1932

Abstract

Pregnancy entails a large negative balance of iron, an essential micronutrient. During pregnancy, iron requirements increase substantially to support both maternal red blood cell expansion and the development of the placenta and fetus. As insufficient iron has long been linked to adverse pregnancy outcomes, universal iron supplementation is common practice before and during pregnancy. However, in high-resource countries with iron fortification of staple foods and increased red meat consumption, the effects of too much iron supplementation during pregnancy have become a concern because iron excess has also been linked to adverse pregnancy outcomes. In this review, we address physiologic iron homeostasis of the mother, placenta, and fetus and discuss perturbations in iron homeostasis that result in pathological pregnancy. As many mechanistic regulatory systems have been deduced from animal models, we also discuss the principles learned from these models and how these may apply to human pregnancy.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-061021-030404
2023-08-21
2024-12-04
Loading full text...

Full text loading...

/deliver/fulltext/nutr/43/1/annurev-nutr-061021-030404.html?itemId=/content/journals/10.1146/annurev-nutr-061021-030404&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Abioye AI, Park S, Ripp K, McDonald EA, Kurtis JD et al. 2018. Anemia of inflammation during human pregnancy does not affect newborn iron endowment. J. Nutr. 148:427–36
    [Google Scholar]
  2. 2.
    Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. 1996. A United States national reference for fetal growth. Obstet. Gynecol. 87:163–68
    [Google Scholar]
  3. 3.
    Allen LH. 2000. Anemia and iron deficiency: effects on pregnancy outcome. Am. J. Clin. Nutr. 71:1280S–84S
    [Google Scholar]
  4. 4.
    Arija V, Hernandez-Martinez C, Tous M, Canals J, Guxens M et al. 2019. Association of iron status and intake during pregnancy with neuropsychological outcomes in children aged 7 years: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Nutrients 11:2999
    [Google Scholar]
  5. 5.
    Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. 2007. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Investig. 117:1933–39
    [Google Scholar]
  6. 6.
    Bacon BR, Phatak P. 2022. Management and prognosis of hereditary hemochromatosis UpToDate, ed. RT Means, JS Tirnauer Wolters Kluwer Waltham, MA: accessed Nov. 1. https://www.uptodate.com/contents/management-and-prognosis-of-hereditary-hemochromatosis
    [Google Scholar]
  7. 7.
    Bah A, Pasricha SR, Jallow MW, Sise EA, Wegmuller R et al. 2017. Serum hepcidin concentrations decline during pregnancy and may identify iron deficiency: analysis of a longitudinal pregnancy cohort in the Gambia. J. Nutr. 147:1131–37
    [Google Scholar]
  8. 8.
    Barad A, Guillet R, Pressman EK, Katzman PJ, Miller RK et al. 2022. Placental iron content is lower than previously estimated and is associated with maternal iron status in women at greater risk of gestational iron deficiency and anemia. J. Nutr. 152:737–46
    [Google Scholar]
  9. 9.
    Bastin J, Drakesmith H, Rees M, Sargent I, Townsend A. 2006. Localisation of proteins of iron metabolism in the human placenta and liver. Br. J. Haematol. 134:532–43
    [Google Scholar]
  10. 10.
    Beguin Y, Lipscei G, Thoumsin H, Fillet G. 1991. Blunted erythropoietin production and decreased erythropoiesis in early pregnancy. Blood 78:89–93
    [Google Scholar]
  11. 11.
    Benson AE, Shatzel JJ, Ryan KS, Hedges MA, Martens K et al. 2022. The incidence, complications, and treatment of iron deficiency in pregnancy. Eur. J. Haematol. 109:6633–42
    [Google Scholar]
  12. 12.
    Best CM, Pressman EK, Cao C, Cooper E, Guillet R et al. 2016. Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans. FASEB J. 30:3541–50
    [Google Scholar]
  13. 13.
    Bothwell TH. 2000. Iron requirements in pregnancy and strategies to meet them. Am. J. Clin. Nutr. 72:257S–64S
    [Google Scholar]
  14. 14.
    Bowers KA, Olsen SF, Bao W, Halldorsson TI, Strom M, Zhang C. 2016. Plasma concentrations of ferritin in early pregnancy are associated with risk of gestational diabetes mellitus in women in the Danish National Birth Cohort. J. Nutr. 146:1756–61
    [Google Scholar]
  15. 15.
