Terapevticheskii arkhivTerapevticheskii arkhiv0040-36602309-5342LLC Obyedinennaya Redaktsiya3292910.26442/terarkh201890104-127Review ArticleVitamin D: effects on pregnancy, maternal, fetal and postnatal outcomesEremkinaA Kparathyroid.enc@gmail.comMokryshevaN G-PigarovaE A-MirnayaS S-National Endocrinology Research Center, Ministry of Health of Russia15102018901011512711042020Copyright © 2018, Consilium Medicum2018A high prevalence of vitamin D deficiency and its negative consequences for health is identified as area of primary concern for scientists and clinicians worldwide. Vitamin D deficiency affects not only bone health but many socially significant acute and chronic diseases. Observational studies support that pregnant and lactating women, children and teenagers represent the high risk groups for developing vitamin D deficiency. Current evidence highlights a crucial role of vitamin D in providing the fetal life-support system and fetus development, including implantation, placental formation, intra - and postpartum periods. Hypovitaminosis D during pregnancy is associated with a higher incidence of placental insufficiency, spontaneous abortions and preterm birth, preeclampsia, gestational diabetes, impaired fetal and childhood growth, increased risk of autoimmune diseases for offsprings. Potential mechanisms for the observed associations contain metabolic, immunomodulatory and antiinflammatory effects of vitamin D. Epigenetic modifications in vitamin D-associated genes and fetal programming are of particular interest. The concept of preventing vitamin D deficiency is actively discussed, including supplementation in different ethnic groups, required doses, time of initiation and therapy duration, influence on gestation and childbirth. An adequate supply of vitamin D during pregnancy improves the maternal and fetal outcomes, short and long term health of the offspring. Still current data on relationship between maternal vitamin D status and pregnancy outcomes remains controversial. The large observational and interventional randomized control trials are required to create evidence-based guidelines for the supplementation of vitamin D in pregnant and lactating women.25(OH)D1,25(OH)2Dvitamin D deficiency/insufficiencypreeclampsiagestational diabetes mellitusplacental insufficiency epigeneticsfetal programmingдефицит/недостаточность витамина Dпреэклампсиягестационный сахарный диабетплацентарная недостаточностьэпигенетикафетальное программирование[Пигарова Е.А., Рожинская Л.Я., Белая Ж.Е., Дзеранова Л.К., Каронова Т.Л., Ильин А.В., Мельниченко Г.А., Дедов И.И. Клинические рекомендации Российской ассоциации эндокринологов по диагностике, лечению и профилактике дефицита витамина D у взрослых. Проблемы эндокринологии. 2016;62(4):60-84. doi: 10.14341/probl201662460-84][Saraf R, Morton S.M.B, Camargo C.A, Grant C.C. Global summary of maternal and newborn vitamin D status - a systematic review. Matern Child Nutr. 2016;12:647-668. doi: 10.1111/mcn.12210][Kaushal M, Magon N. Vitamin D in pregnancy: A metabolic outlook. Indian J Endocrinol Metab. 2013;17(1):76-82. doi: 10.4103/2230-8210.107862][Bikle D.D. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-329. doi: 10.1016/j.chembiol.2013.12.016][Jäpelt R.B, Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Front Plant Sci. 2013;4:136. doi: 10.3389/fpls.2013.00136][Wimalawansa S.J. Vitamin D; What clinicians would like to know. Sri Lanka J Diabetes Endocrinol Metab. 