Skip to main content

Advertisement

Log in

Maternal and fetal vitamin D and their roles in mineral homeostasis and fetal bone development

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

During pregnancy, female physiology adapts to meet the additional mineral demands of the developing fetus. Meanwhile, the fetus actively transports minerals across the placenta and maintains high circulating levels to mineralize the rapidly developing skeleton. Most of this mineral is accreted during the last trimester, including 30 g of calcium, 20 g of phosphate and 0.8 g of magnesium. Given the dependence of calcium homeostasis on vitamin D and calcitriol in the adult and child, it may be expected that vitamin D sufficiency would be even more critical during pregnancy and fetal development. However, the pregnant mother and fetus appear to meet their mineral needs independent of vitamin D. Adaptations in maternal mineral and bone metabolism during pregnancy appear to be invoked independent of maternal vitamin D, while fetal mineral metabolism and skeletal development appear to be protected from vitamin D deficiency and genetic disorders of vitamin D physiology. This review discusses key data from both animal models and human studies to address our current knowledge on the role of vitamin D and calcitriol during pregnancy and fetal development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kovacs CS (2016) Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev 96(2):449–547. https://doi.org/10.1152/physrev.00027.2015

    Article  CAS  PubMed  Google Scholar 

  2. Kovacs CS (2014) Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev 94(4):1143–1218. https://doi.org/10.1152/physrev.00014.2014

    Article  CAS  PubMed  Google Scholar 

  3. Kovacs CS, Chakhtoura M, El-Hajj Fuleihan G (2019) Disorders of mineral and bone metabolism during pregnancy and lactation. In: Kovacs CS, Deal CL (eds) Maternal-fetal and neonatal endocrinology: physiology, pathophysiology, and clinical management. Academic Press, San Diego, pp 329–370

    Google Scholar 

  4. Kovacs CS, Ward LE (2019) Disorders of calcium, phosphorus, and bone metabolism during fetal and neonatal development. In: Kovacs CS, Deal CL (eds) Maternal-fetal and neonatal endocrinology: physiology, pathophysiology, and clinical management. Academic Press, San Diego, pp 755–782

    Google Scholar 

  5. Widdowson EM, Dickerson JW (1964) Chemical composition of the body. In: Comar CL, Bronner F (eds) Mineral metabolism: an advanced treatise, volume II, The elements, Part A. Academic Press, New York, pp 1–247

    Google Scholar 

  6. Givens MH, Macy IC (1933) The chemical composition of the human fetus. J Biol Chem 102:7–17

    Article  CAS  Google Scholar 

  7. Hunt CD, Johnson LK (2007) Calcium requirements: new estimations for men and women by cross-sectional statistical analyses of calcium balance data from metabolic studies. Am J Clin Nutr 86(4):1054–1063. https://doi.org/10.1093/ajcn/86.4.1054

    Article  CAS  PubMed  Google Scholar 

  8. Ross AC, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Manson JE, Mayne ST, Rosen CJ, Shapses SA (2011) Dietary reference intakes for calcium and vitamin D. Institute of Medicine, Washington, DC. doi: 10.17226/13050

  9. Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE (1995) Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 61(3):514–523. https://doi.org/10.1093/ajcn/61.3.514

    Article  CAS  PubMed  Google Scholar 

  10. Heaney RP, Skillman TG (1971) Calcium metabolism in normal human pregnancy. J Clin Endocrinol Metab 33(4):661–670. https://doi.org/10.1210/jcem-33-4-661

    Article  CAS  PubMed  Google Scholar 

  11. Kent GN, Price RI, Gutteridge DH, Rosman KJ, Smith M, Allen JR, Hickling CJ, Blakeman SL (1991) The efficiency of intestinal calcium absorption is increased in late pregnancy but not in established lactation. Calcif Tissue Int 48:293–295

    Article  CAS  PubMed  Google Scholar 

  12. Kent GN, Price RI, Gutteridge DH, Allen JR, Blakeman SL, Bhagat CI, St John A, Barnes MP, Smith M, Evans DV (1991) Acute effects of an oral calcium load in pregnancy and lactation: findings on renal calcium conservation and biochemical indices of bone turnover. Miner Electrolyte Metab 17(1):1–7

    CAS  PubMed  Google Scholar 

  13. Gertner JM, Coustan DR, Kliger AS, Mallette LE, Ravin N, Broadus AE (1986) Pregnancy as state of physiologic absorptive hypercalciuria. Am J Med 81:451–456

    Article  CAS  PubMed  Google Scholar 

  14. Ritchie LD, Fung EB, Halloran BP, Turnlund JR, Van Loan MD, Cann CE, King JC (1998) A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. Am J Clin Nutr 67(4):693–701

    Article  CAS  PubMed  Google Scholar 

  15. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS (2006) Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology 147(9):4010–4021. https://doi.org/10.1210/en.2005-1616

