⊕⊕)

4.4. Causes and therapy of congenital rickets

• Supplementing mothers with 600 IU/d of vitamin D and ensuring they receive recommended calcium intakes, or appropriate therapy of maternal conditions predisposing to hypocalcemia or vitamin D deficiency, prevents congenital rickets. (2⊕○○)

5.1. Assessment of disease burden

• The prevalence of rickets should be determined by population-based samples, by case reports from sentinel centers, or by mandatory reporting. (1⊕⊕⊕)

• Screening for nutritional rickets should be based on clinical features, followed by radiographic confirmation of suspected cases. (1⊕⊕⊕)

• Population-based screening with serum 25OHD, serum ALP, or radiographs is not indicated. (1⊕⊕⊕)

5.2. Public health strategies for rickets prevention

• Universally supplement all infants with vitamin D from birth to 12 months of age, independent of their mode of feeding. Beyond 12 months, supplement all groups at risk and pregnant women. Vitamin D supplements should be incorporated into childhood primary health care programs along with other essential micronutrients and immunizations (1⊕⊕⊕), and into antenatal care programs along with other recommended micronutrients. (2⊕⊕○)

• Recognize nutritional rickets, osteomalacia, and vitamin D and calcium deficiencies as preventable global public health problems in infants, children, and adolescents. (1⊕⊕⊕)

• Implement rickets prevention programs in populations with a high prevalence of vitamin D deficiency and limited vitamin D and/or calcium intakes, and in groups of infants and children at risk of rickets. (1⊕⊕⊕)

• Monitor adherence to recommended vitamin D and calcium intakes and implement surveillance for nutritional rickets. (1⊕⊕⊕)

• Fortify staple foods with vitamin D and calcium, as appropriate, based on dietary patterns. Food fortification can prevent rickets and improve vitamin D status of infants, children, and adolescents if appropriate foods are used and sufficient fortification is provided, if fortification is supported by relevant legislation, and if the process is adequately monitored. Indigenous food sources of calcium should be promoted or subsidized in children. (1⊕⊕⊕)

• Promote addressing the public health impact of vitamin D deficiency as both a clinical and a public health issue. (1⊕⊕⊕)

5.3. Economic cost/benefits of prevention programs

• The cost-effectiveness of supplementation and food fortification programs needs further study. (1⊕⊕○)

Nutritional rickets (NR), secondary to vitamin D deficiency and/or dietary calcium deficiency, remains a significant global, public health problem despite the availability of supplementation and numerous published guidelines for its prevention (1–8). This is concerning because NR can have a major impact on the health of infants, children, and adolescents, with ramifications that persist into adulthood. The morbidity and mortality associated with NR can be devastating, with substantial but poorly recognized consequences for society and health economics. Features of NR and osteomalacia include: 1) hypocalcemic seizures and tetanic spasms; 2) life-threatening hypocalcemic cardiomyopathy; 3) bone pain and muscle weakness; 4) limb and pelvic deformities; 5) failure to thrive; 6) developmental delay; and 7) dental anomalies (9, 10). Alarmingly, NR can also lead to death from heart failure caused by hypocalcemic cardiomyopathy, even in developed countries (11). In addition, narrowing of the pelvic outlet after NR in childhood can result in obstructed labor and maternal and fetal death (12).

Despite intense focus around the role of vitamin D status in health and disease, there has been a worldwide failure to implement public health guidance and eradicate the most severe manifestations of vitamin D and calcium deficiency in our most vulnerable population—NR and osteomalacia of childhood. Therefore, the goal of this Consensus Statement is to provide clinicians with clarity and recommendations on the recognition, societal burden, and treatment of NR and osteomalacia, and to enable clinicians and health policy leaders to establish appropriate clinical and public health interventions to prevent this debilitating, costly, and under-recognized global health problem.

1.1.1. Recommendations

• Nutritional rickets, a disorder of defective chondrocyte differentiation and mineralization of the growth plate and defective osteoid mineralization, is caused by vitamin D deficiency and/or low calcium intake in children. (1⊕⊕⊕)

• The diagnosis of nutritional rickets is made on the basis of history, physical examination, and biochemical testing and is confirmed by radiographs. (1⊕⊕⊕)

1.1.2. Evidence

Bone mineralization requires sufficient supply of the essential mineral ions, calcium and phosphate, with vitamin D optimizing their absorption from the gut. With insufficient serum calcium concentration caused by either vitamin D deficiency or inadequate dietary calcium intake, PTH will stimulate osteoclastic bone resorption to release stored bone minerals into the bloodstream and maintain normal serum calcium (14). Bone disease (rickets and osteomalacia) develops once elevated PTH has led to low serum phosphate levels, as a result of impaired renal phosphate conservation (15).

NR is a disorder of defective growth plate chondrocyte apoptosis and matrix mineralization in children. Osteomalacia is abnormal matrix mineralization in established bone, and although present in children with rickets, it is used to describe bone mineralization defects after completion of growth. Children with an underlying disease such as fat malabsorption, liver disease, renal insufficiency, and illnesses necessitating total parenteral nutrition can also develop NR and are briefly discussed in this review. NR does not include rickets associated with heritable disorders of vitamin D metabolism, including 1-α-hydroxylase deficiency and vitamin D receptor defects, or congenital or acquired hypophosphatemic rickets.

