Ferritin is a 12nm polypeptide comprised of 24 protein chains arranged as a hollow octahedral cage to imprison iron. It is designated H (heavy), or L (light), depending on protein structure, and binds iron cations to protein chains and converts the cations to stable iron-hydroxides in the core of the complex.^{1 2} Serum-ferritin is ordinarily measured using a chemiluminescent antibody assay that quantifies ferritin, not the amount of iron it houses, which can be determined using mass spectrometry if need be.³ Each protein complex can house as many as 4,500 iron atoms, but they are rarely this saturated.^{4 5 6 7 8}

Ferritin is synthesised in the liver and spleen where production is regulated at a post-transcriptional level via an interaction with iron-responsive elements in the mRNA, so under iron homeostasis the rate of intracellular ferritin synthesis is constant.^{9 10 11}

Most ferritin is intracellular with only a small fraction of total body ferritin being found in the serum. Some is leached into the circulation from dead cells and some is actively secreted in the absence of apoptosis,¹² so it can be used as a crude surrogate for whole-body iron storage provided the rate of iron flux in and out of the circulation is constant. In practice this means inflammation must be quiescent, the patient must not be on iron supplements, primary or secondary iron overload pathology must be absent, there is no history of recent blood transfusions or significant bleeding, and the patient cannot be a neonate.

Serum-ferritin’s primary purpose is to encapsulate and safely house circulating iron cations.¹³ It can be high in the presence of true iron overload (hereditary haemochromatosis),¹⁴ high when total body iron is normal (early neonates,)¹⁵ or high despite true net iron stores being low (sepsis, cancer, trauma).¹⁶ Conversely, serum-ferritin can be low despite iron poisoning (months after intravenous iron), low in the setting of adequate body iron stores (healthy young children),¹⁷ and low in the presence of truly reduced body iron (women with menorrhagia). A protean protein.

Diminishing serum-ferritin is typical beyond the first trimester,^{18 19} but this scarcity is maligned because the benefits of gestational iron restriction are unheralded. Dietary iron absorption during the first trimester is so low it fails to recoup obligatory integumentary and gastrointestinal losses, and does not meet basal requirements even once gestational amenorrhoea is taken into account.^{20 21} The ensuing hypoferremia is often assumed to be pathological, but it serves two logical protective purposes:

1. Iron restriction is the host’s primary defence against septicaemia.²² Gestational immune tolerance mediated by beta human chorionic gonadotrophin²³ mitigates rejection of the confined semi-allogenic fetus, but at the expense of diminished cellular immunity, which in turn benefits iron-dependant obligate intracellular organisms during pregnancy (eg. Listeria, Klebsiella).^{24 25} To compensate, iron scarcity impedes bacterial reproduction and also increases the relative abundance of apotransferrin, which then stringently binds any remaining iron and further enhances bacteriostasis by binding divalent cations other than Fe2+ on gram-negative cell walls, increasing susceptibility to host defences.^{26 27}
2. Hypoferremia protects the embryo during critical organogenesis in the absence of the placental barrier by mitigating oxidative stress, since iron catalyses the Fenton Reaction²⁸ which generates free radicals that disrupt DNA synthesis.^{29 30} In circulatory iron-overload pathologies, such as hereditary haemochromatosis, thalassemias, and sickle-cell disease, both miscarriage and infection rates are notorious in part due to the harmful effects of iron toxicity.^{31 32 33 34 35}

Envisaging serum-ferritin as an emergency mop for spilt iron in the circulation rather than a marker of tissue iron stores is a useful analogy and provides a ready explanation for serum-ferritin oscillations. Neonates demonstrate the role of serum-ferritin vividly – within twelve hours of birth, a neonate effectively eliminates circulating iron, mainly by doubling serum-ferritin, to protect against sepsis.³⁶ Once dangerous ionic iron has been mopped up, serum-ferritin falls and remains very low throughout healthy childhood.³⁷ Administering parenteral iron to neonates is associated with increased mortality³⁸ and is contraindicated for this reason. Pregnancy serum-ferritin trajectory is similar, although the initial rise post-conception is more subtle, and the subsequent decline^{39 40} more gradual than that seen in early neonates. If serum-ferritin is already low at conception⁴¹ an initial serum ferritin surge is not seen (superfluous), and ferritin remains low for the entire pregnancy.

