Iron Demands of the Mother and Fetus
Across the 266 days of a human gestation, the fetus must accumulate roughly 300 mg of Fe [8]. This net transfer of Fe to the fetus is substantial when compared to the 1–2 mg of absorbed Fe per day that is typically sufficient to maintain a posi- tive Fe balance prior to pregnancy [9]. Fetal utilization of Fe across pregnancy is not linear; the majority of fetal Fe accretion occurs during the last 90 days of pregnancy [10]. At this time the fetus accrues approximately 5–8 mg of Fe per day [8]. This requirement is four times higher than the amount of Fe typically absorbed per day in non-pregnant women, and represents nearly 50% of the 20 mg of Fe that is released daily from the catabolism of senescent red blood cells [9]. Substantial alternations in maternal Fe absorption, tissue Fe utilization, and Fe partitioning are
needed in order to meet the Fe demands of pregnancy. Recent studies have provided new information on how pregnant women modify non-heme and heme Fe absorp- tion and mobilization of maternal Fe reserves to accommodate Fe requirements across gestation.
In early gestation, pregnant women experience a net Fe gain due to the cessation of menses. These savings that may occur during the early stages of gestation are highly variable, given that daily menstrual losses of Fe can range from 0.65–
4.88 mg/d [11, 12]. By the second trimester of pregnancy, Fe requirements increase substantially to support the ~50% increase in plasma volume and the concurrent
~35% increase in red blood cell mass [13]. During the third trimester of pregnancy, daily Fe demands peak as the fetus grows significantly in size and accrues the major- ity of its total body Fe. Iron utilized in support of these increased demands is obtained from maternal body reserves and from increased absorption of dietary and/or sup- plemental Fe as maternal body Fe stores are depleted. The dynamics of fetal growth, Fe uptake by the fetus, and Fe requirements across gestation are shown in Fig. 1.
Iron Absorption Across Pregnancy
Iron is the only mineral that humans cannot physiologically excrete should excess Fe be accumulated. Because of this unique aspect of Fe physiology, numerous regu- latory processes work to tightly control non-heme Fe absorption and release of Fe into the circulation from existing body Fe reserves. These mechanisms are integral to preventing the adverse effects that can be caused by an excess of non-transferrin bound Fe, but these regulatory systems also make it challenging to quickly replete Fe stores when necessary. Three hormones to date have been found to be integral to the maintenance of Fe homeostasis; erythropoietin (regulated in response to hypoxia), erythroferrone (regulated in response to stress erythropoiesis), and hepci- din (regulated by body Fe stores, hypoxia, and inflammation) [14]. Of the three hormones, hepcidin is responsible for regulating Fe export from cellular body stores and from the enterocyte. This negative regulatory hormone is released in greater amounts by the liver in response to increased body Fe stores. Hepcidin binds to the only cellular Fe export protein (ferroportin) and causes this protein to be internal- ized and degraded, thereby blocking non-heme Fe export into the bloodstream [15].
Using stable Fe isotopes, studies in pregnant women have found that hepcidin explains approximately 30% of the variability in intestinal absorption of non-heme Fe [16]. Similar amounts of variability in Fe absorption are explained by body Fe stores, as monitored by serum ferritin [16]. When Fe stores decrease in pregnant women, Fe absorption increases, but the ability to up-regulate non-heme Fe absorption is limited. During the third trimester of pregnancy Fe absorption has been found to increase on average by 3.6% for every 10 μg/L decrease in serum ferritin concentrations [17].
Nearly all of the focus on Fe absorption across gestation has centered on regula- tion of non-heme Fe absorption. Using stable Fe isotopes, studies have utilized
intrinsically labeled porcine heme Fe to compare absorption of heme Fe to that of ferrous sulfate during the third trimester of pregnancy compared to a control group of non-pregnant women [18]. Using this approach, heme Fe absorption was found to be threefold higher than absorption of non-heme Fe in the non-pregnant women (50.5% versus 15.2% respectively, p < 0.001 n = 11), but in pregnant women (67%
of whom had undetectable hepcidin) the difference observed between heme and non-heme Fe absorption was substantially reduced (47.7% versus 40.4%, p = 0.04, n = 18). Unlike the significant impact of maternal Fe status on absorption of non- heme Fe, absorption of heme Fe was not associated with Fe status or hepcidin in the
Fig. 1 Maternal and fetal iron requirements across gestation. Maternal and fetal iron demands change markedly across gestation. Early in pregnancy maternal Fe demands decrease due to the cessation of menses and little net Fe is accrued by the first trimester fetus. By the start of the second trimester of pregnancy (week 14 of gestation) increased maternal Fe is needed to support the marked increase in maternal red blood cell mass that occurs as plasma volume is expanded, and to provide the Fe needed to support the rapid fetal growth that occurs between weeks 14 to 26 of gestation. At week 14 of gestation the fetus weighs approximately 43 g and contains roughly 30 mg of Fe [10]. By the start of the third trimester of pregnancy the fetus has doubled its total body Fe content to 60 mg of Fe while increasing its body weight roughly 17-fold [10]. Over the last trimester of pregnancy, 3–8 mg of iron per day is needed to support daily fetal Fe acquisition.