The clinical features and consequences of NR are broad and potentially severe (Table 1) (8). Defective mineralization leads to radiographic growth plate widening as well as metaphyseal cupping and fraying, which confirm the diagnosis of NR.

Biochemical testing alone is not sufficient to diagnose NR and may not differentiate whether the primary cause of NR is vitamin D or dietary calcium deficiency because combined deficiencies are common. Typical laboratory findings in NR are decreases in 25OHD, serum phosphorus, serum calcium, and urinary calcium. Conversely, serum PTH, ALP, and urinary phosphorus levels are invariably elevated (10, 16).

Vitamin D status is assessed by measuring blood levels of total 25OHD. Total 25OHD is used, assuming that 25OHD₂ and 25OHD₃ are of equal biological value (16). There is considerable variability between laboratory methods for measuring serum 25OHD concentrations (17). Immunoassays are popular due to their convenience and high sample throughput; however, cross-reactivity between vitamin D metabolites (25OHD₂, 25OHD₃, and 24,25(OH)₂D) and high levels of estimated bias in several automated assays cast doubt on their reliability, particularly at high and low concentrations of 25OHD (18). Higher-order reference measurement procedures for serum 25OHD have been established by the National Institute of Standards and Technology (NIST) (19) and Ghent University (20) based on isotope dilution liquid chromatography-tandem mass spectrometry. In recent years, the accuracy of 25OHD assays has improved, including through activities of the Vitamin D Standardization Program (21), which aims to standardize the results of different measurement techniques to those of the reference measurement procedures (22). Significant reductions in interlaboratory variation in serum 25OHD are observed using liquid chromatography-tandem mass spectrometry with the application of NIST standard reference materials (23).

Dietary calcium deficiency is diagnosed by obtaining a calcium intake history. Because the sources of calcium will vary by country and region, we recommend that clinicians develop a dietary calcium intake questionnaire specific to their country/region.

1.2.1. Recommendation:

• The panel recommends the following classification of vitamin D status, based on serum 25OHD levels: (1⊕⊕⊕)

  • ■ Sufficiency, >50 nmol/L
  • ■ Insufficiency, 30–50 nmol/L
  • ■ Deficiency, <30 nmol/L

1.2.2. Evidence

Our definition of vitamin D deficiency in the context of skeletal mineralization and mineral ion metabolism for prevention of NR is based on strong evidence (1, 2, 24–27) supported by the increased incidence of NR with 25OHD concentrations <30 nmol/L (1 ng/mL = 2.5 nmol/L). Our definition is consistent with that of the IOM (28). The potential health impacts of maintaining a serum concentration >50 nmol/L are beyond the scope of this review and are addressed elsewhere (29). It should be noted that NR has been reported in children with 25OHD concentrations >30 nmol/L (2, 5, 6, 30) and that NR may not occur with very low 25OHD concentrations but is more likely to occur with deficiency sustained over time, ie, chronic deficiency. Most children with vitamin D deficiency are asymptomatic (15), highlighting the interplay between serum 25OHD level and dietary calcium intake in maintaining serum calcium concentrations and bone integrity (Figure 1).

Although the most significant functional outcome of vitamin D deficiency is the development of osteomalacia and NR, biochemical and bone density associations are also reported. Laboratory observations demonstrate that PTH increases when 25OHD levels drop below 34 nmol/L (7). Moreover, all patients with NR in that study had 25OHD levels < 34 nmol/L, and PTH was elevated in all but one patient. Taken together, the evidence suggests that a 25OHD level at 30–34 nmol/L may be the critical cutoff below which NR is more likely to occur.

Seasonal variations in 25OHD of between 13 and 24 nmol/L (31) emphasize the importance of maintaining 25OHD levels > 50 nmol/L (ie, sufficient), so as to prevent prolonged periods of 25OHD levels < 30 nmol/L, with the risk of developing NR.

1.3.1. Recommendation

• Toxicity is defined as hypercalcemia and serum 25OHD > 250 nmol/L with hypercalciuria and suppressed PTH². (1⊕⊕⊕)

1.4.1. Recommendations

• For infants 0–6 and 6–12 months of age, the adequate calcium intake is 200 and 260 mg/d, respectively. (1⊕⊕⊕)

• For children over 12 months of age, dietary calcium intake of <300 mg/d increases the risk of rickets independent of serum 25OHD levels. (1⊕⊕○)

• For children over 12 months of age, the panel recommends the following classification of dietary calcium intake: (1⊕⊕○)

  • ■ Sufficiency, >500 mg/d
  • ■ Insufficiency, 300–500 mg/d
  • ■ Deficiency, <300 mg/d

1.4.2. Evidence

In developing countries where calcium intake is characteristically very low, with few or no dairy products, dietary calcium deficiency is the main cause of NR among children outside the infant age group.