2012;1(2):73-80. doi: 10.4038/sjdem.v2i2.4776][Palermo N.E, Holick M.F. Vitamin D, bone health, and other health benefits in pediatric patients. J Pediatr Rehabil Med. 2014;7:179-192. doi: 10.3233/PRM-140287][Haussler M.R, Haussler C.A, Jurutka P.W, Thompson P.D, Hsieh J.C, Remus L.S, Selznick S.H, Whitfield G.K. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol. 1997;154 Suppl:S57-73.][Zehnder D, Bland R, Williams M.C, et al. Extrarenal expression of 25-hydroxyvitamin D3-1alphahydroxylase. J Clin Endocr Metab. 2001;86(2):888-894. doi: 10.1210/jcem.86.2.7220][Hollis B.W, Wagner C.L. Nutritional vitamin D status during pregnancy: reasons for concern. CMAJ. 2006;174:1287-1290. doi: 10.1503/cmaj.060149][Hollis B.W, Wagner C.L. Vitamin D supplementation during pregnancy: Improvements in birth outcomes and complications through direct genomic alteration. Mol Cell Endocrinol. 2017;453:113-130. doi: 10.1016/j.mce.2017.01.039][Ginde A.A, Sullivan A.F, Mansbach J.M, Camargo C.A. Vitamin D insufficiency in pregnant and nonpregnant women of childbearing age in the United States. Am J Obstet Gynecol. 2010;202:436.e1-8. doi: 10.1016/j.ajog.2009.11.036][Karras S, Paschou S.A, Kandaraki E, Anagnostis P, Annweiler C, Tarlatzis B.C, Hollis B.W, Grant W.B, Goulis D.G. Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review. Eur J Clin Nutr. 2016 Sep;70(9):979-986. doi: 10.1038/ejcn.2016.12][Мокрышева Н.Г., Липатенкова А.К., Таллер Н.А. Первичный гиперпаратиреоз и беременность. Акушерство и гинекология. 2016;(10):18-25. doi: 10.18565/aig.2016.10.18-25][Møller U.K, Streym S, Mosekilde L, Heickendorff L, Flyvbjerg A, Frystyk J, Jensen L.T, Rejnmark L. Changes in calcitropic hormones, bone markers and insulin - like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study. Osteoporos Int. 2013;24:1307-1320. doi: 10.1007/s00198-012-2062-2][Kovacs C.S, Kronenberg H.M. Maternal-Fetal Calcium and Bone Metabolism During Pregnancy, Puerperium, and Lactation. Endocr Rev. 1997;18:832-872. doi: 10.1210/edrv.18.6.0319][Gray T.K, Lester G.E, Lorenc R.S. Evidence for extra - renal 1 alpha - hydroxylation of 25-hydroxyvitamin D3 in pregnancy. Science. 1979;204:1311-1313.][Hollis B.W, Wagner C.L. Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int. 2013;92:128-139. doi: 10.1007/s00223-012-9607-4][Kovacs C.S. Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery. Physiol Rev. 2016;96:449-547. doi: 10.1152/physrev.00027.2015][Zhong Y, Armbrecht H.J, Christakos S. Calcitonin, a regulator of the 25-hydroxyvitamin D3 1alpha - hydroxylase gene. J Biol Chem. 2009;284:11059-11069. doi: 10.1074/jbc.M806561200][Weisman Y, Harell A, Edelstein S, David M, Spirer Z, Golander A. 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature. 1979;281:317-319.][Novakovic B, Sibson M, Ng H.K, Manuelpillai U, Rakyan V, Down T, Beck S, Fournier T, Evain-Brion D, Dimitriadis E, Craig J.M, Morley R, Saffery R. Placenta - specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. J Biol Chem. 2009;284:14838-14848. doi: 10.1074/jbc.M809542200][Adams J.S, Hewison M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys. 2012;523:95-102. doi: 10.1016/j.abb.2012.02.016][Noff D, Edelstein S. Vitamin D and its hydroxylated metabolites in the rat. Placental and lacteal transport, subsequent metabolic pathways and tissue distribution. Horm Res. 1978;9:292-300.][Hossein-nezhad A, Holick M.F. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013 Jul;88(7):720-755. doi: 10.1016/j.mayocp.2013.05.011][Young B.E, Cooper E.M, Mc Intyre A.W, Kent T, Witter F, Harris Z.L, O’Brien K.O. Placental vitamin D receptor (VDR) expression is related to neonatal vitamin D status, placental calcium transfer, and fetal bone length in pregnant adolescents. FASEB J. 2014;28:2029-2037. doi: 10.1096/fj.13-246736][Wuertz C, Gilbert P, Baier W, Kunz C. Cross - sectional study of factors that influence the 25-hydroxyvitamin D status in pregnant women and in cord blood in Germany. Br J Nutr. 2013;110:1895-1902. doi: 10.1017/S0007114513001438][Reichetzeder C, Dwi Putra S.E, Li J, Hocher B. Developmental Origins of Disease - Crisis Precipitates Change. Cell Physiol Biochem. 2016;39:919-938. doi: 10.1159/000447801][Fetahu I.S, Höbaus J, Kállay E. Vitamin D and the epigenome. Front Physiol. 2014;5. doi: 10.3389/fphys.2014.0][Barker D.J, Eriksson J.G, Forsen T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol. 2002;31(6):1235-1239.][Morris G.S, Zhou Q, Hegsted M, Keenan M.J. Maternal consumption of a low vitamin D diet retards metabolic and contractile development in the neonatal rat heart. J Mol Cell Cardiol. 1995;27(6):1245-1250.][Maka N, Makrakis J, Parkington H.C, Tare M, Morley R, Black M.J. Vitamin D deficiency during pregnancy and lactation stimulates nephrogenesis in rat offspring. Pediatr Nephrol. 2008;23(1):55-61. doi: 10.1007/s00467-007-0641-9][Xue J, Schoenroc S.A, Valdar K.W, Tarantino L.M, Ideraabdullah F.Y. Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clin Epigenetics. 2016;8:107. doi: 10.1186/s13148-016-0276-4][Junge K.M, Bauer T, Geissler S, Hirche F, Thurmann L, Bauer M, Trump S, Bieg M, Weichenhan D, Gu L, et al. Increased vitamin D levels at birth and in early infancy increase offspring allergy risk - evidence for involvement of epigenetic mechanisms. J Allergy Clin Immunol. 2015;137:610-613. doi: 10.1016/j.jaci.2015.06.040][Suderman M, Stene L.C, Bohlin J, Page C.M, Holvik K, Parr C.L, Magnus M.C, Håberg S.E, Joubert B.R, Wu M.C, London S.J, Relton C, Nystad W. 25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC). J Steroid Biochem Mol Biol. 2016;159:102-109. doi: 10.1016/j.jsbmb.2016.03.005][Hossein-nezhad A, Spira A, Holick M.F. Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double - blind clinical trial. PLoS One. 2013;8(3):e58725. doi: 10.1371/journal.pone.0058725][Zhou Y, Zhao L.J, Xu X, Ye A, Travers-Gustafson D, Zhou B, Wang H-W, Zhang W, Lee Hamm L, Deng H-W, Recker R.R, Lappe J.M. DNA methylation levels of CYP2R1 and CYP24A1 predict vitamin D response variation. J Steroid Biochem Mol Biol. 2014;144 Pt A:207-214. doi: 10.1016/j.jsbmb.2013.10.004][Bärebring L, Schoenmakers I, Glantz A, Hulthén L, Jagner Å, Ellis J, Bärebring M, Bullarbo M, Augustin H, Vitamin D. Status during Pregnancy in a Multi-Ethnic Population-Representative Swedish Cohort. Nutrients. 2016;8. doi: 10.3390/nu8100655][Crozier S.R, Harvey N.C, Inskip H.M, Godfrey K.M, Cooper C, Robinson S.M, the S.S. Group. Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: findings from the Southampton Women’s Survey. Am J Clin Nutr. 2012;96:57-63. doi: 10.3945/ajcn.112.037473][Vinkhuyzen A, Eyles D, Burne T, Blanken L, Kruithof C, Verhulst F, et al. Prevalence and predictors of vitamin D deficiency based on maternal mid - gestation and neonatal cord bloods: the Generation R Study. J Steroid Biochem Mol Biol. 2015. doi: 10.1016/j.jsbmb.2015.09.018][Perampalam S, Ganda K, Chow K-A, Opie N, Hickman P.E, Shadbolt B, Hennessy A, Grunstein H, Nolan C.J. Vitamin D status and its predictive factors in pregnancy in 2 Australian populations. Aust N Z J Obstet Gynaecol. 