Abstract
Iron is an essential mineral that participates in oxygen transport, DNA synthesis and repair, and as a cofactor for various cellular processes. Iron deficiency is the most common nutritional deficiency worldwide. Due to blood volume expansion and demands from the fetal–placental unit, pregnant women are one of the populations most at risk of developing iron deficiency. Iron deficiency during pregnancy poses major health concerns for offspring, including intrauterine growth restriction and long-term health complications. Although the underlying mechanisms remain unclear, maternal iron deficiency may indirectly impair fetal growth through changes in the structure and function of the placenta. Since the placenta forms the interface between mother and baby, understanding how the placenta changes in iron deficiency may yield new diagnostic indices of fetal stress in affected pregnancies, thereby leading to earlier interventions and improved fetal outcomes. In this review, we compile current data on the changes in placental development and function that occur under conditions of maternal iron deficiency, and discuss challenges and perspectives on managing the high incidence of iron deficiency in pregnant women.
Introduction
Iron is an essential mineral that participates in many cellular processes, including oxygen transport, DNA synthesis and repair, and as an essential cofactor for various enzymes. Iron deficiency (ID) is the most common nutrient deficiency worldwide (McLean et al. 2009). It occurs when iron demands chronically exceed intake, leading to progressive depletion of tissue iron stores, and eventually, functional iron. Since iron is required for hemoglobin (Hb) synthesis, ID can result in anemia – a condition in which the quantity of circulating Hb, and thus oxygen-carrying capacity, falls below clinical thresholds and begins to impact cellular function (Maria de Regil 2010). One of the populations most at risk for ID anemia is pregnant women, due to the increased iron requirements of pregnancy. Iron is essential to support placental and fetal growth and maintain increased maternal red blood cell mass. An estimated 38% of women develop anemia during pregnancy, including 22% in high-income countries, with most cases attributed to ID (Stevens et al. 2013, Lopez et al. 2016).
ID during pregnancy can detrimentally affect fetal health. ID increases the risk of fetal death, preterm birth, and intrauterine growth restriction, and is associated with altered growth trajectories and long-term cognitive, cardiovascular, metabolic, and immune system complications in affected offspring (Krantman et al. 1982, Doom & Georgieff 2014, Alwan et al. 2015, Grandone et al. 2015). Despite repletion of iron stores in children through iron supplementation, health complications persist in children whose mothers exhibited ID during pregnancy, underscoring the importance of sufficient iron being supplied in utero for long-term health (Pasricha et al. 2013). Mechanisms through which maternal ID impairs fetal growth and results in long-term sequelae remain to be elucidated; however, the placenta may play a key role.
The placenta forms the interface between mother and fetus and supports fetal growth and development by facilitating respiratory gas, nutrient, and waste transport between maternal and fetal circulations, producing hormones, and providing immunological support. As an adaptive organ, the placenta can respond to environmental signals through alterations in structure and function, which in turn influence blood flow, nutrient transport, and hormone metabolism to optimize the intrauterine environment. While these adaptations may convey short-term benefits, in some circumstances, they may impair long-term function and have profound impacts on a fetus’ ability to cope in the intrauterine environment. Placental dysfunction may, therefore, connect adverse maternal nutrition and offspring health, and potentially be used as an ‘early warning system’ for fetal complications. In this review, we will briefly introduce placental development and discuss iron requirements during pregnancy. We will then summarize current knowledge detailing how ID affects placental development and function, and discuss new challenges and opportunities to address the impact of ID on placental development and pregnancy outcome.
The placenta
The human placenta is discoid-shaped, hemochorial (maternal blood directly contacts fetal chorion), and is composed of tissues derived from both mother and fetus. The maternal aspect of the placenta is the decidua basalis, which contains stromal cells, glands, leukocytes, and blood vessels (e.g. spiral arteries). The fetal aspect of the placenta is arranged in chorionic villi, which are highly branched structures consisting of an outer layer of syncytialized trophoblast and mononuclear cytotrophoblasts surrounding an inner core containing fibroblasts, macrophages, and blood vessels (Fig. 1). The syncytialized trophoblast layer is the major source of hormones necessary for pregnancy establishment and maintenance. At the tips of large anchoring villi, cytotrophoblasts differentiate into extravillous trophoblasts. Extravillous trophoblasts proliferate into stratified cell columns and then invade into the uterine wall to modify spiral arteries and promote consistent, low-velocity maternal blood flow toward the space surrounding chorionic villi. Blood vessels in the villous core bring deoxygenated, nutrient-poor blood from the fetus. Oxygen and nutrients dissolved in maternal blood pass across the trophoblast layer into blood vessels within the villous core, where they are carried to the fetus. Carbon dioxide and wastes pass from fetal blood into the intervillous space to be carried away via endometrial veins. Substances can move across the placenta by simple diffusion (e.g. oxygen), facilitated diffusion (e.g. glucose), or active transport (e.g. iron). Placental nutrient transfer capacity can be influenced by a wide variety of factors, including villous surface area and thickness, the abundance and activity of transporters, concentration gradients between maternal and fetal blood, placental metabolism, and uteroplacental blood flow, all of which are sensitive to environmental stimuli (Tarrade et al. 2015).
