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The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental outcomes

The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental... FETAL IRON METABOLISMThe fetus has a voracious appetite for iron that increases throughout pregnancy. At the time of term birth, the appropriate‐weight‐for‐gestational age (AGA) fetus will contain approximately 250 mg of elemental iron. More than 80% of this will have been acquired during the third trimester, during which the fetus averages 75 mg of elemental iron per kilogram of body weight.1 This accretion of iron occurs through active transport from the mother, ensuring that up to a point, a fetus will be protected from alterations in maternal iron status, particularly iron deficiency (ID).2 Indeed, the fetus appears to participate in the regulation of this active transport and can upregulate iron transport at the expense of the mother's iron status.2,3 Nevertheless, at some degree of maternal status that has been better defined recently, the entire maternal–placental–fetal triad can become iron deficient with consequences to fetal brain development. A maternal ferritin concentration of less than 13.4 μg/dL has been identified as an inflection point where fetal iron stores are compromised.4Prioritization of iron trafficking occurs not only between the mother and the fetus but also within the fetus. In many mammals, including humans, iron is prioritized to the red blood cells for hemoglobin synthesis over all other organs, including the brain.5 The brain takes priority over the heart, the skeletal muscle, and the liver, respectively.6 Of the 75 mg of iron/kg of body weight in the term AGA newborn, the red cell mass contains approximately 55 mg of iron/kg.1 Humans are born with relatively large iron stores, which ensures a source of iron for growth and erythropoiesis during the period of exclusive feeding of low‐iron human milk. An AGA term newborn has approximately 12 mg of iron/kg body weight of storage iron. The serum ferritin concentration, which reflects iron stores, averages 135 μg/L with a fifth percentile value of 40 μg/L.7 The smallest compartment is the nonheme, nonstorage tissues, which includes the brain, accounting for 8 mg/kg. Nonstorage organs, including the red cells and the brain, are not at risk for ID until liver iron stores are close to depleted.5,6 Neurologic symptoms are seen in newborns when the ferritin level is less than 76 μg/L.8,9 Interestingly, from a nutritional biomarker perspective, that value reflects the 25th rather than the fifth percentile for ferritin and demonstrates the principle that the nutrient level at which brain effects are seen may not be congruent with population norms for what is considered abnormal (i.e., less than the fifth percentile).Fetal iron accretion can be compromised by multiple gestational conditions, including maternal hypertension, ID, smoking, and diabetes mellitus, as well as premature delivery7 (Figure 1). Maternal anemia is by far the most common cause globally and is a result of heavy menstrual blood loss prior to conception and deficiencies in dietary iron intake prior to and during pregnancy. Pregnancy substantially increases the maternal iron requirement, and thus the risk of maternal anemia due to maternal blood volume expansion, coupled with the additional large iron requirements of the placenta and fetus.10 Maternal iron deficiency anemia (IDA) increases the risk of low birth weight due to premature delivery or intrauterine growth restriction.11 Both are risk factors for fetal or early postnatal ID and neurodevelopmental delays, irrespective of whether the ID is present at birth.7,121FIGUREThe additive effects of preconceptional iron deficiency, increased iron demand during pregnancy, and mitigating factors that contribute to the risk of iron deficiency and iron deficiency anemia during pregnancy. Reproduced with permission from Malcolm G. Munro.ROLE OF IRON IN THE DEVELOPING BRAINThe role of iron in the developing brain has been characterized over the past 50 years.13 Proteins with iron clusters (e.g. hydroxylases) and hemoproteins with porphyrin rings (e.g. cytochromes) abound in the brain and determine the iron requirements of the brain. Iron is necessary for monoamine neurotransmitter synthesis because the hydroxylases that synthesize them (i.e. tyrosine hydroxylase and tryptophan hydroxylase) rely on iron for optimal enzymatic function. Alterations to monoamine metabolism are a plausible biological explanation for the abnormalities in socioaffective behaviors of the iron‐deficient child.13 Iron is also critical for desaturases during fatty acid synthesis and thus influences myelination of the brain.14 Altered myelination likely underlies the slower speed of processing in iron‐deficient children. Iron found in cytochromes drives oxidative phosphorylation and ATP production, affecting neuronal complexity and function.15 The effects of ID on the brain depend on which brain region's iron‐dependent critical period of growth and development is disrupted when ID is present—failure to provide iron during the critical periods of regional brain growth results in permanent structural deficits. Iron also directly regulates gene expression through epigenetic mechanisms.16 It catalyzes the activity of the JARID family of histone demethylases,17 which regulates the expression of brain‐derived neurotrophic factor (BDNF), a major growth and synaptic plasticity protein in the developing brain.18 It is also essential for the enzymatic activity of ten‐eleven‐twelve (TET) proteins that mediate hydroxymethylation of DNA CpG sites.16 Overall, fetal and early postnatal iron is needed to develop neural systems mediating affect, learning and memory capacity, speed of processing, and gene regulation. Preclinical models and studies of children with ID demonstrate that the neural systems are affected acutely while iron deficient and long term after the ID has resolved.13 Interventions are more effective early in life (preferably during the fetal period) to protect the developing brain,19 with progressively less ability to influence the outcome as postnatal age advances.20Because ID often leads to anemia, the question of whether the neurobehavioral effects of iron deficiency are directly due to the lack of iron or the hypoxia induced by anemia has been debated. While both factors are important, preclinical genetic models of nonanemic ID, specifically neuronal ID, convincingly demonstrate that the majority of symptoms seen in iron‐deficient anemic individuals are indeed due to the lack of neuronal iron in the absence of anemia.21,22 Clinical studies of nonanemic iron‐deficient toddlers demonstrate adverse effects on social engagement and motor behaviors.23 These findings are relevant to maternal–fetal iron management because while maternal IDA is widespread, the fetus is rarely anemic at birth. Fetal ID, to the degree that affects brain function, is diagnosed by low serum ferritin at birth (<76 μg/L), without concomitant anemia.8,24 While it is not surprising that ID at birth results in abnormal brain function acutely,9,24 long‐term effects are evident years later.8,25The long‐term neurobehavioral effects are ultimately the actual cost to society regarding lost education and job potential, leading to downstream intergenerational effects of underachieved potential.26 The discovery of critical periods for iron in the developing brain and iron‐dependent epigenetic mechanisms in preclinical models provide plausible biological mechanisms for the long‐term effects. They set the stage for a more targeted approach to timing of iron therapy and for potential nutritional interventions such as choline during pregnancy to protect the fetal brain, with potentially life‐long benefits to the offspring.21,22,27 The preclinical models demonstrate that fetal ID affects not only the adult brain expression of essential individual neural‐function genes such as BDNF, but whole gene networks that code for neurologic functions and mental health diseases such as autism, schizophrenia, and mood disorders.28 The effects on the autism and mood disorders gene networks are partially reversed by supplemental choline during pregnancy.28 These findings in the preclinical model are remarkably consistent with clinical data in human populations showing an increased risk of autism and schizophrenia following maternal ID in the first and second trimesters, respectively29,30 (see below).CONSEQUENCES OF FETAL IRON UNDERLOADINGUntil the last decade, the rich literature detailing the harmful effects of postnatal ID on child development largely stood in isolation from a smaller body of evidence on the adverse impact of prenatal ID for two reasons. First, it was assumed that newborns could not be iron deficient because the fetus could accumulate iron at the mother's expense and was not anemic at birth. Second, and partially owing to the first reason, the neonatal iron status of infants and toddlers enrolled in the postnatal studies was not assessed. Thus, it was unclear how much of the prevalence of postnatal ID could be attributed to fetal iron underloading. More importantly, it was also unclear which behaviors that were attributed to postnatal ID were instead attributable in whole or in part to fetal ID. Fortunately, two seminal studies in the last decade provide strong evidence that prenatal and postnatal iron status are more intimately linked than previously thought.4,19,20,31 Their publication represented a major paradigm shift in strategies to protect the fetal brain and, subsequently, the postnatal brain from ID.32The linkage between pre‐ and postnatal iron status was demonstrated in a large study set in China that measured iron status of the mother throughout pregnancy, the fetus through cord blood analysis at birth, and subsequent offspring iron status at 9 months postnatal age.4,31 The study demonstrated that fetal iron stores are compromised at a maternal ferritin concentration of less than 13.4 μg/L.4 The investigators also found that maternal iron status during pregnancy accounts for a far greater proportion of the 9‐month infant iron status than had previously been suspected and that the risk of postnatal ID at 9 months of age was significantly influenced by the degree of maternal ID during pregnancy.31 While the fetus can compensate for mild degrees of maternal ID (e.g. hemoglobin concentration between 100 and 110 g/L) by upregulating placental iron transport, at hemoglobin concentrations less than 100 g/L, the entire maternal–fetal dyad becomes compromised, and the fetus fails to accrete adequate amounts of iron for postnatal life.2–4,31,32 The resultant lack of fetal iron loading results in an earlier onset of postnatal ID and its attendant neurologic sequelae (see below), particularly in settings where delayed cord clamping is not practiced and where breast milk, which is low in iron, is the predominant or exclusive food source for the first 6 months. The human infant relies on the mobilization and utilization of iron stored during gestation as ferritin.33,34 An AGA term newborn who was