New insights into the vitamin D requirements during pregnancy

Abstract

Pregnancy represents a dynamic period with physical and physiological changes in both the mother and her developing fetus. The dramatic 2–3 fold increase in the active hormone 1,25(OH)₂D concentrations during the early weeks of pregnancy despite minimal increased calcium demands during that time of gestation and which are sustained throughout pregnancy in both the mother and fetus suggests an immunomodulatory role in preventing fetal rejection by the mother. While there have been numerous observational studies that support the premise of vitamin D's role in maintaining maternal and fetal well-being, until recently, there have been few randomized clinical trials with vitamin D supplementation. One has to exhibit caution, however, even with RCTs, whose results can be problematic when analyzed on an intent-to-treat basis and when there is high non-adherence to protocol (as if often the case), thereby diluting the potential good or harm of a given treatment at higher doses. As such, a biomarker of a drug or in this case “vitamin” or pre-prohormone is better served. For these reasons, the effect of vitamin D therapies using the biomarker circulating 25(OH)D is a far better indicator of true “effect.” When pregnancy outcomes are analyzed using the biomarker 25(OH)D instead of treatment dose, there are notable differences in maternal and fetal outcomes across diverse racial/ethnic groups, with improved health in those women who attain a circulating 25(OH)D concentration of at least 100 nmol·L⁻¹ (40 ng·mL⁻¹). Because an important issue is the timing or initiation of vitamin D treatment/supplementation, and given the potential effect of vitamin D on placental gene expression and its effects on inflammation within the placenta, it appears crucial to start vitamin D treatment before placentation (and trophoblast invasion); however, this question remains unanswered. Additional work is needed to decipher the vitamin D requirements of pregnant women and the optimal timing of supplementation, taking into account a variety of lifestyles, body types, baseline vitamin D status, and maternal and fetal vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genotypes. Determining the role of vitamin D in nonclassical, immune pathways continues to be a challenge that once answered will substantiate recommendations and public health policies.

Vitamin D: supplementation urged for pregnant women

Larger amounts of vitamin D are needed during pregnancy than are currently recommended assert two experts. In a review article, Bruce Hollis and Carol Wagner from the Medical University of South Carolina in Charleston, USA, argue that current guidelines regarding vitamin D levels during pregnancy fail to take into account the latest research showing that vitamin D supplementation can help protect both the mother from pregnancy-related complications and the developing fetus from autoimmune disorders. The authors describe how, apart from its usual function as a calcium-regulating factor, vitamin D during pregnancy primarily helps maintain a proper immune balance. They argue that a lack of vitamin D during pregnancy or the early months of infancy may be responsible for certain diseases in later life, including asthma and multiple sclerosis.

References

[1] Ross AC, Manson JE, Abrams SA et al. The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. J Am Diet Assoc, 2011, 111: 524-527

[2] World Health Organisation. Vitamin D Supplementation in Infants. Geneva: World Health Organisation. 2014.

[3] De-Regil LM, Palacios C, Ansary A et al.Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev 2012; 2: CD00887.

[4] Heaney RP. Is vitamin D inadequacy in early life an instance of the "Barker Hypothesis"? Nutr Today, 2016, 51: 14-17

[5] Camargo CA Jr, Ingham T, Wickens K et al. Cord-Blood 25-Hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthama. Pediatrics, 2011, 127: e180-e187

[6] Litonjua AA. Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol, 2009, 9: 202-207

[7] Munger KL, Aivo J, Hongell K et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol, 2016, 73: 515-519

[8] Greenberg BM. Vitamin D during pregnancy and multiple sclerosis: an evolving association. JAMA Neurol, 2016, 73: 498-499

[9] Dobson R, Giovannoni G, Ramagopalan S. The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatry, 2013, 84: 427-432

[10] Berlanga-Taylor AJ, Disanto G, Ebers GC et al. Vitamin D-gene interactions in multiple sclerosis. J Neurol Sci, 2011, 311: 32-36

[11] Ebers G. Interactions of environment and genes in multiple sclerosis. J Neurol Sci, 2013, 334: 161-163

[12] Stubbs G, Henley K, Green J. Autism: Will vitamin D supplementation during pregnancy and early childhood reduce the recurrence rate of autism in newborn siblings? Med Hypotheses, 2016, 88: 74-78