Schematic illustration of placental iron transport. Top: illustration of a human placenta. Bottom: diagram showing iron transport from the maternal circulation to the fetal circulation. BCRP, breast cancer resistance protein; CP, ceruloplasmin; DMT, divalent metal transporter-1; FLVCR1/2, feline leukemia subgroup C receptor 1/2; FPN, ferroportin; HO, heme oxygenases; Hp, hemopexin; LRP1, low-density lipoprotein receptor-related protein-1; PCBP, poly(rC)-binding protein; PCFT, proton-coupled folate transporter; STEAP, six-transmembrane epithelial antigen of prostate; Tf, transferrin; TfR1, transferrin receptor 1; ZIP, ZRT/IRT-like protein; ZP, zyklopen.
Citation: Reproduction 160, 4; 10.1530/REP-20-0271
A discoid-shaped, hemochorial placenta also features in many rodent species, including those commonly used in laboratory settings: mice and rats (referred to as ‘laboratory rodents’ unless specified otherwise) (Soares et al. 2012). Although there are inherent differences in placentation between humans and laboratory rodents (e.g. length of gestation, number of conceptuses, and organization of trophoblast subtypes within the placenta), there are also anatomical and functional similarities (Soncin et al. 2018). For instance, placentas of laboratory rodents are composed of both maternal and fetal compartments. The maternal compartment includes the decidua basalis and mesometrial triangle, and contains spiral arteries and a similar composition of cells to that found in humans. In laboratory rodents, the site at which nutrients are exchanged between maternal and fetal blood, referred to as the labyrinth zone because of its maze-like resemblance in cross-section, is compositionally similar to the chorionic villi in humans. Nutrients dissolved in maternal blood pass across three trophoblast layers (including two syncytialized layers) to access the fetal circulation. The junctional zone is a transitional region sandwiched between the labyrinth zone and decidua basalis. It is composed of stratified layers of trophoblasts, a subset of which invade into the maternal compartment and, particularly in rats, contribute to spiral artery transformation. Thus, the junctional zone is functionally analogous to extravillous trophoblasts in human placenta. The junctional zone also has an important endocrine function, which is a major difference between placentas of humans and laboratory rodents (Malassiné et al. 2003). Nevertheless, given the anatomical and functional similarities between human and laboratory rodent placentas and the capacity for experimental manipulation in the latter (Renaud et al. 2011), many studies have used mice and rats to deduce the impact of iron homeostasis on pregnancy outcome. Consequently, although this review will emphasize the impact of iron homeostasis on human placental development, we will also discuss findings using mice, rats, and other species where appropriate.
Iron requirements and regulation in pregnancy
The maternal requirement for iron changes considerably during pregnancy to facilitate maternal blood volume expansion, placental development, and fetal growth (reviewed in Fisher & Nemeth 2017). Most of this demand occurs in the third trimester, reaching an average daily iron requirement of approximately 4.4 mg/day (Milman 2006a). To accommodate the increased iron requirements, women entering pregnancy should have approximately 500 mg of stored iron (Milman et al. 1999), yet only 20–35% of women of reproductive age are estimated to meet this threshold (Milman 2006b, Means 2020). It is, therefore, apparent why many women experience ID during pregnancy.
Several mechanisms enhance iron availability in the maternal circulation throughout pregnancy, including increased intestinal absorption of iron and mobilization of maternal iron reserves. Dietary iron exists in two forms: nonheme (predominantly from plant sources) and heme (from animal sources). As pregnancy progresses, maternal absorption of nonheme iron increases and heme absorption likely follows a similar trend (Barrett et al. 1994, Young et al. 2012). Maternal iron stores become mobilized during pregnancy from depots such as liver and spleen, as shown by studies using pregnant rodents (Hubbard et al. 2013, Gao et al. 2015). Additionally, iron-binding capacity of transferrin (Tf), which transports nonheme iron in blood, increases throughout gestation (Choi et al. 2000). Together, these processes facilitate maternal hematologic adaptation, and increase iron availability for the placenta and fetus.
The regulation of iron availability during pregnancy is dependent on hepcidin, a hormone produced mainly by hepatocytes that controls levels of circulating iron (Nemeth & Ganz 2006). Multiple factors influence hepcidin production, including circulating and stored iron, erythropoietic activity, and inflammation (Sangkhae & Nemeth 2017). Hepcidin binds to the iron export protein, ferroportin (FPN), and promotes its degradation, thereby triggering iron sequestration and decreased efflux into plasma from key sites, including intestine and liver (Fisher & Nemeth 2017). In second and third trimesters, maternal hepcidin concentrations are decreased, presumably to increase iron availability and uptake by the placenta, which constitutes an important period of iron accretion for the fetus (van Santen et al. 2013, Bah et al. 2017). In a study of 19 pregnant women who ingested stable iron isotopes, net dietary nonheme and heme iron transferred to the fetus was inversely correlated with maternal serum hepcidin (Young et al. 2012). Not surprisingly, maternal hepcidin is lowest in pregnant women with ID (Rehu et al. 2010).
Placental iron transport and regulation
Fetal growth and development are dependent on active iron transport across the placenta, therefore this organ plays a crucial role in iron flux throughout pregnancy. Placental iron transport is controlled mainly by the syncytiotrophoblast. A detailed description of placental iron transport mechanisms has recently been reviewed (Sangkhae & Nemeth 2019).