born following adequate fetal iron loading, receives delayed cord clamping, is breastfed, and grows along the 50th percentile of the WHO growth curves has sufficient iron stored as ferritin to meet the iron demands of erythropoiesis and tissue (including brain) growth for 4–6 months, thereby reducing or eliminating the need for postnatal enteral iron supplementation.34 The latter is potentially important because postnatal enteral iron supplementation may increase the risk of growth restriction34 and diseases caused by alterations to the microbiome toward a more pathogenic spectrum.35 It is clear that adequate fetal iron loading is protective of postnatal iron status.The relationship between pre‐ and postnatal iron status and neurodevelopment was also studied in a large trial in China.9,31 Behaviors initially thought to be due solely to postnatal ID were found to be present in infants who had prenatal ID.9,31 The importance of fetal iron loading through maternal supplementation on offspring neurodevelopment during pregnancy was convincingly illustrated in a randomized controlled trial by Christian et al.19,20 in Nepal. Initial randomization of the cohort of pregnant women to supplementation or placebo revealed that the infants born to supplemented mothers had superior long‐term neurodevelopment (i.e. at school age).19 The superiority of maternal–fetal iron supplementation versus postnatal iron supplementation was shown by rerandomizing the offspring of the nonsupplemented gestational placebo control group to receive postnatal iron supplementation or placebo. No neurodevelopmental benefit was achieved by postnatal supplementation, thereby emphasizing the importance of fetal iron accretion in protecting the developing brain.20SHORT‐ AND LONG‐TERM NEURODEVELOPMENTAL CONSEQUENCES OF FETAL IRON UNDERLOADINGThe neurologic consequences of fetal and neonatal ID can be broken down into three categories: acute neurologic deficits; long‐term mental health abnormalities; and earlier postnatal ID neurodevelopmental effects.Neonatal ID, as defined by a serum ferritin concentration less than 76 μg/L8,9 irrespective of the hemoglobin concentration, acutely compromises recognition memory of the mother's voice9,24 and neural speed of processing36 and reduces bonding of the mother to her infant.37 These deficits carry forward as evidenced by persistent deficits in acute and delayed recall of recognition memory events 3.5 years after neonatal ID.25 The deficits at the older age were a function of the neonatal ferritin concentrations.25 These recognition memory deficits evolved into deficits in planning and attention at the age of 10,38 demonstrating that the performance of later developing neural systems such as the frontal lobe relies on the integrity of earlier developing systems that will project to them.39Fetal ID increases the postnatal risk of long‐term mental health abnormalities in the form of psychopathologies that include autism,29 schizophrenia,30 and neurocognitive disorders.8 The risk of these specific disorders is based on whether the maternal ID occurred in the preconceptional period29 or in the first, second, or third trimesters.8,29,30 This role of timing in nutrient deficit brain interactions has been recognized for over 25 years.40 The behavioral phenotype induced by a nutrient deficit is a function of which neural structures required the nutrient at the time of the deficiency. Subsequent neurobehavioral phenotypes map to the functions of the brain regions where growth was disrupted by the lack of nutritional substrate.41Even if the iron‐underloaded newborn does not reach the threshold of ID where the brain is at risk acutely (i.e. <76 μg/L), the infant will still be at risk for earlier onset of postnatal ID and its well‐described neurodevelopmental consequences. These effects can last for years to decades after the initial diagnosis.12,13,42 The neurobehavioral domains affected by ID are extensive and include general cognition, motor function, memory processing, executive function, engagement, affect, and mood.13SUMMARYIron is a critical substrate for fetal and subsequent postnatal neurodevelopment. Iron deficiency without anemia affects brain function; thus, prevention, screening, and treatment of nonanemic and pre‐anemic ID is critical to protect the developing brain. Failure to provide iron during the critical periods of regional brain growth results in permanent structural deficits that likely underlie the long‐term behavioral and neuropsychiatric dysfunction.The major recent paradigm shift in the field of ID is that protection of the offspring brain begins with ensuring that women are iron sufficient prior to becoming pregnant and maintain an iron‐sufficient state throughout pregnancy. Maternal–fetal iron loading is the critical first step for the prevention of acute and long‐term neurobehavioral deficits in the offspring by protecting fetal neural circuit construction, reducing the rate of low birth weight due to intrauterine growth restriction or prematurity, and preventing the early onset of postnatal ID and IDA.POLICY IMPLICATIONSProtecting the developing brain is an investment in society because of the long‐term effects of early nutrient deficits on adult brain function and mental health. Concerning iron, the road to protecting the fetal brain begins preconceptionally in women of reproductive age because of the data linking periconceptional ID with the risk of autism in the offspring.29Ideally, providers caring for women of reproductive age should screen their patients for ID and IDA. Particular