In 2011, the IOM recommended adequate intakes of calcium for infants, children, and adults (16). The adequate intake for infants was based on breast milk calcium content, which is 200 mg/d and 260 mg/d for babies from 0–6 and 6–12 months of age, respectively. For children 1–18 years of age, the IOM set the daily calcium requirement at 700–1300 mg/d, depending on age (28). There is, however, no true definition of dietary calcium deficiency without a reliable biomarker of calcium intake status, and there are little data to indicate what the lowest calcium intake is that prevents NR. Reports from Nigeria, India, and Bangladesh (6, 30, 40–43) highlighted the role of low dietary calcium intake in the pathogenesis of NR among children. Although some of these children also had suboptimal 25OHD, others had values >50 nmol/L, which points to the interplay between calcium and vitamin D in the pathogenesis of NR (Figure 1). These studies suggest that in children >12 months of age, a dietary calcium intake of <300 mg/d significantly increases the risk of NR independent of serum 25OHD levels, and that at a daily intake of >500 mg, no NR was seen.

1.5.1. Recommendations

• Children with radiographically confirmed rickets have an increased risk of fracture. (1⊕⊕○)

• Children with simple vitamin D deficiency are not at increased risk of fracture. (1⊕⊕○)

1.5.2. Evidence

Based on evidence from available observational studies and case reports, children with clinical, biochemical, and radiographic evidence of NR are at increased risk of fracture. A retrospective study found that fractures occurred in seven of 45 (17.5%) infants and toddlers with NR, aged between 2 and 14 months (44). However, fractures only occurred in those who were mobile and had severe radiographic evidence of rickets. Although none of the fractures were considered to be characteristic of nonaccidental injury (child abuse), two infants had lateral or anterior-lateral rib fractures. In a national survey in Canada, 11 of 108 cases of NR (11%) had suffered fractures, although details on the bone sites and numbers of fractures were not provided (1). Fractures also have been reported in cases or case series of NR in toddlers and adolescents (45–50), but details about the number, site, and type of fracture were absent.

It has been suggested that radiographic features of rickets may be mistaken for those characteristic of nonaccidental injury (51, 52), but the necessary biochemical and radiographic data on the cases for validation of the authors' conclusions were absent. In addition, serum 25OHD levels are similar in infants with accidental and nonaccidental injuries (53). Thus, simple vitamin D deficiency, that is, vitamin D deficiency without biochemical or radiological signs of rickets, has not been associated with increased fracture risk in infants and children.

2.1.1. Recommendations

• 400 IU/d (10 μg) is adequate to prevent rickets and is recommended for all infants from birth to 12 months of age, independent of their mode of feeding. (1⊕⊕⊕)

• Beyond 12 months of age, all children and adults need to meet their nutritional requirement for vitamin D through diet and/or supplementation, which is at least 600 IU/d (15 μg), as recommended by the IOM. (1⊕⊕⊕)

2.1.2. Evidence

Few published studies have included the prevention of radiographic or clinical signs of rickets as an outcome. Consequently, we also reviewed studies that assessed the effect of different vitamin D supplementation regimens³ on 25OHD levels and other bone parameters (such as bone mineral density) with the goal of preventing NR by maintaining levels above the rachitic range, ie, >30 nmol/L (54).

In infants and children, 400 IU/d of vitamin D given as a supplement during infancy is sufficient to prevent radiographic signs of rickets in the short term (up to 12 mo) (54). Specifically, an RCT demonstrated that a vitamin D supplement of 400 IU/d was sufficient to prevent radiographic signs of rickets at 6 months of age, even among infants born with vitamin D deficiency (25). Similarly, no cases of radiographically confirmed rickets were seen after administration of 400 IU/d of vitamin D for 12 months, whereas the incidence was 3.8% in Turkish infants and young children who did not receive supplementation (55). In addition, no incident cases of radiographically confirmed rickets were reported in a 2-year surveillance study of Canadian infants who received 400 IU/d of vitamin D (1). Worldwide, there have been no reports of radiographically confirmed rickets in infants or children receiving 400 IU on a regular, daily basis. Furthermore, this dose has been shown in RCTs to achieve 25OHD levels more frequently above the rachitic (severe deficiency) range compared to 100 or 200 IU/d (25).

The prevention of vitamin D deficiency in the absence of NR was also briefly reviewed. In a double-blind RCT of infants without vitamin D deficiency (25OHD > 50 nmol/L), the impact of 400, 800, 1200, and 1600 IU of vitamin D₃ per day was assessed (54). Doses of 400 IU/d maintained 25OHD levels > 50 nmol/L in 97% of infants after 12 months; doses of 800 and 1200 IU/d were of no added benefit to bone mineral density parameters, and 1600 IU/d raised concerns about potential toxicity. A study in infants with vitamin D deficiency (25OHD < 25 nmol/L) found that a single dose of 100 000 IU maintained 25OHD levels above 37.5 nmol/L for 3 months without hypercalcemia, whereas higher doses led to unacceptably high 25OHD levels (56).

Among infants and toddlers with 25OHD levels < 50 nmol/L for whom daily vitamin D supplementation may not be ideal, intermittent bolus doses of 50 to 100 000 IU every 3 months hold promise, although a comprehensive understanding of the safety and efficacy of this approach remains to be studied.