2011;51:353-359. doi: 10.1111/j.1479-828X.2011.01313.x][Nobles C.J, Markenson G, Chasan-Taber L. Early pregnancy vitamin D status and risk for adverse maternal and infant outcomes in a bi - ethnic cohort: the Behaviors Affecting Baby and You (B.A.B.Y.) Study. Br J Nutr. 2015;215:2116-2128. doi: 10.1017/S0007114515003980][Haggarty P, Campbell D, Knox S, Horgan G, Hoad G, Boulton E, et al. Vitamin D in pregnancy at high latitude in Scotland. Br J Nutr. 2013;109:898-905. doi: 10.1017/S0007114512002255][Mcgrath J, Eyles D, Pedersen C, Anderson C, Ko P, Burne T, et al. (2010) Neonatal vitamin D status and risk of schizophrenia: a population - based case - control study. Arch Gen Psychiatry. 2010;67:889-894. doi: 10.1001/archgenpsychiatry.2010.110][Day F, Forouhi N, Ong K, Perry J. (2015) Season of birth is associated with birth weight, pubertal timing, adult body size and educational attainment: a UK Biobank study. Heliyon. 2015;1:e00031. doi: 10.1016/j.heliyon.2015.e00031][Wagner C.L, Greer F.R, American Academy of Pediatrics Section on B, American Academy of Pediatrics Committee on N. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142-1152. doi: 10.1542/peds.2008-1862][Gernand A.D, Bodnar L.M, Klebanoff M.A, Parks W.T, Simhan H.N. Maternal serum 25-hydroxyvitamin D and placental vascular pathology in a multicenter US cohort. Am J Clin Nutr. 2013;98(2):383-388.][Murthi P, Yong H.E, Ngyuen T.P, Ellery S, Singh H, Rahman R, et al. Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies. Front Physiol. 2016;7:43. doi: 10.3389/fphys.2016.00043][Evans K.N, Bulmer J.N, Kilby M.D, Hewison M. Vitamin D and placental - decidual function. J Soc Gynecol Investig. 2004;11:263-271. doi: 10.1016/j.jsgi.2004.02.002][Barrera D, Avila E, Hernández G, Halhali A, Biruete B, Larrea F, Díaz L. Estradiol and progesterone synthesis in human placenta is stimulated by calcitriol. J Steroid Biochem Mol Biol. 2007;103:529-532. doi: 10.1016/j.jsbmb.2006.12.097][Du H, Daftary G.S, Lalwani S.I, Taylor H.S. Direct regulation of HOXA10 by 1,25-(OH)2D3 in human myelomonocytic cells and human endometrial stromal cells. Mol Endocrinol. 2005 Sep;19(9):2222-2233. doi: 10.1210/me.2004-0336][Liu N.Q, Kaplan A.T, Lagishetty V, Ouyang Y.B, Ouyang Y, Simmons C.F, et al. Vitamin D and the regulation of placental inflammation. J Immunol. 2011;186(10):5968-5974. doi: 10.4049/jimmunol.1003332][Пигарова Е.А., Плещева А.В., Дзеранова Л.К. Влияние витамина D на иммунную систему. Иммунология. 2015;(1):62-66.][Barrera D, Avila E, Hernández G, Méndez I, González L, Halhali A, Larrea F, Morales A, Díaz L. Calcitriol affects hCG gene transcription in cultured human. Reprod Biol Endocrinol. 2008 Jan 22;6:3. doi: 10.1186/1477-7827-6-3][Díaz L, Noyolaartínez N, Barrera D, Hernández G, Avila E, Halhali A, Larrea F. Calcitriol inhibits TNF-alpha - induced inflammatory cytokines in human trophoblasts. J Reprod Immunol. 2009;81:17-24. doi: 10.1016/j.jri.2009.02.005][Rolle L, Memarzadeh Tehran M, Morell-García A, Raeva Y, Schumacher A, Hartig R, Costa S.D, Jensen F, Zenclussen A.C. Cutting edge: IL-10-producing regulatory B cells in early human pregnancy. Am J Reprod Immunol. 