[13] McGrath JJ, Eyles DW, Pedersen CB et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry, 2010, 67: 889-894

[14] Cannell JJ. Autism and vitamin D. Med Hypotheses, 2008, 70: 750-759

[15] McGrath JJ, Féron FP, Burne TH et al. Vitamin D3-implications for brain development. J Steroid Biochem Mol Biol, 2004, 89-90: 557-560

[16] Brannon PM, Picciano MF. Vitamin D in pregnancy and lactation in humans. Annu Rev Nutr, 2011, 31: 89-115

[17] Abrams SA. Vitamin D supplementation during pregnancy. J Bone Miner Res, 2011, 26: 2338-2340

[18] Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev, 2014, 72: 48-54

[19] Tian XQ, Chen TC, Matsuoka LY et al. Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin. J Biol Chem, 1993, 268: 14888-14892

[20] Vieth R, Bischoff-Ferrari H, Boucher B et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr, 2007, 85: 649-650

[21] Hollis B. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr, 2005, 135: 317-322

[22] Holick MF, Binkley NC, Bischoff-Ferrari HA et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011, 96: 1911-1930

[23] Hollis BW, Wagner CL. 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, 2013, 98: 4619-4628

[24] Bikle DD, Gee E, Halloran B et al. Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest, 1984, 74: 1966-1971

[25] Kumar R, Cohen WR, Silva P et al. Elevated 1,25-dihydroxyvitamin D plasma levels in normal human pregnancy and lactation. J Clin Invest, 1979, 63: 342-344

[26] Lund B, Selnes A. Plasma 1,25-dihydroxyvitamin D levels in pregnancy and lactation. Acta Endocrinol, 1979, 92: 330-335

[27] Steichen JJ, Tsang RC, Gratton TL et al. Vitamin D homeostasis in the perinatal period: 1,25-dihydroxyvitamin D in maternal, cord, and neonatal blood. N Engl J Med, 1980, 302: 315-319

[28] Seino Y, Ishida M, Yamaoka K et al. Serum calcium regulating hormones in the perinatal period. Calcif Tissue Int, 1982, 34: 131-135

[29] Heaney RP, Armas LA, Shary JR et al. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr, 2008, 87: 1738-1742

[30] Hollis BW, Johnson D, Hulsey TC et al. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res, 2011, 26: 2341-2357

[31] Walker VP, Zhang X, Rastegar I et al. Cord blood vitamin D status impacts innate immune responses. J Clin Endocrinol Metab, 2011, 96: 1835-1843

[32] Eichholzer M, Platz EA, Bienstock JL et al. Racial variation in vitamin D cord blood concentration in white and black male neonates. Cancer Causes Control, 2013, 24: 91-98

[33] Kovacs CS. The role of vitamin D in pregnancy and lactation: insights from animal models and clinical studies. Annu Rev Nutr, 2012, 32: 97-123

[34] Carneiro RM, Prebehalla L, Tedesco MB et al. Lactation and bone turnover: a conundrum of marked bone loss in the setting of coupled bone turnover. J Clin Endocrinol Metab, 2010, 95: 1767-1776

[35] Bell NH, Stern PH, Pantzer E et al. Evidence that increased circulating 1 alpha, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest, 1979, 64: 218-225

[36] Holick MF. The cutaneous photosynthesis of previtamin D3: a unique photoendocrine system. J Invest Dermatol, 1981, 77: 51-58

[37] Hollander D, Muralidhara KS, Zimmerman A. Vitamin D₃ intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate pH on absorption. Gut, 1978, 19: 267-272

[38] Hollis BW, Lowery JW, Pittard WB 3rd et al. Effect of age on the intestinal absorption of vitamin D3-palmitate and nonesterified vitamin D2 in the term human infant. J Clin Endocrinol Metab, 1996, 81: 1385-1388

[39] Heubi JE, Hollis BW, Specker B et al. Bone disease in chronic childhood cholestasis. I. Vitamin D absorption and metabolism. Hepatology, 1989, 9: 258-264

[40] Haddad JG, Matsuoka LY, Hollis BW et al. Human plasma transport of vitamin D after its endogenous synthesis. J Clin Invest, 1993, 91: 2552-2555

[41] Ponchon G, Kennan AL, DeLuca HF. "Activation" of vitamin D by the liver. J Clin Invest, 1969, 48: 2032-2037

