Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement

The recommended level for serum 25‐hydroxyvitamin D (25(OH)D) in infants, children, adolescents and during pregnancy and lactation is ≥ 50 nmol/L. This level may need to be 10–20 nmol/L higher at the end of summer to maintain levels ≥ 50 nmol/L over winter and spring. Sunlight is the most important source of vitamin D. The US recommended dietary allowance for vitamin D is 600 IU daily in children aged over 12 months and during pregnancy and lactation, assuming minimal sun exposure. Risk factors for low vitamin D are: lack of skin exposure to sunlight, dark skin, southerly latitude, conditions affecting vitamin D metabolism and storage (including obesity) and, for infants, being born to a mother with low vitamin D and exclusive breastfeeding combined with at least one other risk factor. Targeted measurement of 25(OH)D levels is recommended for infants, children and adolescents with at least one risk factor for low vitamin D and for pregnant women with at least one risk factor for low vitamin D at the first antenatal visit. Vitamin D deficiency can be treated with daily low‐dose vitamin D supplements, although barriers to adherence have been identified. High‐dose intermittent vitamin D can be used in children and adolescents. Treatment should be paired with health education and advice about sensible sun exposure. Infants at risk of low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the first year of life. There is increasing evidence of an association between low vitamin D and a range of non‐bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.

ow vitamin D levels are a major public health concern across the lifespan. This position statement of the Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia accompanies a position statement on vitamin D and health in adults 1 and updates a 2006 position statement. 2 It is intended for primary care providers and specialists involved in the care of children and pregnant women, and is endorsed by the Australasian Paediatric Endocrine Group, Royal Australasian College of Physicians and Royal Australian and New Zealand College of Obstetricians and Gynaecologists. The consensus process is described in Box 1.

Physiology
A summary of vitamin D physiology is provided in the adult vitamin D position statement. 1 During pregnancy, alterations to vitamin D and calcium homoeostasis allow calcium transfer to the developing fetus. 3 Maternal intestinal calcium absorption is doubled, serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D) levels increase and parathyroid hormone (PTH) levels decrease to the lower end of the normal range in women with adequate calcium and vitamin D status. Maternal calcium absorption and fetal calcium accretion are maximal during the third trimester. Fetal vitamin D is derived from transplacental passage of maternal 25-hydroxyvitamin D (25(OH)D), with neonatal vitamin D status directly related to maternal vitamin D status. Cord blood 25(OH)D levels are about 65% of maternal levels, 4 hence neonates born to vitamin D deficient mothers will also be vitamin D deficient. 3 Further, premature infants have low vitamin D stores solely due to prematurity. 5 During lactation, maternal 1,25(OH) 2 D levels decrease and PTH levels remain low, but the combination of elevated parathyroid hormone-related protein produced by the lactating breast and low oestradiol levels stimulate maternal bone resorption and increased renal calcium reabsorption, enabling adequate calcium to be transferred to breastfeeding infants. 3 This results in transient loss of maternal bone mineral content, with recovery after weaning. Infants depend on their own synthesis, ingestion and metabolism of vitamin D, as there is little vitamin D in breast milk. 6