    Article  CAS  PubMed  Google Scholar 

  16. Fudge NJ, Kovacs CS (2010) Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor. Endocrinology 151(3):886–895. https://doi.org/10.1210/en.2009-1010

    Article  CAS  PubMed  Google Scholar 

  17. Gillies BR, Ryan BA, Tonkin BA, Poulton IJ, Ma Y, Kirby BJ, St-Arnaud R, Sims NA, Kovacs CS (2018) Absence of calcitriol causes increased lactational bone loss and lower milk calcium but does not impair post-lactation bone recovery in Cyp27b1 null mice. J Bone Miner Res 33(1):16–26. https://doi.org/10.1002/jbmr.3217

    Article  CAS  PubMed  Google Scholar 

  18. Kirby BJ, Ardeshirpour L, Woodrow JP, Wysolmerski JJ, Sims NA, Karaplis AC, Kovacs CS (2011) Skeletal recovery after weaning does not require PTHrP. J Bone Miner Res 26(6):1242–1251. https://doi.org/10.1002/jbmr.339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kirby BJ, Ma Y, Martin HM, Buckle Favaro KL, Karaplis AC, Kovacs CS (2013) Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone. J Bone Miner Res 28(9):1987–2000. https://doi.org/10.1002/jbmr.1925

    Article  CAS  PubMed  Google Scholar 

  20. Goss H, Schmidt CL (1930) Calcium and phosphorus metabolism in rats during pregnancy and lactation and the influence of the reaction of the diet thereon. J Biol Chem 86:417–432

    Article  CAS  Google Scholar 

  21. Miller SC, Shupe JG, Redd EH, Miller MA, Omura TH (1986) Changes in bone mineral and bone formation rates during pregnancy and lactation in rats. Bone 7(4):283–287. https://doi.org/10.1016/8756-3282(86)90209-7

    Article  CAS  PubMed  Google Scholar 

  22. Benzie D, Boyne AD, Dalgarno AC, Duckworth J, Hill R, Walker DM (1955) Studies of the skeleton of the sheep. 1. The effect of different level of dietary calcium during pregnancy and lactation on individual bone. J Agric Sci 46:425–444

    Article  CAS  Google Scholar 

  23. Naylor KE, Iqbal P, Fledelius C, Fraser RB, Eastell R (2000) The effect of pregnancy on bone density and bone turnover. J Bone Miner Res 15(1):129–137. https://doi.org/10.1359/jbmr.2000.15.1.129

    Article  CAS  PubMed  Google Scholar 

  24. Black AJ, Topping J, Durham B, Farquharson RG, Fraser WD (2000) A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy. J Bone Miner Res 15(3):557–563. https://doi.org/10.1359/jbmr.2000.15.3.557

    Article  CAS  PubMed  Google Scholar 

  25. Ulrich U, Miller PB, Eyre DR, Chesnut CH 3rd, Schlebusch H, Soules MR (2003) Bone remodeling and bone mineral density during pregnancy. Arch Gynecol Obstet 268(4):309–316. https://doi.org/10.1007/s00404-002-0410-8

    Article  CAS  PubMed  Google Scholar 

  26. Kaur M, Pearson D, Godber I, Lawson N, Baker P, Hosking D (2003) Longitudinal changes in bone mineral density during normal pregnancy. Bone 32(4):449–454. https://doi.org/10.1016/s8756-3282(03)00017-6

    Article  CAS  PubMed  Google Scholar 

  27. Pearson D, Kaur M, San P, Lawson N, Baker P, Hosking D (2004) Recovery of pregnancy mediated bone loss during lactation. Bone 34(3):570–578. https://doi.org/10.1016/j.bone.2003.11.005

    Article  CAS  PubMed  Google Scholar 

  28. Moller UK, Vieth Streym S, Mosekilde L, Rejnmark L (2012) Changes in bone mineral density and body composition during pregnancy and postpartum. A controlled cohort study. Osteoporos Int 23(4):1213–1223. https://doi.org/10.1007/s00198-011-1654-6

    Article  CAS  PubMed  Google Scholar 

  29. Kovacs CS, Ralston SH (2015) Presentation and management of osteoporosis presenting in association with pregnancy or lactation. Osteoporos Int 26(9):2223–2241. https://doi.org/10.1007/s00198-015-3149-3

    Article  CAS  PubMed  Google Scholar 

  30. Dahlman T, Sjoberg HE, Bucht E (1994) Calcium homeostasis in normal pregnancy and puerperium. A longitudinal study. Acta Obstet Gynecol Scand 73(5):393–398. https://doi.org/10.3109/00016349409006250

    Article  CAS  PubMed  Google Scholar 

  31. Seki K, Makimura N, Mitsui C, Hirata J, Nagata I (1991) Calcium-regulating hormones and osteocalcin levels during pregnancy: a longitudinal study. Am J Obstet Gynecol 164(5 Pt 1):1248–1252. https://doi.org/10.1016/0002-9378(91)90694-m