2.2.1. Recommendation

• In healthy children, routine 25OHD screening is not recommended, and consequently, no specific 25OHD threshold for vitamin D supplementation is targeted in this population. (1⊕⊕⊕)

2.3.1. Recommendations

In the absence of food fortification, vitamin D supplementation should be given to:

• Children with a history of symptomatic vitamin D deficiency requiring treatment. (1⊕⊕⊕)

• Children and adults at high risk of vitamin D deficiency with factors or conditions that reduce synthesis or intake of vitamin D. (1⊕⊕⊕)

• Pregnant women (see Section 3.1).

2.3.2. Evidence

Supplementation is a feasible and acceptable way to ensure adequate vitamin D intake independent of nutrition (58). Consensus guidelines for vitamin D supplementation have been drafted from a variety of pediatric/endocrine groups (16, 59–62). Although there are numerous studies regarding vitamin D deficiency in pediatric populations and primary evaluations of the efficacy of various programs for supplementation of pregnant women, breast-feeding mothers, infants, children, and adolescents, there is more opinion than evidence on many aspects of this topic. However, there is strong, high-quality evidence that vitamin D supplementation should be provided for at-risk groups. All at-risk groups (Table 2) are specifically vulnerable and, in the absence of food fortification, require supplementation.

Vitamin D fortification of infant formula is well established and recommended by all European countries, Australia, New Zealand, and the American Academy of Pediatrics (60). Vitamin D fortification of milk is mandated in Canada, and “enriched milk” is voluntarily fortified in the United States (63).

Children with chronic illnesses and conditions affecting vitamin D synthesis/absorption/metabolism may also benefit from supplementation and may require higher doses (58) but are not in the remit of this consensus on NR.

2.4.1. Recommendations

• For treatment of nutritional rickets, the minimal recommended dose of vitamin D is 2000 IU/d (50 μg) for a minimum of 3 months. (1⊕⊕⊕)

• Oral calcium, 500 mg/d, either as dietary intake or supplements, should be routinely used in conjunction with vitamin D in the treatment regardless of age or weight. (1⊕⊕⊕)

2.4.2. Evidence

Most studies claim that the different doses commonly employed to treat vitamin D deficiency are safe, with hypercalcemia and/or hypercalciuria observed as a side effect only in a few individuals and usually seen in the 300 000 to 600 000 IU range (64). In a small study of children with NR (n = 17), doses of 1700 to 4000 IU of vitamin D₂ rapidly increased 25OHD concentrations within 1 week and normalized calcium, phosphate, and ALP levels at 10 weeks (65). In another study in children aged 2–36 months with NR (n = 19), 5000 to 10 000 IU of oral vitamin D₃ and calcium 0.5 to 1.0 g daily normalized serum PTH, calcium, and phosphate within 3 weeks, although ALP levels remained elevated (66).

Simultaneous administration of calcium with vitamin D appears to be adequate and recommended by several studies (67, 68). In 123 Nigerian children with NR due to calcium deficiency, the combined endpoint of an ALP level < 350 U/L and radiographic evidence of near-complete healing of rickets was seen in a higher percentage of patients who received a combination of calcium and vitamin D (58%) or calcium alone (61%) than in those who received vitamin D alone (19%) (5). Similarly, in 67 Indian children with NR due to combined calcium and vitamin D deficiency, complete healing at 12 weeks was seen in a higher percentage with combined therapy (50%) than with vitamin D (15.7%) or calcium alone (11.7%) (30).

Combined treatment is justified because studies have shown that the diet of children and adolescents with NR is generally low in both vitamin D and calcium (5, 6, 30, 69).

2.5.1. Recommendations

• We recommend oral treatment, which more rapidly restores 25OHD levels than IM treatment. (1⊕⊕⊕)

• For daily treatment, both D₂ and D₃ are equally effective. (1⊕⊕⊕)

• When single large doses are used, D₃ appears to be preferable compared to D₂ because the former has a longer half-life. (1⊕⊕⊕)

• Vitamin D treatment is recommended for a minimum of 12 weeks, recognizing that some children may require longer treatment duration. (1⊕⊕⊕)

2.5.2. Evidence

Some studies compared IM and oral administration of vitamin D, but most were conducted in adults and, therefore, may not be entirely relevant for children with NR. Oral or IM vitamin D was given to 24 normal volunteers (age, 50–78 y) in a dose of 600 000 IU of D₂ or D₃ (70). Peak levels of 25OHD were seen at 30 and 120 days in those given oral and IM treatment, respectively. Another study in 92 adults with 25OHD < 75 nmol/L compared 300 000 IU vitamin D₃ IM to 50 000 IU D₃ orally given on six occasions over 3 months (71). A higher proportion of subjects receiving oral treatment had 25OHD > 75 nmol/L at 3 and 6 months than IM subjects.

One RCT in 61 children with NR compared a single IM dose of 600 000 IU vitamin D₃ to a weekly oral dose of 60 000 IU D₃ for 10 weeks (72). There were no differences at 1, 4, and 12 weeks between groups in bone profiles, 25OHD concentrations, or side effects. A meta-analysis of studies comparing the administration of vitamin D₂ and D₃ concluded that, when given as bolus doses, vitamin D₃ was more effective at raising 25OHD concentrations, but no significant differences were seen with daily doses (73).