Placental nonheme iron transport
Nonheme iron is bound to Tf in maternal circulation. The iron-bound Tf binds to the Tf receptor (TfR) and undergoes unidirectional transport. Both TfR1 and TfR2 are expressed on the apical surface of the syncytiotrophoblast; however, the role of TfR2 remains undefined (McArdle et al. 2011). The iron-Tf-TfR1 complex is internalized via clathrin-mediated endocytosis. Acidification of the vesicle causes iron to dissociate from Tf as Fe3+ and becomes reduced by ferrireductases to Fe2+. Potential ferrireductases include six-transmembrane epithelial antigen of prostate-3 (STEAP3) and STEAP4, which are highly expressed in the placenta (Ohgami et al. 2006). TfR and Tf return to the apical surface of syncytiotrophoblast, where Tf is recycled back into the maternal circulation. Fe2+ is transported from endosomes into the cytoplasm, possibly via divalent metal transporter-1 (DMT1), which has been implicated in maternal-fetal iron transfer (Chong et al. 2005). Interestingly, studies in mice suggest the likelihood of an alternative DMT1-independent iron-uptake pathway in the placenta, which may involve ZRT/IRT-like protein-14 (ZIP14), and ZIP8 (Gunshin et al. 2005).
Once in the cytosol, iron may be chaperoned by poly(rC)-binding protein (PCBP) to either be used for cellular processes, stored in ferritin, or transported to the basolateral surface of syncytiotrophoblast, where it is exported into the villous core via FPN. As ferritin levels are low in syncytiotrophoblast, most iron entering the placenta is likely used for cellular processes or transported to the fetus (Bastin et al. 2006). Once exported from the syncytiotrophoblast via FPN, iron may be delivered to fetal Tf via oxidation by placental ferroxidases which may include ceruloplasmin, hephaestin, and zyklopen (Danzeisen et al. 2000, Chen et al. 2010). Alternatively, non-Tf-bound iron is present in the fetal circulation, indicating that it may be transported directly across fetal endothelial cells, although this mechanism is unknown (Evans et al. 2011).
Placental heme iron transport
Placental expression of putative heme influx transporters includes proton-coupled folate transporter (PCFT)/heme carrier protein-1 (HCP1), breast cancer resistance protein (BCRP), and feline leukemia subgroup C receptor-2 (FLVCR2) (Maliepaard et al. 2001, Qiu et al. 2006, Duffy et al. 2010). Low-density lipoprotein receptor-related protein-1 (LRP1) is highly expressed in placenta and may also facilitate heme uptake by recognizing heme complexed to a high-affinity heme-binding plasma protein, hemopexin (Hvidberg et al. 2005). Once imported, heme iron can be processed by heme oxygenases, releasing iron into the cytosol, or may be directly exported by FLVCR1, which may serve to prevent heme toxicity (Jaacks et al. 2011, Levytska et al. 2013). The functional significance of heme iron transport across the placenta is largely unknown. However, following maternal ingestion of 57Fe-heme and 58Fe-nonheme iron, a greater proportion of 57Fe was detected in neonates, suggesting that heme-based iron is more efficiently transferred compared to nonheme iron (Young et al. 2012). Although there are multiple factors that may account for increased enrichment of heme versus nonheme iron in neonatal blood, it is nevertheless apparent that heme is an important source of iron for the fetus.
Regulation of placental iron transport
Several factors influence transport of nutrients (including iron) across the placenta, including uteroplacental and umbilical hemodynamics, placental surface area, metabolism, and expression/activity of transporters. In response to changes in cytosolic iron status, iron regulatory proteins bind to untranslated regions (UTRs) of transcripts encoding transporters and storage proteins (e.g. TfR1, DMT1, ferritin, and FPN), as reviewed in (Lipiński et al. 2013). In general, binding of iron regulatory proteins to the 3′-UTR increases mRNA stability (e.g. for TfR1 and DMT1), whereas binding to the 5′-UTR prevents translation (e.g. for ferritin and FPN). Thus, when cytosolic iron levels are plentiful, iron storage and export are stimulated and import is inhibited.
Maternal and fetal hepcidin levels influence placental iron trafficking. Hepcidin may interact with FPN to facilitate its internalization from the basolateral membrane of syncytiotrophoblast, and also downregulates TfR1 expression in mouse placenta (Martin et al. 2004, Nemeth et al. 2004). Notably, in mouse embryos that overexpress hepcidin, either as a consequence of transgenic hepcidin overexpression or mutations in the hepcidin regulator matriptase-2, placental FPN is downregulated resulting in severe fetal ID (Nicolas et al. 2002, Willemetz et al. 2014). Additionally, mouse embryos lacking hereditary hemochromatosis protein (HFE), a protein that promotes hepcidin production, exhibit increased placental expression of TfR1, DMT1, and FPN (Balesaria et al. 2012). HFE is also expressed on the apical surface of syncytiotrophoblast. In addition to stimulating hepcidin production, it may negatively regulate iron uptake by blocking TfR1 binding to Tf, as it does in hepatocytes (Parkkila et al. 1997, Gruper et al. 2005). In rats, fetal hepcidin levels tightly correlate with maternal liver iron levels, more so even than the association between maternal hepcidin and maternal iron status (Gambling et al. 2009). This may help to ensure fetal iron demands are met during pregnancy. Fetal hepcidin is also upregulated during maternal inflammation, possibly as a protective mechanism to limit iron availability to pathogenic bacteria (Fisher et al. 2020). Notably, hepcidin is also expressed by the placenta at low levels, but its role is unclear (Evans et al. 2011). No correlation exists between placental hepcidin expression and either maternal or neonatal iron status, nor with placental iron transporter expression (Rehu et al. 2010, Best et al. 2016). Similarly, placental hepcidin in pregnant rats is not associated with iron content of maternal diet, or with maternal or fetal liver iron content; in mice, placental hepcidin does not correlate with fetal iron endowment in normal pregnancy or in iron-deficient states (Gambling et al. 2009, Sangkhae et al. 2020a,b).