    Article  CAS  PubMed  Google Scholar 

  32. Rasmussen N, Frolich A, Hornnes PJ, Hegedus L (1990) Serum ionized calcium and intact parathyroid hormone levels during pregnancy and postpartum. Br J Obstet Gynaecol 97(9):857–859. https://doi.org/10.1111/j.1471-0528.1990.tb02585.x

    Article  CAS  PubMed  Google Scholar 

  33. Gallacher SJ, Fraser WD, Owens OJ, Dryburgh FJ, Logue FC, Jenkins A, Kennedy J, Boyle IT (1994) Changes in calciotrophic hormones and biochemical markers of bone turnover in normal human pregnancy. Eur J Endocrinol 131(4):369–374. https://doi.org/10.1530/eje.0.1310369

    Article  CAS  PubMed  Google Scholar 

  34. Ardawi MS, Nasrat HA, BAAqueel HS (1997) Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol 137(4):402–409. https://doi.org/10.1530/eje.0.1370402

    Article  CAS  PubMed  Google Scholar 

  35. Moller UK, Streym S, Mosekilde L, Heickendorff L, Flyvbjerg A, Frystyk J, Jensen LT, Rejnmark L (2013) Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study. Osteoporos Int 24(4):1307–1320. https://doi.org/10.1007/s00198-012-2062-2

    Article  CAS  PubMed  Google Scholar 

  36. Bertelloni S, Baroncelli GI, Pelletti A, Battini R, Saggese G (1994) Parathyroid hormone-related protein in healthy pregnant women. Calcif Tissue Int 54(3):195–197. https://doi.org/10.1007/BF00301677

    Article  CAS  PubMed  Google Scholar 

  37. Yadav S, Yadav YS, Goel MM, Singh U, Natu SM, Negi MP (2014) Calcitonin gene- and parathyroid hormone-related peptides in normotensive and preeclamptic pregnancies: a nested case-control study. Arch Gynecol Obstet 290(5):897–903. https://doi.org/10.1007/s00404-014-3303-8

    Article  CAS  PubMed  Google Scholar 

  38. Ma Y, Samaraweera M, Cooke-Hubley S, Kirby BJ, Karaplis AC, Lanske B, Kovacs CS (2014) Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization. Endocrinology 155(5):1596–1605. https://doi.org/10.1210/en.2013-2061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Seely EW, Brown EM, DeMaggio DM, Weldon DK, Graves SW (1997) A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 176(1 Pt 1):214–217. https://doi.org/10.1016/s0002-9378(97)80039-7

    Article  CAS  PubMed  Google Scholar 

  40. Verhaeghe J, Bouillon R (1992) Calciotropic hormones during reproduction. J Steroid Biochem Mol Biol 41(3–8):469–477. https://doi.org/10.1016/0960-0760(92)90372-p

    Article  CAS  PubMed  Google Scholar 

  41. Bikle DD, Gee E, Halloran B, Haddad JG (1984) Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest 74(6):1966–1971. https://doi.org/10.1172/JCI111617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilson SG, Retallack RW, Kent JC, Worth GK, Gutteridge DH (1990) Serum free 1,25-dihydroxyvitamin D and the free 1,25-dihydroxyvitamin D index during a longitudinal study of human pregnancy and lactation. Clin Endocrinol (Oxf) 32(5):613–622. https://doi.org/10.1111/j.1365-2265.1990.tb00905.x

    Article  CAS  Google Scholar 

  43. Zhang JY, Lucey AJ, Horgan R, Kenny LC, Kiely M (2014) Impact of pregnancy on vitamin D status: a longitudinal study. Br J Nutr 112(7):1081–1087. https://doi.org/10.1017/S0007114514001883

    Article  CAS  PubMed  Google Scholar 

  44. 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(10):2341–2357. https://doi.org/10.1002/jbmr.463

    Article  CAS  PubMed  Google Scholar 

  45. Markestad T, Ulstein M, Aksnes L, Aarskog D (1986) Serum concentrations of vitamin D metabolites in vitamin D supplemented pregnant women. A longitudinal study. Acta Obstet Gynecol Scand 65(1):63–67. https://doi.org/10.3109/00016348609158232

    Article  CAS  PubMed  Google Scholar 

  46. Hillman LS, Haddad JG (1974) Human perinatal vitamin D metabolism. I. 25-Hydroxyvitamin D in maternal and cord blood. J Pediatr 84(5):742–749. https://doi.org/10.1016/s0022-3476(74)80024-7

