Hepcidin and Erythroferrone Levels across Human Pregnancy, and the Effect of IV Iron Infusion - a Revamp Substudy

Abstract

Hepcidin is known to be suppressed in human pregnancy; and while it's known that intravenous iron infusion increases hepcidin levels, it is unknown to what degree this occurs during pregnancy. The REVAMP trial was an open label, individually randomised controlled trial, in 862 Malawian pregnant women in the second trimester, with moderate to severe anaemia (haemoglobin<10.0g/dL). Participants were randomised equally to either intravenous Ferric Carboxymaltose (FCM), or standard of care (Oral iron), and followed up to 28 days post partum. To evaluate hepcidin and erythroferrone levels, a total of 250 participants were randomly selected. This sample was balanced with the main trial with regards to trial arm (FCM 50%, Oral iron 50%), baseline iron deficiency (42.2%), anaemia (96.4%), parity (nulliparous 55.6%), and HIV status (HIV positive 15.3%). Hepcidin and erythroferrone levels were measured by ELISA, on serum samples collected longitudinally across 3 pregnancy timepoints (baseline, 28-days post randomisation, 36-weeks gestation), delivery, and 28-days postpartum. Serum hepcidin levels (reported as: median [IQR]) were not different between the trial arms at baseline (FCM: 11.91ng/ml [5.56-20.53], Oral iron: 12.79ng/ml [6.65-20.40]). At 28 days post randomisation, hepcidin was higher in those treated with FCM (31.92ng/ml [14.80-59.84]) than oral iron (5.85ng/ml [2.50-15.12]), p<0.001. Hepcidin remained significantly increased at 36 weeks gestation (FCM: 21.14ng/ml [11.84-41.62], Oral iron: 10.86ng/ml [8.34-18.03], p<0.001). At delivery levels were higher overall, remaining higher in those who received FCM treatment (80.56ng/ml [25.11-149.6]) than Oral iron (37.39ng/ml [16.35-91.85], p=0.001). At 28days postpartum, hepcidin remained higher in the FCM arm 39.29ng/ml [19.52-76.37] than the Oral arm 17.67ng/ml [11.05-38.21], p<0.001. Erythroferrone levels were not statistically different between arms at any timepoint; values were highest at baseline (FCM median 0.92ng/ml [0.42-1.45], Oral iron 1.06ng/ml [0.52-2.04]). This is the first study examining the effects of modern intravenous iron infusions on hepcidin levels during pregnancy, and demonstrates that there is a statistically significant increase in hepcidin levels after ferric carboxymaltose, throughout pregnancy, persisting to four weeks post partum.