[42] Flanagan JN, Young MV, Persons KS et al. Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D. Anticancer Res, 2006, 26: 2567-2572

[43] Karlgren M, Miura S, Ingelman-Sundberg M. Novel extrahepatic cytochrome P450s. Toxicol Appl Pharmacol, 2005, 207: 57-61

[44] Hosseinpour F, Wikvall K. Porcine microsomal vitamin D(3) 25-hydroxylase (CYP2D25). Catalytic properties, tissue distribution, and comparison with human CYP2D6. J Biol Chem, 2000, 275: 34650-34655

[45] Schuessler M, Astecker N, Herzig G et al. Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D(3): CYP27 in epidermis completes the set of essential vitamin D(3)-hydroxylases. Steroids, 2001, 66: 399-408

[46] Zhu J, DeLuca HF. Vitamin D 25-hydroxylase—four decades of searching, are we there yet? Arch Biochem Biophys, 2012, 523: 30-36

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

[48] Bouillon R, van Baelen H, de Moor P. Comparative study of the affinity of the serum vitamin D-binding protein. J Steroid Biochem, 1980, 13: 1029-1034

[49] Hollis BW. Comparison of equilibrium and disequilibrium assay conditions for ergocalceferol, cholecaliferol and their major metabolites. J Steroid Biochem, 1984, 21: 81-86

[50] Kissmeyer A, Mathiasen IS, Latini S et al. Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP). Endocrine, 1995, 3: 263-266

[51] Vieth R, Kessler MJ, Pritzker KP. Species differences in the binding kinetics of 25-hydroxyvitamin D3 to vitamin D binding protein. Can J Physiol Pharmacol, 1990, 68: 1368-1371

[52] Haddad JG, Hillman L, Rojanasathit S. Human serum binding capacity and affinity for 25-hydroxyergocalciferol and 25-hydroxycholecalciferol. J Clin Endocrinol Metab, 1976, 43: 86-91

[53] Marzolo MP, Farfan P. New insights into the roles of megalin/LRP2 and the regulation of its functional expression. Biol Res, 2011, 44: 89-105

[54] Nykjaer A, Dragun D, Walther D et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell, 1999, 96: 507-515

[55] Rasmussen H, Wong M, Bikle D et al. Hormonal control of the renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. J Clin Invest, 1972, 51: 2502-2504

[56] Akour AA, Gerk P, Kennedy MJ. Megalin expression in human term and preterm placental villous tissues: effect of gestational age and sample processing and storage time. J Pharmacol Toxicol Methods, 2015, 71: 147-154

[57] Jones AR, Shusta EV. Blood-brain barrier transport of therapeutics via receptor-mediation. Pharm Res, 2007, 24: 1759-1771

[58] Safadi FF, Thornton P, Magiera H et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest, 1999, 103: 239

[59] Zella LA, Shevde NK, Hollis BW et al. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D₃ but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology, 2008, 149: 3656-3667

[60] Bodnar LM, Simhan HN, Catov JM et al. Maternal vitamin D status and the risk of mild and severe preeclampsia. Epidemiology, 2014, 25: 207-214

[61] Robinson CJ, Alanis MC, Wagner CL et al. Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia. Am J Obstet Gynecol, 2010, 203: 366.e1-e6

[62] Liu NQ, Ouyang Y, Bulut Y et al. Dietary vitamin D restriction in pregnant female mice is associated with maternal hypertension and altered placental and fetal development. Endocrinology, 2013, 154: 2270-2280

[63] Faulkner JL, Cornelius DC, Amaral LM et al. Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia. Am J Physiol Regul Integr Comp Physiol, 2016, 310: R346-R354

[64] Lykkedegn S, Sorensen GL, Beck-Nielsen SS et al. Vitamin D depletion in pregnancy decreases survival time, oxygen saturation, lung weight and body weight in preterm rat offspring. PLoS One, 2016, 11: e0155203

[65] Calton EK, Keane KN, Newsholme P et al. The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PloS One, 2015, 10: e0141770

[66] McGrath JJ, Eyles DW, Pedersen CB et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry, 2010, 67: 889-894

[67] LaMarca B, Amaral LM, Harmon AC et al. Placental ischemia and resultant phenotype in animal models of preeclampsia. Curr Hypertens Rep, 2016, 18: 38