    Bradley J, Leibold EA, Harris ZL, Wobken JD, Clarke S et al. 2004. Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287:R894–901
    [Google Scholar]
  16. 16.
    Branum AM, Bailey R, Singer BJ. 2013. Dietary supplement use and folate status during pregnancy in the United States. J. Nutr. 143:486–92
    [Google Scholar]
  17. 17.
    Breuer W, Hershko C, Cabantchik ZI. 2000. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus. Sci. 23:185–92
    [Google Scholar]
  18. 18.
    Cao C, Fleming MD. 2016. The placenta: the forgotten essential organ of iron transport. Nutr. Rev. 74:421–31
    [Google Scholar]
  19. 19.
    Cao C, Fleming MD. 2021. Localization and kinetics of the transferrin-dependent iron transport machinery in the mouse placenta. Curr. Dev. Nutr. 5:nzab025
    [Google Scholar]
  20. 20.
    Cao C, Pressman EK, Cooper EM, Guillet R, Westerman M, O'Brien KO 2014. Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status. Reproduction 148:295–302
    [Google Scholar]
  21. 21.
    Carlberg KT, Singer ST, Vichinsky EP. 2018. Fertility and pregnancy in women with transfusion-dependent thalassemia. Hematol. Oncol. Clin. North Am. 32:297–315
    [Google Scholar]
  22. 22.
    Cent. Dis. Control Prev 2002. Iron deficiency–United States, 1999–2000. MMWR Morb. Mortal. Wkly. Rep. 51:897–99
    [Google Scholar]
  23. 23.
    Cepeda-Lopez AC, Osendarp SJ, Melse-Boonstra A, Aeberli I, Gonzalez-Salazar F et al. 2011. Sharply higher rates of iron deficiency in obese Mexican women and children are predicted by obesity-related inflammation rather than by differences in dietary iron intake. Am. J. Clin. Nutr. 93:975–83
    [Google Scholar]
  24. 24.
    Chen H, Attieh ZK, Syed BA, Kuo YM, Stevens V et al. 2010. Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells. J. Nutr. 140:1728–35
    [Google Scholar]
  25. 25.
    Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. 2003. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am. J. Clin. Nutr. 78:773–81
    [Google Scholar]
  26. 26.
    Cornock R, Gambling L, Langley-Evans SC, McArdle HJ, McMullen S. 2013. The effect of feeding a low iron diet prior to and during gestation on fetal and maternal iron homeostasis in two strains of rat. Reproductive Biol. Endocrinol. 11:32
    [Google Scholar]
  27. 27.
    Corwin EJ, Murray-Kolb LE, Beard JL. 2003. Low hemoglobin level is a risk factor for postpartum depression. J. Nutr. 133:4139–42
    [Google Scholar]
  28. 28.
    Cox B, Kotlyar M, Evangelou AI, Ignatchenko V, Ignatchenko A et al. 2009. Comparative systems biology of human and mouse as a tool to guide the modeling of human placental pathology. Mol. Syst. Biol. 5:279
    [Google Scholar]
  29. 29.
    Dao MC, Sen S, Iyer C, Klebenov D, Meydani SN. 2013. Obesity during pregnancy and fetal iron status: Is hepcidin the link?. J. Perinatol. 33:177–81
    [Google Scholar]
  30. 30.
    Delaney KM, Guillet R, Pressman EK, Ganz T, Nemeth E, O'Brien KO 2021. Serum erythroferrone during pregnancy is related to erythropoietin but does not predict the risk of anemia. J. Nutr. 151:1824–33
    [Google Scholar]
  31. 31.
    Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI et al. 2005. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 1:191–200
    [Google Scholar]
  32. 32.
    Du X, She E, Gelbart T, Truksa J, Lee P et al. 2008. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320:1088–92
    [Google Scholar]
  33. 33.
    Evans P, Cindrova-Davies T, Muttukrishna S, Burton GJ, Porter J, Jauniaux E. 2011. Hepcidin and iron species distribution inside the first-trimester human gestational sac. Mol. Hum. Reprod. 17:227–32
    [Google Scholar]
  34. 34.