attention should be paid to women who are planning to become pregnant within 6 months, adolescents who have increased iron demands associated with their own growth, and women with heavy menstrual bleeding. Pregnant women should be screened for ID and anemia in the first trimester because of the high rate of ID in that population43 and the knowledge that pregnancy induces negative iron balance owing to the expansion of the maternal blood volume and the iron requirements of the placenta and fetus.10 Screening and treatment for ID should be done regularly throughout pregnancy to ensure adequate fetal loading and reduce the risk of adverse maternal outcomes that affect neurodevelopment. In addition, pregnant women should be screened and treated for gestational conditions beyond maternal ID that result in restriction of iron delivery to the fetus. These include maternal smoking, hypertension, glucose intolerance, and obesity.7Delayed cord clamping at delivery provides additional blood and iron to the newborn and reduces the need for postnatal iron supplementation in the first postnatal months. Infants with a risk of fetal iron underloading should have their iron status monitored earlier than recommended, usually at 9 months to 1 year. These infants include infants born to iron‐deficient women, those with low birth weight due to either fetal growth restriction or prematurity, and those born to obese or glucose‐intolerant mothers. A bioavailable postnatal source of iron should be introduced by 6 months of age.CONFLICT OF INTEREST STATEMENTOutside of the article, the author reports grants from NIH and the Gates Foundation and participation on a DSMB for an NIH trial of lipids for preterm infants.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no new data were created or analyzed in this study.REFERENCESWiddowson EM, Spray CM. Chemical development in utero. Arch Dis Child. 1951;26:205‐214.Cao C, O'Brien KO. Pregnancy and iron homeostasis: an update. Nutr Rev. 2013;71:35‐51.Georgieff MK, Liebold EA, Wobken JD, Berry SA. Increased placental iron‐regulatory protein expression in diabetic pregnancies complicated by fetal iron deficiency. Placenta. 1999;20:87‐93.Shao J, Lou J, Rao R, et al. Maternal serum ferritin concentration is positively associated with newborn iron stores in women with low ferritin status in late pregnancy. J Nutr. 2012;142:2004‐2009.Georgieff MK. Iron assessment to protect the developing brain. Am J Clin Nutr. 2017;106:1588S‐1593S.Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK. Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr. 1992;121:109‐114.Siddappa AJ, Rao R, Long JD, Widness JA, Georgieff MK. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology. 2007;92:73‐82.Tamura T, Goldenberg RL, Hou J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002;140:165‐170.Geng F, Mai X, Zhan J, et al. Impact of fetal‐neonatal iron deficiency on recognition memory at 2 months of age. J Pediatr. 2015;167:1226‐1232.Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr. 2017;106:1567s‐1574s.Dewey KG, Oaks BM. U‐shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017;106:1694s‐1702s.Berglund SK, Chmielewska A, Starnberg J, et al. Effects of iron supplementation of low‐birth‐weight infants on cognition and behavior at 7 years: a randomized controlled trial. Pediatr Res. 2018;83:111‐118.Lozoff B, Beard J, Connor J, Felt B, Georgieff M, Schallert T. Long‐lasting neural and behavioral effects of early iron deficiency in infancy. Nutr Rev. 2006;64:S34‐S43.Connor JR, Menzies SL. Relationship of iron of oligodendrocytes and myelination. Glia. 1996;17:83‐93.Bastian TW, von Hohenberg WC, Mickelson DJ, Lanier LM, Georgieff MK. Iron deficiency impairs developing hippocampal neuron gene expression, energy metabolism and dendrite complexity. Dev Neurosci. 2016;38:264‐276.Barks AK, Liu SX, Georgieff MK, Hallstrom TC, Tran PV. Early‐life iron deficiency anemia programs the hippocampal epigenomic landscape. Nutrients. 2021;13:3857.Sengoku T, Yokoyama S. Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A. Genes Dev. 2011;25:2266‐2277.Tran PV, Kennedy BC, Lien YC, Simmons RA, Georgieff MK. Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus. Am J Physiol Integr Comp Phys. 2015;308:R276‐R282.Christian P, Murray‐Kolb LE, Khatry SK, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school‐aged children in Nepal. JAMA. 2010;304:2716‐2723.Christian P, Morgan ME, Murray‐Kolb L, et al. Preschool iron‐folic acid and zinc supplementation in children exposed to iron‐folic acid in utero confers no added cognitive benefit in early school‐age. J Nutr. 2011;141:2042‐2048.Carlson ES, Tkac I, Magid R, et al. Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr. 2009;139:672‐679.Fretham SJB, Carlson ES, Wobken J, Tran PV, Petryk A, Georgieff MK. Temporal manipulation of transferrin receptor‐1 dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment. Hippocampus. 2012;22:1691‐1702.Lozoff B, Clark KM, Jing Y, Armony‐Sivan R, Angelilli ML, Jacobson SW. Dose‐response relationships between iron deficiency with or without anemia and infant social‐emotional behavior. J Pediatr. 2008;152:696‐702.Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, de Regnier R‐A. Auditory recognition memory in iron‐deficient infants of diabetic mothers. Pediatr Res. 2004;55:1034‐1041.Riggins T, Miller NC, Bauer PB, Georgieff MK, Nelson CA. Consequences of low neonatal iron status due to maternal diabetes mellitus on explicit memory performance in childhood. Dev Neuropsychol. 