Maternal ID: effect on the placenta
Transplacental iron and nutrient transport
In maternal ID, placental iron transfer is a balancing act to ensure that sufficient iron is available to support its own functions and delivered to the fetus despite low levels in maternal blood. Table 1 summarizes alterations in placental expression of proteins involved in iron transport and metabolism in relation to iron status. The placental protein that is most frequently reported to exhibit altered levels relative to iron status is TfR1. Increased TfR1 expression is frequently reported in placentas from ID pregnancies, and is recapitulated in human trophoblast cells and cell-lines cultured in the presence of the iron chelator, desferoxamine (Kroos et al. 1996, Georgieff et al. 1999, Gambling et al. 2001, Li et al. 2008, 2012, Young et al. 2010, Garcia-Valdes et al. 2015, Best et al. 2016, Sangkhae et al. 2020a). Likewise, increased placental TfR1 expression is evident in pregnant rodents fed ID diets (Gambling et al. 2009, Balesaria et al. 2012, Cornock et al. 2013), whereas rodents fed an iron-replete diet or given parenteral iron supplementation exhibit decreased placental TfR1 expression (Martin et al. 2004, Balesaria et al. 2012). Thus, dynamic expression of TfR1 by the placenta is potentially a key adaptation to guarantee appropriate uptake of iron from maternal blood.
Expression of factors implicated in placental iron trafficking during ID.
| Name | Gene | Changes in mRNA and protein expression | |||
|---|---|---|---|---|---|
| Human Studies | References | Animal studies | References | ||
| Iron influx | |||||
| TfR1 | TFRC | ↑ expression in human placentas ↑ expression in BeWo cells and primary trophoblasts exposed to DFO |
Kroos et al. (1996), Georgieff et al. (1999), Gambling et al. (2001), Li et al. (2008, 2012), Young et al. (2010), Garcia-Valdes et al. (2015), Best et al. (2016), Sangkhae et al. (2020a) | ↑ expression in rat placentas | Gambling et al. (2009), Balesaria et al. (2012), Cornock et al. (2013) |
| HFE | HFE | ↔ mRNA expression in rat and mouse placentas | Gambling et al. (2009), Sangkhae et al. (2020a) | ||
| BCRP | BCRP | ↔ protein expression in human placentas | Jaacks et al. (2011) | ||
| Intracellular iron trafficking and storage | |||||
| DMT1 | SLC11A2 | ↑ expression in human placentas ↑ expression in BeWo cells exposed to DFO |
Gambling et al. (2001), Venkata Surekha et al. (2020) | ↔ mRNA expression in mouse placentas ↑ mRNA expression in rat placentas |
Cornock et al. (2013), Sangkhae et al. (2020a) |
| Ferritin | FTH1 (heavy chain), FTL (light chain) | ↓ mRNA expression in human placentas | Li et al. (2008) | ↔ in expression in rat placentas | Gambling et al. (2009) |
| Iron efflux | |||||
| FPN | SLC40A1 | ↔ or ↑ protein expression in human placentas ↑ expression in BeWo cells exposed to DFO ↓ protein expression in trophoblast cells exposed to DFO |
Li et al. (2008, 2012), Best et al. (2016), Sangkhae et al. (2020a), Venkata Surekha et al. (2020) | ↔ in mRNA expression in rat and mouse placentas ↓ protein expression in mouse placentas |
Gambling et al. (2001), Cornock et al. (2013), Sangkhae et al. (2020a) |
| Ceruloplasmin | CP | ↔ in mRNA expression in human placentas ↔ in mRNA expression in BeWo cells exposed to DFO ↑ protein expression in BeWo cells exposed to DFO |
Danzeisen et al. (2000), Li et al. (2008), Best et al. (2016) | ↔ in mRNA expression in rat placentas | Fleming and Gitlin (1990) |
| Hephaestin | HEPH | ↑ expression in BeWo cells exposed to DFO | Li et al. (2012) | ||
| Zyklopen | ZP | ↑ expression in human placentas | Venkata Surekha et al. (2020) | ↔ in mRNA expression in mouse placentas | Sangkhae et al. (2020a) |
| FLVCR1 | FLVCR1 | ↓ protein expression in human placentas | Jaacks et al. (2011) | ↔ in mRNA expression in mouse placentas | Sangkhae et al. (2020a) |
↑ = Increased; ↔= No change; ↓ = Decreased; BCRP, breast cancer resistance protein; DMT1, divalent metal transporter 1; FLVCR1, feline leukemia virus subgroup C receptor 1; FPN, ferroportin; HFE, human hemochromatosis protein; TfR1, transferrin receptor 1.