Sunlight
Sunlight exposure is the most important determinant of vitamin D levels, even in exclusively breastfed infants, 7 and is estimated to provide over 90% of vitamin D in humans. Skin synthesis of vitamin D occurs through the action of ultraviolet B (UVB) radiation in sunlight, and varies with skin colour, ultraviolet radiation (UVR) protection (eg, clothing, shade, sunscreen), time spent outside, latitude, season, time of day, amount of cloud cover, air pollution Vitamin D and health in pregnancy, infants, children and adolescents in Australia  • There is increasing evidence of an association between low vitamin D and a range of non-bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.
Summary levels and atmospheric ozone levels. 8 Sunscreens reduce transmission of ultraviolet A (UVA) and UVB radiation and have been reported to reduce skin synthesis of vitamin D, 9 but available evidence suggests that normal use of sunscreen does not result in low 25(OH)D levels in adults. 10 There are no data on cutaneous synthesis of vitamin D in Australian children, and no data on sunscreen use and vitamin D status in paediatric age groups. The skin pigment, melanin, acts as a natural sunscreen and effectively absorbs UVB photons. Melanin determines skin colour and regulates how much UVB reaches 7-dehydrocholesterol in the basal skin layers to generate production of cholecalciferol (vitamin D 3 ). Adults with dark skin require three to six times the amount of UVB compared with those with light skin to achieve similar vitamin D levels. 10 No such data for paediatric age groups are available.
Although sunlight exposure is critical for vitamin D synthesis, caution is required when balancing competing risks associated with UVR exposure, which include skin cancers and photoageing. 11 Given the variation of UVR across Australia and New Zealand, multiple factors affecting available UVB and variation in skin colour, it is not possible to make a single recommendation on the sunlight exposure needed to achieve adequate vitamin D levels to suit all Australian and New Zealand children and adolescents. A pragmatic approach is shown in Box 2.

Dietary sources
Breast milk, despite its other benefits, is a poor source of vitamin D, with a vitamin D content of 25 IU/L in mothers with normal 25(OH)D levels. 6 Infant formula in Australia is fortified with vitamin D to a concentration of 360-520 IU/L (9-13 g/L). Few foods naturally contain vitamin D (eg, some fatty fish, including salmon, herring and mackerel), although the vitamin D 2 content of mushrooms can be increased by UV irradiation and a small amount of vitamin D is added to table margarines. Diet is a poor source of vitamin D for most Australians. Dietary intake of vitamin D in children is unlikely to be higher than the current adult intake of 48-104 IU/day (1.2-2.6 g/day). 13 The US dietary reference intakes for vitamin D 14  Defining normal levels of vitamin D 25(OH)D, the major circulating form of vitamin D, is the index of vitamin D input, and is used to assess vitamin D status, although there is a degree of imprecision in current testing (around 10%) and laboratories offering 25(OH)D testing are required to participate in external quality assurance programs. 1 Defining a normal level of vitamin D presents challenges. One physiological definition of vitamin D sufficiency is the level of 25(OH)D at which PTH production and bone resorption are minimised and intestinal 2 Sunlight protection and exposure guidelines for people in Australia  Summer or UV index у 3 † 6-7 minutes exposure with arms (or equivalent area) exposed mid-morning or mid-afternoon most days of the week; avoid sunburn; full sun protection with sunscreen, hat, clothing, shade and sunglasses recommended 15-50 minutes exposure with arms (or equivalent area) exposed mid-morning or mid-afternoon most days of the week; avoid sunburn; intermittent sun exposure without sunscreen can be tolerated, but hat and sunglasses still recommended