A dramatic example of ferritin oscillation is evident following intravenous iron administration. Serum-ferritin rises several hundred-fold within days of an iron infusion, but within weeks recedes from its peak to near pre-injection baseline levels despite virtually none of the injected iron exiting the body.^{42 43} Clearly this precipitous ferritin recoil cannot reflect iron deficiency. The likely explanation is that ferritin is urgently secreted into the circulation to encapsulate unliganded iron, and once sequestered, the levels of ferritin are then safely reduced back to baseline. Manufacturers of iron carboxymaltose (FCM) interpret this ferritin oscillation as supporting evidence for the safety and efficacy of their product.⁴⁴ However, it is contradictory to claim that FCM does not leach unliganded iron into the circulation, yet then claim raised serum-ferritin as evidence for the efficacy of the product, and then lay further claims that declining ferritin levels are evidence of successful iron transfer to the target organs. Serum-ferritin should not surge post-infusion if FCM is as robust as theoretically touted.

Studies of pregnant women randomised to varying levels of oral iron have shown that increased iron fortification during pregnancy yields higher initial postpartum serum-ferritin levels, but at six monthly follow-up these levels fall disproportionately relative to non-fortified patients.^{45 46} This excess fall reflects cessation of excess iatrogenic iron receding with time rather than a drop in tissue iron stores. Again, the ferritin sequestrates excess iron, then recedes as it is no longer needed. Elevated serum-ferritin co-exists with chronic inflammation, and the effects of iron-leaching can be seen in the absence of iatrogenic iron. A common example relevant to obstetrics is that of gestational diabetes⁴⁷ – one likely mechanism is that high blood sugar concentration damages endothelium and ionic iron is then leached into the circulation, which is then encapsulated by ferritin. Diabetic patients are not preferentially endowed with iron, they likely need more circulating ferritin to impound the rogue iron.

Ferritin concentration is an excellent gauge of disease severity because it directly correlates with iron leaching into the circulation, and therefore approximates the degree of cellular damage. Ferritin accurately predicts mortality in patients infected with Covid-19,^{48 49} and it also predicts mortality on admission to intensive care independent of disease aetiology.⁵⁰ It rises with ageing⁵¹ because raised ferritin reflects elderly disease prevalence, not antique iron storage. Geriatrics do not bequeath an iron surplus. The ferritin protein cage itself is normally benign, but in the setting of iron overload it binds to erythrocyte membranes causing premature lysis and increases the propensity to clot.⁵² Raised ferritin during pregnancy should never be comforting, save a transient rise to reduce circulating iron in the first few weeks of gestation.

A collation of two-million Australian ferritin assays demonstrates that around one-quarter to one-third of reproductive aged females who have had serum ferritin analysed have a level less than a nominal value of 30ug/L.⁵³ Admittedly, this is a skewed representation of the population as an unknown number of these tests would have been undertaken to investigate presumed iron deficiency – some being genuinely anaemic, and some not. Regardless, serum ferritin has an extraordinarily wide statistical dispersion for a biochemical marker,⁵⁴ analogous to the Gini coefficient of Brazil. It has a non-Gaussian distribution that is both age and sex dependent, which in turn reflects normal physiological life-stages, as well as a range of disease states. The unrealistic lower limit of 30ug/L adopted by Australian chemical pathologists⁵⁵ and used by most obstetricians in Australia is purely arbitrary and statistically baseless. Studies that have been done throughout pregnancies without interference from iatrogenic iron clearly show that a serum-ferritin less than 30ug/L is entirely normal for a gravid women, regardless of the analytical platform used.^{56 57}

Unsurprisingly, there has never been an agreed lower limit of serum-ferritin during pregnancy,⁵⁸ and nor should there be a need for one, unless low circulating iron is proven detrimental to pregnancy. At present, refining the reputed sensitivity of serum iron assays in an effort to diagnose iron deficiency with alternative markers such as serum transferrin receptor concentration⁵⁹ is futile, as any test that directly or indirectly quantifies circulating iron will inevitably conclude that normal pregnant women have innate biology geared towards restricting circulating iron. Similarly, invasive efforts to truly estimate net body iron stores with a liver biopsy (contraindicated in pregnancy) or a calibrated MRI are pointless. There is no good reason to measure serum-ferritin, transferrin, or serum-iron during pregnancy. Invariably, ferritin will be reduced, together with raised transferrin, and a healthy increased iron binding capacity, but none of this is evidence that a pregnant women is pathologically deficient in iron. Treating the number rather than the patient is poor practice. In privileged settings such as Australia with low prevalence of severe anaemia, low pregnancy serum-ferritin accompanies healthy hypoferremia and appropriate haemodilution, not necessarily deficient disease. Mild to moderate anaemia by World Health Organization standards^{60 61 62 63} is consistent with favourable pregnancy outcomes, and by inference, so is the normal pregnancy iron debt.

