Title: What dose of vitamin D is required to achieve target serum 25-hydroxyvitamin D levels in children?
Funder: Health Education England

Abstract: Background The Department of Health has identified vitamin D deficiency as a key concern for public health. Data suggests that 8-24% of children may have vitamin D deficiency, and a prevalence of 40-90% has been reported among children with chronic kidney disease (CKD), cystic fibrosis (CF) and type 1 diabetes (T1DM). While vitamin D supplementation is an effective means of improving vitamin D status (as measured by serum 25-hydroxyvitamin D [25(OH)D] levels), the evidence underpinning vitamin D dosing regimens is weak. Current vitamin D supplementation strategies include different treatment and maintenance schedules using doses ranging from 200 IU to 10,000 IU/day, leading to as much as 175% difference in dose for children in the same age range. The lack of robust evidence to support vitamin D prescribing practice means that children are at risk of under- and overdosing with potential consequences of therapeutic failure or vitamin D toxicity, respectively. Further, concerns over vitamin D toxicity is increasing, but the 25(OH)D level above which there is an increased risk of adverse effects is uncertain. These knowledge gaps have been highlighted by different scientific committees, including the UK Scientific Advisory Committee on Nutrition, with a call for further research in these areas. Supported by our patient and public involvement group, this project will provide an evidence base for safe and effective vitamin D prescribing in children. Aim To identify the dose of vitamin D required to achieve target 25(OH)D levels in children. ObjectivesTo investigate trends in vitamin D prescribing practices and 25(OH)D level monitoring in children in primary care.To systematically identify and describe the risk factors, clinical features and management of children with 25(OH)D level >250 nmol/l.To characterize the effect of different colecalciferol dosing regimens on steady-state 25(OH)D levels in 4 cohorts (healthy children with vitamin D deficiency, and children with CKD, CF and T1DM), and to investigate the extent of inter-individual variability.Plan of investigation This project will consists of 2 retrospective and 1 prospective cohort studies: Children Three London laboratories providing regional service for vitamin D testing will act as participant identification centres and children 250 nmol/l between 2010 and 2015 will be identified via laboratory databases. Using a criterion-based review method, hospital and GP medical records of these individuals will be reviewed and information on mean 25(OH)D levels, vitamin D prescribing patterns, clinical features and management strategies for hypervitaminosis D will be systematically collected and analysed.200 children Expected benefits This project will provide direct benefits to children requiring vitamin D supplementation in ensuring they achieve their target 25(OH)D levels. This project will also provide the evidence base for scientific committees in developing vitamin D guidelines to facilitate safe and effective clinical practice, as well as improving cost-effectiveness in the NHS.

Lay abstract: Vitamin D is important to keep our bones and teeth healthy. It also helps our bodies to absorb calcium. Without enough vitamin D children are at risk of developing rickets, which causes weak bones that can fracture easily. In addition, recent evidence suggests that vitamin D may also help in the prevention of many other diseases and adequate levels of vitamin D are associated with other health benefits such as supporting heart function, and the immune system. There has been concern that rickets may be re-emerging among children in the UK. Data suggests that up to 16% of children may have low vitamin D status and the prevalence is even higher in children with chronic kidney disease, cystic fibrosis and diabetes. For children who have or are at risk of vitamin D deficiency, vitamin D supplements can help to improve or maintain their vitamin D levels. However, the correct dose of vitamin D to use in children is unclear. There is a lack of agreement among doctors and guideline committees, and the many different preparations on the market, with doses ranging from 400 IU/day to 40,000 IU/week, adds further confusion to the problem. With wide variations in doses used, some children developed very high blood vitamin D levels while others did not achieve target levels. We are not sure why children respond to vitamin D supplementation differently. Some recent evidence suggests that certain groups of children, such as those with chronic kidney disease and cystic fibrosis, may need different amounts of vitamin D supplements to achieve the target vitamin D level. An important point to note is that if doses are not high enough some children will remain vitamin D deficient, however, too much vitamin D will increase the risk of toxicity. Vitamin toxicity can lead to a build-up of calcium in the blood, which can cause poor appetite, vomiting, weakness, confusion, dehydration and kidney problems. However, reports on vitamin D toxicity are mainly cases of extremely high vitamin D levels, while some data suggests that subtle signs of vitamin D toxicity may already be present at lower levels. Currently, we do not know how many children are exposed to vitamin D levels in this lower range, and whether these children are at an increased risk of side effects. CHAR(13) + CHAR(10)The Department of Health and the Chief Medical Officers have identified vitamin D deficiency as a key area of interest and concern for public health. To determine whether our current prescribing strategies are cost-effective, we aim to find out how much vitamin D is prescribed by doctors for children in everyday practice and the vitamin D levels achieved in these children using data from a UK primary care electronic medical record database. In our second study, we will identify, from laboratory databases, children with vitamin D level >250 nmol/l and to look in details at their risk factors, clinical features and how they were managed, to help us to begin to understand about vitamin D toxicity. In our third study, we will investigate how children respond to vitamin D supplements by measuring their blood vitamin D levels at 3-monthly intervals for 6 months, and to identify whether there are any factors which may affect their individual responses. We will recruit a total of 200 children on vitamin D supplements, including children with chronic kidney disease, cystic fibrosis, diabetes and those who are otherwise healthy but have vitamin D deficiency. The results will inform our understanding of what dose of vitamin D is required to achieve target vitamin D levels in different groups of children, and hence lead to more rational use of vitamin D supplements in clinical practice, providing direct benefits to children requiring vitamin D supplements while improving cost-effectiveness in the NHS.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE