Vitamin deficiency D 2.0 – Jan 2020

Vitamin D deficiency 2.0: an update on the current status worldwide

European Journal of Clinical Nutrition (2020)
Karin Amrein, Mario Scherkl, Magdalena Hoffmann, Stefan Neuwersch-Sommeregger, Markus Köstenberger, Adelina Tmava Berisha, Gennaro Martucci, Stefan Pilz & Oliver Malle

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Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a 25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea and is most likely efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important, inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

Portion of Table 1: Risk groups for vitamin D deficiency including high-risk medications.
Chronic disease, particularly kidney, heart, and liver failure, in particular, transplant candidates and recipients
Gastrointestinal diseases including Crohn’s disease, inflammatory bowel disease, and malabsorption syndromes
Granuloma-forming disorders including sarcoidosis and tuberculosis
Hospitalized individuals, especially ICU patients
Hyper- and hypoparathyroidism
Obese children and adults, particularly after bariatric surgery
Older adults with a history of falls and/or fractures, osteoporosis
Oncologic patients
Pregnant and lactating women, preparing for pregnancy
Reduced UV-B exposure or effectiveness
  (shift workers, immobilized patients, chronic neuropsychiatric disease,
   dressing habits, burn and skin cancer survivors, and nonwhite persons)
Respiratory diseases including COPD, asthma, and cystic fibrosis

References

Many are in VitaminDWiki - just copy a portion of the title and paste "PORTION OF TITLE" in the search bar - with quotes

• 1. Crowe FL, Jolly K, MacArthur C, Manaseki-Holland S, Gittoes N, Hewison M, et al. Trends in the incidence of testing for vitamin D deficiency in primary care in the UK: a retrospective analysis of The Health Improvement Network (THIN), 2005–2015. BMJ Open. 2019;9:e028355. https://doi.org/10.1136/bmjopen-2018-028355
• 2. Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016;103:1033–44. https://doi.org/10.3945/ajcn.115.120873
• 3. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673. https://doi.org/10.1136/bmj.l4673
• 4. Amrein K, Martucci G, McNally JD. When not to use meta-analysis: analysing the meta-analyses on vitamin D in critical care. Clin Nutr. 2017;36:1729–30. https://doi.org/10.1016/j.clnu.2017.08.009.
• 5. Bouillon R, Carmeliet G, Lieben L, Watanabe M, Perino A, Auwerx J. et al. Vitamin D and energy homeostasis: of mice and men. Nat Rev Endocrinol. 2014;10:79–87. https://doi.org/10.1038/nrendo.2013.226.
• 6. Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D supplementation and prevention of type 2 diabetes. N. Engl J Med. 2019;381:520–30. https://doi.org/10.1056/NEJMoa1900906
• 7. Manson JE, Cook NR, Lee I-M, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2018;380:33–44. https://doi.org/10.1056/NEJMoa1809944
• 8. Grant WB, Boucher BJ. Why secondary analyses in vitamin d clinical trials are important and how to improve vitamin d clinical trial outcome analyses—a comment on “Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460”. Nutrients. 2019;11:2182.
• 9. Martucci G, Tuzzolino F, Arcadipane A, Pieber TR, Schnedl C, Urbanic Purkart T. et al. The effect of high-dose cholecalciferol on bioavailable vitamin D levels in critically ill patients: a post hoc analysis of the VITdAL-ICU trial. Intensiv Care Med. 2017;43:1732–4. https://doi.org/10.1007/s00134-017-4846-5.
• 10. De Pascale G, Quraishi SA. Vitamin D status in critically ill patients: the evidence is now bioavailable!. Crit Care. 2014;18:449. https://doi.org/10.1186/cc13975.
• 11. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011.