2013 Dec;70(6):448-453. doi: 10.1111/aji.12157][Grayson R, Hawison, M. Vitamin D and human pregnancy. Fetal Maternal Med Rev. 2011;22(1):67-90. doi: 10.1017/S0965539511000039][Selvaraj P. Vitamin D, vitamin D receptor, and cathelicidin in the treatment of tuberculosis. Vitam Horm. 2011;86:307-25. doi: 10.1016/B978-0-12-386960-9.00013-7][Van Oostrum N, De Sutter P, Meys J, Verstraelen H. Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta - analysis. Hum Reprod. 2013;28(7):1809-1815. doi: 10.1093/humrep/det096][Christesen H.T, Falkenberg T, Lamont R.F, Jorgensen J.S. The impact of vitamin D on pregnancy: a systematic review. Acta Obstet Gynecol Scand. 2012;91(12):1357-1367. doi: 10.1111/aogs.12006][Сидорова И.С. Решенные вопросы и нерешенные проблемы преэклампсии в России. Российский вестник акушера - гинеколога. 2015;15(2):4. doi: 10.17116/rosakush20151524-9][Ghulmiyyah L, Sibai В. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012 Feb;36(1):56-59. doi: 10.1053/j.semperi.2011.09.011][Hypponen E. Vitamin D for the prevention of preeclampsia? A hypothesis. Nutr Rev. 2005;63(7):225-232. doi: 10.1301/nr.2005.jul.225-232][Girardi G, Yarilin D, Thurman J.M, Holers V.M, Salmon J.E. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006 Sep 4;203(9):2165-2175. doi: 10.1084/jem.20061022][Romero R, Nien J.K, Espinoza J, Todem D, Fu W, Chung H, Kusanovic J.P, Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine R.J, Karumanchi S.A. A longitudinal study of angiogenic (placental growth factor) and anti - angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008 Jan;21(1):9-23. doi: 10.1080/14767050701830480][Mulligan M.L, Felton S.K, Riek A.E, Bernal-Mizrachi C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol. 2010;202(5):429 e1-9. doi: 10.1016/j.ajog.2009.09.002][Mirzakhani H, Litonjua A.A, Mc Elrath T.F, O'Connor G, Lee-Parritz A, Iverson R, et al. Early pregnancy vitamin D status and risk of preeclampsia. J Clin Invest. 2016;126(12):4702-4715. doi: 10.1172/JCI89031][Pérez-López R, Pasupuleti V, Mezones-Holguin E, Benites-Zapata V.A, Thota P, Deshpande A, Hernandez A.V. Effect of vitamin D supplementation during pregnancy on maternal and neonatal outcomes: a systematic review and meta - analysis of randomized controlled trials. Fertil Steril. 2015;103:1278-1288.e4. doi: 10.1016/j.fertnstert.2015.02.019][Boyle V.T, Thorstensen E.B, Mourath D, Jones M.B, Mc Cowan L.M.E, Kenny L.C, Baker P.N. The relationship between 25-hydroxyvitamin D concentration in early pregnancy and pregnancy outcomes in a large, prospective cohort. Br J Nutr. 2016;116:1409-1415. doi: 10.1017/S0007114516003202][De-Regil L.M, Palacios C, Lombardo L.K, Peña-Rosas J.P. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2016;1:CD008873. doi: 10.1002/14651858.CD008873.pub3][Robinson C.J, Alanis M.C, Wagner C.L, Hollis B.W, Johnson D.D. Plasma 25-hydroxy vitamin D levels in early - onset severe preeclampsia. Am J Obstet Gynecol. 2010;203:e361-e366.][Wagner C.L, Mc Neil R, Hamilton S.A, Winkler J, Rodriguez Cook C, Warner G, Bivens B, Davis D.J, Smith P.G, Murphy M, Shary J.R, Hollis B.W. A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. Am J Obstet Gynecol. 2013;208137.e1-13. doi: 10.1016/j.ajog.2012.10.888][Li N, Wu H.M, Hang F, Zhang Y.S, Li M.J. Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal - maternal interface. Brazil J Med Biol Res. 2017;50(11):e6527. doi: 10.1590/1414-431X20176527][Vijayendra C.A, Hemalatha R, Seshacharyulu M, Vasudeva M.M, Jayaprakash D, Dinesh K.B. Vitamin D deficiency in pregnant women impairs regulatory T cell function. J Steroid Biochem Mol Biol. 2014;147:48-55. doi: 10.1016/j.jsbmb.2014.11.020][Hamzaoui A, Berraïes A, Hamdi B, Kaabachi W, Ammar J, Hamzaoui K. Vitamin D reduces the differentiation and expansion of Th17 cells in young asthmatic children. Immunobiology. 2014;219:873-879. doi: 10.1016/j.imbio.2014.07.009][Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96:365-408. doi: 10.1152/physrev.00014.2015][Taheri M, Baheiraei A, Foroushani A.R, Nikmanesh B, Modarres M. Treatment of vitamin D deficiency is an effective method in the elimination of asymptomatic bacterial vaginosis: A placebo - controlled randomized clinical trial. Indian J Med Res. 2015 Jun;141(6):799-806. doi: 10.4103/0971-5916.160707][Hollis B.W, Johnson D, Hulsey T.C, Ebeling M, Wagner C.L. Vitamin D supplementation during pregnancy: double - blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-2357. doi: 10.1002/jbmr.463][Gernand A.D, Klebanoff M.A, Simhan H.N, Bodnar L.M. Maternal vitamin D status, prolonged labor, cesarean delivery and instrumental delivery in an era with a low cesarean rate. J Perinatol. 2015;35:23-28. doi: 10.1038/jp.2014.139][Merewood A, Mehta S.D, Chen T.C, Bauchner H, Holick M.F. Association between Vitamin D Deficiency and Primary Cesarean Section. J Clin Endocrinol Metab. 2009;94:940-945. doi: 10.1210/jc.2008-1217][Savvidou M.D, Makgoba M, Castro P.T, Akolekar R, Nicolaides K.H. First - trimester maternal serum vitamin D and mode of delivery. Br J Nutr. 2012;108:1972-1975. doi: 10.1017/S0007114512000207][Scholl T.O, Chen X, Stein P. Maternal Vitamin D Status and Delivery by Cesarean. Nutrients. 2012;4:319-330. doi: 10.3390/nu4040319][Cho N.H. IDF Diabetes Atlas. 7th ed. Brussels: International Diabetes Federation; 2015.][Burris H.H, Camargo C.A.Jr. Vitamin D and gestational diabetes mellitus. Curr Diab Rep. 2014;14(1):451. doi: 10.1007/s11892-013-0451-3][Soheilykhah S, Mojibian M, Rashidi M, Rahimi-Saghand S, Jafari F. Maternal vitamin D status in gestational diabetes mellitus. Nutr Clin Pract. 2010;25(5):524-527. doi: 10.1177/0884533610379851][Pittas A.G, Lau J, Hu F.B, et al. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta - analysis. J Clin Endocrinol Metab. 2007;92:2017-2029. doi: 10.1210/jc.2007-0298][Wei S.Q, Qi H.P, Luo Z.C, Fraser W.D. Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta - analysis. J Matern Fetal Neonatal Med. 2013 Jun;26(9):889-899. doi: 10.3109/14767058.2013.765849][Poel Y.H, Hummel P, Lips P et al. Vitamin D and gestational diabetes: a systematic review and meta - analysis. Eur J Intern Med. 2012 Jul;23(5):465-469. doi: 10.1016/j.ejim.2012.01.007][Lu M, Xu Y, Lv L, Zhang M. Association between vitamin D status and the risk of gestational diabetes mellitus: a meta - analysis. Arch Gynecol Obstet. 2016. doi: 10.1007/s00404-016-4010-4][Zhou J, Su L, Liu M, Liu Y, Cao X, Wang Z, Xiao H. Associations between 25-hydroxyvitamin D levels and pregnancy outcomes: a prospective observational study in southern China. Eur J Clin Nutr. 2014;68:925-930. doi: 10.1038/ejcn.2014.99][Soheilykhah S, Mojibian M, Moghadam M.J, Shojaoddiny-Ardekani A. The effect of different doses of vitamin D supplementation on insulin resistance during pregnancy. Gynecol Endocrinol. 2013;29(4):396-399. doi: 10.3109/09513590.2012.752456][Yap C, Cheung N.W, Gunton J.E et al. Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. Diabetes Care. 2014 Jul;37(7):1837-1844. doi: 10.2337/dc14-0155][Akbari M, Mosazadeh M, Lankarani K.B, Tabrizi R, Samimi M, Karamali M, Jamilian M, Kolahdooz F, Asemi Z. The Effects of Vitamin D Supplementation on Glucose Metabolism and Lipid Profiles in Patients with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Horm Metab Res. 2017 Sep;49(9):647-653. doi: 10.1055/s-0043-115225][Curtis E.M, Moon R.J, Dennison E.M, Harvey N.C. Prenatal calcium and vitamin D intake, and bone mass in later life. Curr Osteoporos Rep. 2014;12:194-204. doi: 10.1007/s11914-014-0210-7][Glazier D, Mawer E.B, Sibley C.P, Calbindin-D9K gene expression in rat chorioallantoic placenta is not regulated by 1,25-dihydroxyvitamin D3. Pediatr Res. 1995;37:720-725. doi: 10.1203/00006450-199506000-00008][Kovacs C.S, Woodland M.L, Fudge N.J, Friel J.K. The vitamin D receptor is not required for fetal mineral homeostasis or for the regulation of placental calcium transfer in mice. Am J Physiol Endocrinol Metab. 2005;289:E133-144. doi: 10.1152/ajpendo.00354.2004][Javaid M.K, Crozier S.R, Harvey N.C, Gale C.R, Dennison E.M, Boucher B.J, Arden N.K, Godfrey K.M, Cooper C. Princess Anne Hospital Study Group, Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet. 2006;367:36-43. doi: 10.1016/S0140-6736(06)67922-1][Lawlor D.A, Wills A.K, Fraser A, Sayers A, Fraser W.D, Tobias J.H. Association of maternal vitamin D status during pregnancy with bone - mineral content in offspring: a prospective cohort study. Lancet. 2013;381:2176-2183. doi: 10.1016/S0140-6736(12)62203-X][Cooper C, Harvey N.C, Bishop N.J, Kennedy S, Papageorghiou A.T, Schoenmakers I, Fraser R, Gandhi S.V, Carr A, D’Angelo S, Crozier S.R, Moon R.J, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double - blind, randomised placebo - controlled trial. Lancet Diabetes Endocrin. 2016;4(5):393-402. doi: 10.1016/S2213-8587(16)00044-9][Miliku K, Vinkhuyzen A, Blanken L.M, Mc Grath J.J, Eyles D.W, Burne T.H, Hofman A, Tiemeier H, Steegers E.A, Gaillard R, Jaddoe V.W. Maternal vitamin D concentrations during pregnancy, fetal growth patterns, and risks of adverse birth outcomes. Am J Clin Nutr. 2016. doi: 10.3945/ajcn.115.123752][Chen Y-H, Fu L, Hao J-H, Yu Z, Zhu P, Wang H, Xu Y-Y, Zhang C, Tao F-B, Xu D-X. Maternal vitamin D deficiency during pregnancy elevates the risks of small for gestational age and low birth weight infants in Chinese population. J Clin Endocrinol Metab. 2015;100:1912-1919. doi: 10.1210/jc.2014-4407.J][Tyrrell J, Richmond R.C, Palmer T.M, Feenstra B, Rangarajan J, Metrustry S, Cavadino A, Paternoster L, Armstrong L.L. Early Growth Genetics (EGG) Consortium, Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. JAMA. 2016;315:1129-1140. doi: 10.1001/jama.2016.1975][Walsh J.M, Mc Gowan C.A, Kilbane M, Mc Kenna M.J, Mc Auliffe F.M. The Relationship Between Maternal and Fetal Vitamin D, Insulin Resistance, and Fetal Growth. Reprod Sci. 2013;20(5):536-541. doi: 10.1177/1933719112459222][Leffelaar E.R, Vrijkotte T.G.M, van Eijsden M. Maternal early pregnancy vitamin D status in relation to fetal and neonatal growth: results of the multi - ethnic Amsterdam Born Children and their Development cohort. Br J Nutr. 2010;104:108-117. doi: 10.1017/S000711451000022X][Marjamäki L, Niinistö S, Kenward M.G, Uusitalo L, Uusitalo U, Ovaskainen M-L, Kronberg-Kippilä C, Simell O, Veijola O.R, Ilonen J, Knip M, Virtanen S.M. Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring. Diabetologia. 