MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group

Trials

Cyrus Cooper⁵  Ann Prentice⁶  Inez Schoenmakers⁶  Saurabh V Gandhi¹  Robert Fraser¹  Aris T Papageorghiou²  Stephen Kennedy²  Nicholas Bishop³  Kassim Javaid⁴  Nicholas C Harvey⁵ 

[1] Sheffield Hospitals NHS Trust (University of Sheffield), Sheffield, UK;Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK;Academic Unit of Child Health, Sheffield Children's Hospital, University of Sheffield, Sheffield, UK;Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford, UK;MRC Lifecourse Epidemiology Unit, (University of Southampton), Southampton General Hospital, Southampton, UK;MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK

关键词: neonate;    pregnancy;    DXA;    osteoporosis;    trial;    supplementation;    cholecalciferol;    Vitamin D;   

Others  :  1095688
DOI  :  10.1186/1745-6215-13-13

 received in 2011-08-15, accepted in 2012-02-07,  发布年份 2012

【 摘 要 】

MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.

Background

Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.

Methods/Design

Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.

Discussion

As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.

【 授权许可】

   
2012 Harvey et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis Am J Med 1993, 94:646-650.
• [2]van Staa TP, Dennison EM, Leufkens HG, Cooper C: Epidemiology of fractures in England and Wales. Bone 2001, 29(6):517-522.
• [3]Harvey N, Cooper C: Disease prevention: Osteoporosis and hip fracture. In Public Health Nutrition. Edited by Gibney M, Margetts B, Kearney J, Arab L. Oxford: Blackwell Publishing; 2004:357-369.
• [4]Hernandez CJ, Beaupre GS, Carter DR: A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 2003, 14:843-847.
• [5]Gale CR, Martyn CN, Kellingray S, Eastell R, Cooper C: Intrauterine programming of adult body composition. J Clin Endocrinol Metab JID - 0375362 2001, 86:267-272.
• [6]Jones G, Riley M, Dwyer T: Maternal smoking during pregnancy, growth, and bone mass in prepubertal children. J Bone Miner Res 1999, 14(1):146-151.
• [7]Dennison EM, Syddall HE, Sayer AA, Gilbody HJ, Cooper C: Birth weight and weight at 1 year are independent determinants of bone mass in the seventh decade: the Hertfordshire cohort study. Pediatr Res 2005, 57:582-586.
• [8]Jones IE, Williams SM, Goulding A: Associations of birth weight and length, childhood size, and smoking with bone fractures during growth: evidence from a birth cohort study. Am J Epidemiol 2004, 159:343-350.
• [9]Cooper C, Eriksson JG, Forsen T, Osmond C, Tuomilehto J, Barker DJ: Maternal height, childhood growth and risk of hip fracture in later life: a longitudinal study. Osteoporos Int JID - 9100105 2001, 12(8):623-629.
• [10]Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, Cooper C: Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res JID - 8610640 2001, 16:1694-1703.
• [11]Harvey NC, Javaid MK, Arden NK, Poole JR, Crozier SR, Robinson SM, Inskip HM, Godfrey KM, Dennison EM, Cooper C: Maternal predictors of neonatal bone size and geometry: the Southampton Women's Survey. Journal of Developmental Origins of Health and Disease 2010, 1:35-41.
• [12]Cole ZA, Gale CR, Javaid MK, Robinson SM, law C, Boucher BJ, Crozier SR, Godfrey KM, Dennison EM, Cooper C: Maternal dietary patterns during pregnancy and childhood bone mass: a longitudinal study. J Bone Miner Res 2009, 24:663-668.
• [13]Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C: Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006, 367:36-43.
• [14]Ginde AA, Sullivan AF, Mansbach JM, Camargo CA Jr: Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States. Am J Obstet Gynecol 2010, 202(5):436.e1-8.
