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Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review

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Abstract

A considerable number of studies have examined vitamin D status during pregnancy. Although data from observational studies denote vitamin D hypovitaminosis (deficiency or insufficiency) during pregnancy is associated with a plethora of adverse maternal and neonatal outcomes, data from interventional (supplementation) trials fail to reveal a significant impact on maternal and offspring health. The aim of this narrative review was to critically appraise the methodology of the most representative published randomized controlled trials in an attempt to explain the difference between observational and supplementation results. We found that this difference could be attributed to a variety of factors, namely: (i) study design (lack of a specific outcome in conjunction with timing of supplementation, enrolment of participants with heterogeneous vitamin D status); (ii) pitfalls in the interpretation of vitamin D equilibrium (lack of determination of plasma half-life); (iii) supplementation regimen (administration of a wide range of regimens, in terms of dose, bolus and form); (iv) geographical characteristics (vitamin D needs could vary significantly within a country, particularly in areas with a wide range of latitude gradient); (v) adaptations of vitamin D metabolism during pregnancy (vitamin D and calcium equilibrium are changed during pregnancy compared with the non-pregnant state) and (vi) supplementation of populations with low baseline 25(OH)D values would likely manifest beneficial effects. All these parameters should be taken into consideration in the design of future vitamin D supplementation trials.

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References

  1. Lukaszewski MA, Eberlé D, Vieau D, Breton C (2013) Nutritional manipulations in the perinatal period program adipose tissue in offspring. Am J Physiol Endocrinol Metab 305:E1195–E1207

    Article  CAS  PubMed  Google Scholar 

  2. Drever N, Saade GR, Bytautiene E (2010) Fetal programming: early-life modulations that affect adult outcomes. Curr Allergy Asthma Rep 10:453–459

    Article  PubMed  Google Scholar 

  3. Poston L (2007) Influences of maternal nutritional status on vascular function in the offspring. Curr Drug Targets 8:914–922

    Article  CAS  PubMed  Google Scholar 

  4. Kulkarni B, Hills AP, Byrne NM (2014) Nutritional influences over the life course on lean body mass of individuals in developing countries. Nutr Rev 72:190–204

    Article  PubMed  Google Scholar 

  5. Berti C, Cetin I, Agostoni C, et al. (2014) Pregnancy and infants’ outcome: nutritional and metabolic implications. Crit Rev Food Sci Nutr

  6. Karras SN, Anagnostis P, Bili E et al (2014) Maternal vitamin D status in pregnancy and offspring bone development: the unmet needs of vitamin D era. Osteoporos Int 25:795–805

    Article  CAS  PubMed  Google Scholar 

  7. Kovacs CS (2008) Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies. Am J Clin Nutr 88:520S–528S

    CAS  PubMed  Google Scholar 

  8. Bodnar LM, Simhan HN (2010) Vitamin D may be a link to black-white disparities in adverse birth outcomes. Obstet Gynecol Surv 65(4):273–284

    Article  PubMed Central  PubMed  Google Scholar 

  9. Looker AC (2008) Pfeifer Serum 25-hydroxyvitamin D status of the US population. Am J Clin Nutr 88(6):1519–1527

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF (2009) Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab 94(3):940–945

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM (2007) Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab 92(9):3517–3522

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Bodnar LM, Catov JM, Zmuda JM, Cooper ME, Parrott MS, Roberts JM, Marazita ML, Simhan HN (2010) Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr 140(5):999–1006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zhang C, Qiu C, Hu FB et al (2008) Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS ONE 3:e3753

    Article  PubMed Central  PubMed  Google Scholar 

  14. Lacroix M, Battista MC, Doyon M et al (2014) Lower vitamin D levels at first trimester are associated with higher risk of developing gestational diabetes mellitus. Acta Diabetol 51:609–616

    Article  CAS  PubMed  Google Scholar 

  15. Zuhur SS, Erol RS, Kuzu I, Altuntas Y (2013) The relationship between low maternal serum 25-hydroxyvitamin D levels and gestational diabetes mellitus according to the severity of 25-hydroxyvitamin D deficiency. Clinics (Sao Paulo) 68:658–664