There are no RCTs on the duration of treatment for children with NR, and most of the literature consists of review articles. The review commissioned by the PES recommends that daily oral treatment be given for 8 to 12 weeks (74). Similar durations between 8 and 12 weeks of daily treatment are recommended in reviews from the United Kingdom (75, 76). A duration of 3 months is recommended in a consensus statement from Australia and New Zealand (77). Given the limited evidence, we recommend minimum treatment duration of 12 weeks to achieve a comprehensive healing and normalization of ALP, recognizing that some children may require longer treatment.

Several studies explored the concept of “stoss therapy,” ie, the administration of a large dose given as a single dose or in divided doses over several days. This approach has been advocated for ease of use and compliance with therapy. Three different single oral doses (150 000, 300 000, or 600 000 IU) in 56 Turkish children aged 3–36 months with NR did not affect the rate of improvement of rickets at 30 days (64).

However, eight subjects (two in the 300 000-IU group, six in the 600 000-IU group) developed hypercalcemia. A recent study in India compared single oral doses of 300 000 vs 600 000 IU of vitamin D₃ in 76 rachitic children aged 6 months to 5 years (78). At 12 weeks, all children demonstrated radiographic healing with comparable decreases in ALP and PTH. However, hypercalcemia occurred in five children (6.5%)—two receiving 300 000 IU and three receiving 600 000 IU. Several review articles advocate different recommendations with stoss therapy that are not supported by evidence (75–77). The few studies comparing daily treatment to stoss therapy contained groups with different subject characteristics. Although we recommend daily treatment as the first line of management, we recognize that in some situations, stoss therapy may be more practical. Therefore, we provide vitamin D dose recommendations for both treatment options (Table 3). Any treatment needs to be followed by supplementation (see Sections 2.1 and 2.3).

3.1.1. Recommendations

• Maternal vitamin D deficiency should be avoided by ensuring that women of childbearing age meet the intakes of 600 IU/d recommended by the IOM. (1⊕⊕⊕)

• Pregnant women should receive 600 IU/d of vitamin D, preferably as a combined preparation with other recommended micronutrients such as iron and folic acid. (2⊕⊕○)

3.1.2. Evidence

Maternal diet and nutrient intake as a predictor of infantile rickets have not been addressed in the literature as an a priori hypothesis. However, available data have been collected during vitamin D intervention studies, case studies, or case series in women during pregnancy.

Many cases of NR included data on maternal 25OHD and, in some cases, dietary information (79–81). Neonatal vitamin D deficiency is always caused by maternal deficiency and can have life-threatening consequences such as hypocalcemic seizures and dilated cardiomyopathy in unsupplemented infants (11). Hypocalcemia (see Section 4.1.2) or other early biochemical signs of rickets (such as elevated ALP and PTH) are present before radiographic signs of NR occur in unsupplemented neonates and infants (82, 83). A high percentage of mothers of infants with symptomatic vitamin D deficiency are from high-risk groups who are vitamin D deficient and exclusively breast-feeding (11, 24, 83–85).

In a Canadian case series, six First Nation infants presented with hypocalcemic seizures within the first 30 days of life, with suspected or confirmed maternal vitamin D deficiency and a lack of supplementation during pregnancy (86). All were formula fed, which suggests that although their intake of vitamin D would have been sufficient in normal circumstances, in these infants the oral vitamin D supply via formula milk was insufficient to treat their pre-existing severe neonatal deficiency.

Prevention of maternal deficiency is critical, and all mothers should meet their nutritional requirement for vitamin D, which is currently set at 600 IU/d, although this value is not based on direct evidence from RCTs of vitamin D supplementation in pregnant women (28). Potentially, a higher intake of vitamin D may be required to prevent both maternal and neonatal deficiency (87). Prevention of congenital vitamin D deficiency is described in Section 4.4.

3.2.1. Recommendations

• In addition to an intake of 400 IU/d of vitamin D, complementary foods introduced no later than 26 weeks should include sources rich in calcium. (1⊕⊕⊕)

• An intake of at least 500 mg/d of elemental calcium must be ensured during childhood and adolescence. (1⊕⊕⊕)

3.2.2. Evidence

There is abundant, yet low-quality evidence from multiple case reports, case series (11, 48, 49, 88), and observational studies (1, 2, 45, 50, 85, 89–99) that exclusive breast-feeding without vitamin D supplementation is a major risk factor for NR in infants. Furthermore, prolonged breast-feeding with late introduction of complementary feeding is associated with NR in infants not receiving vitamin D supplements (26, 100–105). Abundant observational data (55, 106–111) and one RCT (25) suggest that infants receiving vitamin D supplementation in the first year of life are not at risk of developing NR. Evidence for providing 400 IU/d vitamin D to infants is presented in Section 2.1.