Encourage physical activity outside
Winter 7-40 minutes exposure (depending on latitude) § with face, arms and hands exposed at lunchtime most days of the week; if UV index < 3, sun protection not required unless in alpine regions, outside for extended periods, or near highly reflective surfaces such as snow or water . The guidelines are based on articles on vitamin D dosing in paediatric age groups and during pregnancy and lactation, which were identified by a systematic search of the MEDLINE database (1946 to July 2011). Details of the search strategy and evidence tables are available on request. An initial draft was prepared for expert comment, the revised draft and evidence summaries were provided to ANZBMS members for feedback, and revisions were incorporated with consensus from the working group. Authors of the position statement on vitamin D and health in adults 1 were also consulted. Senior members of the ANZBMS and Australasian Paediatric Endocrine Group reviewed the final manuscript.
calcium absorption is stabilised, without adverse effects. 15 There are paediatric data which suggest that stabilisation of PTH occurs at 25(OH)D levels of 75-90 nmol/L, 16,17 and elevated PTH is seen at 25(OH)D levels below 40-60 nmol/ L. [18][19][20][21] There are difficulties with this approach, as the interplay between vitamin D levels and dietary calcium intake in maintaining PTH suppression and the effect of PTH suppression on bone development in the growing skeleton are unclear. Further, there are no data to indicate that vitamin D supplementation during childhood to achieve 25(OH)D levels > 50 nmol/L is associated with improved bone mineral density. 22,23 Emerging data from studies in adults examining the relationship between vitamin D status and other health outcomes suggest that 25(OH)D levels of > 75 nmol/L may be optimal. 1 Until there is stronger evidence, the recommended target level of 25(OH)D for infants, children and adolescents for optimal bone health remains у 50 nmol/L. This level may need to be 10-20 nmol/L higher at the end of summer to maintain levels у 50 nmol/L over winter and spring. Definitions of vitamin D status are shown in Box 4. Further data are required before recommendations for 25(OH)D levels in children can be based on non-calcaemic actions of vitamin D (Box 5, Box 6).
Defining normal vitamin D status during pregnancy is even more challenging, with the need to optimise both maternal and fetal health. No studies have addressed whether optimal 25(OH)D levels in pregnant women are different from optimal levels in non-pregnant women. 3 PTH levels tend to decrease during pregnancy, so PTH suppression may not be an appropriate measure of vitamin D status. Passage of maternal 25(OH)D to the fetus could, in theory, decrease maternal levels, although there is no evidence that clearly shows this. Alternatively, optimal 25(OH)D status during pregnancy could be defined as the level that ensures neonatal sufficiency, with cord blood levels being about 65% of maternal levels. 4 Until there is stronger evidence, the recommended adequate 25(OH)D levels for pregnant and lactating women remain the same as those for adults, at у 50 nmol/L; this level may need to be 10-20 nmol/L higher at the end of summer to maintain levels у 50 nmol/L over winter and spring. Some authors recommend a higher target level of 80 nmol/L during pregnancy, 35,49 and data emerging from randomised trials suggest improved pregnancy outcomes with 25(OH)D levels > 100 nmol/L. 48

Effects of low vitamin D
Biochemical changes in people with vitamin D deficiency are variable and depend on the degree of deficiency, dietary calcium intake, and presence and duration of secondary hyperparathyroidism. 50 Vitamin D deficiency is often asymptomatic, although symptoms may include non-specific bone pain (often reported in the lower limbs in children and the axial skeleton in adults), muscle pain, poor exercise tolerance and fatigue. Young children may present with delayed gross motor milestones and irritability, rather than overt pain. Vitamin D deficiency is associated with osseous and non-osseous clinical findings (Box 7). Rickets is the best recognised association; it represents a generalised disruption of skeletal mineralisation (osteomalacia), together with abnormal growth plate mineralisation and development. Rachitic changes at growth plates are only seen during linear growth, with peak incidence during the rapid growth phase of infancy. 50 Rickets is usually associated with 25(OH)D levels < 30 nmol/L, although it may occur at higher 25(OH)D levels in situations of low calcium intake. 51 Infants, children and adolescents with low vitamin D levels may present with symptoms of hypocalcaemia, including seizures (more common in infants younger than 6 months), stridor, muscle cramps, muscle weakness or carpopedal spasm.
A number of studies suggest an association between low vitamin D status during pregnancy and childhood and adverse health effects (Box 5), and several suggest that vitamin D supplementation during pregnancy or childhood is associated with improved health outcomes (Box 6). While these observational studies suggest early life vitamin D status may influence a range of non-bone health outcomes, there is a lack of data from robust randomised controlled trials of vitamin D supplementation. Vitamin D toxicity can be caused by excessive oral intake, through supplementation, but not by prolonged exposure of the skin to sunlight. Levels > 500 nmol/L are likely to be toxic and toxicity may occur below this level. ◆ vitamin D. Cultural practices that restrict UVR exposure, such as covering clothing or staying inside during the postpartum period, may increase the risk of low vitamin D for both the mother and infant. In Australia, a latitude gradient is seen in cohorts of pregnant women 28,52-54 and African refugee children, [55][56][57] with increased prevalence of vitamin D deficiency in the southern states. Obesity is associated with lower 25(OH)D levels after synthesis or ingestion of vitamin D in adults 58 and is associated with lower 25(OH)D levels in adolescents. 59 The effect of obesity on vitamin D status in children is not clear.