    Article  CAS  PubMed  Google Scholar 

  47. Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, Robinson VP, Winder SM (1980) Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 280(6216):751–754. https://doi.org/10.1136/bmj.280.6216.751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Roth DE, Al Mahmud A, Raqib R, Akhtar E, Perumal N, Pezzack B, Baqui AH (2013) Randomized placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in Bangladesh: the AViDD trial. Nutr J 12(1):47. https://doi.org/10.1186/1475-2891-12-47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cooper C, Harvey NC, Javaid MK, Bishop NJ, Kennedy S, Papageorghiou AT, Fraser R, Gandhi SV, D'Angelo A, Crozier SR, Moon RJ, Arden NK, Dennison EM, Godfrey KM, Inskip HM, Schoenmakers I, Prentice A, Mughal Z, Eastell R, Reid DM (2015) Effectiveness of maternal vitamin D supplementation: a multicentre randomized, double-blind, placebo controlled trial (MAVIDOS). Osteoporos Int 26(Suppl 1):C40

    Google Scholar 

  50. Morley R, Carlin JB, Pasco JA, Wark JD (2006) Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab 91(3):906–912. https://doi.org/10.1210/jc.2005-1479

    Article  CAS  PubMed  Google Scholar 

  51. Cooper C, Harvey NC, Bishop NJ, Kennedy S, Papageorghiou AT, Schoenmakers I, Fraser R, Gandhi SV, Carr A, D’Angelo S, Crozier SR, Moon RJ, Arden NK, Dennison EM, Godfrey KM, Inskip HM, Prentice A, Mughal MZ, Eastell R, Reid DM, Javaid MK, Group MS (2016) Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 4(5):393–402. https://doi.org/10.1016/S2213-8587(16)00044-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wagner CL, McNeil R, Hamilton SA, Winkler J, Rodriguez Cook C, Warner G, Bivens B, Davis DJ, Smith PG, Murphy M, Shary JR, Hollis BW (2013) A randomized trial of vitamin D supplementation in 2 community health center networks in South Carolina. Am J Obstet Gynecol 208(2):137e1–137e13. https://doi.org/10.1016/j.ajog.2012.10.888

    Article  CAS  Google Scholar 

  53. Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS (1986) Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr 109(2):328–334. https://doi.org/10.1016/s0022-3476(86)80396-1

    Article  CAS  PubMed  Google Scholar 

  54. Turner M, Barre PE, Benjamin A, Goltzman D, Gascon-Barre M (1988) Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy? Miner Electrolyte Metab 14:246–252

    CAS  PubMed  Google Scholar 

  55. Nguyen TM, Halhali A, Guillozo H, Garabedian M, Balsan S (1988) Thyroid and parathyroid-independent increase in plasma 1,25-dihydroxyvitamin D during late pregnancy in the rat. J Endocrinol 116(3):381–385. https://doi.org/10.1677/joe.0.1160381

    Article  CAS  PubMed  Google Scholar 

  56. Pioszak AA, Parker NR, Gardella TJ, Xu HE (2009) Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides. J Biol Chem 284(41):28382–28391. https://doi.org/10.1074/jbc.M109.022905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Carpenter TO (2012) The expanding family of hypophosphatemic syndromes. J Bone Miner Metab 30(1):1–9. https://doi.org/10.1007/s00774-011-0340-2

    Article  CAS  PubMed  Google Scholar 

  58. Ohata Y, Yamazaki M, Kawai M, Tsugawa N, Tachikawa K, Koinuma T, Miyagawa K, Kimoto A, Nakayama M, Namba N, Yamamoto H, Okano T, Ozono K, Michigami T (2014) Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. J Bone Miner Res 29(7):1627–1638. https://doi.org/10.1002/jbmr.2186

    Article  CAS  PubMed  Google Scholar 

  59. Christakos S, Li S, De La Cruz J, Shroyer NF, Criss ZK, Verzi MP, Fleet JC (2020) Vitamin D and the intestine: review and update. J Steroid Biochem Mol Biol 196:105501. https://doi.org/10.1016/j.jsbmb.2019.105501

    Article  CAS  PubMed  Google Scholar 

  60. Halloran BP, DeLuca HF (1980) Calcium transport in small intestine during pregnancy and lactation. Am J Physiol 239(1):E64–68. https://doi.org/10.1152/ajpendo.1980.239.1.E64

    Article  CAS  PubMed  Google Scholar 

  61. Brommage R, Baxter DC, Gierke LW (1990) Vitamin D-independent intestinal calcium and phosphorus absorption during reproduction. Am J Physiol 259(4 Pt 1):G631–638. https://doi.org/10.1152/ajpgi.1990.259.4.G631

    Article  CAS  PubMed  Google Scholar 

  62. Kirby BJ, Ryan BA, Sellars KB, St-Arnaud R, Kovacs CS (2018) Intestinal calcium absorption increases markedly during pregnancy and lactation despite absence of the vitamin D receptor (VDR) or calcitriol. J Bone Miner Res 33:M0895

