The Journal of Nutrition
Editorial
Ironing Out the Effects of Overweight and
Obesity on Hepcidin Production during
Pregnancy
David M Frazer1,2,3 and Gregory J Anderson4,5
1
Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; 2 School of Biomedical
Sciences, The University of Queensland, St Lucia, Queensland, Australia; 3 School of Biomedical Sciences, The Queensland University of
Technology, Gardens Point, Queensland, Australia; 4 Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston,
Queensland, Australia; and 5 School of Chemistry and Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
Pregnancy has the highest iron demand of any physiological
event occurring in adulthood, with each fetus carried to
term requiring >1000 mg Fe over the course of gestation
(1). Unfortunately, at the time of conception, the average
premenopausal woman has iron stores that are far lower
than this, particularly in developing countries where dietary
iron intake is generally poor (1). As a result, >20% of
pregnant women worldwide are estimated to suffer from iron
deficiency anemia, with far more having depleted iron stores
(2). The consequences of iron deficiency during pregnancy
can be devastating, and include an increased risk of pre-
eclampsia, preterm delivery, and intrauterine growth restriction
(3). Iron deficiency can also have lifelong consequences for the
developing fetus, and adverse effects on brain development can
lead to permanent cognitive impairment (4).
Although inadequate dietary iron intake and low prepreg-
nancy iron stores are the major risk factors for iron deficiency
in pregnant women, other potential contributors are emerging,
with increased adiposity being one such factor. In nonpregnant
individuals, being overweight or obese is often associated with
reduced iron stores and an increased risk of iron deficiency,
both of which are likely linked to the iron-regulatory hormone
hepcidin (5). This peptide, often referred to as the master
regulator of iron homeostasis, is produced predominantly by
the liver and secreted into the circulation, where it binds to
the iron export protein ferroportin on the surface of target
cells (6). This causes the entire complex to be internalized
and degraded, thereby inhibiting cellular iron release. Because
ferroportin is essential for both dietary iron absorption and the
release of iron stored in the liver and reticuloendothelial system,
increasing hepcidin reduces total body iron and decreases the
bioavailability of iron already in the body. It makes sense then
that hepcidin is normally decreased when the body’s demand
for iron is high, such as during pregnancy, because this allows
more iron to be absorbed from the diet and more stored
iron to be released into the bloodstream. However, hepcidin
is also induced by inflammation (6), and obesity is a chronic
inflammatory state. Thus, increased serum hepcidin is a feature
The authors reported no funding received for this study.
Author disclosures: the authors report no conflicts of interest.
GJA is a member of the Journal’s Editorial Board.
Address correspondence to DMF (e-mail: david.frazer@qimrberghofer.edu.au).

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First published online June 22, 2021; doi: https://doi.org/10.1093/jn/nxab200.
See corresponding article on page 2296.
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of obesity and can often disrupt normal iron homeostasis,
leading to lower body iron stores and, in some cases, anemia
(5).
The effect of obesity on iron status and hepcidin expression
during pregnancy, however, is less clear. This is an important
area of research in view of the high rates of obesity in many
developed countries, as demonstrated by studies showing that
over half of all women of childbearing age in the United
States are overweight and another one-third are obese (7).
Also of concern is the increasing prevalence of obesity in
many developing countries with traditionally high rates of iron
deficiency. In this issue of The Journal of Nutrition, Jones
et al. (8) aim to provide greater insight into the effect of
obesity on iron status in pregnant women. They examined iron
status markers and serum hepcidin in blood samples taken
mid-gestation from 405 pregnant rural Chinese women and
in corresponding cord blood samples. The authors found that
mid-pregnancy maternal hepcidin positively correlated with
maternal iron status, but not maternal overweight or obese
status. They also report that cord blood hepcidin showed a
positive correlation with neonate iron status and that maternal
overweight or obese status was associated with lower cord
blood hepcidin. Path analyses suggested that being overweight
or obese during pregnancy most likely affects fetal hepcidin
indirectly by reducing iron stores in the fetus.