Evidence primarily from developing countries demonstrates that traditional diets low in calcium cause NR (30, 43, 69, 93, 112–114). Therefore, special diets during infancy such as those that avoid milk and dairy products, those using soy or rice milk that are not specifically designed for infants, and/or vegan and macrobiotic diets may predispose infants to NR (115–120). Recommendations on sufficient calcium intake are presented in Section 1.4.

3.3.1. Recommendations

• Because UVB rays trigger epidermal synthesis of previtamin D₃, restricted exposure to sun increases the risk of vitamin D deficiency and nutritional rickets. (1⊕⊕⊕)

• Environmental factors such as latitude, season, time of day, cloud cover, and pollution affect availability of UVB, whereas personal factors such as time spent outdoors, skin pigmentation, skin coverage, age, body composition, and genetics affect the dose-response to UVB exposure and circulating 25OHD. (2⊕⊕○)

• No safe threshold of UV exposure allows for sufficient vitamin D synthesis across the population without increasing skin cancer risk. (2⊕⊕○)

3.3.2. Evidence

Solar radiation (UVB band of 290 to 315 nm) stimulates synthesis of previtamin D from epidermal 7-dehydrocholesterol, which isomerizes to cholecalciferol and is subsequently metabolized to 25OHD. Sun exposure increases circulating 25OHD (121–123). Assuming UVB availability, an individual's capacity to synthesize vitamin D increases with longer epidermal exposure. However, exposure can be affected by environmental factors such as latitude, altitude, season, time of day, cloud cover, and air quality (123–129) as well as personal factors such as occupation, lifestyle, culture such as clothing, and preference which may modify time spent outdoors and/or the surface area of skin exposed to sunlight (130–133). Finally, the dose-response of circulating 25OHD to cutaneous UVB exposure is dependent on skin pigmentation, age, body composition, genetic factors, and baseline 25OHD levels, among others (121, 131, 134–138).

Abundant global observational data report an association between restricted epidermal exposure and NR as a consequence of vitamin D deficiency (85, 139–143). UV radiation causes skin cancer, and exposure to UV radiation from sunlight and artificial sources early in life elevates the risk of developing skin cancer (144). Without firm evidence to account for variations in age, skin color, latitude, time of day, and time of year, it is currently impractical to provide prescriptive advice on safe solar exposure to the population as a whole. All risk factors are summarized in Table 2.

4.1.1. Recommendations

• Pregnant women should receive 600 IU/d of supplemental vitamin D. This will ensure adequacy of maternal 25OHD, especially in women at risk of deficiency, to prevent elevated cord blood ALP, increased fontanelle size, neonatal hypocalcemia and congenital rickets, and to improve dental enamel formation. (2⊕⊕○)

• There is little evidence that maternal supplementation with vitamin D will protect or improve birth anthropometry (2⊕○○), and there is no evidence that supplementation with vitamin D will protect or improve short- or long-term growth or bone mass accretion. (2⊕⊕○)

4.1.2. Evidence

There is moderate evidence that low maternal vitamin D status during pregnancy is associated with elevated cord blood ALP and larger fontanelle size at birth (145, 146). Moderate to strong evidence from two RCTs (145, 147), two controlled trials (148, 149), and one observational study (150) indicated that low maternal vitamin D status during pregnancy increases the risk of neonatal hypocalcemia; however, a smaller RCT and a controlled trial did not support these findings (146, 151). A single large controlled trial suggests that vitamin D supplementation during pregnancy improves dental enamel formation of offspring (148).

There are conflicting data about the association between maternal vitamin D status during pregnancy and birth anthropometry. Three RCTs of moderate to high quality using daily dose or single high-dose regimens did not find an association (151–153), whereas two controlled trials of moderate-grade evidence found a positive association (146, 147). Three low- to high-quality RCTs did not find any difference in birth anthropometry in offspring of mothers supplemented with 400, 2000, or 4000 IU/d; none of the studies had a placebo group (87, 154, 155).

There are inconsistent data on the association between maternal serum 25OHD levels and linear growth during the first year of life (152, 157, 162) and insufficient to weak evidence for an association between maternal serum 25OHD levels and bone mass or density at birth (150, 158–161) or in later childhood (162–164).

4.2.1. Recommendation

• Pregnant women do not need calcium intakes above recommended nonpregnant intakes to improve neonatal bone. (1⊕⊕⊕)

4.3.1. Recommendations

• Lactating women should ensure they meet the dietary recommendations for vitamin D (600 IU/d) for their own needs, but not for the needs of their infant. (1⊕⊕⊕)

• Lactating women should not take high amounts of vitamin D as a means of supplementing their infant. (2⊕⊕○)

• Pregnant and lactating women should meet the recommended intakes of calcium. Maternal calcium intake during pregnancy or lactation is not associated with breast milk calcium concentrations. (1⊕⊕⊕)

4.3.2. Evidence

Maternal vitamin D intake during lactation correlates with milk vitamin D activity. Several double-blind RCTs found that high maternal intakes of vitamin D (2000, 4000, and 6400 IU/d) were associated with higher breast milk vitamin D concentration (Figure 2) (168–171).