2009;34:762‐779.Walker SP, Wachs TD, Gardner JM, et al. Child development: risk factors for adverse outcomes in developing countries. Lancet. 2007;369:145‐157.Kennedy BC, Dimova JG, Siddappa AJM, Tran PV, Gewirtz JC, Georgieff MK. Prenatal choline supplementation ameliorates the long‐term neurobehavioral effects of fetal‐neonatal iron deficiency in rats. J Nutr. 2014;144:1858‐1865.Tran PV, Kennedy BC, Pisansky MT, et al. Prenatal choline supplementation diminishes early‐life iron deficiency‐induced preprogramming of networks associated with behavioral abnormalities in the adult rat hippocampus. J Nutr. 2016;146:484‐493.Schmidt RJ, Tancredi DJ, Krakowiak P, Hansen RL, Ozonoff S. Maternal intake of supplemental iron and risk of autism spectrum disorder. Am J Epidemiol. 2014;180:890‐900.Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS. Maternal iron deficiency and the risk of schizophrenia in offspring. Arch Gen Psychiatry. 2008;65:1136‐1144.Shao J, Richards B, Kaciroti N, Zhu B, Clark KM, Lozoff B. Contribution of iron status at birth to infant iron status at 9 months: data from a prospective maternal‐infant birth cohort in China. Eur J Clin Nutr. 2021;75:364‐372.Georgieff MK. Iron deficiency in pregnancy. Am J Obstet Gynecol. 2020;223:516‐524.Ziegler EE, Nelson SE, Jeter JM. Iron supplementation of breastfed infants from an early age. Am J Clin Nutr. 2009;89:525‐532.Lönnerdal B. Excess iron intake as a factor in growth, infections, and development of infants and young children. Am J Clin Nutr. 2017;106:1681s‐1687s.Paganini D, Zimmermann MB. The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr. 2017;106:1688S‐1693S.Amin SB, Orlando M, Eddins A, Mac Donald M, Monczynski C, Wang H. In utero iron status and auditory neural maturation in premature infants as evaluated by auditory brainstem response. J Pediatr. 2010;156:377‐381.Wachs TD, Pollitt E, Cueto S, Jacoby E, Creed‐Kanashiro H. Relation of neonatal iron status to individual variability in neonatal temperament. Dev Psychobiol. 2005;46:141‐153.Jabès A, Thomas KM, Langworthy S, Georgieff MK, Nelson CA. Functional and anatomic consequences of diabetic pregnancy on memory in ten‐year‐old children. J Dev Behav Pediatr. 2015;36:529‐535.Wachs TD, Georgieff M, Cusick S, McEwen BS. Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann N Y Acad Sci. 2014;1308:89‐106.Kretchmer N, Beard JL, Carlson S. The role of nutrition in the development of normal cognition. Am J Clin Nutr. 1996;63:997s‐1001s.Cusick SE, Georgieff MK. Nutrient supplementation and neurodevelopment: timing is the key. Arch Ped Adolesc Med. 2012;155:481‐482.Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long‐term deficits in executive function and recognition memory. Nutri Neurosci. 2010;13:54‐70.Auerbach M, Abernathy J, Juul S, Short V, Derman R. Prevalence of iron deficiency in first trimester, nonanemic pregnant women. J Matern Fetal Neonatal Med. 2021;34:1002‐1005. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Gynecology & Obstetrics Wiley

The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental outcomes

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Wiley
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Copyright © 2023 International Federation of Gynecology and Obstetrics
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0020-7292
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10.1002/ijgo.14951
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Abstract

FETAL IRON METABOLISMThe fetus has a voracious appetite for iron that increases throughout pregnancy. At the time of term birth, the appropriate‐weight‐for‐gestational age (AGA) fetus will contain approximately 250 mg of elemental iron. More than 80% of this will have been acquired during the third trimester, during which the fetus averages 75 mg of elemental iron per kilogram of body weight.1 This accretion of iron occurs through active transport from the mother, ensuring that up to a point, a fetus will be protected from alterations in maternal iron status, particularly iron deficiency (ID).2 Indeed, the fetus appears to participate in the regulation of this active transport and can upregulate iron transport at the expense of the mother's iron status.2,3 Nevertheless, at some degree of maternal status that has been better defined recently, the entire maternal–placental–fetal triad can become iron deficient with consequences to fetal brain development. A maternal ferritin concentration of less than 13.4 μg/dL has been identified as an inflection point where fetal iron stores are compromised.4Prioritization of iron trafficking occurs not only between the mother and the fetus but also within the fetus. In many mammals, including humans, iron is prioritized to the red blood cells for hemoglobin synthesis over all other organs, including the brain.5 The brain takes priority over the heart, the skeletal muscle, and the liver, respectively.6 Of the 75 mg of iron/kg of body weight in the term AGA newborn, the red cell mass contains approximately 55 mg of iron/kg.1 Humans are born with relatively large iron stores, which ensures a source of iron for growth and erythropoiesis during the period of exclusive feeding of low‐iron human milk. An AGA term newborn has approximately 12 mg of iron/kg body weight of storage iron. The serum ferritin concentration, which reflects iron stores, averages 135 μg/L with a fifth percentile value of 40 μg/L.7 The smallest compartment is the nonheme, nonstorage tissues, which includes the brain, accounting for 8 mg/kg. Nonstorage organs, including the red cells and the brain, are not at risk for ID until liver