• 12. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1911–30. https://doi.org/10.1210/jc.2011-0385
• 13. EFSA Panel on Dietetic Products N, Allergies. Dietary reference values for vitamin D. EFSA J. 2016;14:e04547. https://doi.org/10.2903/j.efsa.2016.4547
• 14. Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, Fewtrell M, et al. Vitamin D in the healthy european paediatric population. J Pediatr Gastroenterol Nutr. 2013;56:692–701. https://doi.org/10.1097/MPG.0b013e31828f3c05
• 15. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016;101:394–415. https://doi.org/10.1210/jc.2015-2175
• 16. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. https://doi.org/10.1136/bmj.i6583
• 17. Cashman KD. Vitamin D deficiency: defining, prevalence, causes, and strategies of addressing. Calcif Tissue Int. 2019. https://doi.org/10.1007/s00223-019-00559-4
• 18. Schleicher RL, Sternberg MR, Looker AC, Yetley EA, Lacher DA, Sempos CT, et al. National estimates of serum total 25-Hydroxyvitamin D and metabolite concentrations measured by liquid chromatography–Tandem mass spectrometry in the US population during 2007–2010. J Nutr. 2016;146:1051–61. https://doi.org/10.3945/jn.115.227728
• 19. Sarafin K, Durazo-Arvizu R, Tian L, Phinney KW, Tai S, Camara JE, et al. Standardizing 25-hydroxyvitamin D values from the Canadian Health Measures Survey. Am J Clin Nutr. 2015;102:1044–50. https://doi.org/10.3945/ajcn.114.103689
• 20. Courbebaisse M, Alberti C, Colas S, Prie D, Souberbielle JC, Treluyer JM. et al. Vitamin D supplementation in renAL transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI in renal transplant recipients: study protocol for a double-blind, randomized, controlled trial. Trials. 2014;15:430. https://doi.org/10.1186/1745-6215-15-430.
• 21. Vos R, Ruttens D, Verleden SE, Vandermeulen E, Bellon H, Van Herck A, et al. High-dose vitamin D after lung transplantation: a randomized trial. J Heart Lung Transplant. 2017;36:897–905. https://doi.org/10.1016/j.healun.2017.03.008.
• 22. Zhou Q, Li L, Chen Y, Zhang J, Zhong L, Peng Z, et al. Vitamin D supplementation could reduce the risk of acute cellular rejection and infection in vitamin D deficient liver allograft recipients. Int Immunopharmacol. 2019;75:105811 https://doi.org/10.1016/j.intimp.2019.105811.
• 23. Cariolou M, Cupp MA. Importance of vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis. Crit care (Lond, Engl). 2019;9:e027666. 10.1136/bmjopen-2018-027666.
• 24. Lee P, Nair P, Eisman JA, Center JR. Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality? Intensive care Med. 2009;35:2028–32. https://doi.org/10.1007/s00134-009-1642-x.
• 25. Martucci G, McNally D, Parekh D, Zajic P, Tuzzolino F, Arcadipane A. et al. Trying identify who may benefit most future Vitam D intervention trials: a post hoc Anal VITDAL-ICU study excluding early deaths. Crit Care. 2019;23:200. https://doi.org/10.1186/s13054-019-2472-z.
• 26. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual High-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815–22. https://doi.org/10.1001/jama.2010.594
• 27. Amrein K, Papinutti A, Mathew E, Vila G, Parekh D. Vitamin D and critical illness: what endocrinology can learn from intensive care and vice versa. Endocr Connect. 2018;7:R304–R315. https://doi.org/10.1530/EC-18-0184
• 28. Hollis BW, Wagner CL. The role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013;98:4619–28. https://doi.org/10.1210/jc.2013-2653
• 29. Roth DE, Martz P, Yeo R, Prosser C, Bell M, Jones AB. Are national vitamin D guidelines sufficient to maintain adequate blood levels in children? Can J Public Health. 2005;96:443–9. e-pub ahead of print 2005/12/15.
• 30. Rucker D, Allan JA, Fick GH, Hanley DA. Vitamin D insufficiency in a population of healthy western Canadians. CMAJ. 2002;166:1517–24.
• 31. Vieth R, Cole DE, Hawker GA, Trang HM, Rubin LA. Winter time vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it. Eur J Clin Nutr. 2001;55:1091–7. https://doi.org/10.1038/sj.ejcn.1601275.
• 32. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204–10. https://doi.org/10.1093/ajcn/77.1.204.
• 33. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6–18. https://doi.org/10.1093/ajcn/85.1.6
• 34. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15:1113–8. https://doi.org/10.1359/jbmr.2000.15.6.1113
• 35. Medicine Io. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. The Washington, DC: National Academies Press; 1997.