    Google Scholar 

  63. Pedersen EB, Johannesen P, Kristensen S, Rasmussen AB, Emmertsen K, Moller J, Lauritsen JG, Wohlert M (1984) Calcium, parathyroid hormone and calcitonin in normal pregnancy and preeclampsia. Gynecol Obstet Invest 18(3):156–164. https://doi.org/10.1159/000299073

    Article  CAS  PubMed  Google Scholar 

  64. Frenkel Y, Barkai G, Mashiach S, Dolev E, Zimlichman R, Weiss M (1991) Hypocalciuria of preeclampsia is independent of parathyroid hormone level. Obstet Gynecol 77:689–691

    CAS  PubMed  Google Scholar 

  65. Seely EW, Wood RJ, Brown EM, Graves SW (1992) Lower serum ionized calcium and abnormal calciotropic hormone levels in preeclampsia. J Clin Endocrinol Metab 74(6):1436–1440. https://doi.org/10.1210/jcem.74.6.1592891

    Article  CAS  PubMed  Google Scholar 

  66. Lalau JD, Jans I, el Esper N, Bouillon R, Fournier A (1993) Calcium metabolism, plasma parathyroid hormone, and calcitriol in transient hypertension of pregnancy. Am J Hypertens 6(6 Pt 1):522–527. https://doi.org/10.1093/ajh/6.6.522

    Article  CAS  PubMed  Google Scholar 

  67. Halhali A, Villa AR, Madrazo E, Soria MC, Mercado E, Diaz L, Avila E, Garabedian M, Larrea F (2004) Longitudinal changes in maternal serum 1,25-dihydroxyvitamin D and insulin like growth factor I levels in pregnant women who developed preeclampsia: comparison with normotensive pregnant women. J Steroid Biochem Mol Biol 89–90(1–5):553–556. https://doi.org/10.1016/j.jsbmb.2004.03.069

    Article  CAS  PubMed  Google Scholar 

  68. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR (2014) Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 6(6):CD001059. https://doi.org/10.1002/14651858.CD001059.pub4

    Article  Google Scholar 

  69. Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW (2013) Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab 98(6):2337–2346. https://doi.org/10.1210/jc.2013-1154

    Article  CAS  PubMed  Google Scholar 

  70. Grant CC, Stewart AW, Scragg R, Milne T, Rowden J, Ekeroma A, Wall C, Mitchell EA, Crengle S, Trenholme A, Crane J, Camargo CA Jr (2014) Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. Pediatrics 133(1):e143–153. https://doi.org/10.1542/peds.2013-2602

    Article  PubMed  Google Scholar 

  71. Vaziri F, Dabbaghmanesh MH, Samsami A, Nasiri S, Shirazi PT (2016) Vitamin D supplementation during pregnancy on infant anthropometric measurements and bone mass of mother-infant pairs: a randomized placebo clinical trial. Early Hum Dev 103:61–68. https://doi.org/10.1016/j.earlhumdev.2016.07.011

    Article  CAS  PubMed  Google Scholar 

  72. Roth DE, Morris SK, Zlotkin S, Gernand AD, Ahmed T, Shanta SS, Papp E, Korsiak J, Shi J, Islam MM, Jahan I, Keya FK, Willan AR, Weksberg R, Mohsin M, Rahman QS, Shah PS, Murphy KE, Stimec J, Pell LG, Qamar H, Al Mahmud A (2018) Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med 379(6):535–546. https://doi.org/10.1056/NEJMoa1800927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hollis BW, Wagner CL (2013) Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int 92(2):128–139. https://doi.org/10.1007/s00223-012-9607-4

    Article  CAS  PubMed  Google Scholar 

  74. Wagner CL, McNeil RB, Johnson DD, Hulsey TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW (2013) Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol 136:313–320. https://doi.org/10.1016/j.jsbmb.2013.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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. https://doi.org/10.1016/j.jsbmb.2014.11.013

    Article  CAS  PubMed  Google Scholar 

  76. Khaing W, Vallibhakara SA, Tantrakul V, Vallibhakara O, Rattanasiri S, McEvoy M, Attia J, Thakkinstian A (2017) Calcium and vitamin D supplementation for prevention of preeclampsia: a systematic review and network meta-analysis. Nutrients. https://doi.org/10.3390/nu9101141

    Article  PubMed  PubMed Central  Google Scholar 

  77. De-Regil LM, Palacios C, Lombardo LK, Pena-Rosas JP (2016) Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev 1(1):CD008873. https://doi.org/10.1002/14651858.CD008873.pub3

    Article  Google Scholar 

  78. Hypponen E, Cavadino A, Williams D, Fraser A, Vereczkey A, Fraser WD, Banhidy F, Lawlor D, Czeizel AE (2013) Vitamin D and pre-eclampsia: original data, systematic review and meta-analysis. Ann Nutr Metab 63(4):331–340. https://doi.org/10.1159/000358338