    Faupel-Badger JM, Hsieh CC, Troisi R, Lagiou P, Potischman N. 2007. Plasma volume expansion in pregnancy: implications for biomarkers in population studies. Cancer Epidemiol. Biomarkers Prev. 16:1720–23
    [Google Scholar]
  35. 35.
    Fillebeen C, Gkouvatsos K, Fragoso G, Calve A, Garcia-Santos D et al. 2015. Mice are poor heme absorbers and do not require intestinal Hmox1 for dietary heme iron assimilation. Haematologica 100:e334–37
    [Google Scholar]
  36. 36.
    Finkenstedt A, Widschwendter A, Brasse-Lagnel CG, Theurl I, Hubalek M et al. 2012. Hepcidin is correlated to soluble hemojuvelin but not to increased GDF15 during pregnancy. Blood Cells Mol. Dis. 48:233–37
    [Google Scholar]
  37. 37.
    Fisher AL, Nemeth E. 2017. Iron homeostasis during pregnancy. Am. J. Clin. Nutr. 106:1567S–74S
    [Google Scholar]
  38. 38.
    Fisher AL, Sangkhae V, Balusikova K, Palaskas NJ, Ganz T, Nemeth E. 2021. Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy. Nat. Commun. 12:4026
    [Google Scholar]
  39. 39.
    Fisher AL, Sangkhae V, Presicce P, Chougnet CA, Jobe AH et al. 2020. Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy. JCI Insight 5:e135321
    [Google Scholar]
  40. 40.
    Flores-Quijano ME, Montalvo-Velarde I, Vital-Reyes VS, Rodriguez-Cruz M, Rendon-Macias ME, Lopez-Alarcon M. 2016. Longitudinal analysis of the interaction between obesity and pregnancy on iron homeostasis: role of hepcidin. Arch. Med. Res. 47:550–56
    [Google Scholar]
  41. 41.
    Fozza C, Asara MA, Vacca N, Caggiari S, Monti A et al. 2017. Pregnancy outcome among women with beta-thalassemia major in North Sardinia. Acta Haematol. 138:166–67
    [Google Scholar]
  42. 42.
    Fuqua BK, Lu Y, Darshan D, Frazer DM, Wilkins SJ et al. 2014. The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice. PLOS ONE 9:e98792
    [Google Scholar]
  43. 43.
    Galvez-Peralta M, He L, Jorge-Nebert LF, Wang B, Miller ML et al. 2012. ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PLOS ONE 7:e36055
    [Google Scholar]
  44. 44.
    Gambling L, Czopek A, Andersen HS, Holtrop G, Srai SK et al. 2009. Fetal iron status regulates maternal iron metabolism during pregnancy in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296:R1063–70
    [Google Scholar]
  45. 45.
    Ganz T. 2013. Systemic iron homeostasis. Physiol. Rev. 93:1721–41
    [Google Scholar]
  46. 46.
    Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. 2008. Immunoassay for human serum hepcidin. Blood 112:4292–97
    [Google Scholar]
  47. 47.
    Garcia-Valdes L, Campoy C, Hayes H, Florido J, Rusanova I et al. 2015. The impact of maternal obesity on iron status, placental transferrin receptor expression and hepcidin expression in human pregnancy. Int. J. Obes. 39:571–78
    [Google Scholar]
  48. 48.
    Georgieff MK. 2011. Long-term brain and behavioral consequences of early iron deficiency. Nutr. Rev. 69:Suppl. 1S43–48
    [Google Scholar]
  49. 49.
    Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR. 2000. Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta. Placenta 21:799–804
    [Google Scholar]
  50. 50.
    Godfray HCJ, Aveyard P, Garnett T, Hall JW, Key TJ et al. 2018. Meat consumption, health, and the environment. Science 361:eaam5324
    [Google Scholar]
  51. 51.
    Goldenberg RL, Tamura T, DuBard M, Johnston KE, Copper RL, Neggers Y. 1996. Plasma ferritin and pregnancy outcome. Am. J. Obstet. Gynecol. 175:1356–59
    [Google Scholar]
  52. 52.
    Golub MS, Hogrefe CE, Germann SL, Capitanio JP, Lozoff B. 2006. Behavioral consequences of developmental iron deficiency in infant rhesus monkeys. Neurotoxicol. Teratol. 28:3–17
    [Google Scholar]
  53. 53.