Oral iron in early pregnancy is poorly absorbed, and causes black stools, constipation and worsens haemorrhoids. Unfortunately, this instructive clinical gift is often misinterpreted by well-meaning clinicians as treatment malfunction rather than malfunctional treatment, reduced serum-ferritin is misconstrued as evidence for iron deficiency, and the affliction of intravenous iron follows suit. Tellingly, there is no evidence intravenous iron supplementation during pregnancy improves any tangible obstetric outcomes,^{64 65} but it is a lucrative pharmaceutical. Cunning and persistent marketing backed by drug funded research^{66 67 68} has hoodwinked the Australian federal government into a pharmaceutical benefits listing, in the process bankrolling $257.52 AUD per infusion. Vifor Pharma reported an annual increase in Ferrinject sales in Europe, Australia and New Zealand of 22% in 2021, totalling $480million AUD. Not all of this pertains to pregnancy therapy, but a sizeable proportion does.

Obstetricians do not treat mid-trimester hypotension with intravenous inotropes just because the patient feels a bit faint. Until a large double-blinded placebo controlled trial proves otherwise, permissive tolerance of gestational hypoferremia should also be encouraged in antenatal care, rather than reverting to 1000mg of intravenous iron just because the patient asked for it, or because she feels understandably tired, or because her serum-ferritin is healthy for pregnancy – low.

Our feature articles represent the views of our authors and do not necessarily represent the views of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), who publish O&G Magazine. While we make every effort to ensure that the information we share is accurate, we welcome any comments, suggestions or correction of errors in our comments section below, or by emailing the editor at [email protected].

1. Theil EC. Ferritin: the protein nanocage and iron biomineral in health and in disease. Inorg Chem. 2013;52(21):12223. doi:10.1021/ic400484n
2. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
3. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
4. Theil EC. Ferritin: the protein nanocage and iron biomineral in health and in disease. Inorg Chem. 2013;52(21):12223. doi:10.1021/ic400484n
5. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
6. Knovich MA, Storey JA, Coffman LG, et al. Ferritin for the clinician. Blood Rev. 2009;23(3):95-104. doi:10.1016/j.blre.2008.08.001
7. Garcia-Casal MN, Peña-Rosas JP, Urrechaga E, et al. Performance and comparability of laboratory methods for measuring ferritin concentrations in human serum or plasma: A systematic review and meta-analysis. PLoS One. 2018;13(5):e0196576. doi:10.1371/journal.pone.0196576
8. Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275(3):161-203. doi:10.1016/0005-2728(96)00022-9
9. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99(10):3505-16. doi:10.1182/blood.v99.10.3505
10. Dignass A, Farrag K, Stein J. Limitations of Serum Ferritin in Diagnosing Iron Deficiency in Inflammatory Conditions. Int J Chronic Dis. 2018;2018:9394060. doi:10.1155/2018/9394060
11. Costa Matos L, Batista P, Monteiro N, et al. Iron stores assessment in alcoholic liver disease. Scand J Gastroenterol. 2013;48(6):712-8. doi:10.3109/00365521.2013.781217
12. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
13. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
14. Pietrangelo A. Hereditary hemochromatosis. Biochim Biophys Acta-Mol Cell Res. 2006;1763:700–10.
15. Cross JH, Jarjou O, Mohammed NI, et al. Early postnatal hypoferremia in low birthweight and preterm babies: A prospective cohort study in hospital-delivered Gambian neonates. EBioMedicine. 2020;52:102613. doi: 10.1016/j.ebiom.2019.102613.
16. Lan P, Pan KH, Wang SJ, et al. High Serum Iron level is Associated with Increased Mortality in Patients with Sepsis. Sci Rep. 2018;8(1):11072. doi: 10.1038/s41598-018-29353-2.
17. Royal College of Pathologists of Australasia. Iron studies standardized reporting protocol. Second Edition: November 2021.
18. Milman N, Agger AO, Nielsen OJ. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled trial in 207 Danish women. Dan Med Bull. 1991;38:471–6.
19. Kaufer M, Casanueva E. Relation of prepregnancy serum ferritin levels to haemoglobin levels throughout pregnancy. Eur J Clin Nutr. 1990;44:709–15.

