Women with low iron intake, such as vegetarians or patients with gastrointestinal disorders, are at an increased risk of developing ID due to increased physiological iron requirements during pregnancy. Daily oral iron supplementation can decrease maternal anemia and full-term iron deficiency (37). When maternal ID is mild, iron is supplied preferentially to the fetus to ensure adequate fetal iron stores. However, when maternal ID is moderate or severe, fetal iron homeostasis is disrupted (2). Currently, it is believed that ID in pregnancy is defined as serum ferritin (SF) <30 μg/L (38). Fetal ID will occur when maternal ferritin concentration is less than 12 μg/L (39). Severe maternal ID is clinically manifested as iron deficiency anemia (IDA). When the maternal hemoglobin (Hb) concentration is <85 g/L, umbilical cord serum ferritin is <60 μg/L, indicating impaired fetal iron stores. When maternal Hb is <60 g/L, umbilical cord serum ferritin concentration is <30 μg/L, and umbilical cord Hb concentration is also decreased, indicating a progressive decline in umbilical cord ferritin levels as maternal anemia severity increases (40).

Maternal obesity and rapid weight gain are independent risk factors for fetal ID and are associated with elevated hepcidin levels (41–43). During pregnancy, high maternal body mass index (BMI) could induce maternal inflammatory responses, such as increased concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP), which in turn lead to overexpression of hepcidin (44, 45). The increased number of macrophages in the placenta suggests that the inflammatory response in obese mothers extends to the uterus (46). Ultimately, fetal iron status is impaired. The released IL-6 forms a complex with the IL-6 receptor and glycoprotein 130 (gp130) to activate Janus kinase (JAK) (47). JAK phosphorylates tyrosine residues, which activates signal transducer and activator of transcription 3 (STAT3), and then enters the nucleus, binds to the hepcidin promoter, and induces hepcidin expression (48). In addition, maternal obesity increases the size of fat cells to produce more leptin, which induces hepcidin overexpression (49). In conclusion, obese women have a smaller decrease in hepcidin levels during pregnancy than non-obese women. Fpn located in intestinal cells, reticulocytes, and hepatocytes can bind more to hepcidin and be internalized and hydrolyzed by lysosomes, which can increase iron concentration in cells and reduce iron transport to plasma. However, some studies have shown that maternal obesity does not affect maternal and fetal iron status (50, 51), which may be related to the different degrees of maternal obesity and race.

The offspring of diabetic mothers have abnormal iron distribution and decreased brain iron concentration, which may be associated with impaired iron transport (52, 53). In pregnant women with insulin-dependent diabetes, increased N-glycosylation of transferrin receptor (TfR) released from the placenta can reduce its binding capacity to transferrin (Tf), thereby reducing iron transport in the placenta (54). Then, decreased fetal iron reserve leads to increased expression of placental iron regulatory protein-1 (IRP-1), which binds to iron-responsive elements on the TfR mRNA and plays a stabilizing role in the upregulation of its expression (55, 56). However, Yang et al. (57) found that maternal iron transport to the fetus was reduced in gestational diabetes but was not associated with TfR expression.

Prenatal stress can lead to sex-specific fetal ID, which occurs predominantly in male fetuses and is associated with the fetal stress response system (58–63). Chronic stress can alter maternal expression of the acetylcholinesterase (AChE) gene, thereby converting the normal AChE-S splicing variant into an unstable AChE-R variant. On the one hand, the ratio of AChE-S to AChE-R can downregulate the expression of Fpn and metal ion transporters by modulating cholinergic pathway signaling via microglial α7 nicotinic acetylcholine receptors (α7nAChR) (64). On the other hand, elevated AChE-R is associated with chronic inflammation, which may lead to an increase in hepcidin (65). The above changes can reduce extracellular iron, thus affecting maternal and fetal iron homeostasis.

Fetal ID is associated with maternal smoking and is influenced by the frequency and number of days smoked. Iron stores might not be significantly impaired in pregnant women who smoke, but they are reduced in newborns. First, maternal smoking increases catecholamines in the maternal blood, which affects blood flow and vascular resistance in the placenta, as well as reduces blood nutrients and oxygen delivered to the fetus (66). Second, carbon monoxide in tobacco causes carboxyhemoglobinemia, which reduces the supply of hemoglobin to the fetus (67). Third, cyanide compounds contained in tobacco can exacerbate fetal hypoxia by impairing fetal oxidative mechanisms (67). Fourth, maternal smoking is positively associated with increased fetal lead concentration, which may contribute to hypoxia by interfering with hemoglobin synthesis and reducing the number of red blood cells (68). Conversely, a study showed that fetal iron homeostasis was not affected when women were exposed to smokeless tobacco during pregnancy (69).