• 36. Aloia JF, Patel M, DiMaano R, Li-Ng M, Talwar SA, Mikhail M, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008;87:1952–8. https://doi.org/10.1093/ajcn/87.6.1952
• 37. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the institute of medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53–58. https://doi.org/10.1210/jc.2010-2704
• 38. EFSA Panel on Dietetic Products N, Allergies. Scientific opinion on the tolerable upper intake level of vitamin D. EFSA J. 2012;10:2813. https://doi.org/10.2903/j.efsa.2012.2813
• 39. Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD, Cole DEC, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ. 2010;182:E610–E618. https://doi.org/10.1503/cmaj.080663. e-pub ahead of print 2010/07/12
• 40. Pietras SM, Obayan BK, Cai MH, Holick MF. Vitamin D2 treatment for vitamin D deficiency and insufficiency for up to 6 Years. JAMA Intern Med. 2009;169:1806–18. https://doi.org/10.1001/archinternmed.2009.361
• 41. McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, et al. Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLOS ONE. 2018;13:e0199265. https://doi.org/10.1371/journal.pone.0199265
• 42. Madden JM, Murphy L, Zgaga L, Bennett K. De novo vitamin D supplement use post-diagnosis is associated with breast cancer survival. Breast Cancer Res Treat. 2018;172:179–90. https://doi.org/10.1007/s10549-018-4896-6
• 43. Mirhosseini N, Vatanparast H, Kimball SM. The association between Serum 25(OH)D status and blood pressure in participants of a community-based program taking vitamin D supplements. Nutrients. 2017;9:1244.
• 44. Rusińska A, Płudowski P, Walczak M, Borszewska-Kornacka MK, Bossowski A, Chlebna-Sokół D, et al. Vitamin D supplementation guidelines for general population and groups at risk of vitamin D deficiency in poland—recommendations of the polish society of pediatric endocrinology and diabetes and the expert panel with participation of national specialist consultants and representatives of scientific societies. Front Endocrinol. 2018;9. https://doi.org/10.3389/fendo.2018.00246
• 45.Dudenkov DV, Yawn BP, Oberhelman SS, Fischer PR, Singh RJ, Cha SS, et al. Changing incidence of serum 25-Hydroxyvitamin D values above 50 ng/mL: a 10-year population-based study. Mayo Clin Proc. 2015;90:577–86. https://doi.org/10.1016/j.mayocp.2015.02.012
• 46. Holick MF. Vitamin D is not as toxic as was once thought: a historical and an up-to-date perspective. Mayo Clin Proc. 2015;90:561–4. https://doi.org/10.1016/j.mayocp.2015.03.015
• 47. Tebben PJ, Singh RJ, Kumar R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr Rev. 2016;37:521–47. https://doi.org/10.1210/er.2016-1070
• 48. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88:582S–586S. https://doi.org/10.1093/ajcn/88.2.582S
• 49. Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, et al. Hypervitaminosis D associated with drinking milk. N. Engl J Med. 1992;326:1173–7. https://doi.org/10.1056/nejm199204303261801
• 50. Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, et al. The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr. 2017;105:1512–20. https://doi.org/10.3945/ajcn.116.151415
• 51.Madsen KH, Rasmussen LB, Andersen R, Mølgaard C, Jakobsen J, Bjerrum PJ, et al. Randomized controlled trial of the effects of vitamin D–fortified milk and bread on serum 25-hydroxyvitamin D concentrations in families in Denmark during winter: the VitmaD study. Am J Clin Nutr. 2013;98:374–82. https://doi.org/10.3945/ajcn.113.059469
• 52. Hayes A, Duffy S, O’Grady M, Jakobsen J, Galvin K, Teahan-Dillon J, et al. Vitamin D–enhanced eggs are protective of wintertime serum 25-hydroxyvitamin D in a randomized controlled trial of adults. Am J Clin Nutr. 2016;104:629–37. https://doi.org/10.3945/ajcn.116.132530
• 53. Manson JE, Cook NR, Lee I-M, Christen W, Bassuk SS, Mora S, et al. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl J Med. 2018;380:23–32. https://doi.org/10.1056/NEJMoa1811403
• 54. Scragg RKR. Overview of results from the Vitamin D assessment (ViDA) study. J Endocrinol Invest. 2019. https://doi.org/10.1007/s40618-019-01056-z
• 55. Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: a randomized clinical trial. JAMA Cardiol. 2017;2:608–16. https://doi.org/10.1001/jamacardio.2017.0175
• 56. Bischoff-Ferrari H, Vitamin D3—Omega3—home exercise—healthy ageing and longevity trial (DO-HEALTH). ClinicalTrials.gov; 2012. https://clinicaltrials.gov/ct2/show/NCT01745263.
