Background: Hepcidin, an iron-regulatory hormone, plays a key role in preventing iron overload. Few studies have investigated the regulation of hepcidin in low-birth-weight (LBW) infants who are vulnerable to iron imbalance. Objectives: To identify perinatal factors associated with serum hepcidin levels in LBW infants. Methods: Ninety-two LBW infants with a median gestational age (GA) of 32.6 weeks and birth weight of 1,587 g were prospectively enrolled. Serum hepcidin-25 (Hep25) levels were measured from umbilical cord blood using liquid chromatography-tandem mass spectrometry. The relationship between Hep25 levels and prematurity or other possible hepcidin-regulatory factors was evaluated. Results: The median Hep25 level was 7.3 ng/mL (interquartile range: 2.85-16.38). log(Hep25) correlated with birth weight (r = 0.229, p = 0.028), log(interleukin-6 [IL-6]) (r = 0.408, p < 0.001), log(erythropoietin) (r = -0.302, p = 0.004), transferrin saturation (r = 0.29, p = 0.005), soluble transferrin receptor (r = -0.500, p < 0.001), and log(ferritin) (r = 0.696, p < 0.001). Serum iron and hemoglobin levels did not correlate with log(Hep25). Hep25 levels were higher among infants with chorioamnionitis and infants born vaginally and lower among infants born to mothers with pregnancy-induced hypertension than among infants without the respective characteristics. Stepwise multiple linear regression analysis confirmed the significant association of log(Hep25) with GA, log(IL-6), log(erythropoietin), and soluble transferrin receptor. Conclusions: Among LBW infants, GA, IL-6, erythropoietin, and soluble transferrin receptor were associated with Hep25 levels. Therefore, prematurity, inflammation, hypoxia, and erythropoietic activity may be important perinatal factors that affect hepcidin levels.

Keywords:
Inflammation, Hypoxia, Erythropoiesis, Neonate, Prematurity, Iron, Cord blood
1.
Hirano K, Morinobu T, Kim H, Hiroi M, Ban R, Ogawa S, Ogihara H, Tamai H, Ogihara T: Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants. Arch Dis Child Fetal Neonatal Ed 2001;84:F188-F193.
2.
Rao R, Georgieff MK: Iron therapy for preterm infants. Clin Perinatol 2009;36:27-42.
3.
Collard KJ: Iron homeostasis in the neonate. Pediatrics 2009;123:1208-1216.
4.
Korhonen P, Tammela O, Koivisto AM, Laippala P, Ikonen S: Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants. Early Hum Dev 1999;54:245-258.
5.
Romagnoli C: Risk factors and growth factors in ROP. Early Hum Dev 2009;85(suppl 10): S79-S82.
6.
Collard KJ: Transfusion related morbidity in premature babies: possible mechanisms and implications for practice. World J Clin Pediatr 2014;3:19-29.
7.
Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806-7810.
8.
Ganz T: Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783-788.
9.
Rishi G, Wallace DF, Subramaniam VN: Hepcidin: regulation of the master iron regulator. Biosci Rep 2015;35:e00192.
10.
Zhao N, Zhang AS, Enns CA: Iron regulation by hepcidin. J Clin Invest 2013;123:2337-2343.
11.
Lorenz L, Herbst J, Engel C, Peter A, Abele H, Poets CF, Westerman M, Franz AR: Gestational age-specific reference ranges of hepcidin in cord blood. Neonatology 2014;106:133-139.
12.
Müller KF, Lorenz L, Poets CF, Westerman M, Franz AR: Hepcidin concentrations in serum and urine correlate with iron homeostasis in preterm infants. J Pediatr 2012;160:949-953.e2.
13.
Itabashi K, Fujimura M, Kusuda S, Tamura M, Hayashi T, Takahashi T, Goishi K: The new standard of birth weight for gestational age (in Japanese). J Jpn Pediatr Soc 2011;114:1271-1293.
14.
Blanc W: Perinatal disease; in Naeye RL, Kissane JM, Kaufman N (eds): Pathology of the Placenta, Membranes, and Umbilical Cord in Bacterial, Fungal, and Viral Infections in Man. Baltimore, Williams & Wilkins, 1981, pp 67-132.
15.
Kaneko Y, Miyajima H, Piperno A, Tomosugi N, Hayashi H, Morotomi N, Tsuchida K, Ikeda T, Ishikawa A, Ota Y, Wakusawa S, Yoshioka K, Kono S, Pelucchi S, Hattori A, Tatsumi Y, Okada T, Yamagishi M: Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders. J Gastroenterol 2010;45:1163-1171.
16.
Ganz T, Nemeth E: Iron sequestration and anemia of inflammation. Semin Hematol 2009;46:387-393.
17.
Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-1276.
18.
Malamitsi-Puchner A, Protonotariou E, Boutsikou T, Makrakis E, Sarandakou A, Creatsas G: The influence of the mode of delivery on circulating cytokine concentrations in the perinatal period. Early Hum Dev 2005;81:387-392.
19.
Nemeth E, Ganz T: Anemia of inflammation. Hematol Oncol Clin North Am 2014;28:671-681.
20.
Silvers KM, Gibson AT, Russell JM, Powers HJ: Antioxidant activity, packed cell transfusions, and outcome in premature infants. Arch Dis Child Fetal Neonatal Ed 1998;78:F214-F219.
21.
Herzlich J, Litmanovitz I, Regev R, Bauer S, Sirota G, Steiner Z, Arnon S: Iron homeostasis after blood transfusion in stable preterm infants - an observational study. J Perinat Med 2016;44:919-929.
22.
Teramo KA, Widness JA: Increased fetal plasma and amniotic fluid erythropoietin concentrations: markers of intrauterine hypoxia. Neonatology 2009;95:105-116.
23.
Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman R, Maxwell PH, Choi P: Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 2010;95:505-508.
24.
Honda H, Kobayashi Y, Onuma S, Shibagaki K, Yuza T, Hirao K, Yamamoto T, Tomosugi N, Shibata T: Associations among erythroferrone and biomarkers of erythropoiesis and iron metabolism, and treatment with long-term erythropoiesis-stimulating agents in patients on hemodialysis. PLoS One 2016;11: e0151601.
25.
Infusino I, Braga F, Dolci A, Panteghini M. Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A meta-analysis. Am J Clin Pathol 2012;138:642-649.
26.
Skikne BS: Serum transferrin receptor. Am J Hematol 2008;83:872-875.
27.
Rehu M, Punnonen K, Ostland V, Heinonen S, Westerman M, Pulkki K, Sankilampi U: Maternal serum hepcidin is low at term and independent of cord blood iron status. Eur J Haematol 2010;85:345-352.
28.
Kroot JJ, Laarakkers CM, Geurts-Moespot AJ, Grebenchtchikov N, Pickkers P, van Ede AE, Peters HP, van Dongen-Lases E, Wetzels JF, Sweep FC, Tjalsma H, Swinkels DW: Immunochemical and mass-spectrometry-based serum hepcidin assays for iron metabolism disorders. Clin Chem 2010;56:1570-1579.
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