20. Svanberg B, Arvidsson B, Norrby A, et al Absorption of supplemental iron during pregnancy – a longitudinal study with repeated bone-marrow studies and absorption measurements. Acta Obstet Gynecol Scand Suppl. 1975;48:87-108. doi:10.3109/00016347509156332

21. Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr. 2000;72(1 Suppl):257S-264S. doi:10.1093/ajcn/72.1.257S
22. Cross JH, Jarjou O, Mohammed NI, et al. Early postnatal hypoferremia in low birthweight and preterm babies: A prospective cohort study in hospital-delivered Gambian neonates. EBioMedicine. 2020;52:102613. doi: 10.1016/j.ebiom.2019.102613.
23. Schumacher A. Human Chorionic Gonadotropin as a Pivotal Endocrine Immune Regulator Initiating and Preserving Fetal Tolerance. Int J Mol Sci. 2017;18(10):2166. doi:10.3390/ijms18102166
24. Leber A, Zenclussen ML, Teles A, et al. Pregnancy: tolerance and suppression of immune responses. Methods Mol Biol. 2011;677:397-417. doi:10.1007/978-1-60761-869-0_25
25. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014;370(23):2211-8. doi:10.1056/NEJMra1213566
26. Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013;13(5):509-19. doi:10.1016/j.chom.2013.04.010
27. Parrow NL, Fleming RE, Minnick MF. Sequestration and scavenging of iron in infection. Infect Immun. 2013;81(10):3503-14. doi:10.1128/IAI.00602-13
28. Wardman P, Candeias LP. Fenton chemistry: an introduction. Radiat Res. 1996;145(5):523-31.
29. Von Sonntag, C. The chemical basis of radiation biology, Taylor and Francis, London, 1987.
30. Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Progress in Nucleic Acid Research and Molecular Biology. 1988;35:95–125. doi:10.1016/s0079-6603(08)60611-x.
31. Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis. 2007;11:482–7.
32. Pietrangelo A. Hereditary hemochromatosis. Biochim Biophys Acta-Mol Cell Res. 2006;1763:700–10.
33. Serjeant GR, Loy LL, Crowther M, et al. Outcome of pregnancy in homozygous sickle cell disease. Obstet Gynecol. 2004;103:1278–85.
34. Nassar AH, Usta IM, Rechdan JB, et al. Pregnancy in patients with β-thalassemia intermedia: outcome of mothers and newborns. Am J of Hematol. 2006;81(7):499–502.
35. Nassar AH, Naja M, Cesaretti C, et al. Pregnancy outcome in patients with β-thalassemia intermedia at two tertiary care centers, in Beirut and Milan. Haematologica. 2008;93(10):1586–7.
36. Cross JH, Jarjou O, Mohammed NI, et al. Early postnatal hypoferremia in low birthweight and preterm babies: A prospective cohort study in hospital-delivered Gambian neonates. EBioMedicine. 2020;52:102613. doi: 10.1016/j.ebiom.2019.102613.
37. Royal College of Pathologists of Australasia. Iron studies standardized reporting protocol. Second Edition: November 2021.
38. Barry DM, Reeve AW. Increased incidence of gram negative neonatal sepsis with intramuscular iron administration. Pediatrics. 1977;60:908–12.
39. Milman N, Agger AO, Nielsen OJ. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled trial in 207 Danish women. Dan Med Bull. 1991;38:471–6.
40. Kaufer M, Casanueva E. Relation of prepregnancy serum ferritin levels to haemoglobin levels throughout pregnancy. Eur J Clin Nutr. 1990;44:709–15.
41. Kaufer M, Casanueva E. Relation of prepregnancy serum ferritin levels to haemoglobin levels throughout pregnancy. Eur J Clin Nutr. 1990;44:709–15.
42. Australian Public Assessment Report for Ferric Carboxymaltose. AusPAR Ferinject Ferric carboxymaltose Vifor Pharma Pty Ltd PM-2009-01623-3-4. Final 24 May 2011
43. Moore RA, Gaskell H, Rose P, Allan J. Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data. BMC Blood Disord. 2011;11:4. doi:10.1186/1471-2326-11-4
44. Australian Public Assessment Report for Ferric Carboxymaltose. AusPAR Ferinject Ferric carboxymaltose Vifor Pharma Pty Ltd PM-2009-01623-3-4. Final 24 May 2011