In pregnant women, prenatal alcohol exposure (PAE) increases maternal ferritin levels and decreases maternal hemoglobin-to-log (ferritin) ratio (70). In the fetus, PAE can decrease iron concentration and iron utilization in the brain (71). This may be related to elevated maternal and fetal hepcidin and the transfer of iron from the fetal brain and erythrocytes to the liver for storage. PAE can increase maternal and fetal inflammatory cytokines, such as IL-6, and activate hepcidin transcription, which impairs fetal iron homeostasis through the JAK/STAT signaling pathway (72). Due to PAE, serum ferritin (SF), Tf, and TfR cannot be upregulated in time, while fetal brain iron level drops (73). In addition, PAE upregulates the expression of the IL-1β gene in the placenta, which increases iron storage via promoting iron uptake into macrophages, the destruction of erythrocytes, and ferritin biosynthesis, as well as blocks the transport of iron in cells by inhibiting FPN-1 (74).

Gene–diet interactions and diseases indicate that genetic variations can also influence iron absorption and utilization. Haptoglobin (Hp) prevents oxidative damage mediated by free heme iron by removing it from cells (75). Hp gene polymorphisms constitute three main phenotypes: Hp 1-1, Hp 2-1, and Hp 2-2 (76). During mid-to-late stages of pregnancy, Hp phenotypes may increase susceptibility to ID in pregnant women. Pregnant women carrying the Hp 1 alleles may have increased susceptibility to ID if they do not have sufficient dietary iron intake or use prenatal supplements related to erythropoiesis. Additionally, obese women carrying the Hp 2-2 phenotype may have an increased risk of developing functional ID (77).

Prenatal ID is associated with the inhibition of neurogenesis in the hippocampus of offspring mice and a reduction in the number of pyramidal cells and granule cells. The occurrence of ID at different stages of pregnancy may contribute to selectively change the volume of different parts of the fetal hippocampus and affect corresponding memory function. The critical time for susceptibility of the CA1 region of the hippocampus to ID is prenatal, and the dentate gyrus region of the hippocampus is susceptible to ID both prenatally and postnatally. Prenatal ID induces reduced neurogenesis and altered hippocampal volumes in the offspring, which may be associated with reduced brain-derived neurotrophic factor (BDNF) signaling (78).

ID is associated with myelin degeneration in both human studies and animal models. In human studies, the latency of auditory brainstem potentials as indirect markers of myelination is prolonged in infants with ID (79). In a rat model, severe ID may lead to persistent hypomyelination, the production of immature astrocytes, and increased pericyte permeability in offspring exposed to a maternal iron-deficient diet (80). Delayed myelination in specific parts of the brain is associated with behavioral disorders in rats (81). Oligodendrocyte progenitor cells (OPCs) and mature myelin oligodendrocytes are rich in iron and play an important role in myelination. In the brain, insufficient iron supply affects enzyme synthesis, which further affects the proliferation and differentiation of OPCs and myelin synthesis (82, 83). On the one hand, TfR expression on OPCs peaks during oligodendrocyte maturation and declines in mature myelinating cells to maintain iron homeostasis and development (84–86). Due to ID in the brain, the binding of apo-Tf produced by oligodendrocytes and epithelial choroid plexus cells to iron is decreased. This impairs holo-Tf formation, which is required for high-affinity binding to TfR, ultimately leading to a decreased iron uptake by OPCs (87). The effects of apo-Tf on oligodendrocyte maturation and myelination may be mediated by the following signaling pathways: (1) Apo-Tf injection improves oligodendrocyte maturation and myelination by the Notch signaling pathway, which participates in focal demyelination and regeneration by increasing the F3/contact protein levels and Hes5 expression (88, 89). (2) The Fyn/MEK/ERK and PI3K/Akt pathways are also active post apo-Tf treatment (90, 91). Iron-related pathways (e.g., Fyn/MEK/ERK, PI3K/Akt, Notch) are closely related to neurological diseases, such as cognitive impairment and schizophrenia (92–94). On the other hand, ferritin in oligodendrocytes consists of an equal combination of heavy chain (Fth) and light chain (Ftl) (87). As an antioxidant protein, Fth may prevent the formation of reactive oxygen species, but it also increases cytoplasmic iron levels and oxidative stress (87). In oligodendrocyte-specific Fth1 KO mice, knocking out Fth in oligodendrocytes leads to neuronal loss and oxidative damage, thus affecting myelination (95).

