Relevant BNF section: C 9.6
In recent years, the prevalence of vitamin D (calciferol) deficiency has increased and rickets has re-emerged in the UK and other developed countries as a public health problem.1–3 Infants, toddlers and adolescents in 'at risk' ethnic minorities (e.g. Asian, African Caribbean and Middle Eastern) are particularly likely to be vitamin D-deficient or to have rickets.1,4–6 Also at particular risk are babies and toddlers who have been exclusively breast-fed during infancy without receiving vitamin supplements,7 or whose mothers did not have vitamin D supplements during pregnancy.8 Here we discuss the management of children with primary vitamin D deficiency (i.e. that due to nutrient deficiency).
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Relevant BNF section: C 9.6
About vitamin D
The major biological functions of vitamin D are to regulate calcium and phosphate absorption and metabolism, and to maintain plasma calcium levels via bone resorption and formation. These actions help to form and maintain healthy bones. Observational studies suggest that vitamin D also helps to maintain a healthy immune system and regulate cell growth and differentiation, so could protect against certain cancers.9
Vitamin D deficiency
Deficiency of vitamin D leads to defective mineralisation of bone. In children, this process involves growing bone and can result in rickets. Children with rickets classically present with bony abnormalities such as leg-bowing and knock-knees. There may also be bony deformities of the chest, pelvis and skull, fractures in severe cases, delayed dentition, poor growth, and, rarely, bone pain. Symptoms of hypocalcaemia, such as neuromuscular irritability (e.g. convulsions, tetany), cardiomyopathy or cardiac arrest may be the presenting feature, particularly in very young infants.1,10–12 The commonest cause of rickets is simple nutrient deficiency of vitamin D (from sunlight, diet or both), that is, deficiency in the absence of any other cause such as malabsorption, or disorders of the liver, kidneys or metabolism. After closure of the epiphyses, vitamin D deficiency results in osteomalacia, not rickets.
The overall prevalence of vitamin D deficiency in children in the UK is not known. The condition can occur in Caucasians, but appears particularly prevalent among non-European ethnic minorities.4–6,13–19 For example, observational studies suggest that, in these minority groups, vitamin D deficiency occurs in around 50% of pregnant women and their neonates,13,14 up to 40% of toddlers,6,15 up to 45% of schoolchildren16,17 and over 70% of adolescents.4,5,18
Sources of vitamin D
About 80% of the body's vitamin D comes from the action of UVB (290-320nm) sunlight on 7-dehydrocholesterol in the skin, which results in the formation of vitamin D3 (colecalciferol). The rest comes from the diet. Synthesis is decreased by lack of exposure to sunlight, due to extensive covering with clothing,20 failure to venture outdoors, or the use of anti-UVB sunscreens.21 During the winter, very little UVB radiation reaches the Earth's surface.3 As a result, little or no vitamin D is synthesised in the skin of people living at latitudes above or below about 35 (such as in the UK).3 In the UK, in those with fair skin, exposure (for about 15 minutes) of the hands, arms, face, or back to suberythemal doses of sunlight from April to September, two or three times a week, results in sufficient skin synthesis of vitamin D.3,22 However, care must be taken to avoid sunburn. People with darker skin may need longer exposure than those with white skin to synthesise the same amount of vitamin D in their skin.23
Vitamin D can be obtained from the diet, either as vitamin D2 (ergocalciferol) or vitamin D3. Vitamin D is found in only a few foods; good sources include oily fish, fish oils, and eggs. In most developed countries, including the UK, some foods such as infant formulas, margarine and breakfast cereals are fortified with vitamin D. Liver and liver products are good sources of vitamin D, but are rich in vitamin A, so should not be eaten more than once a week, and should be avoided by pregnant women, due to the risk of vitamin A toxicity.
Vitamin D metabolism
Vitamin D, as either D2 or D3, is physiologically inactive and requires two hydroxylation steps before becoming fully activated. The first stage occurs in the liver and involves hydroxylation at the 25-position of the molecule to form 25-hydroxycholecalciferol (25OHD), also known as calcidiol (or as the medicine calcifediol). This circulates in plasma, bound to a specific vitamin D binding protein. Its plasma concentration is directly related to supply of vitamin D, whatever the source, and reflects the size of available vitamin D stores. Plasma concentrations of 25OHD peak about a month after appropriate sunlight exposure.24 The second hydroxylation step occurs in the kidneys. It involves addition of a further hydroxyl group at position 1 of the 25OHD molecule to form active 1α,25-dihydroxycholecalciferol (1α,25(OH)2D), also known as calcitriol. This process is highly regulated by the influence of parathyroid hormone (PTH) and plasma phosphate - high concentrations of the former and low concentrations of the latter stimulate hydroxylation. The concentration of 1α,25(OH)2D does not reflect vitamin D status, as it may be low, normal or even elevated when vitamin D supplies are inadequate but not completely deficient; and it rises to supraphysiological levels on treatment of vitamin D deficiency with vitamin D.25,26
Diagnosing vitamin D deficiency
A child may present with clinical features suggestive of vitamin D deficiency. However, definitive diagnosis of rickets requires radiography of a long bone that shows cupping, splaying and fraying of the metaphysis (e.g. champagne glass wrist).