[8] An average sized neonate contains approximately 300 mg of iron at birth, the majority of which is found as neonatal hemoglobin. At delivery, additional Fe is lost as the placental and umbilical cord are delivered (~90 mg) and due to maternal blood losses at delivery (~150 mg) [92]. The net iron cost of pregnancy has been estimated to total 580 mg [92]
non-pregnant or pregnant women [18]. Relative bioavailability of heme Fe during pregnancy has also been examined in 90 pregnant women who were randomized to receive either ferric fumarate alone (27 mg) or ferric fumarate and heme Fe (24 mg of ferric fumarate and 3 mg heme Fe) from week 20 of pregnancy through 24 weeks’
postpartum. Women randomized to the heme-containing supplement exhibited increased Fe stores at the end of pregnancy and greater maternal Fe stores at 24 weeks’ postpartum [19].
The mechanisms of enterocyte heme Fe uptake and export remains poorly char- acterized. Heme has been postulated to enter the enterocyte via a specific cellular protein (heme carrier protein 1 [HCP]/proton coupled folate transporter [PCFT]) or by a less-specific endocytic pathway. Once internalized into the enterocyte, heme may be catabolized into inorganic Fe (using heme oxygenase 1) and exported using ferroportin or if it is not catabolized within the enterocyte, the heme Fe may be exported intact using a heme export protein such as FLVCR1 (feline leukemia virus subgroup C receptor 1) which is known to be expressed in the enterocyte [20]. If heme is exported intact, it may also be preferentially utilized by the fetus. In the isotopic study of heme versus non-heme Fe mentioned above [18], Fe isotopic enrichment of the maternally ingested heme and non-heme Fe were evaluated in neonatal cord blood at birth. Using multiple approaches, in all instances there was a significantly greater neonatal enrichment of dietary Fe of heme origin, even after adjusting for the greater maternal absorption of heme [21]. This study suggests that heme Fe may be exported intact by the enterocyte, and if exported intact as heme Fe, it may be taken up by the myriad of heme trafficking proteins that have recently been found to be highly expressed in the human placenta [22].
Physiological Adaptations in Non-Heme Fe Absorption in Response to Fe Supplementation
Given the known associations between maternal Fe status and non-heme Fe absorp- tion, one would predict that maternal responses to inorganic Fe supplementation would be heavily influenced by baseline Fe status. Most Fe supplementation studies, however, have not attempted to control for pre-pregnancy Fe status or stratify the study population by entry level hematological status. A large Fe supplementation study (n = 1268) by Roberfroid et al. supplemented pregnant women with either a daily Fe folate supplement (containing 60 mg of Fe) or a UNIMMAP multiple micro- nutrient supplement (containing 30 mg of Fe) at entry into the study (week 17.3 ± 7.6 weeks of gestation) [23]. Response to supplementation was uniquely eval- uated as a function of entry-level hemoglobin concentrations; women who were ane- mic at baseline exhibited a significant increase in hemoglobin across gestation while women in the Fe replete population at baseline exhibited a decrease in hemoglobin concentrations across pregnancy (regardless of supplement ingested). Both groups ended the study with comparable hemoglobin concentrations, and 52% of women
remained anemic at late gestation while receiving Fe supplementation [23]. These findings highlight both the physiological decrease in hemoglobin that occurs over the course of gestation and the ability to appropriately regulate absorption of non-heme Fe in relation to gestational Fe demands. Had the study population not been stratified by baseline Fe status, the impact of Fe supplementation from either supplement would likely have been blunted, and the ability to regulate Fe absorption as a function of maternal Fe status may not have been appreciated. This example highlights the responsiveness of the enterocyte to physiological demands and draws attention to the mixed results that may be evident in supplementation studies dependent on the degree of anemia or Fe insufficiency that is evident when supplementation is initiated.