Under ID, the increased proliferation of astrocytes and the decreased expression of glial fibrillary acidic protein (GFAP) and connexin 43 (CX43) suggest that astrocyte maturation is impeded (96). Astrocytes can inhibit remyelination by secreting cytotoxic factors and conversely promote myelin repair by secreting trophic factors, such as tumor necrosis factor-α (TNF-α) and cytokines interleukin-1β (IL-1β) (97–99). Insulin-like growth factor 1 (IGF-1) in response to TNF-α and fibroblast growth factor 2 (FGF-2) in response to IL-1β are important for myelination (97, 100). Astrocytes have high expression of iron influx proteins and iron efflux proteins and, thus can safely uptake and recycle iron in the brain during demyelination (101). Iron distribution in astrocytes is critical for the remyelination process. When the iron efflux transporter Fpn is knocked out in astrocytes, there is a decrease in the proliferation of OPCs and a decrease in the expression of IL-1β and IGF-1, which are associated with decreased remyelination (102). When multi-copper ferroxidases are knocked out in astrocytes, iron efflux is impaired and free radical production is increased, which ultimately drives myelin damage (103).

Synaptic plasticity is defined as the ability of synapses to change their structure, connectivity, and function in response to internal or external stimuli (104). In newborns, a previous study has shown that low maternal iron intake accelerates the decline of fractional anisotropy (FA) values in gray matter, indicating reduced synaptic formation and dendritic arborization in offspring (105). In rodents, fetal ID regionally affects dendrite morphology and branching before adulthood, despite subsequent iron supplementation in the brain (106–108). ID reduces the basal dendrite length of pyramidal neurons in the hippocampus without affecting branch complexity and increases the proximal branches of apical dendrites without affecting total length. In contrast, both apical and basal dendrite branch complexity are reduced in cortical neurons, but total length remained unchanged (107). The decreased long-term potentiation (LTP) indicates abnormal synaptic plasticity in fetal iron-deficient mice (109). ID leads to the reduction of four synaptic proteins: CaMKIIα, PSD-95, Fkbp1a, and Vamp1 (110). During repeated stimulation, iron deficiency can change synaptic plasticity by keeping the content of synaptic vesicles constant but reducing their release, and iron supplementation partially reverses this (111).

Iron is involved in the synthesis of neurotransmitters as a cofactor of enzymes such as tyrosine hydroxylase and tryptophan hydroxylase (112). The striatum, one of the basal ganglia of the brain, delivers dopamine-rich substances to the prefrontal cortex and is involved in cognitive and motor functions (8). Altered dopamine function has been associated with an increased risk of schizophrenia in adult offspring of maternal ID (113). In the striatum, dopamine concentration is high due to high iron concentration (114). When ID occurs, cellular uptake of dopamine is reduced because the density and function of dopamine transporters as well as dopamine receptors are reduced in the caudate-putamen (115, 116). Injection of physiological iron concentrations into the ventral midbrain (VMB) alleviates ID-induced decrease in dopamine concentration in the striatum (117). Thy-1 is a cell adhesion molecule that regulates the release of neurotransmitter vesicles, and the fact that ID leads to a decrease in Thy-1 provides a new explanation for impaired dopaminergic transmission in the brain (118). Changes in local monoamine metabolism across various brain regions are sensitive, proportional to the degree of ID, and occur prior to the severe decrease in brain iron concentration (114, 119). Prenatal ID is associated with impaired monoamine metabolism in the offspring's brain, leading to abnormalities in learning and memory functions. These changes cannot be treated by postpartum iron supplementation (120). In addition, ID can also alter the density of serotonin transporters and norepinephrine transporters, which is more pronounced in male offspring (121).

Psychomotor development mainly encompasses gross and fine motor skills, and if impaired, it can affect an individual's cognitive and emotional development (136). The gross motor scores consist of three parts: reflexes, locomotion, and stationary subscales. Reflexes are automatic responses to environmental changes, such as the righting reflex. The assessment of locomotion is based on the ability to move from one place to another. In addition, the assessment of stationary is based on the ability to control the center of gravity and maintain balance (137). Fine movement mainly focuses on the use of body muscles to complete specific actions, such as finger movements and hand–eye coordination (138). During pregnancy, the offspring of anemic mothers with low hemoglobin concentration have slightly low gross and fine motor scores, which are positively correlated when maternal hemoglobin is below 110 g/L (139). Children whose mothers had a low dietary iron intake or low umbilical cord ferritin concentration during pregnancy have lower gross motor and fine motor scores than children whose mothers had a diet rich in protein and micronutrients (22, 140). The severity of impaired motor development is related to the timing and duration of ID. When ID occurs in the third trimester of pregnancy, the Peabody Developmental Motor Scales, Second Edition (PDMS-2) gross motor scores are lower (141). However, a study showed that prenatal ID or IDA were not associated with motor development in the offspring despite low umbilical serum ferritin concentration, possibly because iron supplementation was not considered during pregnancy (142).