Expression of other proteins involved in iron transport or metabolism has also been measured in maternal ID, although patterns are less clear. Placental expression of DMT1 is reported to be increased in some studies using rodent models of maternal ID, which may facilitate intracellular iron trafficking (Gambling et al. 2001, Cornock et al. 2013); although in other studies, no change in DMT1 was detected (Sangkhae et al. 2020a). In placentas collected from mothers with mild-to-moderate anemia, no change in FPN expression is evident (Li et al. 2008, Best et al. 2016, Sangkhae et al. 2020a). However, in placentas collected from mice exposed to severe iron deficiency, or primary human trophoblasts treated with chelating agents, FPN expression is paradoxically reduced, suggesting that the placenta may sequester iron to preserve its own metabolic function rather than ensure fetal sustenance (Sangkhae et al. 2020a).
Maternal ID may also affect the expression of putative heme transporters. In pregnant adolescents, maternal anemia is associated with decreased expression of the placental heme export protein FLVCR1 (Jaacks et al. 2011). Fetal iron status more closely reflects the expression of the placental heme transporters FLVCR1 and PCFT than with nonheme transporters (Best et al. 2016), suggesting that heme transporters may respond to fetal iron demand rather than maternal iron availability. Given that the placenta efficiently uptakes heme iron, a better understanding of placental heme transport during normal and ID pregnancies is warranted.
In addition to increased expression of placental iron transporters, maternal adaptations also occur that facilitate iron availability for the placenta (Cao & Fleming 2016). In rat models of ID, anemic dams exhibit increased intestinal absorption of iron, reduced liver iron content, and decreased maternal hepcidin expression compared to controls (Gambling et al. 2004, 2009, Cornock et al. 2013). Despite various adaptive changes in maternal metabolism and placental transport to optimize iron transfer to the fetus, babies born from severely anemic women have lower cord Hb levels compared to controls (Kumar et al. 2008, El-Farrash et al. 2012). Thus, under conditions of moderate iron deficiency, placental iron transport may be accelerated in favor of fetal demands. However, there appears to be a threshold of maternal iron status when a sufficient supply of iron cannot be delivered to the fetus, at which point the placenta establishes a new hierarchy in which iron is prioritized for its own function rather than delivered to the fetus.
Appropriate fetal growth and development also depend on the availability of nutrients, including glucose, amino acids, and fatty acids. Dysfunction in the transplacental transport of these nutrients may contribute to intrauterine growth restriction and other complications observed in maternal ID. In rats, maternal ID causes reduced fetal growth, correlating with decreased fetal plasma levels of triacylglycerol, cholesterol, and several amino acids, including taurine, phenylalanine, and tyrosine. Maternal plasma levels of these nutrients are unaffected, suggesting impaired placental transport (Lewis et al. 2001a). However, no studies to date have directly assessed placental expression or activity of nutrient transporters in the context of maternal ID.
Placental hypoxia, oxidative stress, and inflammation
Hypoxia is a condition in which oxygen availability is reduced in cells or tissues. Since ID restricts Hb synthesis and oxygen transport, hypoxia is a potential consequence. Cells adapt to hypoxic conditions in part through stabilization of hypoxia-inducible factor alpha (HIFA) subunits, which interact with HIFA subunits to alter transcription of numerous genes that alter cell growth, metabolism, and survival. Stabilization of HIFA subunits is facilitated by reduced activity of prolyl hydroxylases, which are enzymes that hydroxylate HIFA when oxygen is replete, leading to its ubiquitination and degradation. Expression of HIF1A in the placenta is high in early pregnancy due to the low oxygen environment in which the placenta develops, and in normal circumstances expression declines by the end of the first trimester as oxygen tension increases (Ietta et al. 2006). However, in ID pregnancies, term placentae exhibit increased expression of HIF1A (Michalitsi et al. 2015). Likewise, in rat models of ID anemia, no change in mRNA expression of Hif1a in placenta is evident, but higher HIF1A protein expression is detected (Lewis et al. 2001b, Toblli et al. 2012). Whether the increased HIF1A expression is attributed to hypoxia per se is unclear, because iron is a critical cofactor for prolyl hydroxylase activity (Bishop & Ratcliffe 2015), and therefore HIF1A expression may be increased irrespective of oxygen levels (Woo et al. 2006). Indeed, using pimonidazole, which forms stable adducts with thiol groups of proteins in hypoxic cells, Woodman et al. found no evidence of placental hypoxia with maternal ID in pregnant rats, despite robust signals in various fetal organs (Woodman et al. 2017). Notwithstanding, the increased placental HIF1A may contribute to dysregulated expression of genes, such as those encoding inflammatory cytokines, which affect placental function and contribute to pregnancy complications (Gambling et al. 2002).
Oxidative stress is characterized by amplified production of reactive oxygen species beyond the capacity of antioxidant defense mechanisms, and is a normal occurrence throughout pregnancy (Mannaerts et al. 2018). As gestation advances, antioxidant defenses are enhanced to prevent oxidative damage to the placenta and fetus (Furukawa et al. 2016). In pregnant rat models of ID anemia, increased oxidative stress, lipid peroxidation, mitochondrial damage, and inflammatory cytokine production (e.g. tumor necrosis factor (TNF) and interleukin-6) is evident (Gambling et al. 2002, Walter et al. 2002, Toblli et al. 2012). Like the case with prolyl hydroxylases described above, iron is an essential cofactor for several antioxidant enzymes, including catalase. ID may thus impair the function of antioxidant defenses, exacerbating generation of reactive oxygen species and contributing to placental damage and dysfunction.