    Article  CAS  PubMed  Google Scholar 

  79. Thorne-Lyman A, Fawzi WW (2012) Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 26(Suppl 1):75–90. https://doi.org/10.1111/j.1365-3016.2012.01283.x

    Article  PubMed  Google Scholar 

  80. Roth DE, Leung M, Mesfin E, Qamar H, Watterworth J, Papp E (2017) Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials. BMJ 359:j5237. https://doi.org/10.1136/bmj.j5237

    Article  PubMed  PubMed Central  Google Scholar 

  81. Harvey NC, Holroyd C, Ntani G, Javaid K, Cooper P, Moon R, Cole Z, Tinati T, Godfrey K, Dennison E, Bishop NJ, Baird J, Cooper C (2014) Vitamin D supplementation in pregnancy: a systematic review. Health Technol Assess 18(45):1–190. https://doi.org/10.3310/hta18450

    Article  PubMed  PubMed Central  Google Scholar 

  82. Lee CY, Koren G (2010) Maternal obesity: effects on pregnancy and the role of pre-conception counselling. J Obstet Gynaecol 30(2):101–106. https://doi.org/10.3109/01443610903474355

    Article  CAS  PubMed  Google Scholar 

  83. Edouard T, Alos N, Chabot G, Roughley P, Glorieux FH, Rauch F (2011) Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J Clin Endocrinol Metab 96(1):82–89. https://doi.org/10.1210/jc.2010-1340

    Article  CAS  PubMed  Google Scholar 

  84. Marx SJ, Swart EG Jr, Hamstra AJ, DeLuca HF (1980) Normal intrauterine development of the fetus of a woman receiving extraordinarily high doses of 1,25-dihydroxyvitamin D3. J Clin Endocrinol Metab 51(5):1138–1142. https://doi.org/10.1210/jcem-51-5-1138

    Article  CAS  PubMed  Google Scholar 

  85. Malloy PJ, Tiosano D, Feldman D (2011) Hereditary 1,25-dihydroxyvitamin-D-resistant rickets. In: Feldman D, Pike JW, Adams JS (eds) Vitamin D, 3rd edn. Academic Press, San Diego, pp 1197–1232

    Chapter  Google Scholar 

  86. Kovacs CS, Ward LE (2019) Physiology of calcium, phosphorus, and bone metabolism during fetal and neonatal development. In: Kovacs CS, Deal CL (eds) Maternal-fetal and neonatal endocrinology: physiology, pathophysiology, and clinical management. Academic Press, San Diego, pp 573–586

    Google Scholar 

  87. Simmonds CS, Karsenty G, Karaplis AC, Kovacs CS (2010) Parathyroid hormone regulates fetal-placental mineral homeostasis. J Bone Miner Res 25(3):594–605. https://doi.org/10.1359/jbmr.090825

    Article  CAS  PubMed  Google Scholar 

  88. Kovacs CS, Chafe LL, Fudge NJ, Friel JK, Manley NR (2001) PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. Endocrinology 142(11):4983–4993. https://doi.org/10.1210/endo.142.11.8509

    Article  CAS  PubMed  Google Scholar 

  89. Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM (2001) Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 107(8):1007–1015. https://doi.org/10.1172/JCI11321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8(3):277–289. https://doi.org/10.1101/gad.8.3.277

    Article  CAS  PubMed  Google Scholar 

  91. Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM (1996) Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci U S A 93(26):15233–15238. https://doi.org/10.1073/pnas.93.26.15233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ma Y, Kirby BJ, Fairbridge NA, Karaplis AC, Lanske B, Kovacs CS (2017) FGF23 is not required to regulate fetal phosphorus metabolism but exerts effects within 12 hours after birth. Endocrinology 158(2):252–263. https://doi.org/10.1210/en.2016-1369

    Article  CAS  PubMed  Google Scholar 

  93. Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF (1996) Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem 271(40):24371–24381. https://doi.org/10.1074/jbc.271.40.24371

    Article  CAS  PubMed  Google Scholar 

  94. Care AD, Abbas SK, Pickard DW, Barri M, Drinkhill M, Findlay JB, White IR, Caple IW (1990) Stimulation of ovine placental transport of calcium and magnesium by mid-molecule fragments of human parathyroid hormone-related protein. Exp Physiol 75(4):605–608. https://doi.org/10.1113/expphysiol.1990.sp003437

    Article  CAS  PubMed  Google Scholar 

  95. Wieland P, Fischer JA, Trechsel U, Roth HR, Vetter K, Schneider H, Huch A (1980) Perinatal parathyroid hormone, vitamin D metabolites, and calcitonin in man. Am J Physiol 239(5):E385–390. https://doi.org/10.1152/ajpendo.1980.239.5.E385