iron stores are close to depleted.5,6 Neurologic symptoms are seen in newborns when the ferritin level is less than 76 μg/L.8,9 Interestingly, from a nutritional biomarker perspective, that value reflects the 25th rather than the fifth percentile for ferritin and demonstrates the principle that the nutrient level at which brain effects are seen may not be congruent with population norms for what is considered abnormal (i.e., less than the fifth percentile).Fetal iron accretion can be compromised by multiple gestational conditions, including maternal hypertension, ID, smoking, and diabetes mellitus, as well as premature delivery7 (Figure 1). Maternal anemia is by far the most common cause globally and is a result of heavy menstrual blood loss prior to conception and deficiencies in dietary iron intake prior to and during pregnancy. Pregnancy substantially increases the maternal iron requirement, and thus the risk of maternal anemia due to maternal blood volume expansion, coupled with the additional large iron requirements of the placenta and fetus.10 Maternal iron deficiency anemia (IDA) increases the risk of low birth weight due to premature delivery or intrauterine growth restriction.11 Both are risk factors for fetal or early postnatal ID and neurodevelopmental delays, irrespective of whether the ID is present at birth.7,121FIGUREThe additive effects of preconceptional iron deficiency, increased iron demand during pregnancy, and mitigating factors that contribute to the risk of iron deficiency and iron deficiency anemia during pregnancy. Reproduced with permission from Malcolm G. Munro.ROLE OF IRON IN THE DEVELOPING BRAINThe role of iron in the developing brain has been characterized over the past 50 years.13 Proteins with iron clusters (e.g. hydroxylases) and hemoproteins with porphyrin rings (e.g. cytochromes) abound in the brain and determine the iron requirements of the brain. Iron is necessary for monoamine neurotransmitter synthesis because the hydroxylases that synthesize them (i.e. tyrosine hydroxylase and tryptophan hydroxylase) rely on iron for optimal enzymatic function. Alterations to monoamine metabolism are a plausible biological explanation for the abnormalities in socioaffective behaviors of the iron‐deficient child.13 Iron is also critical for desaturases during fatty acid synthesis and thus influences myelination of the brain.14 Altered myelination likely underlies the slower speed of processing in iron‐deficient children. Iron found in cytochromes drives oxidative phosphorylation and ATP production, affecting neuronal complexity and function.15 The effects of ID on the brain depend on which brain region's iron‐dependent critical period of growth and development is disrupted when ID is present—failure to provide iron during the critical periods of regional brain growth results in permanent structural deficits. Iron also directly regulates gene expression through epigenetic mechanisms.16 It catalyzes the activity of the JARID family of histone demethylases,17 which regulates the expression of brain‐derived neurotrophic factor (BDNF), a major growth and synaptic plasticity protein in the developing brain.18 It is also essential for the enzymatic activity of ten‐eleven‐twelve (TET) proteins that mediate hydroxymethylation of DNA CpG sites.16 Overall, fetal and early postnatal iron is needed to develop neural systems mediating affect, learning and memory capacity, speed of processing, and gene regulation. Preclinical models and studies of children with ID demonstrate that the neural systems are affected acutely while iron deficient and long term after the ID has resolved.13 Interventions are more effective early in life (preferably during the fetal period) to protect the developing brain,19 with progressively less ability to influence the outcome as postnatal age advances.20Because ID often leads to anemia, the question of whether the neurobehavioral effects of iron deficiency are directly due to the lack of iron or the hypoxia induced by anemia has been debated. While both factors are important, preclinical genetic models of nonanemic ID, specifically neuronal ID, convincingly demonstrate that the majority of symptoms seen in iron‐deficient anemic individuals are indeed due to the lack of neuronal iron in the absence of anemia.21,22 Clinical studies of nonanemic iron‐deficient toddlers demonstrate adverse effects on social engagement and motor behaviors.23 These findings are relevant to maternal–fetal iron management because while maternal IDA is widespread, the fetus is rarely anemic at birth. Fetal ID, to the degree that affects brain function, is diagnosed by low serum ferritin at birth (<76 μg/L), without concomitant anemia.8,24 While it is not surprising that ID at birth results in abnormal brain function acutely,9,24 long‐term effects are evident years later.8,25The long‐term neurobehavioral effects are ultimately the actual cost to society regarding lost education and job potential, leading to downstream intergenerational effects of underachieved potential.26 The discovery of critical periods for iron in the developing brain and iron‐dependent epigenetic mechanisms in preclinical models provide plausible biological mechanisms for the long‐term effects. They set the stage for a more targeted approach to timing of iron therapy and for potential nutritional interventions such as choline during pregnancy to protect the fetal brain, with potentially life‐long benefits to the offspring.21,22,27 The preclinical models demonstrate that fetal ID affects not only the adult brain expression