Infants, children and adolescents
Population surveys from Australia 28 18 and levels < 37.5 nmol/L in 31% of New Zealand children. 63 As expected, deficiency is more prevalent in high-risk groups, with 25(OH)D levels < 37.5 nmol/L in 59% of Pacific Islander children and 41% of Maori children in New Zealand, 63 and levels < 50 nmol/L in 61%-100% of predominantly African refugees in Victoria, New South Wales and South Australia [55][56][57]64 and 36% of Karen refugee children in Victoria. 65 In Australian studies of children with vitamin D deficiency rickets, this condition was associated with dark skin and maternal covering clothing, and 96%-98% of the children were migrants or born to migrant parents. [66][67][68] There are no published data on vitamin D status in Aboriginal children.

Pregnancy
Population surveys of pregnant women have found the prevalence of 25(OH)D levels < 50 nmol/L to be 10% in Queensland (during winter and spring), 54 25.7% in Sydney (during spring and summer), 53 25.8% in regional Victoria (during winter and summer), 52 35% in Canberra (across seasons), 53 and 48% in a multiethnic population in NSW (across seasons). 28 In women attending a gestational diabetes clinic in NSW, the prevalence of 25(OH)D levels < 50 nmol/L was 41%. 34 Australian and New Zealand studies suggest that 60%-80% of veiled and/or dark-skinned women attending antenatal clinics have vitamin D levels < 25 nmol/L, 28,69,70 identifying these groups as being at particularly high risk.

Infants, children and adolescents
There is inadequate evidence to recommend populationwide screening for vitamin D status in infants, children and adolescents in Australia and New Zealand. Those with one or more risk factors for low vitamin D (Box 8) should have their serum 25(OH)D, calcium, phosphate and alkaline phosphatase (ALP) levels measured; PTH should also be measured in those with symptoms or signs of deficiency, multiple risk factors or inadequate calcium intake. Infants, 6 Results of studies on non-bone health outcomes associated with vitamin D supplementation* Infants, children and adolescents with low 25(OH)D levels should be treated to restore their 25(OH)D levels to the normal range (Box 9). A pragmatic approach is required, balancing levels, season, risk factors and capacity for behavioural change. The cost and convenience of daily vitamin D supplements may be prohibitive in large families, especially when needed for several children for prolonged periods, and adherence is often a problem. Highdose intermittent vitamin D therapy (у 50,000 IU/dose) may facilitate adherence, although there is insufficient evidence to support the use of high-dose therapy in children younger than 3 months. It is also important to provide education about vitamin D, risk factors for low vitamin D, and sun protection and exposure (Box 2), and to encourage regular outside play and physical activity. Infants, children and adolescents should have adequate calcium intake (typically through cows milk or calciumfortified soy milk), and calcium supplements may be needed if dietary intake is poor.
Infants, children and adolescents with ongoing risk factors for low vitamin D require ongoing monitoring of vitamin D status with annual testing, as well as a longterm plan to maintain normal 25(OH)D levels and calcium status through behavioural change, where possible, and/or supplementation if behavioural change is inadequate. It may not be possible for people with risk factors (especially multiple risk factors) to maintain their 25(OH)D levels during winter in the southern parts of Australia and in New Zealand. Recently arrived migrant children at risk of low vitamin D may have normal 25(OH)D levels on initial health screening, so testing should be repeated at the end of their first winter in Australia or New Zealand. Some children with significant ongoing risk factors (eg, dark skin and covering clothing) may require high-dose vitamin D supplementation more than once a year. Levels at the start and end of winter can be useful to guide dosing frequency. Children who do not respond to high-dose vitamin D supplementation require specialist review.
Exclusively breastfed infants with at least one other risk factor for low vitamin D should be supplemented with 400 IU vitamin D 3 daily for at least the first year of life and adherence should be monitored, particularly after the first months of supplementation. Infants who are fed formula only should receive adequate vitamin D from this source. Consider checking 25(OH)D levels or adding daily vitamin D supplements in infants with other risk factors for low vitamin D who are fed a mixture of breast milk and formula, or who have appropriately reduced their formula intake after the introduction of solids.