    Article  Google Scholar 

  16. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM (2013) Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. Br Med J 346:f1169

    Article  Google Scholar 

  17. Haugen M, Brantsaeter AL, Alexander J, Meltzer HM (2008) Dietary supplements contribute substantially to the total nutrient intake in pregnant Norwegian women. Ann Nutr Metab 52:272–280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Hyppönen E, Cavadino A, Williams D et al (2013) Vitamin D and pre-eclampsia: original data, systematic review and meta-analysis. Ann Nutr Metab 63:331–340

    Article  PubMed  Google Scholar 

  19. Marya RK, Rathee S, Manrow M (1987) Effect of calcium and vitamin D supplementation on toxaemia of pregnancy. Gynecol Obstet Invest 24:38–42

    Article  CAS  PubMed  Google Scholar 

  20. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL (2011) Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 26:2341–2357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Baker AM, Haeri S, Camargo C, Stuebe AM, Boggess KA (2012) First trimester maternal vitamin D status and risk for gestational diabetes mellitus: a nested case-control study. Diabetes Metab Res Rev 28:164–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Hossain N, Kanani FH, Ramzan S, Kausar R, Ayaz S, Khanani R, Pal L (2014) Obstetric and neonatal outcomes of maternal vitamin D supplementation: results of an open label randomized controlled trial of antenatal vitamin D supplementation in Pakistani women. J Clin Endocrinol Metab 99:2448–2455

    Article  CAS  PubMed  Google Scholar 

  23. Yap C, Cheung NW, Gunton JE et al (2014) Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. Diabetes Care 37:1837–1844

    Article  CAS  PubMed  Google Scholar 

  24. Kramer CK, Swaminathan B, Hanley AJ, Connelly PW, Sermer M, Zinman B, Retnakaran R (2014) Vitamin D and parathyroid hormone status in pregnancy: effect on insulin sensitivity, β-cell function, and gestational diabetes mellitus. J Clin Endocrinol Metab 99(12):4506–4513

    Article  CAS  PubMed  Google Scholar 

  25. Yu C, Newton L, Robinson S, Teoh TG, Sethi M (2009) Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol (Oxf) 70:685–690

    Article  CAS  Google Scholar 

  26. Marya RK, Rathee S, Dua V, Sangwan K (1988) Effect of vitamin D supplementation during pregnancy on foetal growth. Indian J Med Res 88:488–492

    CAS  PubMed  Google Scholar 

  27. Brooke OG, Brown IR, Bone CD et al (1980) Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 280(6216):751–754

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS (1986) Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr 109:328–334

    Article  CAS  PubMed  Google Scholar 

  29. Mallet E, Gügi B, Brunelle P, Hénocq A, Basuyau JP, Lemeur H (1986) Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstet Gynecol 68:300–304

    Article  CAS  PubMed  Google Scholar 

  30. Roth DE, Perumal N, Al Mahmud A, Baqui AH (2013) Maternal vitamin D3 supplementation during the third trimester of pregnancy: effects on infant growth in a longitudinal follow-up study in Bangladesh. J Pediatr 163:1605–1611

    Article  CAS  PubMed  Google Scholar 

  31. Hypponen E, Sovio U, Wjst M et al (2004) Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966. Ann N Y Acad Sci 1037:84–95

    Article  CAS  PubMed  Google Scholar 

  32. Goldring ST, Griffiths CJ, Martineau AR et al (2013) Prenatal vitamin d supplementation and child respiratory health: a randomised controlled trial. PLoS ONE 8:e66627

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Weyland PG, Grant WB, Howie-Esquivel J (2014) Does sufficient evidence exist to support a causal association between vitamin D status and cardiovascular disease risk? An assessment using Hill’s criteria for causality. Nutrients 6:3403–3430

    Article  PubMed Central  PubMed  Google Scholar 

  34. Heaney RP (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 72:48–54

    Article  PubMed  Google Scholar 

  35. Gray RW, Weber HP, Dominguez JH, Lemann J Jr (1974) The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans. J Clin Endocrinol Metab 39:1045–1056