Whereas these results broadly agree with other studies
showing the reduced iron status of neonates born to obese
mothers (9–12), they differ from those showing an effect of
BMI on maternal hepcidin mid-gestation (9, 13, 14). These
diverging results highlight the complex nature of hepcidin
regulation. The amount of hepcidin produced by hepatocytes
is controlled by a complicated array of signals, with some,
such as reduced serum iron concentration or increased RBC
synthesis, decreasing hepcidin expression, and others, including
increasing iron stores and inflammation, stimulating production
(6). When multiple competing pathways are active, the amount
of circulating hepcidin is determined by the strength of the
individual signals. For example, mice given an inflammatory
stimulus increase hepcidin production, but this effect is blunted
if animals are first made iron deficient (15). Thus, it is possible
that any influence of obesity on hepcidin production in the
current study cohort is being moderated by the iron demands of
pregnancy. As noted by the authors, the degree of obesity in the
2087
current study was relatively mild when compared with studies
showing increased maternal hepcidin, suggesting that the signals
to upregulate hepcidin production may not be as strong.
The authors also found that cord blood hepcidin correlates
most closely with neonatal serum ferritin, indicating that
hepcidin responds to infant iron stores rather than signals
from an overweight or obese mother. They also show that
neonatal serum ferritin was reduced in those born to overweight
or obese mothers and suggest that this is due to lower iron
stores in these infants. This implies that maternal BMI can
affect placental iron transfer to the fetus. Why this occurs is
not known. The expression of placental transferrin receptor
1 (TFR1), the protein mediating uptake of iron from the
maternal circulation, is unchanged in obese pregnancies (16).
Likewise, the reduction in circulating hepcidin in neonates from
overweight or obese mothers makes it unlikely that placental
iron export via ferroportin is reduced, although this has not
been measured directly to our knowledge. This suggests that
the ability of the placenta to transfer iron from the maternal
circulation to the fetus is not compromised by high maternal
BMI. However, there is evidence that the supply of iron to the
placenta might be. The authors report that soluble TFR1 in
the maternal circulation is increased in overweight or obese
pregnant women, indicating that the delivery of iron to maternal
tissues, including the maternal side of the placenta, is less than
ideal, possibly limiting iron supply to the fetus and explaining
the results presented.
Other potentially confounding factors can also influence the
apparent iron status of infants born to mothers with a high BMI.
Although not seen in the current study, elevated hemoglobin,
triggered by hypoxia-induced increases in erythropoietin in the
fetal circulation, has been reported previously in newborns from
obese mothers (11, 17, 18). This suggests that the lower serum
ferritin often detected in these neonates may, at least in part,
be due to the redistribution of storage iron to hemoglobin. Evi-
dence for this was reported in a study of 316 mother/infant pairs
which found that, with maternal obesity, the total amount of
iron transferred to the fetus was unchanged when the increased
fetal hemoglobin iron pool was taken into account (17). How-
ever, because the infants born to obese mothers were heavier
than those born to mothers with normal BMI, there remained a
decrease in the relative amount of iron per unit body weight.
The current study and those preceding it demonstrate that
infants born to obese or overweight mothers will generally
have lower iron stores for their size, increasing their chance
of developing iron deficiency in early childhood. Indeed, a
recent study showed that infants born to obese mothers had
an increased risk of developing iron deficiency anemia by 6 mo
of age (19). Because maternal BMIs are increasing beyond
the healthy range in many countries, it may be prudent to
consider screening programs specifically targeting infants born
to overweight or obese mothers to limit the detrimental effects
of iron deficiency.
Acknowledgments
The authors’ responsibilities were as follows—DMF: drafted
the manuscript; GJA: revised the manuscript; and both authors:
read and approved the final manuscript.
2088 Editorial
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