    Article  CAS  PubMed  Google Scholar 

  96. Kovacs CS, Woodland ML, Fudge NJ, Friel JK (2005) 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 289(1):E133–144. https://doi.org/10.1152/ajpendo.00354.2004

    Article  CAS  PubMed  Google Scholar 

  97. Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM (1998) Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J Clin Invest 101(12):2812–2820. https://doi.org/10.1172/JCI2940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Johnson JA, Grande JP, Roche PC, Kumar R (1996) Ontogeny of the 1,25-dihydroxyvitamin D3 receptor in fetal rat bone. J Bone Miner Res 11(1):56–61. https://doi.org/10.1002/jbmr.5650110109

    Article  CAS  PubMed  Google Scholar 

  99. Kovacs CS, Chafe LL, Woodland ML, McDonald KR, Fudge NJ, Wookey PJ (2002) Calcitropic gene expression suggests a role for the intraplacental yolk sac in maternal-fetal calcium exchange. Am J Physiol Endocrinol Metab 282(3):E721–732. https://doi.org/10.1152/ajpendo.00369.2001

    Article  CAS  PubMed  Google Scholar 

  100. Ryan BA, Alhani K, Sellars KB, Kirby BJ, St-Arnaud R, Kaufmann M, Jones G, Kovacs CS (2019) Mineral homeostasis in murine fetuses is sensitive to maternal calcitriol but not to absence of fetal calcitriol. J Bone Miner Res 34(4):669–680. https://doi.org/10.1002/jbmr.3642

    Article  CAS  PubMed  Google Scholar 

  101. Halloran BP, De Luca HF (1981) Effect of vitamin D deficiency on skeletal development during early growth in the rat. Arch Biochem Biophys 209(1):7–14. https://doi.org/10.1016/0003-9861(81)90251-4

    Article  CAS  PubMed  Google Scholar 

  102. Miller SC, Halloran BP, DeLuca HF, Jee WS (1983) Studies on the role of vitamin D in early skeletal development, mineralization, and growth in rats. Calcif Tissue Int 35(4–5):455–460. https://doi.org/10.1007/BF02405076

    Article  CAS  PubMed  Google Scholar 

  103. Brommage R, DeLuca HF (1984) Placental transport of calcium and phosphorus is not regulated by vitamin D. Am J Physiol 246(4 Pt 2):F526–529. https://doi.org/10.1152/ajprenal.1984.246.4.F526

    Article  CAS  PubMed  Google Scholar 

  104. Lachenmaier-Currle U, Breves G, Harmeyer J (1989) Role of 1,25-(OH)2D3 during pregnancy; studies with pigs suffering from pseudo-vitamin D-deficiency rickets, type I. Q J Exp Physiol 74(6):875–881. https://doi.org/10.1113/expphysiol.1989.sp003358

    Article  CAS  PubMed  Google Scholar 

  105. Lachenmaier-Currle U, Harmeyer J (1989) Placental transport of calcium and phosphorus in pigs. J Perinat Med 17(2):127–136. https://doi.org/10.1515/jpme.1989.17.2.127

    Article  CAS  PubMed  Google Scholar 

  106. Lieben L, Stockmans I, Moermans K, Carmeliet G (2013) Maternal hypervitaminosis D reduces fetal bone mass and mineral acquisition and leads to neonatal lethality. Bone 57(1):123–131. https://doi.org/10.1016/j.bone.2013.07.029

    Article  CAS  PubMed  Google Scholar 

  107. Bruns ME, Bruns DE, Avioli LV (1979) Vitamin D-dependent calcium-binding protein of rat intestine: changes during postnatal development and sensitivity to 1,25-dihydroxycholecalciferol. Endocrinology 105(4):934–938. https://doi.org/10.1210/endo-105-4-934

    Article  CAS  PubMed  Google Scholar 

  108. Bruns ME, Wallshein V, Bruns DE (1982) Regulation of calcium-binding protein in mouse placenta and intestine. Am J Physiol 242(1):E47–52. https://doi.org/10.1152/ajpendo.1982.242.1.E47

    Article  CAS  PubMed  Google Scholar 

  109. Marche P, Delorme A, Cuisinier-Gleizes P (1978) Intestinal and placental calcium-binding proteins in vitamin D-deprived or -supplemented rats. Life Sci 23(26):2555–2561. https://doi.org/10.1016/0024-3205(78)90370-3

    Article  CAS  PubMed  Google Scholar 

  110. Glazier JD, Mawer EB, Sibley CP (1995) Calbindin-D9K gene expression in rat chorioallantoic placenta is not regulated by 1,25-dihydroxyvitamin D3. Pediatr Res 37(6):720–725. https://doi.org/10.1203/00006450-199506000-00008