Pregnancy and lactation
Pregnant women with one or more risk factors for low vitamin D (Box 8) should have their serum 25(OH)D levels measured at their first antenatal visit. Although there is a case for routine screening of all pregnant women in Australian and New Zealand (based on the high prevalence of vitamin D deficiency in pregnancy and potential for adverse effects on maternal and fetal health), there is geographic variation in the prevalence of vitamin D deficiency and insufficient evidence on the impact of vitamin D supplementation during pregnancy on maternal and child health to support a stronger recommendation for universal screening. While the cost of measuring 25(OH)D levels is significant, pregnant women undergo screening for conditions of much lower prevalence, and there are no data or cost-effectiveness studies on alternative management strategies (such as supplementation without testing during winter).
Pregnant women found to have low 25(OH)D levels should be treated to achieve 25(OH)D levels у 50 nmol/L, although data on the optimal dosing regimen are lacking. Vitamin D doses < 1000 IU/daily are inadequate to ensure 25(OH)D levels > 50 nmol/L during pregnancy. 71,72 Pregnant women with 25(OH)D levels < 50 nmol/L should be started on 1000 IU vitamin D 3 daily, and women with levels < 30 nmol/L should be started on 2000 IU vitamin D 3 daily. Testing should be repeated at 28 weeks' gestation; in women whose 25(OH)D levels have corrected to > 50 nmol/L, a minimum of 600 IU vitamin D 3 daily should be given throughout the remainder of pregnancy. 14 Given the supplements available in Australia, 1000 IU daily may be more practical. Doses of 4000 IU vitamin D 3 daily during pregnancy from 12 to 16 weeks gestation until birth appear to be safe. 48,73 There is inadequate evidence to support the use of intermittent high-dose vitamin D during pregnancy.
A small study of vitamin D supplementation during lactation found 1000 IU daily for 6 weeks was inadequate to increase 25(OH)D levels to > 50 nmol/L in women with low baseline 25(OH)D levels. 74 Small trials in breastfeeding women suggest that 2000 IU vitamin D daily to the mother can raise low infant levels to the sufficient range (in a cohort of women with 25(OH)D levels > 50 nmol/L) 5,75,76 and can raise both maternal and infant levels (in a cohort of women with low 25(OH)D levels). 77 At present, given the lack of evidence, a pragmatic approach is to achieve adequate 25(OH)D levels during pregnancy, give 1000 IU vitamin D 3 daily during lactation to women with ongoing risk factors for low vitamin D, and give 400 IU vitamin D 3 daily to exclusively breastfed infants with other risk factors for low vitamin D. Breastfeeding women with low 25(OH)D levels should be started on 2000 IU vitamin D 3 8 Risk factors for low vitamin D • Lack of skin exposure to ultraviolet B radiation from sunlight (due to lifestyle factors, chronic illness or hospitalisation, complex disability, covering clothing for religious or cultural reasons or southerly latitude) • Dark skin (Fitzpatrick types V and VI)* • Medical conditions or medications affecting vitamin D metabolism and storage (obesity, end-stage liver disease, renal disease, drugs that increase vitamin D degradation such as rifampicin and anticonvulsants, or fat malabsorption [eg, in cystic fibrosis, coeliac disease and inflammatory bowel disease]) • In infants, maternal vitamin D deficiency and exclusive breastfeeding combined with at least one other risk factor * Dark skin is less likely to be a significant risk factor in people with regular sun exposure in climates with high incident ultraviolet radiation (eg, northern parts of Australia), but there is a lack of prevalence data for these populations. ◆ daily. There is inadequate evidence to support the use of high-dose vitamin D during lactation. Treatment of low vitamin D during pregnancy and lactation should be paired with health education and advice on sensible sun exposure and regular outside physical activity.