    Article  CAS  PubMed  Google Scholar 

  36. Smith JE, Goodman DS (1971) The turnover and transport of vitamin, D and a polar metabolite with the properties of 25-hydroxycholecalciferol in human plasma. J Clin Invest 50:2159–2167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Heaney RP, Armas LA (2015) Quantifying the vitamin D economy. Nutr Rev 73(1):51–67

    Article  PubMed  Google Scholar 

  38. Jones KS, Assar S, Vanderschueren D, Bouillon R, Prentice A, Schoenmakers I (2015) Predictors of 25(OH)D half life and plasma 25(OH)D concentration in the Gambia and the UK. Osteoporos Int 26(3):1137–1146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Hollis BW, Wagner CL (2013) Clinical review: 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 98:4619–4628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Vieth R, Chan PC, MacFarlane GD (2001) Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 73:288–294

    CAS  PubMed  Google Scholar 

  41. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210

    CAS  PubMed  Google Scholar 

  42. Wagner CL, Baggerly C, McDonnell SL, Baggerly L, Hamilton SA, Winkler J, Warner G, Rodriguez C, Shary JR, Smith PG, Hollis BW (2015) Post-hoc comparison of vitamin D status at three timepoints during pregnancy demonstrates lower risk of preterm birth with higher vitamin D closer to delivery. J Steroid Biochem Mol Biol 148:256–260

    Article  CAS  PubMed  Google Scholar 

  43. Holick M (2014) Sunlight, ultraviolet-radiation, vitamin D and skin cancer. How much sunlight do we need? In: Reichrath J (ed) Sunlight, Vitamin D and Skin Cancer, 2nd edn. Landes Bioscience and Springer Science, New York, pp 1–16

    Google Scholar 

  44. Armas LA, Hollis BW, Heaney RP (2004) Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 89(11):5387–5391

    Article  CAS  PubMed  Google Scholar 

  45. Tripkovic L, Lambert H, Hart K et al (2012) Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 95:1357–1364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Heaney RP, Recker RR, Grote J et al (2011) Vitamin D3 is more potent than vitamin D2 in humans. J Clin Endocrinol Metab 96(3):E447–E452. doi:10.1210/jc.2010-2230

    Article  CAS  PubMed  Google Scholar 

  47. Tjellesen L, Hummer L, Christiansen C et al (1986) Serum concentration of vitamin D metabolites during treatment with vitamin D2 and D3 in normal premenopausal women. Bone Miner 1(5):407–413

    CAS  PubMed  Google Scholar 

  48. Binkley N, Gemar D, Engelke J et al (2011) Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab 96(4):981–988

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Karras SN, Anagnostis P, Annweiler C et al (2014) Maternal vitamin D status during pregnancy: the Mediterranean reality. Eur J Clin Nutr 68:864–869

    Article  CAS  PubMed  Google Scholar 

  50. Xiang F et al (2013) High prevalence of vitamin D insufficiency in pregnant women working indoors and residing in Guiyang, China. J Endocrinol Investig 36:503–507

    CAS  Google Scholar 

  51. Prentice A, Schoenmakers I, Jones KS, Jarjou LM, Goldberg GR (2009) Vitamin D deficiency and its health consequences in Africa. Clin Rev Bone Miner Metab 7:94–106

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Kaushal M, Magon N (2013) Vitamin D in pregnancy: a metabolic outlook. Indian J Endocrinol Metab 17:76–82

    Article  PubMed Central  PubMed  Google Scholar 

  53. Kimlin MG, Olds WJ, Moore MR (2007) Location and vitamin D synthesis: is the hypothesis validated by geophysical data? J Photochem Photobiol, B 86:234–239

    Article  CAS  Google Scholar 

  54. Van der Meer IM, Middelkoop BJ, Boeke AJ, Lips P (2011) Prevalence of vitamin D deficiency among Turkish, Moroccan, Indian and sub-Sahara African populations in Europe and their countries of origin: an overview. Osteoporos Int 22:1009–1021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Karras SN, Anagnostis P, Paschou SA, Kandaraki E, Goulis DG. Vitamin D status during pregnancy: time for a more unified approach beyond borders? Eur J Clin Nutr. 2015