Supplementing mothers with high amounts of vitamin D has been suggested as a means of increasing both maternal (Figure 3) and infant serum 25OHD concentrations (172–175). Maternal vitamin D intakes up to 4000 IU/d are likely safe during pregnancy and lactation (16). However, the finding that infants of mothers supplemented with 2000 IU/d or more have similar serum 25OHD concentrations as infants receiving 400 IU/d (Figure 4), as well as safety concerns, and our own recommendation that all infants receive 400 IU vitamin D per day lead us to advise that mothers should take recommended amounts (600 IU/d) rather than higher doses of vitamin D.

Maternal calcium intake during pregnancy or lactation does not influence breast milk calcium concentrations. Only one observational study found a weak association between maternal calcium intakes during pregnancy and breast milk calcium level at day 40 (mature milk) (176). Numerous studies, including two RCTs (177, 178) and two observational studies (179, 180) have not found a relationship between maternal calcium intake and breast milk calcium concentrations.

No studies have investigated the effect of maternal vitamin D intake during pregnancy on either milk calcium or vitamin D concentrations. Two double-blind RCTs found that maternal serum 25OHD concentration or maternal intake of vitamin D (up to 4000 IU/d) during lactation was not associated with milk calcium concentrations (181, 182).

4.4.1. Recommendation

• Supplementing mothers with 600 IU/d of vitamin D and ensuring they receive recommended calcium intakes, or appropriate therapy of maternal conditions predisposing to hypocalcemia or vitamin D deficiency, prevents congenital rickets. (2⊕○○)

4.4.2. Evidence

Approximately 80 cases of congenital rickets, defined as babies presenting within the first 4 weeks of life with biochemical and radiographic signs of rickets, have been described in the medical literature. Typically, mothers of babies with congenital rickets have osteomalacia with severe vitamin D deficiency, low calcium intake, and hypocalcemia at delivery and had not taken vitamin D supplementation during pregnancy (83, 183–197). In rare cases, congenital rickets can occur when mothers have had severe prolonged hypocalcemia not primarily caused by vitamin D deficiency such as poorly treated hypoparathyroidism (198–201), renal failure (202–206), received phosphate-containing enemas (207), or iatrogenic hypermagnesemia (208).

The mechanisms for the development of congenital rickets remain poorly understood, especially how diminished maternal calcium supply as the common primary maternal abnormality in all cases affects fetal mineralization. Clearly, congenital rickets only occurs in extreme metabolic situations. It is fair to state that all reported cases of congenital rickets could have been prevented by vitamin D supplementation, normal calcium intake during pregnancy, and adequate therapy of maternal conditions associated with prolonged hypocalcemia or vitamin D deficiency. Evidence is very limited on the therapy for congenital rickets, but rickets generally is responsive to vitamin D with or without calcium supplementation.

5.1.1. Recommendations

• The prevalence of rickets should be determined by population-based samples, by case reports from sentinel centers, or by mandatory reporting. (1⊕⊕⊕)

• Screening for nutritional rickets should be based on clinical features, followed by radiographic confirmation of suspected cases. (1⊕⊕⊕)

• Population-based screening with serum 25OHD, serum ALP, or radiographs is not indicated. (1⊕⊕⊕)

5.1.2. Evidence

NR has been increasingly reported in high- and low-income countries (55, 209–213). Using different methodology, the incidence of NR has been reported as 2.9, 4.9, 7.5, and 24 per 100 000 in Canada (1), Australia (2), the United Kingdom (3), and the United States (99), respectively. Many studies are hospital based but provide additional insight into the burden of NR. Infants with NR may present with hypocalcemic seizures. The incidence of dilated cardiomyopathy associated with NR and hypocalcemia is unknown, but it is potentially the deadliest and most economically costly complication of NR (11). The methods used for the diagnosis of NR in case reports (102) and small to large case series (104, 214–217) are widely variable and many lack radiographic confirmation (209). Physician-based surveys can estimate the burden of disease, but few have been done (1, 2). Population-based studies provide the most accurate assessment of the disease burden (3, 99, 211, 218–221). Despite differing methodologies, published reports indicate the greatest burden of NR is in Africa, Asia, and the Middle East due to sun avoidance or dietary calcium insufficiency (209, 213).

Even high-income countries have observed a resurgence of NR, mainly among immigrants of African, Asian, or Middle-Eastern origin. This overall increase in the incidence of NR in high-income countries corresponds to an increase in the number of individuals in ethnic minority, immigrant, and refugee groups (1–4, 99, 222). The incidence among established Caucasian populations is stable or decreasing. In regions with a low prevalence of NR, inclusion of NR as a reportable disease is potentially the most cost-effective means of case identification and surveillance (1, 2, 4, 99, 222).

Measurement of serum 25OHD is useful for the diagnosis of vitamin D deficiency in NR, but not for population screening (223, 224). Raised serum ALP has been used as a screening tool for NR (225). However, acute illness, drugs, liver disease, growth spurts, and transient hyperphosphatasemia of infancy and childhood can all elevate ALP values. Because of the invasiveness of venipuncture, high cost, and low positive predictive values, serum ALP and 25OHD cannot be recommended for population screening. Although radiographs of the wrists and knees provide definitive confirmation of active rickets (226), radiation exposure precludes recommending screening radiographs in asymptomatic children.