• [15]Brooke OG, Brown IR, Cleeve HJ, Sood A: Observations on the vitamin D state of pregnant Asian women in London. Br J Obstet Gynaecol JID - 7503752 1981, 88:18-26.
• [16]Marya RK, Rathee S, Lata V, Mudgil S: Effects of vitamin D supplementation in pregnancy. Gynecol Obstet Invest JID - 7900587 1981, 12:155-161.
• [17]Marya RK, Rathee S, Dua V, Sangwan K: Effect of vitamin D supplementation during pregnancy on foetal growth. Indian J Med Res JID - 0374701 1988, 88:488-492.
• [18]Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS: Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr JID - 0375410 1986, 109:328-334.
• [19]Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H: Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstet Gynecol JID - 0401101 1986, 68(5):300-304.
• [20]Roy DK, Berry JL, Pye SR, Adams JE, Swarbrick CM, King Y, Silman AJ, O'Neill TW: Vitamin D status and bone mass in UK South Asian women. Bone 2007, 40:200-204.
• [21]Holick MF: Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004, 80(6 Suppl):1678S-1688S.
• [22]Harvey NC, Javaid MK, Poole JR, Taylor P, Robinson SM, Inskip HM, Godfrey KM, Cooper C, Dennison EM: Paternal skeletal size predicts intrauterine bone mineral accrual. J Clin Endocrinol Metab 2008, 93:1676-1681.
• [23]Sayers A, Tobias JH: Estimated maternal ultraviolet B exposure levels in pregnancy influence skeletal development of the child. J Clin Endocrinol Metab 2009, 94:765-771.
• [24]Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, Swaminathan R, Cooper C, Godfrey K: Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res 2010, 25:14-19.
• [25]Martin R, Harvey NC, Crozier SR, Poole JR, Javaid MK, Dennison EM, Inskip HM, Hanson M, Godfrey KM, Cooper C, Lewis R: Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual. Bone 2007, 40:1203-1208.
• [26]Cockburn F, Belton NR, Purvis RJ, Giles MM, Brown JK, Turner TL, Wilkinson EM, Forfar JO, Barrie WJ, McKay GS, Pocock SJ: Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. Br Med J JID - 0372673 1980, 281:11-14.
• [27]Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, Robinson VP, Winder SM: Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J JID - 0372673 1980, 280:751-754.
• [28]Congdon P, Horsman A, Kirby PA, Dibble J, Bashir T: Mineral content of the forearms of babies born to Asian and white mothers. Br Med J (Clin Res Ed) JID - 8302911 1983, 286:1233-1235.
• [29]Mahomed K, Gulmezoglu AM: Vitamin D supplementation in pregnancy. Cochrane Database Syst Rev JID - 100909747 2000, CD000228.
• [30]Committee on Medical Aspects of Food and Nutrition Policy: Nutrition and bone health with particular reference to calcium and vitamin D. London, HMSO; 1998.
• [31]Hollis BW, Wagner CL: Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004, 79:717-726.
• [32]Harvey NC, Mahon PA, Robinson SM, Nisbet CE, Javaid MK, Crozier SR, Inskip HM, Godfrey KM, Arden NK, Dennison EM, Cooper C: Different indices of fetal growth predict bone size and volumetric density at 4 years of age. J Bone Miner Res 2010, 25:920-927.
• [33]White IR, Horton NJ, Carpenter J, Pocock SJ: Strategy for intention to treat analysis in randomised trials with missing outcome data. BMJ 2011, 342:d40.
• [34]Gale CR, Robinson SM, Harvey NC, Javaid MK, Jiang B, Martyn CN, Godfrey KM, Cooper C: Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 2008, 62:68-77.
• [35]Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW: Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 2007, 85(3):788-795.
• [36]Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S, Helms PJ, Seaton A, Weiss ST: Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007, 85(3):853-859.
• [37]Camargo CA Jr, Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ, Town GI, Pattemore PK, Espinola JA, Crane J: Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011, 127(1):e180-e187.