Placental structure
Since the placenta forms the interface between mother and fetus, its structure is a key determinant for oxygen and nutrient delivery to the fetus. The efficiency of nutrient and oxygen transfer to the fetus can be affected by changes in the total surface area available for exchange, thickness of the placental exchange surface, proportion of specialized placental regions, and vascularization. Therefore, the impact of maternal ID on placental structure is an important consideration.
When compared to fetal/neonatal weight, placental weight can be used as a proxy for placental efficiency, and an indication of how placental development and function has adapted to sustain fetal requirements (Fowden et al. 2009). Studies in both humans (Table 2) and animals (Table 3) show that maternal ID has an effect on placental weight and placental:fetal birth weight ratios. For example, several studies suggest that placental weight and placental:fetal weight ratios increase with maternal anemia (Beischer et al. 1970, Godfrey et al. 1991, Lao & Wong 1997, Lao & Tam 2000, Huang et al. 2001, Baptiste-Roberts et al. 2008, Lelic et al. 2014, Larsen et al. 2016). Among these studies, two were conducted using large cohorts of 8648 (Godfrey et al. 1991), and 57,062 (Larsen et al. 2016) human pregnancies, in which a negative correlation between placental weight and maternal Hb concentration was reported. It is possible that decreased iron and/or Hb evokes compensatory placental hypertrophy that increases surface area and enhances oxygen and nutrient exchange. Conversely, some studies have found no correlation between low Hb and placental weight (Reshetnikova et al. 1995) or decreased placental weights in anemic mothers (Rusia et al. 1988, Mongia et al. 2011, Kiran et al. 2015). Multiple factors may account for these discrepancies, including severity of anemia, timing of anemia onset, number of samples analyzed, ethnic populations, and possibility of maternal malnutrition or other nutritional deficits. In some cases, gestational age was not controlled, which confounds the interpretation of placental size and its relationship to fetal weight.
Placental and fetal outcomes from maternal ID anemia in human pregnancy.
| Placental morphology | Fetal features | Maternal Hb (g/L) | n | References |
|---|---|---|---|---|
| ↑ placental weight, placental volume and/or placental/fetal weight ratio | ||||
| ↑ placental weight ↑ chorionic plate area |
Not reported | Control: >100 Anemic: <100 |
23,420 | Baptiste-Roberts et al. (2008) |
| ↑ placental weight ↑ placental/fetal weight ratio |
Not reported | Control: >100 Anemic: <80 |
4974 | Beischer et al. (1970) |
| ↑ placental/fetal weight ratio | ↓ fetal weight | Control: >110 Anemic: <110 |
8648 | Godfrey et al. (1991) |
| ↑ placental weight ↑ surface area of capillaries in maternal villi |
Not reported | 122 | PS: 1650; PM: 17 |
Hindmarsh et al. (2000) |
| ↑ placental volume ↑ area of intervillous space ↔ membrane thickness ↔ placental Hb or iron |
↑ fetal weight | Control: 127 Moderate: 106 Severe: 86 |
26 | Huang et al. (2001) |
| ↑ placental weight ↑ chorionic plate area ↑ placental/fetal weight ratio |
↔in fetal weight | Control: >100 Anemic: <100 |
511 | Lao and Wong (1997) |
| ↔ placental weight ↑ placental/fetal weight ratio |
↓ fetal weight ↓ gestational age |
Control: >100 Anemic: <100 |
437 | Lao and Tam (2000) |
| ↑ placental weight and placental/fetal weight ratio with ↓ Hb concentration | ↓ fetal weight in low and high Hb concentrations | High: 135 Intermediate: 90–135 Low: <90 |
57,062 | Larsen et al. (2016) |
| ↑ placental/fetal weight ratio | ↓ fetal weight | Control: >110 Anemic: <110 |
2507 | Williams et al. (1997) |
| ↔ or ↓ placental weight, placental volume or placental/fetal weight ratio | ||||
| ↓ placental weight with increasing severity of ID ↑ placental infarcts ↑ number of syncytial knots |
Not reported | Control: >110 Mild: 100–109 Moderate: 70–99 Severe: <70 |
75 | Kiran et al. (2015) |
| ↔ placental weight and volume ↑ volume of villous blood vessels |
↓ fetal weight ↓ gestational age |
Control: >105 Anemic: <105 |
100 | Lelic et al. (2014) |
| ↓ placental weight ↑ fibrosis and syncytial knots ↑ cytotrophoblast proliferation ↑ capillaries per villus |
↓ fetal weight Premature birth |
Control: >110 Anemic: <110 |
120 | Mongia et al. (2011) |
| ↔ placental weight ↓ villous surface area ↑ volume of fetal capillaries ↓ placental membrane thickness |
↔ in fetal weight | Control: 119 Anemic: 90 |
20 | Reshetnikova et al. (1995) |
| ↓ placental weight and volume ↔ placental surface area ↓ number of cotyledons |
↓ fetal weight | Control: >110 Mild: 86–109 Moderate: 61–85 Severe: <60 |
85 | Singla et al. (1978) |
↑, increased; ↔, no change; ↓, decreased; Hb, hemoglobin; PM, placental morphology; PS, placental size.