of essential individual neural‐function genes such as BDNF, but whole gene networks that code for neurologic functions and mental health diseases such as autism, schizophrenia, and mood disorders.28 The effects on the autism and mood disorders gene networks are partially reversed by supplemental choline during pregnancy.28 These findings in the preclinical model are remarkably consistent with clinical data in human populations showing an increased risk of autism and schizophrenia following maternal ID in the first and second trimesters, respectively29,30 (see below).CONSEQUENCES OF FETAL IRON UNDERLOADINGUntil the last decade, the rich literature detailing the harmful effects of postnatal ID on child development largely stood in isolation from a smaller body of evidence on the adverse impact of prenatal ID for two reasons. First, it was assumed that newborns could not be iron deficient because the fetus could accumulate iron at the mother's expense and was not anemic at birth. Second, and partially owing to the first reason, the neonatal iron status of infants and toddlers enrolled in the postnatal studies was not assessed. Thus, it was unclear how much of the prevalence of postnatal ID could be attributed to fetal iron underloading. More importantly, it was also unclear which behaviors that were attributed to postnatal ID were instead attributable in whole or in part to fetal ID. Fortunately, two seminal studies in the last decade provide strong evidence that prenatal and postnatal iron status are more intimately linked than previously thought.4,19,20,31 Their publication represented a major paradigm shift in strategies to protect the fetal brain and, subsequently, the postnatal brain from ID.32The linkage between pre‐ and postnatal iron status was demonstrated in a large study set in China that measured iron status of the mother throughout pregnancy, the fetus through cord blood analysis at birth, and subsequent offspring iron status at 9 months postnatal age.4,31 The study demonstrated that fetal iron stores are compromised at a maternal ferritin concentration of less than 13.4 μg/L.4 The investigators also found that maternal iron status during pregnancy accounts for a far greater proportion of the 9‐month infant iron status than had previously been suspected and that the risk of postnatal ID at 9 months of age was significantly influenced by the degree of maternal ID during pregnancy.31 While the fetus can compensate for mild degrees of maternal ID (e.g. hemoglobin concentration between 100 and 110 g/L) by upregulating placental iron transport, at hemoglobin concentrations less than 100 g/L, the entire maternal–fetal dyad becomes compromised, and the fetus fails to accrete adequate amounts of iron for postnatal life.2–4,31,32 The resultant lack of fetal iron loading results in an earlier onset of postnatal ID and its attendant neurologic sequelae (see below), particularly in settings where delayed cord clamping is not practiced and where breast milk, which is low in iron, is the predominant or exclusive food source for the first 6 months. The human infant relies on the mobilization and utilization of iron stored during gestation as ferritin.33,34 An AGA term newborn who was born following adequate fetal iron loading, receives delayed cord clamping, is breastfed, and grows along the 50th percentile of the WHO growth curves has sufficient iron stored as ferritin to meet the iron demands of erythropoiesis and tissue (including brain) growth for 4–6 months, thereby reducing or eliminating the need for postnatal enteral iron supplementation.34 The latter is potentially important because postnatal enteral iron supplementation may increase the risk of growth restriction34 and diseases caused by alterations to the microbiome toward a more pathogenic spectrum.35 It is clear that adequate fetal iron loading is protective of postnatal iron status.The relationship between pre‐ and postnatal iron status and neurodevelopment was also studied in a large trial in China.9,31 Behaviors initially thought to be due solely to postnatal ID were found to be present in infants who had prenatal ID.9,31 The importance of fetal iron loading through maternal supplementation on offspring neurodevelopment during pregnancy was convincingly illustrated in a randomized controlled trial by Christian et al.19,20 in Nepal. Initial randomization of the cohort of pregnant women to supplementation or placebo revealed that the infants born to supplemented mothers had superior long‐term neurodevelopment (i.e. at school age).19 The superiority of maternal–fetal iron supplementation versus postnatal iron supplementation was shown by rerandomizing the offspring of the nonsupplemented gestational placebo control group to receive postnatal iron supplementation or placebo. No neurodevelopmental benefit was achieved by postnatal supplementation, thereby emphasizing the importance of fetal iron accretion in protecting the developing brain.20SHORT‐ AND LONG‐TERM NEURODEVELOPMENTAL CONSEQUENCES OF FETAL IRON UNDERLOADINGThe neurologic consequences of fetal and neonatal ID can be broken down into three categories: acute neurologic deficits; long‐term mental health abnormalities; and earlier postnatal ID neurodevelopmental effects.Neonatal ID, as defined by a serum ferritin concentration less than 76 μg/L8,9 irrespective of the hemoglobin concentration, acutely compromises recognition memory of the mother's voice9,24 and neural speed of processing36 and reduces bonding of the mother to her infant.37 These deficits carry forward as evidenced