The mainstay in the diagnosis of vitamin D deficiency is the serum concentration of 25OHD.3 However, there is some debate about the definition of a replete or deficient vitamin state with respect to 25OHD concentrations.3,27,28 A concentration of 25OHD below around 25nmol/L (10?g/L) is probably consistent with vitamin D deficiency in children, in which both clinical and biochemical abnormalities (e.g. rickets or symptomatic hypocalcaemia) may occur.29 Concentrations of 30-50nmol/L (12-20?g/L) are frequently associated with biochemical disturbances (particularly raised PTH, which is considered a sign of vitamin D insufficiency), but not clinical problems.30 Consequently, some specialists have argued that true vitamin D sufficiency, in which all parameters of calcium metabolism are entirely normal, only occurs when serum 25OHD concentrations are at least 50nmol/L (20?g/L).31 If there is any suspicion that a child has vitamin D deficiency or rickets, the GP should measure serum concentrations of 25OHD and send the child for appropriate X-rays. Children found to have rickets should be referred to a paediatrician for further monitoring and treatment.
Ideally, investigation of vitamin D deficiency should also include measurement of serum levels of calcium, phosphate and alkaline phosphatase.29 In the early stages of vitamin D deficiency, there is a fall in calcium concentration accompanied by a rise in PTH concentration. If the hypocalcaemia is severe enough, the patient will present with hypocalcaemic convulsions or tetany, but may not have radiological evidence of rickets.1 As vitamin D deficiency worsens, serum PTH concentrations rise further. As a result, plasma calcium concentrations normalise to a certain extent and phosphate concentrations fall. As vitamin D concentrations fall further, hypocalcaemia and hypophosphataemia worsen, and rickets becomes more severe and may be accompanied by fractures.
Preventing vitamin D deficiency
Guidance from the Committee on Medical Aspects of Food and Nutrition Policy (COMA) states that the reference nutrient intake (RNI) for vitamin D should be 10?g (400 IU) daily for pregnant and breast-feeding women, 8.5?g (340 IU) daily for infants under 6 months of age and 7?g (280 IU) daily for children from the age of 6 months to 3 years.32 The guidance recommends that, in practice, these groups need to receive vitamin D supplements to achieve adequate plasma concentrations of vitamin D. By comparison, in the USA, the Institute of Medicine of the National Academy of Sciences has set an 'Adequate Intake' for vitamin D of 5?g (200 IU) daily for children from birth to 18 years of age.33 Current Department of Health (DH) guidance states that, to avoid vitamin D deficiency, all pregnant and nursing mothers should take supplements containing 10?g (400 IU) of vitamin D daily and all children aged under 5 years of age should take supplements containing 7?g (280 IU) daily.22 The level of supplementation recommended is equivalent to the RNIs, as it is assumed this will not cause toxicity even in those who already have adequate concentrations of vitamin D. There are no DH recommendations for supplementing older children or adolescents.
In contrast to the advice from COMA and the DH, guidance from the National Institute for Health and Clinical Excellence (NICE) states that there is not enough evidence to evaluate the effectiveness of vitamin D in pregnancy and, that in the absence of evidence of benefit, vitamin D supplementation should not be offered routinely to pregnant women.34
Vitamin D supplementation in pregnancy
Inadequate vitamin D concentrations in pregnant women contribute to vitamin D deficiency, hypocalcaemia and rickets in their babies.19,29 Three published randomised controlled studies have assessed the effects of vitamin D supple- mentation on pregnant women and their infants, using higher doses than currently recommended.14,35,36
In one, double-blind, study, 126 Asian women in the UK took either ergocalciferol 25?g (1,000 IU) daily or placebo during the last trimester of pregnancy.14 At the start of the trial (28 weeks gestation), the mean serum 25OHD concentration was 20.1nmol/L. At term, the concentration had fallen to a mean of 16.2nmol/L in the untreated group, but had risen to 168.0nmol/L in the treated group. Cord blood concentrations correlated well with maternal serum concentrations. The mothers who received vitamin D supplements gained more weight during the third trimester and none of their infants had symptomatic hypocalcaemia, compared with 7.5% of the control mothers' infants (p<.01). A follow-up study showed that the infants of the supplemented mothers were heavier at all ages studied (3, 6, 9 and 12 months), despite not routinely receiving vitamin D supplements.37
The second, single-blind, trial involved 77 white women in northwest France who were due to give birth in February or March.35 They were either given a vitamin D supplement of 25?g (1,000 IU) daily for the last 3 months of a winter pregnancy or a single large oral dose of 5,000?g (200,000 IU) at 7 months gestation, or acted as unsupplemented controls. Supplemented groups had 25OHD concentrations at term that had reached levels of 25.3nmol/L and 26.0nmol/L, respectively. In contrast, the unsupplemented group had concentrations at term of only 9.4nmol/L. One infant in the unsupplemented group developed symptomatic delayed neonatal hypocalcaemia. There were no differences in birth weights between any of the groups.