[68] Gibson CC, Davis CT, Zhu W et al. Dietary vitamin D and its metabolites non-genomically stabilize the endothelium. PLoS One, 2015, 10: e0140370

[69] Gibson CC, Zhu W, Davis CT et al. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation, 2015, 131: 289-299

[70] Black JA, Carter RE. Association between aortic stenosis and facies of severe infantile hypercalcemia. Lancet, 1963, 2: 745-749

[71] Garcia RE, Friedman WF, Kaback M et al. Idiopathic hypercalcemia and supravalvular aortic stenosis: documentation of a new syndrome. N Engl J Med, 1964, 271: 117-120

[72] Friedman WF. Vitamin D as a cause of the supravalvular aortic stenosis syndrome. Am Heart J, 1967, 73: 718-720

[73] Antia AV, Wiltse HE, Rowe RD et al. Pathogenesis of the supravalvular aortic stenosis syndrome. J Pediatr, 1967, 71: 431-441

[74] Seelig MS. Vitamin D and cardiovascular, renal and brain damage in infancy and childhood. Ann N Y Acad Sci, 1969, 147: 539-582

[75] Latorre G. Effect of overdose of vitamin D₂ on pregnancy in the rat. Fertil Steril, 1961, 12: 343-345

[76] Friedman WF, Roberts WC. Vitamin D and the supravalvular aortic stenosis syndrome. The transplacental effects of vitamin D on the aorta of the rabbit. Circulation, 1966, 34: 77-86

[77] Morris CA, Mervis CB. William's syndrome and related disorders. Annu Rev Genomics Hum Genet, 2000, 1: 461-484

[78] Aravena T, Castillo S, Carrasco X et al. Williams syndrome: clinical, cytogenetical, neurophysiological and neuroanatomic study. Rev Med Chil, 2002, 130: 631-637

[79] Garabédian M, Jacqz E, Guillozo H et al. Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies. N Engl J Med, 1985, 312: 948-952

[80] Becroft DM, Chambers D. Supravalvular aortic stenosis-infantile hypercalcemia syndrome: in vitro hypersensitivitiy to vitamin D and calcium. J Med Genet, 1976, 13: 223-228

[81] Taylor AB, Stern PH, Bell NH. Abnormal regulation of circulating 25-hydroxyvitamin D on the Williams Syndrome. N Engl J Med, 1982, 306: 972-975

[82] Cooper C, Harvey NC, Bishop NJ et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol, 2016, 4: 393-402

[83] Olsen SF, Secher NJ. A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: indications from a 50-year-old controlled trial. Br J Nutr, 1990, 64: 599-609

[84] Bodnar LM, Catov JM, Simhan HN et al. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endorcrinol Metab, 2007, 92: 3517-3522

[85] Baker AM, Haeri S, Camargo CA Jr et al. A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab, 2010, 95: 5105-5109

[86] Gernand AD, Bodnar LM, Klebanoff MA et al. Maternal serum 25-hydroxyvitamin D and placental vascular pathology in a multicenter US cohort. Am J Clin Nutr, 2013, 98: 383-388

[87] Merewood A, Mehta SD, Chen TC et al. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab, 2009, 94: 940-945

[88] Zhang C, Qiu C, Hu FB et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS One, 2008, 3: e3753

[89] Bodnar LM, Simhan HN. Vitamin D may be a link to black-white disparities in adverse birth outcomes. Obstet Gynecol Surv, 2010, 65: 273-284

[90] Pal L, Zhang H, Williams J et al. Vitamin D status relates to reproductive outcome in women with polycystic ovary syndrome: secondary analysis of a multicenter randomized controlled trial. J Clin Endocrinol Metab, 2016, 101: 3027-3035

[91] Miliku K, Vinkhuyzen A, Blanken LM et al. Maternal vitamin D concentrations during pregnancy, fetal growth patterns, and risks of adverse birth outcomes. Am J Clin Nutr, 2016, 103: 1514-1522

[92] Hou W, Yan XT, Bai CM et al. Decreased serum vitamin D levels in early spontaneous pregnancy loss. Eur J Clin Nutr, 2016, 70: 1004-1008

[93] Lindqvist PG, Silva AT, Gustafsson SA et al. Maternal vitamin D deficiency and fetal distress/birth asphyxia: a population-based nested case-control study. BMJ Open, 2016, 6: e009733