    Gonzalez-Fernandez D, Nemeth E, Pons EDC, Rueda D, Sinisterra OT et al. 2021. INTERGROWTH-21 identifies high prevalence of low symphysis-fundal height in indigenous pregnant women experiencing multiple infections, nutrient deficiencies, and inflammation: the Maternal Infections, Nutrient Deficiencies, and Inflammation (MINDI) cohort. Curr. Dev. Nutr. 5:nzab012
    [Google Scholar]
  54. 54.
    Gulec S, Anderson GJ, Collins JF. 2014. Mechanistic and regulatory aspects of intestinal iron absorption. Am. J. Physiol. Gastrointest. Liver Physiol. 307:G397–409
    [Google Scholar]
  55. 55.
    Guller S, Buhimschi CS, Ma YY, Huang ST, Yang L et al. 2008. Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia. Lab. Investig. 88:1057–67
    [Google Scholar]
  56. 56.
    Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. 2005. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Investig. 115:1258–66
    [Google Scholar]
  57. 57.
    Guo Y, Zhang N, Zhang D, Ren Q, Ganz T et al. 2019. Iron homeostasis in pregnancy and spontaneous abortion. Am. J. Hematol. 94:184–88
    [Google Scholar]
  58. 58.
    Hallberg L, Rossander-Hulten L. 1991. Iron requirements in menstruating women. Am. J. Clin. Nutr. 54:1047–58
    [Google Scholar]
  59. 59.
    Harris ZL, Durley AP, Man TK, Gitlin JD. 1999. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. PNAS 96:10812–17
    [Google Scholar]
  60. 60.
    Hayward CE, Lean S, Sibley CP, Jones RL, Wareing M et al. 2016. Placental adaptation: What can we learn from birthweight:placental weight ratio?. Front. Physiol. 7:28
    [Google Scholar]
  61. 61.
    Hecht JL, Kliman HJ, Allred EN, Pflueger SM, Chang CH et al. 2007. Reference weights for placentas delivered before the 28th week of gestation. Placenta 28:987–90
    [Google Scholar]
  62. 62.
    Hedengran KK, Nelson D, Andersen MR, Stender S, Szecsi PB. 2016. Hepcidin levels are low during pregnancy and increase around delivery in women without iron deficiency—a prospective cohort study. J. Matern. Fetal Neonatal Med. 29:1506–8
    [Google Scholar]
  63. 63.
    Helman SL, Wilkins SJ, McKeating DR, Perkins AV, Whibley PE et al. 2021. The placental ferroxidase zyklopen is not essential for iron transport to the fetus in mice. J. Nutr. 151:2541–50
    [Google Scholar]
  64. 64.
    Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin BH et al. 2011. The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth. PLOS ONE 6:e18059
    [Google Scholar]
  65. 65.
    Horiguchi H, Oguma E, Kayama F. 2005. The effects of iron deficiency on estradiol-induced suppression of erythropoietin induction in rats: implications of pregnancy-related anemia. Blood 106:67–74
    [Google Scholar]
  66. 66.
    Hou Y, Zhang S, Wang L, Li J, Qu G et al. 2012. Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene 511:398–403
    [Google Scholar]
  67. 67.
    Hurrell R, Egli I. 2010. Iron bioavailability and dietary reference values. Am. J. Clin. Nutr. 91:1461S–67S
    [Google Scholar]
  68. 68.
    Hynes M. 1948. Iron metabolism. J. Clin. Pathol. 1:57–67
    [Google Scholar]
  69. 69.
    Hytten F. 1985. Blood volume changes in normal pregnancy. Clin. Haematol. 14:601–12
    [Google Scholar]
  70. 70.
    Ikeda Y, Tajima S, Izawa-Ishizawa Y, Kihira Y, Ishizawa K et al. 2012. Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes. PLOS ONE 7:e40465
    [Google Scholar]
  71. 71.
    Kammerer L, Mohammad G, Wolna M, Robbins PA, Lakhal-Littleton S. 2020. Fetal liver hepcidin secures iron stores in utero. Blood 136:1549–57
    [Google Scholar]
  72. 72.
    Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. 2014. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46:678–84
    [Google Scholar]
  73. 73.
    Keel SB, Doty RT, Yang Z, Quigley JG, Chen J et al. 2008. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319:825–28
    [Google Scholar]
  74. 74.