It is not clear why there were such marked differences in the 25OHD concentrations at term between the supplemented women in the two studies. On the basis of these two studies, a systematic review concluded there was not enough evidence to support routine supplementation of women in pregnancy. The review did not comment on the fact that one study was done in Asian women and the other in white women.38
The third, single-blind, study was not included in the systematic review because no clinical outcomes were given.36 It involved 40 pregnant women in France given 25?g (1,000 IU) vitamin D3 daily for the last trimester or no supplementation. The study showed that, while both groups had similar concentrations (about 10nmol/L) of 25OHD at 27 weeks of pregnancy prior to the start of supplementation, concentrations in the treated group rose, while those in the controls stayed the same, at 33 weeks (22nmol/L vs. 11nmol/L, p<.0005) and at term (26nmol/L vs. 13nmol/L, p<.0005).
Vitamin D supplementation in the newborn
The amount of nutritional vitamin D needed in infancy is related to the stores built up in utero and through exposure to sunlight after birth. If their mothers are vitamin D-deficient at the birth, infants are at considerable risk of developing symptoms associated with vitamin D deficiency. Infants who are fed on formula milk are likely to receive the recommended 10?g (400 IU) vitamin D daily. Breast milk usually contains very little vitamin D, so breast-fed infants are largely reliant on any stores present at birth unless supplements are given. The results of clinical trials suggest that supplementation of breast-fed infants with 10?g vitamin D daily should be sufficient to maintain satisfactory concentrations.39,40 According to our specialists, this may not be sufficient to prevent clinical symptoms of vitamin D deficiency in infants severely deficient at birth. Such children might need doses of at least 20-25?g (800-1,000 IU) daily.
An alternative method of ensuring adequate supplies of vitamin D to breast-fed infants may be to supplement their mothers during lactation, since the vitamin D content of breast milk increases with rising maternal vitamin D concentrations. Two double-blind randomised controlled trials have examined the effect of high-dose maternal vitamin D supplements on the nutritional vitamin D status of breast-feeding mothers and nursing infants.40,41 One included 18 women enrolled at 1 month after giving birth and found that a maternal intake of 100?g (4,000 IU) vitamin D could help to improve both maternal and neonatal nutritional vitamin D status.41 The other included 77 mothers randomised to placebo, 12.5?g (500 IU) or 25?g (1,000 IU) of vitamin D2 daily, or a control group in which the infants received 10?g (400 IU) vitamin D3 daily.40 It found a direct relationship between maternal and infant plasma concentrations of 25OHD at 6 weeks, levels being higher in the infants of mothers who were supplemented (p<.01). However, the control group had even higher concentrations of 25OHD (p<.01), suggesting that infant supplementation is more effective than maternal supplementation.
Treating primary vitamin D deficiency
Once primary vitamin D deficiency is diagnosed, the patient should be treated, ideally with colecalciferol or ergocalciferol.42 A randomised controlled study, involving 20 children aged 3-18 months with nutritional rickets, compared daily treatment with 150?g (6,000 IU) of calcifediol or 150?g (6,000 IU) of colecalciferol for 20 days and found no differences in the healing rate of the rickets or biochemical parameters.43
Two randomised controlled trials have assessed giving one-off large doses of vitamin D to treat nutritional vitamin D deficiency. One involved 56 infants and children aged 3-36 months with rickets, given one of three single oral doses of vitamin D (3,750?g, 7,500?g or 15,000?g [150,000 IU, 300,000 IU and 600,000 IU, respectively]). There was clinical and radiological improvement of rickets in all children followed-up at 60 days.44 Asymptomatic hypercalcaemia was present in 2 infants given 7,500?g and 6 infants given 15,000?g. In the other trial, which involved 42 children aged 6-30 months with rickets, a single intramuscular dose of 7,500?g vitamin D was compared with oral calcium (3g) alone or vitamin D plus calcium in the same doses as when given alone.45 At follow-up after 4 weeks, only the combination produced an increase in serum calcium (p=0.04), but all three treatments produced a decrease in alkaline phosphatase levels.