Prenatal IDA or low cord ferritin concentration is associated with impaired cognitive and intellectual development in offspring (22, 143–146). Memory is categorized into two distinct types: explicit memory, employed to recall past events, and implicit memory, related to motor and skill tasks and cognition (147). The explicit memory is assessed by electrophysiological measurements and behavioral memory performance, which include evoked imitation of immediate recall and delayed imitation of 1-week delayed recall. The study shows that prenatal ID can have a lasting effect on memory function in offspring, as evidenced by impaired recall and compromised encoding and retrieval processes (148). Fetuses with low cord ferritin or high ratio of porphyrin/heme zinc in the umbilical cord blood allocated more attentional resources to mother's voice and face recognition memory (24, 149, 150). Both the timing of the onset of ID and the age at which the infant's recognition memory is assessed influence the results (150). In the animal model, prenatal ID in rats impairs hippocampus-dependent trace fear conditioning and eye-blinking conditioning in offspring, indicating implicit memory is impaired (127, 128). The offspring of prenatal iron-deficient rats are more likely to rely on the striatum to navigate spatial memory tasks (126).

Accumulating evidence suggests that prenatal ID is associated with affective disorders in the offspring. In mice, prenatal ID reduces brain iron levels and increases susceptibility to anxiety- and depression-like behaviors in offspring (23). In rats, prenatal ID is associated with autism-like and schizophrenia-like behaviors in offspring, exhibiting abnormal pre-pulse inhibition of offspring's acoustic shock and sensitivity in novel environments (151). In humans, low maternal iron intake or ferritin level during pregnancy are related to an increased risk of autism in offspring (152, 153). In addition, offspring with low maternal hemoglobin concentration or anemia during pregnancy have an increased risk of schizophrenia, suggesting that maternal ID is a risk factor for schizophrenia in offspring (154).

Epigenetic regulation refers to chemical modifications of DNA and histones that affect gene expression without altering the genetic code, such as DNA methylation, histone modification, regulation of non-coding RNA, and chromatin remodeling (155, 156). In animal models, maternal ID-induced dysregulation of gene expression in hippocampal neuronal development and functional pathways is related to aberrant DNA methylation (157). These pathways are the β-adrenergic signaling pathway, the CAMP-PKA signaling pathway, Rho GTPase signaling, and reelin signaling, all of which are involved in synaptogenesis and synaptic plasticity (157). In humans, lower levels of DNA methylation in the umbilical cord are related to lower maternal serum ferritin concentrations during the first trimester, and these relationships partially persist in children (158). The concentration of transferrin in pregnant women is associated with increased DNA methylation at cg09996156 (KIAA1324L), a regulator of the bone morphogenetic protein (BMP) pathway, which participates in apoptosis and autophagy and affects the development of the embryonic nervous system (158, 159). Iron is involved in two families of epigenetic modifications—Ten-Eleven Translocation (TET) proteins and Jumonji and AT-rich interaction domain-containing (JARID) proteins—both of which regulate gene expression during critical periods of brain development (160). The TET enzyme demethylates DNA by catalyzing the oxidation of 5-methylcytosine to form 5-hydroxymethylcytosine (5hmC), which serves as a stable epigenetic marker for neurons (161, 162). Syt1 and Nav2 are genes with high levels of 5hmC that play a role in neurogenesis and synaptic transmission (162, 163).

Histone modifications include methylation, acetylation, phosphorylation, and ubiquitination, with methylation and acetylation being the most common (164). The expression of JARID1B gene is downregulated in the hippocampus of the offspring of maternal iron-deficient rats (165) due to enrichment of histone deacetylase 1 (HDAC1) at the JARID1B promoter and the low acetylation level of H3K9 (166). Proteins containing JmjC domain are known as demethylases and can regulate transcription by removing methyl groups from lysine residues in the tail of histones (167, 168). Low JARID1B (Kdm5b) demethylation from trimethylated and dimethylated histone H3 lysine 4 (H3K4me1/2) leads to an increase in chromatin compaction and a decrease in transcriptional activity, whereas low JMJD3 (Kdm6b) and JHDM1d demethylates from H3K9me3 and H3K27me3 leads to a decrease in transcriptional repression of chromatin conformation (169–171). Therefore, alteration of JARID1B expression under ID can regulate transcription levels by altering chromatin structure, such as BDNF-related genes (165). Increased levels of H3K27me3 labeling are associated with promoter inhibition, and increased levels of H3K4me3 labeling are associated with promoter activity (172). Iron-deficient fetuses have an increased concentration of H3K27me3 and a decreased concentration of H3K4me3 in the hippocampus, which may be one of the mechanisms for decreased transcriptional activity of Bdnf-P4 (165, 173). Iron supplementation during the critical period of hippocampal development could partially increase JARID, but the recovery ability is limited (166). Choline supplementation during pregnancy reduces the expression of histone methyltransferase G9a and Suv39h1 in the hippocampus, which may be a potential mechanism for reversing maternal ID-induced HDAC1 enrichment and reduced H3K4me3 levels (173, 174).