• 57. Tuomainen T-P, Finnish vitamin D trial (FIND). ClinicalTrials.gov; 2011. https://clinicaltrials.gov/ct2/show/NCT01463813.
• 58. London School of Hygiene & Tropical Medicine. Vitamin D and longevity (VIDAL) trial: randomised feasibility study. ISRCTN Registry; 2011. https://doi.org/10.1186/ISRCTN46328341.
• 59. Schoenmakers I, Francis RM, McColl E, Chadwick T, Goldberg GR, Harle C, et al. Vitamin D supplementation in older people (VDOP): Study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3. Trials. 2013;14:299. https://doi.org/10.1186/1745-6215-14-299
• 60. Ng K, Nimeiri HS, McCleary NJ, Abrams TA, Yurgelun MB, Cleary JM, et al. Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: the SUNSHINE randomized clinical trial. JAMA. 2019;321:1370–9. https://doi.org/10.1001/jama.2019.2402
• 61. Rosendahl J, Valkama S, Holmlund-Suila E, Enlund-Cerullo M, Hauta-alus H, Helve O, et al. Effect of higher vs standard dosage of vitamin D3 supplementation on bone strength and infection in healthy infants: a randomized clinical trial. JAMA Pediatrics. 2018;172:646–54. https://doi.org/10.1001/jamapediatrics.2018.0602
• 62. Sluyter JD, Camargo CA Jr., Stewart AW, Waayer D, Lawes CMM, Toop L, et al. Effect of monthly, high-dose, long-term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy. J Am Heart Assoc. 2017;6:e006802. https://doi.org/10.1161/JAHA.117.006802
• 63. Thompson BT. Vitamin D to improve outcomes by leveraging early treatment (VIOLET). ClinicalTrials.gov; 2017. https://clinicaltrials.gov/ct2/show/NCT03096314
• 64. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48–54. https://doi.org/10.1111/nure.12090
• 65. Brenner H, Jansen L, Saum K-U, Holleczek B, Schöttker B. Vitamin D supplementation trials aimed at reducing mortality have much higher power when focusing on people with low serum 25-hydroxyvitamin D concentrations. J Nutr. 2017;147:1325–33. https://doi.org/10.3945/jn.117.250191
• 66. Avenell A, Mak JCS, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post‐menopausal women and older men. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD000227.pub4
• 67. Bjelakovic G, Nikolova D, Bjelakovic M, Gluud C. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev. 2015. https://doi.org/10.1002/14651858.CD011564
• 68. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—A review of recent evidence. Autoimmun Rev. 2013;12:976–89. https://doi.org/10.1016/j.autrev.2013.02.004
• 69. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Datab Syst Rev. 2014. https://doi.org/10.1002/14651858.CD007470.pub3
• 70. Gaksch M, Jorde R, Grimnes G, Joakimsen R, Schirmer H, Wilsgaard T, et al. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PLOS ONE. 2017;12:e0170791. https://doi.org/10.1371/journal.pone.0170791
• 71. Aspelund T, Grübler MR, Smith AV, Gudmundsson EF, Keppel M, Cotch MF, et al. Effect of genetically low 25-hydroxyvitamin D on mortality risk: mendelian randomization analysis in 3 large european cohorts. Nutrients. 2019;11:74. https://doi.org/10.3390/nu11010074
• 72. Berlanga-Taylor AJ, Leclair TR, Zakai N, Bunn JY, Gianni M, Heyland DK, et al. Vitamin D supplementation in mechanically ventilated patients in the medical intensive care unit. BMJ Open. 2019. https://doi.org/10.1136/bmjopen-2018-02766610.1002/jpen.
• 73. Quraishi SA, De Pascale G, Needleman JS, Nakazawa H, Kaneki M, Bajwa EK. et al. Effect of cholecalciferol supplementation on vitamin D status and cathelicidin levels in sepsis: a randomized, placebo-controlled trial. Crit Care Med. 2015;43:1928–37. https://doi.org/10.1111/ene.1278810.1097/ccm.0000000000001148.
• 74. Palacios C, Trak-Fellermeier MA, Martinez RX, Lopez-Perez L, Lips P, Salisi JA. et al. Regimens of vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2019;10:Cd013446 https://doi.org/10.1002/14651858.cd013446. e-pub ahead of print 2019/10/04.