Placental and fetal outcomes in rodent models of maternal ID.
| Animals | Placental morphology | Fetal features | ID model diets | References |
|---|---|---|---|---|
| Studies reporting increased placental weight, placental volume, or placental/fetal weight ratio | ||||
| Rowett Hooded Lister Rats | ↔placental weight ↓ placental iron ↑ placental/fetal weight |
↓ fetal bodyweight Asymmetric growth ↓ fetal Hb |
Dams fed diet starting 4w before pregnancy Control: 50 mg iron/kg Mild: 37.5 mg iron/kg Moderate: 12.5 mg iron/kg Severe: 7.5 mg iron/kg |
Gambling et al. (2002) |
| Wistar Rats | ↑ placental weight ↔labyrinth zone area ↑ placental Hif1a mRNA |
↓ fetal bodyweight ↓ fetal Hb ↓ hematocrit ↓ red blood cell volume |
Control: Dams fed 150 mg iron/kg diet starting 2w before pregnancy Moderate: Dams fed 3 mg iron/kg diet starting 1w before pregnancy Severe: Dams fed 3 mg iron/kg diet starting 2w before pregnancy |
Lewis et al. (2001a) |
| Mice (C57BL/6J) | ↔placental weight ↑ placental/fetal weight ratio ↔ placental heme iron ↓ placental non-heme iron |
↓ fetal Hb ↓ hematocrit |
Control: Dams fed 185 ppm iron diet starting 2w before pregnancy ID: Mice fed 4 ppm iron diet starting 2w before pregnancy |
Sangkhae et al. (2020a) |
| Sprague Dawley Rats | ↑ placental weight ↑ placental/fetal weight |
↓ fetal bodyweight ↓ fetal Hb |
Control: Dams fed 37 mg iron/kg diet starting 2w before pregnancy Moderate: Dams fed 10 mg iron/kg starting 2w before pregnancy Severe: Dams fed 3 mg iron/kg starting 2w before pregnancy |
Woodman et al. (2018) |
| Sprague Dawley Rats | ↑ placental weight ↑ placental/fetal weight ↔ placental hypoxia ↑ umbilical artery resistance ↑ pulsatility index (in severe ID) |
↓ fetal bodyweight ↓ fetal Hb |
Control: Dams fed 35 mg iron/kg diet throughout pregnancy until GD 21.5 Moderate: 12w-old dams fed 3 mg iron/kg diet starting 2w before pregnancy Severe: 6w-old dams fed 3 mg iron/kg starting 2w before pregnancy |
Woodman et al. (2017) |
| Studies reporting decreased placental weight, placental volume, or placental/fetal weight ratio | ||||
| Sprague Dawley Rats | ↓ placental weight ↓ placental/fetal weight |
↓ fetal Hb | Control: Dams fed standard chow starting 3-4w before pregnancy ID: Dams fed <6 ppm iron diet starting 3-4w before pregnancy |
Crowe et al. (1995) |
| Sprague Dawley Rats | ↓ placental weight ↑ protein expression of HIF1A, TNF and IL6 |
↓ fetal bodyweight | Control: Rats fed 60 ppm iron diet 8w before mating ID: Rats fed 10-20 ppm iron diet 8w before pregnancy |
Toblli et al. (2012) |
↑, increased; ↔, no change; ↓, decreased; ID, iron deficiency; Hb, hemoglobin; w, weeks.
Rodents fed iron-deficient diets have been used to study the impact of ID anemia on pregnancy outcome. In these models, diets lacking iron are invariably associated with reduced fetal size (Lewis et al. 2001a, Gambling et al. 2002, Toblli et al. 2012, Woodman et al. 2017, 2018). However, conflicting effects of maternal anemia on placental weight have been reported, with many studies showing an increase in placental weight (Lewis et al. 2001a,b, Gambling et al. 2009, Woodman et al. 2017, 2018), and others reporting a decrease in placental weight (Toblli et al. 2012). As in the clinical studies, the differing effects may relate to the duration and severity of anemia. Low maternal iron and/or Hb may result in a compensatory hypertrophic response by the placenta to offset reduced oxygen or iron supply to the fetus. However, there may be a critical threshold of maternal iron and Hb, below which placental oxidative stress, inflammation, and damage occur, hindering the capacity of the placenta to adapt.
Maternal ID is also associated with altered placental composition and morphology. In placentas exposed to ID, increased placental vascularization, capillary density, and dilation of villous sinusoids is observed (Reshetnikova et al. 1995, Burton et al. 1996, Kadyrov et al. 1998, Mongia et al. 2011, Lelic et al. 2014, Lelić et al. 2014). Such changes are a principal adaptation of the placenta to hypoxia or result from differences in hemodynamic forces during fetal development (Stanek 2013). Indeed, fetal cardiovascular adaptations have been associated with maternal anemia in sheep, including increased heart weight and cardiac output, which may explain altered placental capillary vascularization (Davis & Hohimer 1991). Placentas exposed to maternal ID have smaller placental villous trees and thinner chorionic villous membranes, the latter possibly an adaptation to maintain the diffusion capacity of the exchange surface (Reshetnikova et al. 1995). Similar results are observed in rat models of maternal ID, in which the labyrinth zone (the region of rodent placentas where nutrients and gases are exchanged between maternal and fetal blood) is reduced in thickness (Awad et al. 2017).