[94] Kiely ME, Zhang JY, Kinsella M et al. Vitamin D status is associated with uteroplacental dysfunction indicated by pre-eclampsia and small-for-gestational-age birth in a large prospective pregnancy cohort in Ireland with low vitamin D status. Am J Clin Nutr, 2016, 104: 354-361

[95] Qin Lu-Lu, Lu Fang-Guo, Yang Sheng-Hui, Xu Hui-Lan, Luo Bang-An. Does Maternal Vitamin D Deficiency Increase the Risk of Preterm Birth: A Meta-Analysis of Observational Studies. Nutrients, 2016, 8 5 301

[96] Hollis B, Wagner C. Assessment of dietary vitamin D requirements during pregnancy and Lactation. Am J Clin Nutr, 2004, 79: 717-726

[97] Bodnar LM, Catov JM, Roberts JM. Racial/ethnic differences in the monthly variation of preeclampsia incidence. Am J Obstet Gynecol, 2007, 196: 324.e1-e5

[98] Weiss S, Wolsk H, Mirzakhani H et al.Asthma/wheeze and preeclampsia outcomes in the VDAART trial: the influcence of baseline and treatment levels of vitamin D on treatment response. Boston: The Vitamin D Workshop, 2016. Available at: http://www.vitamindworkshop.org/

[99] Litonjua AA, Carey VJ, Laranjo N et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: The VDAART Randomized Clinical Trial. JAMA, 2016, 315: 362-370

[100] Mirzakhani H, Harshfield B, Carey V et al.(eds). Association of maternal asthma and early pregnancy serum vitamin D level with risk of preeclampsia. Boston: The Vitamin D Workshop. 2016. Available at http://www.vitamindworkshop.org/

[101] Wolsk H, Harshfield BJ, Laranjo N et al. (eds). Vitamin D supplementation in pregnant women of different races and the risk of asthma/recurrent wheeze in the child: findings from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Boston: The Vitamin D Workshop. 2016. Available at http://www.vitamindworkshop.org/

[102] Wolsk H, Litonjua A, Chawes B et al. Prenatal vitamin D supplementation and risk of asthma/wheeze at 3 years of age: a meta-analysis of randomized controlled trials. JAMA, 2016, 315: 353-361

[103] Wagner CL, McNeil R, Hamilton SA et al. A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. Am J Obstet Gynecol, 2013, 208: 137.e1-e13

[104] Wagner CL, Baggerly C, McDonnell S 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 2009-2011 rates. J Steroid Biochem Mol Biol, 2016, 155: 245-251

[105] Liu PT, Stenger S, Li H et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 2006, 311: 1770-1773

[106] Fabri M, Stenger S, Shin DM et al. Vitamin D is required for IFN-{gamma}-mediated antimicrobial activity of human macrophages. Sci Transl Med, 2011, 3: 104ra102

[107] Liu NQ, Hewison M. Vitamin D, the placenta and pregnancy. Arch Biochem Biophys, 2011, 523: 37-47

[108] Lagishetty V, Liu NQ, Hewison M. Vitamin D metabolism and innate immunity. Mol Cell Endocrinol, 2011, 347: 97-105

[109] Liu NQ, Kaplan AT, Lagishetty V et al. Vitamin D and the regulation of placental inflammation. J Immunol, 2011, 186: 5968-5974

[110] Vieth R. Vitamin D supplementation, 25-hydroxy-vitamin D concentrations, and safety. Am J Clin Nutr, 1999, 69: 842-856

[111] Heaney R, Davies K, Chen T et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr, 2003, 77: 204-210

[112] Souberbielle JC, Cormier C, Kindermans C et al. Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab, 2001, 86: 3086-3090

[113] Hollis BW, Wagner CL. Vitamin d and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int, 2013, 92: 128-139

[114] Wagner CL, McNeil RB, Johnson DD et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol, 2013, 136: 313-320

[115] Goldring ST, Griffiths CJ, Martineau AR et al. Prenatal vitamin d supplementation and child respiratory health: a randomised controlledtrial. PLoS One, 2013, 8: e66627

[116] Sablok A, Batra A, Thariani K et al. Supplementation of vitamin D in pregnancy and its correlation with feto-maternal outcome. Clin Endocrinol (Oxf), 2015, 83: 536-541

