Blood
Vol. 24 No 1 | Autumn 2022
Feature
Normal serum-ferritin in pregnancy: less is more
Dr Barton Smith
BSc (hons 1st), PhD, MBBS, FRANZCOG

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 decline39 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 standards60 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 research66 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].

 

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