The daily doses of ergocalciferol for children recommended by the BNF for Children (BNFC) are, for those aged 1-6 months, 75?g (3,000 IU); 6 months-12 years, 150?g (6,000 IU); and 12-18 years, 250?g (10,000 IU); with all doses adjusted as necessary.42 These doses are at the higher end of the treatment doses used in the above trials and patients may need to be monitored for hypercalcaemia. Some clinicians use half these doses with good effect.46 We know of no published randomised controlled trials comparing vitamin D with the medicines alfacalcidol or calcitriol, and neither is licensed for primary vitamin D deficiency in children.
Vitamin D toxicity
Vitamin D has a wide therapeutic index, but taken orally in very large quantities causes hypercalcaemia.47 After food fortification was introduced in the UK in the 1940s, rickets virtually disappeared, but there were several reports of infants with significant hypercalcaemia.48 Many of these infants were probably receiving more than 100?g (4,000 IU) daily of vitamin D due to over-enthusiastic fortification of milk and cereals. As a consequence, fortification of formula feeds was modified and routine supplementation of cow's milk ceased. The Food Standards Agency states that taking 25?g (1,000 IU) of vitamin D supplements daily is unlikely to cause any harm in the general population.27,47 Excess vitamin D in animals has been shown to have teratogenic effects;47 during pregnancy, high systemic doses of vitamin D should be avoided. With all these factors in mind, the currently recommended dose for supplementation during pregnancy and breast-feeding (10?g [400 IU] daily) seems reasonable.
There is a wide range of supplements containing vitamin D: D2 from plant sources or D3 from animal sources (see cost table; doses and costs for adults will be included in a future article about primary vitamin D deficiency in adults). Those available as multivitamins also contain vitamin A and so are unsuitable in pregnancy because of the risk of fetal anomalies with high levels of vitamin A. All other 'standard' dose supplements contain calcium, which some people find unpalatable and is unnecessary in primary vitamin D deficiency. Only high-dose supplements for the treatment of vitamin D deficiency and rickets contain vitamin D alone.
The DH runs a Welfare Food Scheme (WFS) that gives vitamin supplements free of charge to pregnant or breast-feeding women and children aged under 5 years, from families fulfilling certain criteria.49 The DH is currently introducing its next initiative, 'Healthy Start', to promote the wellbeing of infants and children from birth, which will include a programme to promote vitamin D supplementation.50 Products containing the recommended vitamins for pregnant and breast-feeding women and infants are theoretically available as either drops or tablets. However, neither is currently manufactured in the UK, and the DH has tenders out to various manufacturers for products that will replace the discontinued tablets and drops. Alternatives for infants and nursing mothers, which contain similar amounts of vitamins A and D, are available as either Abidec or Dalivit. Both are free of charge under the WFS and can also be bought over the counter. As these preparations contain vitamin A, they cannot be given to pregnant women. In this case, the only available alternatives are preparations that contain both vitamin D and calcium.
Click here to view a table showing the approximate annual cost of vitamin D therapy for children.
Vitamin D deficiency remains a public health problem in the UK and other developed countries. It can cause rickets and hypocalcaemic convulsions in children. It is most common in infants, toddlers and adolescents in 'at risk' ethnic minorities (e.g. Asian, African Caribbean and Middle Eastern), but breast-fed babies and children in other groups may also be at risk. Current Department of Health (DH) advice is that all infants and children under 5 years of age should take supplements containing at least 7?g (280 IU) of vitamin D daily (available free to those eligible under the Welfare Food Scheme). The DH also recommends that all pregnant and breast-feeding women in the UK should take supplements containing 10?g (400 IU) of vitamin D daily to prevent vitamin D deficiency in themselves and their babies. These recommendations appear reasonable on current knowledge about the extent of vitamin D deficiency and on the limited clinical trial evidence available. However, there is a pressing need for research to establish the effectiveness of this population-wide approach and the optimal dose to use in supplementation. Research is also needed into ways of preventing vitamin D deficiency in older children and adolescents. Oral therapy with ergocalciferol will treat the clinical manifestations of primary vitamin D deficiency, and addresses the underlying problem of deficiency.
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