Another feature of placentas exposed to maternal ID is an increased number of placental infarcts, syncytial knots, and fibrinoid necrosis, which could affect functional villous mass (Begum et al. 1970, Huang et al. 2001, Mongia et al. 2011, Nausheen Rumana 2012, Kiran et al. 2015). These features are typically associated with maternal vascular malperfusion resulting from insufficient or pulsatile uteroplacental blood flow and reduced oxygen supply, which may contribute to the increased incidence of adverse pregnancy outcomes in maternal ID. Women with maternal ID also exhibit increased cytotrophoblast proliferation, possibly to facilitate syncytiotrophoblast repair in response to ischemia (Kosanke et al. 1998, Biswas et al. 2014). Together, these studies demonstrate that maternal ID impacts several aspects of placental structure.
Challenges and opportunities
Although screening for ID is recommended for all pregnant women (Abdulrehman et al. 2019), a study commissioned by the United States Preventive Services Task Force reported that the evidence is inconclusive about the efficacy of supplementation for improving maternal and infant health outcomes despite improving maternal hematological indices (Cantor et al. 2015, Achebe & Gafter-Gvili 2017). Routine screening for ID and iron supplementation is only recommended in women of reproductive age if anemia is diagnosed. Consequently, many women enter pregnancy with marginal iron stores and do not receive treatment until they exhibit symptoms of severe anemia. Treatment recommendations for maternal ID anemia include increased dietary intake of iron-rich foods and oral iron supplementation, most commonly with ferrous sulfate. Although inexpensive and readily available in many developed countries, oral iron supplementation causes gastrointestinal discomfort in more than 70% of those to whom it is prescribed, including metallic taste, gastric irritation, and worsening constipation, resulting in poor adherence (Tolkien et al. 2015). Furthermore, serum hepcidin levels are increased for approximately 48 h after ingestion of iron supplements, restricting iron absorption from the intestine (Moretti et al. 2015). Prolonged-release preparations of oral iron supplements may offer solutions to these issues while conferring similar bioavailability (Santiago 2012). Other formulations are available that purport enhanced efficacy and tolerability (iron-polysaccharide complexes, heme iron polypeptide), though these claims have been questioned in light of several clinical trial outcomes (Santiago 2012, Moe et al. 2019). Although more expensive, intravenous iron has lower toxicity and is more effective than orally-administered iron (Auerbach et al. 2017); although it has not been rigorously tested in pregnant women and it is uncertain how well it is tolerated by the mother, placenta, and fetus.
Given the high incidence of maternal ID and its potential impacts on placental and fetal health, there is urgent need to better understand placental iron metabolism and develop strategies to prevent, detect, and treat maternal ID during pregnancy. Early detection of ID can be improved by implementing routine prenatal screening, irrespective of Hb level. Public health strategies to prevent ID include improvements in dietary diversity, food fortification with iron and other micronutrients, and distribution of iron-containing supplements; although indiscriminate iron supplementation may be problematic due to gastric irritation and potential toxicity described previously, and may be deleterious in regions where certain infectious diseases are prevalent. Other public health strategies include better control of infections like malaria that compromise red blood cell integrity, and access to education for reproductive health and family planning. Additionally, a better understanding of how ID affects placental and fetal development may lead to identification of biomarkers that better reflect fetal/placental distress in ID (e.g. ratio of placental FPN/TfR1 (Sangkhae et al. 2020a)), and provide opportunities to intervene in utero, thereby reducing the risk of long-term health complications. Accessible and cost-effective interventions will help to reduce the burden of maternal ID and long-term consequences on offspring health.
Conclusions
Iron is a crucial mineral for many cellular and physiological processes. ID during pregnancy remains a global problem with significant health implications for both mothers and offspring. Depending on the severity and duration, low levels of maternal iron and Hb may result in decreased oxygenation that progress to hypoxic and inflammatory conditions in the placenta. This may stimulate placental hypertrophy, increased vascularization, structural changes at the fetal-maternal exchange surface, and altered expression or activity of nutrient transporters (Fig. 2). Future studies are needed to clarify structural and functional modifications in the placenta during maternal ID, and determine whether these modifications are adaptive responses striving to maintain iron sustenance and support fetal growth and development, or pathological changes contributing to maternal and fetal adversity. Since the placenta forms the interface between mother and baby, understanding how the placenta changes in ID may yield new diagnostic indices of fetal stress in affected pregnancies, thereby leading to earlier interventions and improved fetal outcomes.
Schematic depicting the potential impact of maternal iron deficiency on the placenta.
Citation: Reproduction 160, 4; 10.1530/REP-20-0271
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by the Canadian Institutes of Health Research Project Grant (152983, S J R).
Author contribution statement
H R and S J R wrote the initial draft of the manuscript. S L B and S J R critically revised the manuscript. All authors read, revised, and approved the final manuscript.
Acknowledgement
The authors wish to thank Jenna Yuen for illustrative assistance.
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