45. Casanueva E, Viteri FE. Iron and oxidative stress in pregnancy. J Nutr. 2003;133(5 Suppl 2):1700S-1708S. doi:10.1093/jn/133.5.1700S
46. Casanueva E, Mares-Galindo M, Meza C, et al. Iron supplementation in non-anaemic pregnant women. 2002. SCN News. Geneva. 25:37–8.
47. Bowers KA, Olsen SF, Bao W, et al. 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. 2016;146(9):1756-61. doi:10.3945/jn.115.227793
48. Ahmed S, Ansar Ahmed Z, Siddiqui I, et al. Evaluation of serum ferritin for prediction of severity and mortality in COVID-19- A cross sectional study. Ann Med Surg (Lond). 2021;63:102163. doi: 10.1016/j.amsu.2021.02.009.
49. Alroomi M, Rajan R, Omar AA, et al. Ferritin level: A predictor of severity and mortality in hospitalized COVID-19 patients. Immun Inflamm Dis. 2021;9(4):1648-55. doi: 10.1002/iid3.517.
50. Lan P, Pan KH, Wang SJ, et al. High Serum Iron level is Associated with Increased Mortality in Patients with Sepsis. Sci Rep. 2018;8(1):11072. doi: 10.1038/s41598-018-29353-2.
51. Royal College of Pathologists of Australasia. Iron studies standardized reporting protocol. Second Edition: November 2021.
52. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
53. Royal College of Pathologists of Australasia. Iron studies standardized reporting protocol. Second Edition: November 2021.
54. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
55. Royal College of Pathologists of Australasia. Iron studies standardized reporting protocol. Second Edition: November 2021.
56. Milman N, Agger AO, Nielsen OJ. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled trial in 207 Danish women. Dan Med Bull. 1991;38:471–6.
57. Kaufer M, Casanueva E. Relation of prepregnancy serum ferritin levels to haemoglobin levels throughout pregnancy. Eur J Clin Nutr. 1990;44:709–15.
58. Daru J, Allotey J, Peña-Rosas JP, Khan KS. Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review. Transfus Med. 2017;27(3):167-74. doi:10.1111/tme.12408
59. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. doi:10.1039/c3mt00347g
60. Steer P, Alam MA, Wadsworth J, Welch A. Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. BMJ. 1995;310(6978):489-91. doi:10.1136/bmj.310.6978.489
61. Little MP, Brocard P, Elliott P, Steer PJ. Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study. Am J Obstet Gynecol. 2005;193(1):220-6. doi:10.1016/j.ajog.2004.11.053
62. Jung J, Rahman MM, Rahman MS, et al. Effects of hemoglobin levels during pregnancy on adverse maternal and infant outcomes: a systematic review and meta-analysis. Ann N Y Acad Sci. 2019;1450(1):69-82. doi: 10.1111/nyas.14112.
63. Young MF, Oaks BM, Tandon S, et al. Maternal hemoglobin concentrations across pregnancy and maternal and child health: a systematic review and meta-analysis. Ann N Y Acad Sci. 2019;1450(1):47-68. doi: 10.1111/nyas.14093.
64. Qassim A, Mol BW, Grivell RM, Grzeskowiak LE. Safety and efficacy of intravenous iron polymaltose, iron sucrose and ferric carboxymaltose in pregnancy: A systematic review. ANZJOG. 2018;58(1):22-39. doi:10.1111/ajo.12695
65. Neogi SB, Devasenapathy N, Singh R, et al. Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Glob Health. 2019;7:e1706-e1716S. doi.org/10.1016/S2214-109X(19)30427-9.
66. Moore RA, Gaskell H, Rose P, Allan J. Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data. BMC Blood Disord. 2011;11:4. doi:10.1186/1471-2326-11-4
67. Pels A, Ganzevoort W. Safety and Efficacy of Ferric Carboxymaltose in Anemic Pregnant Women: A Retrospective Case Control Study. Obstet Gynecol Int. 2015;2015:728952. doi:10.1155/2015/728952
68. Ortiz R, Toblli JE, Romero JD, et al. Efficacy and safety of oral iron(III) polymaltose complex versus ferrous sulfate in pregnant women with iron-deficiency anemia: a multicenter, randomized, controlled study. J Matern Fetal Neonatal Med. 2011;24(11):1347-52. doi:10.3109/14767058.2011.599080erences