    Article  CAS  PubMed  Google Scholar 

  111. Verhaeghe J, Thomasset M, Brehier A, Van Assche FA, Bouillon R (1988) 1,25(OH)2D3 and Ca-binding protein in fetal rats: relationship to the maternal vitamin D status. Am J Physiol 254(4 Pt 1):E505–512. https://doi.org/10.1152/ajpendo.1988.254.4.E505

    Article  CAS  PubMed  Google Scholar 

  112. Rummens K, van Cromphaut SJ, Carmeliet G, van Herck E, van Bree R, Stockmans I, Bouillon R, Verhaeghe J (2003) Pregnancy in mice lacking the vitamin D receptor: normal maternal skeletal response, but fetal hypomineralization rescued by maternal calcium supplementation. Pediatr Res 54(4):466–473. https://doi.org/10.1203/01.PDR.0000081302.06915.D3

    Article  CAS  PubMed  Google Scholar 

  113. Brustad N, Garland J, Thorsen J, Sevelsted A, Krakauer M, Vinding RK, Stokholm J, Bonnelykke K, Bisgaard H, Chawes BL (2020) Effect of high-dose vs standard-dose vitamin D supplementation in pregnancy on bone mineralization in offspring until age 6 years: a prespecified secondary analysis of a double-blinded, randomized clinical trial. JAMA Pediatr 174(5):1–9. https://doi.org/10.1001/jamapediatrics.2019.6083

    Article  PubMed Central  Google Scholar 

  114. Maxwell JP, Miles LM (1925) Osteomalacia in China. Proc R Soc Med 18(Obstet Gynaecol Sect):48–66

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Ward LM, Gaboury I, Ladhani M, Zlotkin S (2007) Vitamin D-deficiency rickets among children in Canada. CMAJ 177(2):161–166. https://doi.org/10.1503/cmaj.061377

    Article  PubMed  PubMed Central  Google Scholar 

  116. Teotia M, Teotia SPS, Singh RK (1979) Metabolism of fluoride in pregnant women residing in endemic fluorosis areas. Fluoride 12(2):58–64

    CAS  Google Scholar 

  117. Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, Swaminathan R, Cooper C, Godfrey K, Group SWSS (2010) Low maternal vitamin D status and fetal bone development: cohort study. J Bone Miner Res 25(1):14–19. https://doi.org/10.1359/jbmr.090701

    Article  CAS  PubMed  Google Scholar 

  118. Viljakainen HT, Saarnio E, Hytinantti T, Miettinen M, Surcel H, Makitie O, Andersson S, Laitinen K, Lamberg-Allardt C (2010) Maternal vitamin D status determines bone variables in the newborn. J Clin Endocrinol Metab 95(4):1749–1757. https://doi.org/10.1210/jc.2009-1391

    Article  CAS  PubMed  Google Scholar 

  119. Ioannou C, Javaid MK, Mahon P, Yaqub MK, Harvey NC, Godfrey KM, Noble JA, Cooper C, Papageorghiou AT (2012) The effect of maternal vitamin D concentration on fetal bone. J Clin Endocrinol Metab 97(11):E2070–2077. https://doi.org/10.1210/jc.2012-2538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C, Princess Anne Hospital Study G (2006) Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 367(9504):36–43. https://doi.org/10.1016/S0140-6736(06)67922-1

    Article  CAS  PubMed  Google Scholar 

  121. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH (2013) Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study. Lancet 381(9884):2176–2183. https://doi.org/10.1016/S0140-6736(12)62203-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Garcia AH, Erler NS, Jaddoe VWV, Tiemeier H, van den Hooven EH, Franco OH, Rivadeneira F, Voortman T (2017) 25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study. Lancet Diabetes Endocrinol 5(5):367–376. https://doi.org/10.1016/S2213-8587(17)30064-5

    Article  CAS  PubMed  Google Scholar 

  123. Hauta-Alus HH, Kajantie E, Holmlund-Suila EM, Rosendahl J, Valkama SM, Enlund-Cerullo M, Helve OM, Hytinantti TK, Viljakainen H, Andersson S, Makitie O (2019) High pregnancy, cord blood, and infant vitamin D concentrations may predict slower infant growth. J Clin Endocrinol Metab 104(2):397–407. https://doi.org/10.1210/jc.2018-00602

    Article  PubMed  Google Scholar 

  124. Kovacs CS, Kronenberg HM (1997) Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev 18(6):832–872. https://doi.org/10.1210/edrv.18.6.0319

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Supported by operating grants from the Canadian Institutes of Health Research (#165969, #133413 and #126469), and Discipline of Medicine, Memorial University [to CSK].

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. S. Kovacs.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

No informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ryan, B.A., Kovacs, C.S. Maternal and fetal vitamin D and their roles in mineral homeostasis and fetal bone development. J Endocrinol Invest 44, 643–659 (2021). https://doi.org/10.1007/s40618-020-01387-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01387-2

Keywords

Navigation