    Khambalia AZ, Collins CE, Roberts CL, Morris JM, Powell KL et al. 2015. High maternal serum ferritin in early pregnancy and risk of spontaneous preterm birth. Br. J. Nutr. 114:455–61
    [Google Scholar]
  75. 75.
    Lamparelli RD, Friedman BM, MacPhail AP, Bothwell TH, Phillips JI, Baynes RD. 1989. The fate of intravenously injected tissue ferritin in pregnant guinea-pigs. Br. J. Haematol. 72:100–5
    [Google Scholar]
  76. 76.
    Lao TT, Tam KF, Chan LY. 2000. Third trimester iron status and pregnancy outcome in non-anaemic women; pregnancy unfavourably affected by maternal iron excess. Hum. Reprod. 15:1843–48
    [Google Scholar]
  77. 77.
    Lawton LN, Bonaldo MF, Jelenc PC, Qiu L, Baumes SA et al. 1997. Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene 203:17–26
    [Google Scholar]
  78. 78.
    Lee S, Guillet R, Cooper EM, Westerman M, Orlando M et al. 2016. Prevalence of anemia and associations between neonatal iron status, hepcidin, and maternal iron status among neonates born to pregnant adolescents. Pediatr. Res. 79:42–48
    [Google Scholar]
  79. 79.
    Lee S, Guillet R, Cooper EM, Westerman M, Orlando M et al. 2014. Maternal inflammation at delivery affects assessment of maternal iron status. J. Nutr. 144:1524–32
    [Google Scholar]
  80. 80.
    Lehtihet M, Bonde Y, Beckman L, Berinder K, Hoybye C et al. 2016. Circulating hepcidin-25 is reduced by endogenous estrogen in humans. PLOS ONE 11:e0148802
    [Google Scholar]
  81. 81.
    Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC 1999. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21:396–99
    [Google Scholar]
  82. 82.
    Li JY, Paragas N, Ned RM, Qiu AD, Viltard M et al. 2009. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev. Cell 16:35–46
    [Google Scholar]
  83. 83.
    Li L, Fang CJ, Ryan JC, Niemi EC, Lebron JA et al. 2010. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. PNAS 107:3505–10
    [Google Scholar]
  84. 84.
    Li X, Rhee DK, Malhotra R, Mayeur C, Hurst LA et al. 2016. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J. Clin. Investig. 126:389–401
    [Google Scholar]
  85. 85.
    Li YQ, Bai B, Cao XX, Zhang YH, Yan H et al. 2012. Divalent metal transporter 1 expression and regulation in human placenta. Biol. Trace Elem. Res. 146:6–12
    [Google Scholar]
  86. 86.
    Lonnerdal B. 2017. Excess iron intake as a factor in growth, infections, and development of infants and young children. Am. J. Clin. Nutr. 106:1681S–87S
    [Google Scholar]
  87. 87.
    Lorenz L, Herbst J, Engel C, Peter A, Abele H et al. 2014. Gestational age-specific reference ranges of hepcidin in cord blood. Neonatology 106:133–39
    [Google Scholar]
  88. 88.
    Lozoff B, Georgieff MK. 2006. Iron deficiency and brain development. Semin. Pediatr. Neurol. 13:158–65
    [Google Scholar]
  89. 89.
    Lyall F, Barber A, Myatt L, Bulmer JN, Robson SC. 2000. Hemeoxygenase expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function. FASEB J. 14:208–19
    [Google Scholar]
  90. 90.
    MacQueen BC, Christensen RD, Ward DM, Bennett ST, O'Brien EA et al. 2017. The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study. J. Perinatol. 37:436–40
    [Google Scholar]
  91. 91.
    Manis JG, Schachter D. 1962. Active transport of iron by intestine: effects of oral iron and pregnancy. Am. J. Physiol. 203:81–86
    [Google Scholar]
  92. 92.
    Mao J, McKean DM, Warrier S, Corbin JG, Niswander L, Zohn IE. 2010. The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure. Development 137:3079–88
    [Google Scholar]
  93. 93.
    McArdle HJ, Gambling L, Kennedy C. 2014. Iron deficiency during pregnancy: the consequences for placental function and fetal outcome. Proc. Nutr. Soc. 73:9–15
    [Google Scholar]
  94. 94.