by persistent deficits in acute and delayed recall of recognition memory events 3.5 years after neonatal ID.25 The deficits at the older age were a function of the neonatal ferritin concentrations.25 These recognition memory deficits evolved into deficits in planning and attention at the age of 10,38 demonstrating that the performance of later developing neural systems such as the frontal lobe relies on the integrity of earlier developing systems that will project to them.39Fetal ID increases the postnatal risk of long‐term mental health abnormalities in the form of psychopathologies that include autism,29 schizophrenia,30 and neurocognitive disorders.8 The risk of these specific disorders is based on whether the maternal ID occurred in the preconceptional period29 or in the first, second, or third trimesters.8,29,30 This role of timing in nutrient deficit brain interactions has been recognized for over 25 years.40 The behavioral phenotype induced by a nutrient deficit is a function of which neural structures required the nutrient at the time of the deficiency. Subsequent neurobehavioral phenotypes map to the functions of the brain regions where growth was disrupted by the lack of nutritional substrate.41Even if the iron‐underloaded newborn does not reach the threshold of ID where the brain is at risk acutely (i.e. <76 μg/L), the infant will still be at risk for earlier onset of postnatal ID and its well‐described neurodevelopmental consequences. These effects can last for years to decades after the initial diagnosis.12,13,42 The neurobehavioral domains affected by ID are extensive and include general cognition, motor function, memory processing, executive function, engagement, affect, and mood.13SUMMARYIron is a critical substrate for fetal and subsequent postnatal neurodevelopment. Iron deficiency without anemia affects brain function; thus, prevention, screening, and treatment of nonanemic and pre‐anemic ID is critical to protect the developing brain. Failure to provide iron during the critical periods of regional brain growth results in permanent structural deficits that likely underlie the long‐term behavioral and neuropsychiatric dysfunction.The major recent paradigm shift in the field of ID is that protection of the offspring brain begins with ensuring that women are iron sufficient prior to becoming pregnant and maintain an iron‐sufficient state throughout pregnancy. Maternal–fetal iron loading is the critical first step for the prevention of acute and long‐term neurobehavioral deficits in the offspring by protecting fetal neural circuit construction, reducing the rate of low birth weight due to intrauterine growth restriction or prematurity, and preventing the early onset of postnatal ID and IDA.POLICY IMPLICATIONSProtecting the developing brain is an investment in society because of the long‐term effects of early nutrient deficits on adult brain function and mental health. Concerning iron, the road to protecting the fetal brain begins preconceptionally in women of reproductive age because of the data linking periconceptional ID with the risk of autism in the offspring.29Ideally, providers caring for women of reproductive age should screen their patients for ID and IDA. Particular attention should be paid to women who are planning to become pregnant within 6 months, adolescents who have increased iron demands associated with their own growth, and women with heavy menstrual bleeding. Pregnant women should be screened for ID and anemia in the first trimester because of the high rate of ID in that population43 and the knowledge that pregnancy induces negative iron balance owing to the expansion of the maternal blood volume and the iron requirements of the placenta and fetus.10 Screening and treatment for ID should be done regularly throughout pregnancy to ensure adequate fetal loading and reduce the risk of adverse maternal outcomes that affect neurodevelopment. In addition, pregnant women should be screened and treated for gestational conditions beyond maternal ID that result in restriction of iron delivery to the fetus. These include maternal smoking, hypertension, glucose intolerance, and obesity.7Delayed cord clamping at delivery provides additional blood and iron to the newborn and reduces the need for postnatal iron supplementation in the first postnatal months. Infants with a risk of fetal iron underloading should have their iron status monitored earlier than recommended, usually at 9 months to 1 year. These infants include infants born to iron‐deficient women, those with low birth weight due to either fetal growth restriction or prematurity, and those born to obese or glucose‐intolerant mothers. A bioavailable postnatal source of iron should be introduced by 6 months of age.CONFLICT OF INTEREST STATEMENTOutside of the article, the author reports grants from NIH and the Gates Foundation and participation on a DSMB for an NIH trial of lipids for preterm infants.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no new data were created or analyzed in this study.REFERENCESWiddowson EM, Spray CM. Chemical development in utero. Arch Dis Child. 1951;26:205‐214.Cao C, O'Brien KO. Pregnancy and iron homeostasis: an update. Nutr Rev. 2013;71:35‐51.Georgieff MK, Liebold EA, Wobken JD, Berry SA. 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Journal

International Journal of Gynecology & Obstetrics – Wiley

Published: Aug 1, 2023

Keywords: brain; fetus; iron; iron deficiency; iron deficiency anemia; mother; neurodevelopment; pregnancy

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