• 75. Palacios C, Kostiuk LK, Pena-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2019;7:Cd008873 https://doi.org/10.1002/14651858.CD008873.pub4. e-pub ahead of print 2019/07/28.
• 76. Holick MF. A call to action: pregnant women in-deed require vitamin D supplementation for better health outcomes. J Clin Endocrinol Metab. 2018;104:13–15. https://doi.org/10.1210/jc.2018-01108
• 77. Mithal A, Wahl DA, Bonjour J-P, Burckhardt P, Dawson-Hughes B, Eisman JA, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807–20. https://doi.org/10.1007/s00198-009-0954-6
• 78. Fogacci S, Fogacci F, Banach M, Michos ED, Hernandez AV, Lip GYH, et al. Vitamin D supplementation and incident preeclampsia: a systematic review and meta-analysis of randomized clinical trials. Clin Nutr. 2019. https://doi.org/10.1016/j.clnu.2019.08.015
• 79. Rodrigues MRK, Lima SAM, Mazeto GMFDSS, Calderon IMP, Magalhães CG, Ferraz GAR. et al. Mazeto GMFdS, Calderon IMP, Magalhães CG, Ferraz GAR et al. Efficacy of vitamin D supplementation in gestational diabetes mellitus: systematic review and meta-analysis of randomized trials. PLOS ONE. 2019;14:e0213006. https://doi.org/10.1371/journal.pone.0213006.
• 80. Akbari S, Khodadadi B, Ahmadi SAY, Abbaszadeh S, Shahsavar F. Association of vitamin D level and vitamin D deficiency with risk of preeclampsia: a systematic review and updated meta-analysis. Taiwan J Obstet Gynecol. 2018;57:241–7. https://doi.org/10.1016/j.tjog.2018.02.013
• 81. McDonnell SL, Baggerly KA, Baggerly CA, Aliano JL, French CB, Baggerly LL, et al. Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. PloS ONE. 2017;12:e0180483–e0180483. https://doi.org/10.1371/journal.pone.0180483
• 82. Wagner CL, Baggerly C, McDonnell S, Baggerly KA, French CB, Baggerly L. et al. Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009–211 rates. J Steroid Biochem Mol Biol. 2016;155:245–51. https://doi.org/10.1016/j.jsbmb.2015.10.022.
• 83. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Min Res. 2011;26:2341–57. https://doi.org/10.1002/jbmr.463
• 84. Rostami M, Tehrani FR, Simbar M, Bidhendi Yarandi R, Minooee S, Hollis BW, et al. Effectiveness of prenatal vitamin D deficiency screening and treatment program: a stratified randomized field trial. J Clin Endocrinol Metab. 2018;103:2936–48. https://doi.org/10.1210/jc.2018-00109
• 85. Hossein-nezhad A, Holick MF. Optimize dietary intake of vitamin D: an epigenetic perspective. Curr Opin Clin Nutr Metab Care. 2012;15:567–79. https://doi.org/10.1097/MCO.0b013e3283594978
• 86. Novakovic B, Sibson M, Ng HK, Manuelpillai U, Rakyan V, Down T, et al. Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaterial interface. J Biol Chem. 2009;284:14838–48. https://doi.org/10.1074/jbc.M809542200
• 87. McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, et al. Serum 25-hydroxyvitamin D concentrations ≥40 g/ml are associated with >65% lower cancer risk: pooled analysis of randomized trial and prospective cohort study. PLOS ONE. 2016;11:e0152441 https://doi.org/10.1371/journal.pone.0152441
• 88. Colston K, Colston MJ, Feldman D. 1,25-Dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology. 1981;108:1083–6. https://doi.org/10.1210/endo-108-3-1083
• 89. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227–31. https://doi.org/10.1093/ije/9.3.227
• 90. Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer. 2014;111:976. https://doi.org/10.1038/bjc.2014.294
• 91. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, et al. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD007469.pub2
• 92. Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317:1234–43. https://doi.org/10.1001/jama.2017.2115
• 93. Chatterjee R, Erban JK, Fuss P, Dolor R, LeBlanc E, Staten M, et al. Vitamin D supplementation for prevention of cancer: the D2d cancer outcomes (D2dCA) study. Contemp Clin Trials. 2019;81:62–70. https://doi.org/10.1016/j.cct.2019.04.015
• 94. Greer RM, Portelli SL, Hung BS-M, Cleghorn GJ, McMahon SK, Batch JA, et al. Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes. Pediatr Diabetes. 2013;14:31–41. https://doi.org/10.1111/j.1399-5448.2012.00890.x
• 95. Daga RA, Laway BA, Shah ZA, Mir SA, Kotwal SK, Zargar AH. High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in north India. Arquivos Brasileiros de Endocrinologia Metabologia. 2012;56:423–8.