  56. O’Brien KO, Donangelo CM, Ritchie LD, Gildengorin G, Abrams S, King JC (2012) Serum 1,25-dihydroxyvitamin D and calcium intake affect rates of bone calcium deposition during pregnancy and the early postpartum period. Am J Clin Nutr 96(1):64–72

    Article  PubMed Central  PubMed  Google Scholar 

  57. Thota C, Menon R, Fortunato SJ, Brou L, Lee JE, Al-Hendy A (2014) 1,25-Dihydroxyvitamin D deficiency is associated with preterm birth in African American and Caucasian women. Reprod Sci 21(2):244–250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Ardawi MS, Nasrat HA, BA’Aqueel HS (1997) Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 137:402–409

    Article  CAS  PubMed  Google Scholar 

  59. Rousseau AF, Damas P, Janssens M et al (2014) Critical care and vitamin D status assessment: what about immunoassays and calculated free 25OH-D? Clin Chim Acta 437:43–47

    Article  CAS  PubMed  Google Scholar 

  60. Powe CE, Evans MK, Wenger J et al (2013) Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 369:1991–2000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Hollis BW, Bikle DD (2014) Vitamin D-binding protein and vitamin D in blacks and whites. N Engl J Med 370(9):879–880

    PubMed Central  PubMed  Google Scholar 

  62. Aslani S, Hossein-Nezhad A, Mirzaei K, Maghbooli Z, Afshar AN, Karimi F (2011) VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications. Gynecol Endocrinol 27:1055–1060

    Article  CAS  PubMed  Google Scholar 

  63. Karras SN, Shah I, Petroczi A et al (2013) An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: implications of a new assay on the roles of vitamin D forms. Nutr J 12:77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Shah I, Petroczi A, Tabet N, Klugman A, Isaac M, Naughton DP (2012) Low 25OH vitamin D2 levels found in untreated Alzheimer’s patients, compared to acetylcholinesterase-inhibitor treated and controls. Curr Alzheimer Res 9:1069–1076

    Article  CAS  PubMed  Google Scholar 

  65. Shah I, James R, Barker J, Petroczi A, Naughton DP (2011) Misleading measures in Vitamin D analysis: a novel LC-MS/MS assay to account for epimers and isobars. Nutr J 10:46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Shah I, Petroczi A, Naughton DP (2012) Method for simultaneous analysis of eight analogues of vitamin D using liquid chromatography tandem mass spectrometry. Chem Central J 6:112

    Article  CAS  Google Scholar 

  67. Shah I, Petroczi A, Naughton DP (2014) Exploring the role of vitamin D in type 1 diabetes, rheumatoid arthritis and Alzheimer’s disease: new insights from accurate analysis of ten forms. J Clin Endocrinol Metab 99:808–816

    CAS  PubMed  Google Scholar 

  68. Naughton DP, Petroczi A (2014) Vitamin D status and ill health. Lancet Diabetes Endocrinol 2:274–275

    Article  PubMed  Google Scholar 

  69. Karras SN, Petroczi A, Anagnostis P, Naughton DP (2015) Vitamin D epimer: a significant bio regulator or an inactive compound?. Osteoporos Int

  70. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2014; 6(1):e983401-1-10

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Authors and Affiliations

  1. Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    S. N. Karras, P. Anagnostis & D. G. Goulis

  2. School of Life Sciences, Kingston University, Kingston upon Thames, London, UK

    D. Naughton & A. Petroczi

  3. Robarts Research Institute, The University of Western Ontario, London, ON, Canada

    C. Annweiler

  4. Department of Geriatric Medicine, UPRES EA 4638, University Hospital Angers, Angers, France

    C. Annweiler

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  1. S. N. Karras
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  2. P. Anagnostis
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  3. D. Naughton
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  4. C. Annweiler
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  5. A. Petroczi
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  6. D. G. Goulis
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Correspondence to S. N. Karras.

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Karras, S.N., Anagnostis, P., Naughton, D. et al. Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review. J Endocrinol Invest 38, 1265–1275 (2015). https://doi.org/10.1007/s40618-015-0363-y

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