[117] Mojibian M, Soheilykhah S, Fallah Zadeh MA et al. The effects of vitamin D supplementation on maternal and neonatal outcome: a randomized clinical trial. Iran J Reprod Med, 2015, 13: 687-696

[118] Chawes BL, Bonnelykke K, Stokholm J et al. Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. JAMA, 2016, 315: 353-361

[119] Grant CC, Crane J, Mitchell EA et al. Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial. Allergy, 2016, 71: 1325-1334

[120] Zhang Q, Cheng Y, He M et al. Effect of various doses of vitamin D supplementation on pregnant women with gestational diabetes mellitus: a randomized controlled trial. Exp Ther Med, 2016, 12: 1889-1895

[121] Zerofsky MS, Jacoby BN, Pedersen TL et al. Daily cholecalciferol supplementation during pregnancy alters markers of regulatory immunity, inflammation, and clinical outcomes in a randomized controlled trial. J Nutr, 2016, 146: 2388-2397

[122] Brehm JM, Celedon JC, Soto-Quiros ME et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med, 2009, 179: 765-771

[123] Brehm JM, Schuemann B, Fuhlbrigge AL et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol, 2010, 126: 52-8 e5

[124] von Mutius E, Martinez FD. Inconclusive results of randomized trials of prenatal vitamin D for asthma prevention in offspring: curbing the enthusiasm. JAMA, 2016, 315: 347-348

[125] Oxford Centre for Evidence-based Medicine-Levels of Evidence 2009. Available at http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/.

[126] Zhu H, Wagner C, Pan Y et al.Maternal vitamin D supplementation and cord blood genome-wide DNA methylation analysis. (abstract). Boston: Vitamin D Workshop, 2016. Available at http://www.vitamindworkshop.org/

[127] Schulz EV, Cruze L, Wei W et al. Maternal vitamin D sufficiency and reduced placental gene expression in angiogenic biomarkers related to comorbidities of pregnancy. J Steroid Biochem Mol Biol 2017. pii: S0960-0760(17)30038-9.

[128] Al-Garawi A, Carey VJ, Chhabra D et al. The role of vitamin D in the transcriptional program of human pregnancy. PLoS One, 2016, 11: e0163832

[129] Mirzakhani H, Litonjua A, Sharma A et al.Higher Vitamin D Levels in Early Pregnancy and Risk of Preeclampsia. Boston: The Vitamin D Workshop, 2016. Available at http://www.vitamindworkshop.org/

[130] Kiely M, Zhang J, Kinsella M et al.Vitamin D Status is Associated with Utero-placental Dysfunction in a Large Prospective Pregnancy Cohort with Low 25(OH)D3 and Ubiquitous 3-epi-25(OH)D3 and 25(OH)D3 and 25(OH)D2. Boston: The Vitamin D Workshop, 2016, Available at http://www.vitamindworkshop.org/

[131] Anderson CM, Ralph JL, Johnson L et al. First trimester vitamin D status and placental epigenomics in preeclampsia among Northern Plains primiparas. Life Sci, 2015, 129: 10-15

[132] Strid H, Care A, Jansson T et al. Parathyroid hormone-related peptide (38-94) amide stimulates ATP-dependent calcium transport in the Basal plasma membrane of the human syncytiotrophoblast. J Endocrinol, 2002, 175: 517-524

[133] Deftos LJ, Burton DW, Brandt DW et al. Neoplastic hormone-producing cells of the placenta produce and secrete parathyroid hormone-related protein. Studies by immunohistology, immunoassay, and polymerase chain reaction. Lab Invest, 1994, 71: 847-852

[134] Mokry LE, Ross S, Ahmad OS et al. Vitamin D and risk of multiple sclerosis: a Mendelian randomization study. PLoS Med, 2015, 12: e1001866

[135] Whitehouse AJ, Holt BJ, Serralha M et al. Maternal serum vitamin d levels during pregnancy and offspring neurocognitive development. Pediatrics, 2012, 129: 485-493

[136] Chen J, Xin K, Wei J et al. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. J Psychosom Res, 2016, 89: 98-101

[137] Gould JF, Anderson AJ, Yelland LN et al. Association of cord blood vitamin D with early childhood growth and neurodevelopment. J Paediatr Child Health, 2017, 53: 75-83

[138] Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J, 2014, 28: 2398-2413

[139] Patrick RP, Ames BN. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J, 2015, 29: 2207-2222