• 96. Federico G, Genoni A, Puggioni A, Saba A, Gallo D, Randazzo E, et al. Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents. Pediatr Diabetes. 2018;19:923–9. https://doi.org/10.1111/pedi.12673
• 97. Rasoul MA, Al-Mahdi M, Al-Kandari H, Dhaunsi GS, Haider MZ. Low serum vitamin D status is associated with high prevalence and early onset of type-1 diabetes mellitus in Kuwaiti children. BMC Pediatr. 2016;16:95–95. https://doi.org/10.1186/s12887-016-0629-3
• 98. Sørensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC. Maternal serum levels of 25-hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes. 2012;61:175. https://doi.org/10.2337/db11-0875
• 99. Jacobsen R, Moldovan M, Vaag AA, Hypponen E, Heitmann BL. Vitamin D fortification and seasonality of birth in type 1 diabetic cases: D-tect study. J Devel Orig Health Dis. 2016;7:114–9. https://doi.org/10.1017/S2040174415007849. e-pub ahead of print 2015/10/27.
• 100. Dong J-Y, Zhang W, Chen JJ, Zhang Z-L, Han S-F, Qin L-Q. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients. 2013;5:3551–62.
• 101. Stene LC, Joner G, Group NCDS. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr. 2003;78:1128–34. https://doi.org/10.1093/ajcn/78.6.1128
• 102. Raab J, Giannopoulou EZ, Schneider S, Warncke K, Krasmann M, Winkler C, et al. Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression. Diabetologia. 2014;57:902–8. https://doi.org/10.1007/s00125-014-3181-4
• 103. Mäkinen M, Mykkänen J, Koskinen M, Simell V, Veijola R, Hyöty H, et al. Serum 25-hydroxyvitamin D concentrations in children progressing to autoimmunity and clinical type 1 diabetes. J Clin Endocrinol Metab. 2016;101:723–9. https://doi.org/10.1210/jc.2015-3504
• 104. Simpson M, Brady H, Yin X, Seifert J, Barriga K, Hoffman M, et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia. 2011;54:2779. https://doi.org/10.1007/s00125-011-2278-2
• 105.Rak K, Bronkowska M. Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of type 1 diabetes mellitus—a narrative review. Molecules. 2018;24:53.
• 106.Thrailkill KM, Jo C-H, Cockrell GE, Moreau CS, Fowlkes JL. Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? J Clin Endocrinol Metab. 2011;96:142–9. https://doi.org/10.1210/jc.2010-0980
• 107.Kayaniyil S, Vieth R, Retnakaran R, Knight JA, Qi Y, Gerstein HC, et al. Association of vitamin d with insulin resistance and β-Cell dysfunction in subjects at risk for type 2 diabetes. Diabetes Care. 2010;33:1379–81. https://doi.org/10.2337/dc09-2321
• 108.Kawahara T, Suzuki G, Inazu T, Mizuno S, Kasagi F, Okada Y, et al. Rationale and design of Diabetes Prevention with active Vitamin D (DPVD): a randomised, double-blind, placebo-controlled study. BMJ Open. 2016;6:e011183. https://doi.org/10.1136/bmjopen-2016-011183
• 109.Galior K, Grebe S, Singh R. Development of vitamin D toxicity from overcorrection of vitamin D deficiency: a review of case reports. Nutrients. 2018;10:953.
• 110.Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, et al. Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia. N Engl J Med. 2011;365:410–21. https://doi.org/10.1056/NEJMoa1103864
• 111. National Heart, Lung, and Blood Institute, PETAL Clinical Trials Network, Ginde A, Brower R, et al. Early high-dose vitamin D3 for critically Ill, vitamin D–deficient patients. N Engl J Med. 2019. https://doi.org/10.1056/NEJMoa1911124
• 112. Amrein K, Schnedl C, Holl A, Riedl R, Christopher KB, Pachler C, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically Ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312:1520–30. https://doi.org/10.1001/jama.2014.13204