2010;53:1599-1607. doi: 10.1007/s00125-010-1734-8][Stene L.C, Joner G. Norwegian Childhood Diabetes Study Group, 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;78:1128-1134.][Sørensen I.M, Joner G, Jenum P.A, Eskild A, Torjesen P.A, Stene L.C. Maternal serum levels of 25-hydroxyvitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes. 2012;61:175-178. doi: 10.2337/db11-0875][Brekke H.K, Ludvigsson J. Vitamin D supplementation and diabetes - related autoimmunity in the ABIS study. Pediatr Diabetes. 2007;8:11-14. doi: 10.1111/j.1399-5448.2006.00223.x][Hyppönen E, Läärä E, Reunanen A, Järvelin M.R, Virtanen S.M. Intake of vitamin D and risk of type 1 diabetes: a birth - cohort study. Lancet. 2001;358:1500-1503. doi: 10.1016/S0140-6736(01)06580-1][Fronczak C.M, Barón A.E, Chase H.P, Ross C, Brady H.L, Hoffman M, Eisenbarth G.S, Rewers M, Norris J.M. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care. 2003;26:3237-3242.][Munger K.L, Åivo J, Hongell K, Soilu-Hänninen M, Surce H-M, Ascherio A. 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. doi: 10.1001/jamaneurol.2015.4800][Erkkola M, Kaila M, Nwarг B.I, Kronberg-Kippilä C, Ahonen S, Nevalainen J, Veijola R, Pekkanen J, Ilonen J, Simell O, Knip M, Virtanen S.M. Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year - old children. Clin Exp Allergy. 2009;39:875-882. doi: 10.1111/j.1365-2222.2009.03234.x][Weisse K, Winkler S, Hirche F, Herberth G, Hinz D, Bauer M, Röder S, Rolle-Kampczyk U, von Bergen M, Olek S, Sack U, Richter T, Diez U, Borte M, Stangl G.I, Lehmann I. Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy. 2013;68:220-228. doi: 10.1111/all.12081][Zosky G.R, Hart P.H, Whitehouse A.J.O, et al. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc. 2014;11(4):571-577. doi: 10.1513/AnnalsATS.201312-423OCpmid:24601713][Camargo C.A. Jr, Ingham T, Wickens K, et al. Cord - blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics. 2011;127(1): e180-e187. doi: 10.1542/peds.2010-0442][Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91(5):1255-1260. doi: 10.3945/ajcn.2009.29094][Levenson C.W, Figueirôa S.M. Gestational vitamin D deficiency: long - term effects on the brain. Nutr Rev. 2008;66:726-729. doi: 10.1111/j.1753-4887.2008.00122.x][Eyles D, Brown J, Mackay-Sim A, et al. Vitamin D3 and brain development. Neuroscience. 2003;118:641-653. doi: 10.1016/s0306-4522(03)00040-x][Grant W.B, Soles C.M. Epidemiologic evidence supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism. Dermatoendocrinology. 2009;1:223-228.][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. doi: 10.1016/j.mehy.2016.01.015][N. and A. (NDA) EFSA Panel on Dietetic Products, Dietary reference values for vitamin D. EFSA J. 2016;14:n/a-n/a. doi: 10.2903/j.efsa.2016.4547][Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011.][Munns C.F, Shaw N, Kiely M, Specker B.L, Thacher T.D, Ozono K, Michigami T, Tiosano D, et al. Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. J Clin Endocrinol Metab. 2016;101:394-415. doi: 10.1210/jc.2015-2175][Dawodu A, Saadi H.F, Bekdache G, Javed Y, Altaye M, Hollis B.W. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab. 2013;98:2337-2346. doi: 10.1210/jc.2013-1154][Grant C.C, Stewart A.W, Scragg R, Milne T, Rowden J, Ekeroma A, Wall C, Mitchell E.A, Crengle S, Trenholme A, Crane J, Camargo C.A. Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics. 2014;133:e143-153. doi: 10.1542/peds.2013-2602]