    Michie EA. 1966. Oestrogen levels in urine and amniotic fluid in pregnancy with live anencephalic foetus and the effect of intra-amniotic injection of sodium dehydroepiandrosterone sulphate on these levels. Acta Endocrinol. 51:535–42
    [Google Scholar]
  95. 95.
    Millard KN, Frazer DM, Wilkins SJ, Anderson GJ. 2004. Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat. Gut 53:655–60
    [Google Scholar]
  96. 96.
    Milman N, Agger AO, Nielsen OJ. 1991. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in 207 Danish women. Dan. Med. Bull. 38:471–76
    [Google Scholar]
  97. 97.
    Mok H, Mendoza M, Prchal JT, Balogh P, Schumacher A. 2004. Dysregulation of ferroportin 1 interferes with spleen organogenesis in polycythaemia mice. Development 131:4871–81
    [Google Scholar]
  98. 98.
    Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S et al. 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Investig. 113:1271–76
    [Google Scholar]
  99. 99.
    Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. 2003. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–63
    [Google Scholar]
  100. 100.
    Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C et al. 2002. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. PNAS 99:4596–601
    [Google Scholar]
  101. 101.
    Ohgami RS, Campagna DR, McDonald A, Fleming MD. 2006. The Steap proteins are metalloreductases. Blood 108:1388–94
    [Google Scholar]
  102. 102.
    Parmley RT, Barton JC, Conrad ME, Austin RL, Holland RM. 1981. Ultrastructural cytochemistry and radioautography of hemoglobin–iron absorption. Exp. Mol. Pathol. 34:131–44
    [Google Scholar]
  103. 103.
    Preziosi P, Prual A, Galan P, Daouda H, Boureima H, Hercberg S. 1997. Effect of iron supplementation on the iron status of pregnant women: consequences for newborns. Am. J. Clin. Nutr. 66:1178–82
    [Google Scholar]
  104. 104.
    Ratajczak CK, Fay JC, Muglia LJ. 2010. Preventing preterm birth: the past limitations and new potential of animal models. Dis. Models Mech. 3:407–14
    [Google Scholar]
  105. 105.
    Rigg LA, Lein A, Yen SS. 1977. Pattern of increase in circulating prolactin levels during human gestation. Am. J. Obstet. Gynecol. 129:454–56
    [Google Scholar]
  106. 106.
    Robertson LS, Iwanowicz LR, Marranca JM. 2009. Identification of centrarchid hepcidins and evidence that 17β-estradiol disrupts constitutive expression of hepcidin-1 and inducible expression of hepcidin-2 in largemouth bass (Micropterus salmoides). Fish Shellfish Immunol. 26:898–907
    [Google Scholar]
  107. 107.
    Rossant J, Cross JC. 2001. Placental development: lessons from mouse mutants. Nat. Rev. Genet. 2:538–48
    [Google Scholar]
  108. 108.
    Ryu MS, Zhang D, Protchenko O, Shakoury-Elizeh M, Philpott CC. 2017. PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J. Clin. Investig. 127:1786–97
    [Google Scholar]
  109. 109.
    Saldanha LG, Dwyer JT, Andrews KW, Brown LL. 2019. The chemical forms of iron in commercial prenatal supplements are not always the same as those tested in clinical trials. J. Nutr. 149:890–93
    [Google Scholar]
  110. 110.
    Salomon LJ, Bernard JP, Ville Y. 2007. Estimation of fetal weight: reference range at 20–36 weeks' gestation and comparison with actual birth-weight reference range. Ultrasound Obstet. Gynecol. 29:550–55
    [Google Scholar]
  111. 111.
    Sangkhae V, Fisher AL, Chua KJ, Ruchala P, Ganz T, Nemeth E. 2020. Maternal hepcidin determines embryo iron homeostasis in mice. Blood 136:2206–16
    [Google Scholar]
  112. 112.
    Sangkhae V, Fisher AL, Wong S, Koenig MD, Tussing-Humphreys L et al. 2020. Effects of maternal iron status on placental and fetal iron homeostasis. J. Clin. Investig. 130:625–40
    [Google Scholar]
  113. 113.
    Sangkhae V, Nemeth E. 2017. Regulation of the iron homeostatic hormone hepcidin. Adv. Nutr. 8:126–36
    [Google Scholar]
  114. 114.