5.2.1. Recommendation

• Universally supplement all infants with vitamin D from birth to 12 months of age, independent of their mode of feeding. Beyond 12 months, supplement all groups at risk and pregnant women. Vitamin D supplements should be incorporated into childhood primary health care programs along with other essential micronutrients and immunizations (1⊕⊕⊕), and into antenatal care programs along with other recommended micronutrients. (2⊕⊕○)

• Recognize nutritional rickets, osteomalacia, and vitamin D and calcium deficiencies as preventable global public health problems in infants, children, and adolescents. (1⊕⊕⊕)

• Implement rickets prevention programs in populations with a high prevalence of vitamin D deficiency or limited vitamin D and/or calcium intakes and in groups of infants and children at risk of rickets. (1⊕⊕⊕)

• Monitor adherence to recommended vitamin D and calcium intakes and implement surveillance for nutritional rickets. (1⊕⊕⊕)

• Fortify staple foods with vitamin D and calcium, as appropriate, based on dietary patterns. Food fortification can prevent rickets and improve vitamin D status of infants, children, and adolescents if appropriate foods are used and sufficient fortification is provided, if fortification is supported by relevant legislation, and if the process is adequately monitored. Indigenous food sources of calcium should be promoted or subsidized in children. (1⊕⊕⊕)

• Promote addressing the public health impact of vitamin D deficiency as both a clinical and a public health issue. (1⊕⊕⊕)

5.2.2. Evidence

Vitamin D supplementation

Infants aged 0–12 months and adolescents are at increased risk of NR and osteomalacia from vitamin D deficiency due to rapid growth. Vitamin D is found in a limited number of foods, and dietary intakes apart from fortified foods have little impact on overall vitamin D status. Programs that deliver micronutrient supplements provide the fastest improvement in micronutrient status of individuals or targeted populations (227, 228).

Food fortification with vitamin D

Food fortification of commonly consumed staple foods safely provides adequate intake to prevent deficiency at minimal cost. Mandatory fortification of staple foods with vitamin D and calcium ensures nutritional adequacy (229). After vitamin D fortification of milk in North America and of milk, margarine, and cereals in the United Kingdom, the prevalence of NR dramatically declined, so much so that it was considered almost eradicated (16, 63, 228).

Studies in adults and children highlight the need for appropriate foods (230) to be adequately fortified and consumed by the at-risk segments of the population (231) so that vitamin D intakes of most members of a population approach dietary recommendations (232, 233). Because vitamin D fortification of foods rich in calcium is optimal for bone health, dairy products are commonly fortified. In countries where dairy products are not widely consumed, flour, margarine, cooking oil, or soy-based foods can be fortified with vitamin D.

Although several studies have assessed the effectiveness of vitamin D fortification of food to increase 25OHD concentrations in different age groups and communities, relatively few fortification studies have targeted children. A systematic review and meta-analysis concluded from food-based RCTs that vitamin D-fortified foods increase serum 25OHD and reduce the prevalence of deficiency (<30 nmol/L) in adults, provided appropriate vehicles are chosen based on analysis of habitual diet (234). Fortification of chupatty flour (6000 IU/kg) raised 25OHD from approximately 12.5 nmol/L to approximately 48 nmol/L in children over a 6-month period (235). Fortification of fluid milk and margarine was estimated to increase vitamin D intake in 4-year-old children from 176 to 360 IU/d (4.4 to 9 μg/d) and 25OHD concentrations from 55 to 65 nmol/L (236). Milk fortification has also been a successful strategy to improve the vitamin D status of schoolchildren in India (237). Fortification and supplementation requirements may vary with population exposure to sunshine (see Section 3) (238).

Health promotion

Education of medical providers and organizations, health insurers, policy makers, governments, public health officials, and the general public is vital to address the public health issue of NR and vitamin D deficiency. They should be provided with guidelines on the importance of adequate vitamin D and calcium intakes in children, adolescents, and pregnant and lactating women (244). National and global public health promotion strategies are essential to raise professional and community awareness, and global action to protect all children from vitamin D and calcium deficiency is imperative.

5.3.1. Recommendation

• The cost-effectiveness of supplementation and food fortification programs needs further study. (1⊕⊕○)

5.3.2. Evidence

Very weak evidence supports a policy of providing vitamin D supplementation to Asian children in the United Kingdom for the first 2 years of life (245). However, this report had methodological limitations that preclude any conclusions.

Urgent research is required to model the cost-effectiveness of alternative vitamin D supplementation strategies and food fortification programs. Future economic models should include:

• Resources associated with different supplementation strategies

• Indirect costs of treatment and complications

• Resource use of current practice

• Effectiveness of different approaches

• Expected adherence

• Outcomes such as quality of life associated with 25OHD levels, and

• Health care costs of disease caused by both skeletal and extraskeletal effects of vitamin D deficiency.

Costs of vitamin D supplementation and/or fortification programs will differ depending on the target 25OHD level and population characteristics. Subgroup analyses targeting high-risk groups, such as people with darkly pigmented skin, limited sun exposure, and low calcium intakes, should be conducted.