Association between Elevated Iron Status and the Risk of Preeclampsia: A Systematic Review and Meta-analysis

Hepcidin associated with Preeclampsia

  • Changhong Li Hainan Women and Children's Medical Center
  • Xiaohui Xu Hainan Women and Children's Medical Center
  • Min Qian General Hospital of Eastern Theater Command, PLA
DOI: https://doi.org/10.5937/jomb0-64058
Keywords: Hepcidin, Iron, Meta-analysis, Preeclampsia

Abstract


Background: This review aims to conduct a comprehensive and systematic report of the currently published information on the association between elevated hepcidin levels and the risk of preeclampsia by meta-analysis of published prospective case-control studies or cross-sectional studies combined with follow-up to provide a comprehensive and reliable basis for early intervention and clinical decision making in the disease.

Methods: We searched five databases such as Pubmed, Web of Science, Cochrane, China National Knowledge Infrastructure, and WAN FANG DATA to retrieve articles related to the relationship between elevated levels of hepcidin and the risk of preeclampsia up to February 2025. We calculated the standardized mean deviation (SMD) and 95% confidence interval (95% CI) for comparison using a random-effects model.

Results: A total of 8 articles were included in this review. The results found that higher serum hepcidin and serum iron levels and lower serum transferrin levels were observed in pregnant women presenting with preeclampsia compared with normotensive pregnant women (serum hepcidin: SMD = 1.08, 95%CI: 0.03, 2.14; serum iron: SMD = 0.63, 95%CI: 0.41, 0.86; serum transferrin: SMD = -0.50, 95%CI: -0.73, -0.27).

Conclusions: Similar to the previous review, this systematic review and meta-analysis showed that high serum iron levels might be associated with a higher risk for preeclampsia. In addition, this meta-analysis summarized two mechanisms for the failure of hepcidins to reduce serum iron levels in pregnant mothers with preeclampsia in late pregnancy. And this meta-analysis would guide further clinical studies.

References

1. Jim B, Karumanchi SA. Preeclampsia: Pathogenesis, Prevention, and Long-Term Complications. Semin Nephrol 2017; 37(4): 386-97.
2. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertension 2018; 13: 291-310.
3. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? British Journal of Obstetrics and Gynaecology 1998; 105(11): 1177-84.
4. Casu C, Nemeth E, Rivella S. Hepcidin agonists as therapeutic tools. Blood 2018; 131(16): 1790-4.
5. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014; 10(1): 9-17.
6. Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D, Fernandez PL, et al. Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 2012; 119(10): 2368-75.
7. Lunova M, Goehring C, Kuscuoglu D, Mueller K, Chen Y, Walther P, et al. Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload. J Hepatol 2014; 61(3): 633-41.
8. Entman SS, Richardson LD, Killam AP. Altered ferrokinetics in toxemia of pregnancy: a possible indicator of decreased red cell survival. Clinical and Experimental Hypertension. Part B, Hypertension in Pregnancy 1983; 2(1): 171-8.
9. Raman L, Pawashe AB, Yasodhara P. Hyperferritinemia in pregnancy induced hypertension and eclampsia. J Postgrad Med 1992; 38(2): 65-7.
10. Siddiqui IA, Jaleel A, Kadri HMFA, Saeed WA, Tamimi W. Iron status parameters in preeclamptic women. Arch Gynecol Obstet 2011; 284(3): 587-91.
11. Koenig MD, Tussing-Humphreys L, Day J, Cadwell B, Nemeth E. Hepcidin and iron homeostasis during pregnancy. Nutrients 2014; 6(8): 3062-83.
12. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276(11): 7811-9.
13. Cardaropoli S, Todros T, Nuzzo AM, Rolfo A. Maternal serum levels and placental expression of hepcidin in preeclampsia. Pregnancy Hypertension 2018; 11: 47-53.
14. Nila SG, Bobby Z, Dorairajan G, Jacob SE. Diagnostic ability of hepcidin in predicting fetal outcome in preeclampsia. The Journal of Maternal-Fetal & Neonatal Medicine: The Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2021; 34(22): 3678-83.
15. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica 2020; 105(2): 260-72.
16. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev-London 2015; 4(1): 1.
17. Billesbølle CB, Azumaya CM, Kretsch RC, Powers AS, Gonen S, Schneider S, et al. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature 2020; 586(7831): 807-11.
18. Harris RJ, Bradburn MJ, Deeks JJ, Harbord RM, Altman DG, Sterne JAC. metan: fixed- and random-effects meta-analysis. Stata J 2008; 8(1): 3-28.
19. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health 2014; 72(1): 39.
20. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997; 315(7109): 629-34.
21. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56(2): 455-63.
22. Toldi G, Stenczer B, Molvarec A, Takáts Z, Beko G, Rigó JJ, et al. Hepcidin concentrations and iron homeostasis in preeclampsia. Clin Chem Lab Med 2010; 48(10): 1423-6.
23. Shaji Geetha N, Bobby Z, Dorairajan G, Jacob SE. Increased hepcidin levels in preeclampsia: a protective mechanism against iron overload mediated oxidative stress? The Journal of Maternal-Fetal & Neonatal Medicine: The Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2022; 35(4): 636-41.
24. Brunacci F, Rocha VS, De Carli E, Espósito BP, Ruano R, Colli C. Increased serum iron in preeclamptic women is likely due to low hepcidin levels. Nutrition Research (New York, N.Y.) 2018; 53: 32-9.
25. Abboud E, Chrayteh D, Boussetta N, Dalle H, Malerba M, Wu T, et al. Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment. Nat Commun 2024; 15(1): 6718.
26. Song Q, Luo W, Zhang C. High serum iron level is associated with an increased risk of hypertensive disorders during pregnancy: a meta-analysis of observational studies. Nutrition Research (New York, N.Y.) 2015; 35(12): 1060-9.
27. Lewandowska M, Sajdak S, Lubiński J. Can Serum Iron Concentrations in Early Healthy Pregnancy Be Risk Marker of Pregnancy-Induced Hypertension? Nutrients 2019; 11(5): 1086.
28. Vela D. Hepcidin, an emerging and important player in brain iron homeostasis. J Transl Med 2018; 16(1): 25.
29. Simavli S, Derbent AU, Keskin EA, Gumus II, Uysal S, Turhan N. Do the first, second and third trimester maternal serum hepcidin concentrations clarify obstetric complications? The Journal of Maternal-Fetal & Neonatal Medicine: The Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2015; 28(7): 854-7.
30. Duvan CI, Simavli S, Keskin EA, Onaran Y, Turhan NO, Koca C. Is the level of maternal serum prohepcidin associated with preeclampsia? Hypertens Pregnancy 2015; 34(2): 145-52.
31. Amstad Bencaiova G, Vogt DR, Hoesli I. Serum hepcidin and iron status parameters in pregnant women and the association with adverse maternal and fetal outcomes: a study protocol for a prospective cohort study. Bmj Open 2019; 9(11): e032280.
Published
2026/02/12
Issue
Ahead of print
Section
Original paper

Copyright (c) 2026 Changhong Li, Xiaohui Xu, Min Qian

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.

Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.