    Sangkhae V, Nemeth E. 2018. Placental iron transport: the mechanism and regulatory circuits. Free Radic. Biol. Med. 133:254–61
    [Google Scholar]
  115. 115.
    Sangkhae V, Yu V, Coffey R, O'Brien KO, Ganz T, Nemeth E. 2022. Erythroferrone contributes to iron mobilization for embryo erythropoiesis in iron-deficient mouse pregnancies. Am. J. Hematol. 97:1348–58
    [Google Scholar]
  116. 116.
    Santana-Codina N, Mancias JD. 2018. The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals 11:114
    [Google Scholar]
  117. 117.
    Scanlon KS, Yip R, Schieve LA, Cogswell ME. 2000. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet. Gynecol. 96:741–48
    [Google Scholar]
  118. 118.
    Schock H, Zeleniuch-Jacquotte A, Lundin E, Grankvist K, Lakso HA et al. 2016. Hormone concentrations throughout uncomplicated pregnancies: a longitudinal study. BMC Pregnancy Childbirth 16:146
    [Google Scholar]
  119. 119.
    Scholl TO. 1998. High third-trimester ferritin concentration: associations with very preterm delivery, infection, and maternal nutritional status. Obstet. Gynecol. 92:161–66
    [Google Scholar]
  120. 120.
    Scholl TO, Reilly T. 2000. Anemia, iron and pregnancy outcome. J. Nutr. 130:443S–47S
    [Google Scholar]
  121. 121.
    Schulze KJ, Christian P, Ruczinski I, Ray AL, Nath A et al. 2008. Hepcidin and iron status among pregnant women in Bangladesh. Asia Pac. J. Clin. Nutr. 17:451–56
    [Google Scholar]
  122. 122.
    Shawki A, Engevik MA, Kim RS, Knight PB, Baik RA et al. 2016. Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 311:G423–30
    [Google Scholar]
  123. 123.
    Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK. 2007. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology 92:73–82
    [Google Scholar]
  124. 124.
    Simavli S, Derbent AU, Uysal S, Turhan NO. 2014. Hepcidin, iron status, and inflammation variables among healthy pregnant women in the Turkish population. J. Matern. Fetal Neonatal Med. 27:75–79
    [Google Scholar]
  125. 125.
    Stefanova D, Raychev A, Arezes J, Ruchala P, Gabayan V et al. 2017. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood 130:245–57
    [Google Scholar]
  126. 126.
    Stefanova D, Raychev A, Deville J, Humphries R, Campeau S et al. 2018. Hepcidin protects against lethal Escherichia coli sepsis in mice inoculated with isolates from septic patients. Infect. Immun. 86:e00253–18
    [Google Scholar]
  127. 127.
    Tabbah SM, Buhimschi CS, Rodewald-Millen K, Pierson CR, Bhandari V et al. 2018. Hepcidin, an iron regulatory hormone of innate immunity, is differentially expressed in premature fetuses with early-onset neonatal sepsis. Am. J. Perinatol. 35:865–72
    [Google Scholar]
  128. 128.
    Taher AT, Iolascon A, Matar CF, Bou-Fakhredin R, de Franceschi L et al. 2020. Recommendations for pregnancy in rare inherited anemias. Hemasphere 4:e446
    [Google Scholar]
  129. 129.
    Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P et al. 2007. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 13:1096–101
    [Google Scholar]
  130. 130.
    Taylor CL, Brannon PM. 2017. Introduction to workshop on iron screening and supplementation in iron-replete pregnant women and young children. Am. J. Clin. Nutr. 106:1547S–54S
    [Google Scholar]
  131. 131.
    Toldi G, Stenczer B, Molvarec A, Takats Z, Beko G et al. 2010. Hepcidin concentrations and iron homeostasis in preeclampsia. Clin. Chem. Lab Med. 48:1423–26
    [Google Scholar]
  132. 132.
    Tuck SM, Jensen CE, Wonke B, Yardumian A. 1998. Pregnancy management and outcomes in women with thalassaemia major. J. Pediatr. Endocrinol. Metab. 11:Suppl. 3923–28
    [Google Scholar]
  133. 133.