MicroRNAs are non-coding single-stranded RNAs of approximately 22 nucleotides in length that are widely involved in the regulation of neurogenesis, development, apoptosis, cell differentiation, proliferation, and other biological processes by inhibiting the translation of messenger RNAs or promoting mRNA degradation (175). Prenatal ID alters miRNA expression in the brain, such as miR-200a and miR-200b, which may increase the risk of depression and anxiety-like behaviors in the offspring (23).

Iron is involved in enzymes that make up the electron transport chain and the tricarboxylic acid cycle; therefore, it can influence brain development through energy metabolism (176). ID in hippocampal neurons alters the mRNA levels of genes related to mitochondrial function and energy metabolism, causing impaired mitochondrial respiration and glycolysis, which in turn affects the dendritic growth and branching (177). In the early stage of ID, only the oxidative capacity of mitochondria is affected, but in the later stage, the density of mitochondria is reduced, suggesting that there may be long-term effects on neurons (177). There are three main approaches in which chronic ID alters dendritic mitochondrial movement: first, an increase in the frequency of dendritic mitochondrial pauses decreases the speed of mitochondrial motion (178). On the one hand, a reduction in localized transient ATP may influence the ATPase activity utilized by motor proteins, such as dynein motor proteins and dynamins in transporting mitochondria (179, 180). On the other hand, ID may enhance the mRNA expression levels of blood–brain barrier and neuronal glucose transporters in the hippocampus (181). Extracellular glucose alters Milton GlcNAcylation, which regulates the mitochondrial motility by O-GlcNAc transferase (OGT) (182). Second, changes in mitochondrial fusion and fission gene expression in response to ID can reduce mitochondrial size by inhibiting OPA1-mediated fusion and stimulating DRP1-mediated fission (183, 184). Third, reduced anterograde mitochondrial movement and increased retrograde segmental velocity are observed in ID, while overall retrograde motion remains unchanged (178). Therefore, mitochondrial malfunction due to ID may contribute to long-term neurological damage and psychiatric disorders in offspring.

Stress leads to activation of the hypothalamic–pituitary–adrenal (HPA) axis, which elevates glucocorticoid (GC) concentrations (185). Elevated GC leads to the apoptosis and atrophy of hippocampal neurons, which impairs neuroplasticity and leads to abnormal behavior (186). Glucocorticoid receptor (GR) in the hippocampus can regulate glucocorticoid levels through a negative feedback loop (187). GR binds to the cytoplasmic heat shock protein (Hsp) 40 and Hsp70 to form a GR–Hsp40/Hsp70 complex, which promotes GR folding and localization to the intermediate domain of Hsp90. The GR–Hsp90 complex alters the structure of the protein to allow it to bind GC (188–190). The binding of FK506-binding protein (FKBP51) and p23 to the GR–Hsp90 complex increases the binding affinity of GR to GC. After GC binds to the GR–Hsp90 complex, FKBP51 is replaced by FKBP52, which assists in nuclear translocation of the GC–GR heterocomplex and inhibits gene transcription of corticotropin-releasing hormone (CRH) in the nucleus (191, 192). On the one hand, when GC concentration is elevated, the increased expression of FKBP5 gene inhibits GR activity by limiting the translocation of the receptor complex to the nucleus (193). On the other hand, alterations in the self-phosphorylation state of GR regulate its transport from the cytoplasm to the nucleus (193, 194). The cognitive impairment of iron-deficient offspring may be related to the elevated serum glucocorticoid level and the reduced GR activity. In a mouse model of the offspring of iron-deficient mothers, serum glucocorticoid level is increased and GR activity is significantly reduced (195). In the case of ID in the brain, the hippocampus GC–GR signaling pathway can be inhibited by impaired GR–HSP90 complex formation and nuclear translocation, which affects the negative feedback regulation function of GR and hyperactivates the HPA axis (195). Therefore, HPA axis dysfunction due to prenatal ID may also be one of the important pathways for neurodevelopmental and behavioral abnormalities in offspring.