    Tussing-Humphreys LM, Nemeth E, Fantuzzi G, Freels S, Guzman G et al. 2010. Elevated systemic hepcidin and iron depletion in obese premenopausal females. Obesity 18:1449–56
    [Google Scholar]
  134. 134.
    van Santen S, Kroot JJ, Zijderveld G, Wiegerinck ET, Spaanderman ME, Swinkels DW. 2013. The iron regulatory hormone hepcidin is decreased in pregnancy: a prospective longitudinal study. Clin. Chem. Lab. Med. 51:1395–401
    [Google Scholar]
  135. 135.
    Vulpe CD, Kuo YM, Murphy TL, Cowley L, Askwith C et al. 1999. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 21:195–99
    [Google Scholar]
  136. 136.
    Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A et al. 2012. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J. Biol. Chem. 287:34032–43
    [Google Scholar]
  137. 137.
    Wang J, Liu G, Xu Z, Dai J, Song P et al. 2015. Hepcidin levels in hyperprolactinemic women monitored by nanopore thin film based assay: correlation with pregnancy-associated hormone prolactin. Nanomed. Nanotechnol. Biol. Med. 11:871–78
    [Google Scholar]
  138. 138.
    Wei S, Liu W, Qi Y, Guo Y, Zhang S et al. 2021. Disordered serum erythroferrone and hepcidin levels as indicators of the spontaneous abortion occurrence during early pregnancy in humans. Br. J. Haematol. 192:643–51
    [Google Scholar]
  139. 139.
    Widdowson EM, Spray CM. 1951. Chemical development in utero. Arch. Dis. Child. 26:205–14
    [Google Scholar]
  140. 140.
    Wilkinson N, Pantopoulos K. 2014. The IRP/IRE system in vivo: insights from mouse models. Front. Pharmacol. 5:176
    [Google Scholar]
  141. 141.
    Willemetz A, Lenoir A, Deschemin JC, Lopez-Otin C, Ramsay AJ et al. 2014. Matriptase-2 is essential for hepcidin repression during fetal life and postnatal development in mice to maintain iron homeostasis. Blood 124:441–44
    [Google Scholar]
  142. 142.
    World Health Organ. (WHO) 2012. Guideline: Daily iron and folic acid supplementation in pregnant women WHO Geneva:
    [Google Scholar]
  143. 143.
    Wu F, Tian FJ, Lin Y, Xu WM. 2016. Oxidative stress: placenta function and dysfunction. Am. J. Reprod. Immunol. 76:258–71
    [Google Scholar]
  144. 144.
    Yanatori I, Richardson DR, Imada K, Kishi F. 2016. Iron export through the transporter ferroportin 1 is modulated by the iron chaperone PCBP2. J. Biol. Chem. 291:17303–18
    [Google Scholar]
  145. 145.
    Yang Q, Jian J, Katz S, Abramson SB, Huang X. 2012. 17β-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology 153:3170–78
    [Google Scholar]
  146. 146.
    Yin S, Zhou Y, Li H, Cheng Z, Zhang Y et al. 2020. Association of maternal BMI during early pregnancy with infant anemia: a large Chinese birth cohort. Nutr. Metab. 17:32
    [Google Scholar]
  147. 147.
    Young MF, Griffin I, Pressman E, McIntyre AW, Cooper E et al. 2010. Utilization of iron from an animal-based iron source is greater than that of ferrous sulfate in pregnant and nonpregnant women. J. Nutr. 140:2162–66
    [Google Scholar]
  148. 148.
    Young MF, Griffin I, Pressman E, McIntyre AW, Cooper E et al. 2012. Maternal hepcidin is associated with placental transfer of iron derived from dietary heme and nonheme sources. J. Nutr. 142:33–39
    [Google Scholar]
  149. 149.
    Zaman B, Rasool S, Jasim S, Abdulah D. 2019. Hepcidin as a diagnostic biomarker of iron deficiency anemia during pregnancy. J. Matern. Fetal Neonatal Med. 34:1288–96
    [Google Scholar]
  150. 150.
    Zhen AW, Nguyen NH, Gibert Y, Motola S, Buckett P et al. 2013. The small molecule, genistein, increases hepcidin expression in human hepatocytes. Hepatology 58:1315–25
    [Google Scholar]
/content/journals/10.1146/annurev-nutr-061021-030404
Loading
/content/journals/10.1146/annurev-nutr-061021-030404
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error