Certain gestational conditions associated with decreased fetal iron delivery and/or increased fetal iron demand beyond the placental transport capacity can result in perinatal iron deficiency. As in other ages, available iron is prioritized to support erythropoiesis in perinatal iron deficiency. When maternal–fetal iron delivery is inadequate for this purpose, depletion of storage and non-storage tissue iron occurs.
The prevalence of iron deficiency is greater in women of reproductive age, even in developed countries. Pregnancy requires approximately 1000 mg of additional iron to support the expanding maternal RBC and plasma volumes and the growth of the fetal–placental unit.3,4
Maternal iron deficiency affects 30–50% of pregnancies3,5,6
and is the most common cause of perinatal iron deficiency worldwide. More than 80% of pregnant women in developing countries are estimated to be affected.6
In addition to inadequate dietary iron intake, iron loss due to parasitic infestations, chronic gastrointestinal hemorrhage and high dietary fiber content contribute to iron deficiency in these mothers. In the United States, iron-deficiency anemia has been demonstrated in 27% of pregnant ethnic minority women during the third trimester.3
Teenagers, recent immigrants from developing countries, women from socially disadvantaged populations and multiparous women with short interpregnancy intervals are particularly affected. Despite iron supplementation, 30% of pregnant women have a low serum ferritin concentration at the end of pregnancy.7
Maternal iron deficiency, with or without associated anemia, adversely affects fetal iron status. A maternal Hb concentration <85 g/L is associated with decreased fetal iron stores (cord serum ferritin <60 μg/L). More severe maternal anemia (Hb <60 g/L) is associated with lower cord Hb concentration, as well as cord serum ferritin concentration <30 μg/L, a level suggestive of severe depletion of storage iron and potential brain iron deficiency (see below).8
A maternal ferritin concentration <12 μg/L appears to be the threshold below which fetal iron accretion is affected6
; 14% of full-term infants born to iron-deficient mothers have a serum ferritin concentration <30 μg/L at birth. Finally, even when iron endowment appears to be adequate at birth, infants of mothers with mild to moderate iron deficiency anemia are at risk for iron deficiency throughout infancy, especially between 6 and 12 months of age.5,9
Intrauterine growth restriction (IUGR), maternal smoking and poorly controlled diabetes mellitus during pregnancy are important causes of perinatal iron deficiency in developed countries. All three gestational conditions are characterized by intrauterine fetal hypoxia and augmented erythropoiesis that requires additional iron. Approximately 10% of all pregnancies are complicated by IUGR. Whereas maternal malnutrition is likely responsible in developing countries, pre-existing or pregnancy-induced maternal hypertension is responsible for IUGR in developed countries. In pregnancies associated with IUGR due to maternal hypertension, placental iron transport is decreased due to placental vascular disease and impaired uteroplacental blood flow. Approximately 50% of IUGR infants are iron deficient at birth, as suggested by cord serum ferritin concentration <60 μg/L.10
The liver and brain iron concentrations are decreased in IUGR infants without a significant effect on Hb at birth. In severe cases, brain iron concentration could be decreased by 33%.11
Maternal smoking during gestation is associated with fetal hypoxia due to carbon monoxide and decreased uteroplacental blood flow due to nicotine and catecholamine-induced vasoconstriction. The augmented erythropoiesis stimulated by fetal hypoxia results in depletion of iron stores in the offspring of these mothers.12-14
Cord Hb is increased and ferritin concentrations in cord blood and the placenta are decreased 40% and 20%, respectively, in infants of mothers who smoked during pregnancy.12
To our knowledge, the tissue iron concentration in this infant population has not been assessed.
Between 5% and 10% of pregnancies are complicated by maternal diabetes mellitus. Poorly controlled diabetes mellitus during gestation is associated with maternal and fetal hyperglycemia, fetal hyperinsulinemia, increased fetal metabolic rate and oxygen consumption. The increased fetal oxygen consumption in a relatively hypoxic intrauterine environment stimulates erythropoiesis and expands the fetal RBC mass. The additional iron required for the augmented erythropoiesis cannot be met by increasing maternal–fetal transport. Whereas placental transferrin receptor expression is increased in pregnancies complicated by diabetes mellitus, the affinity of the receptor to maternal transferrin is decreased, probably due to hyperglycosylation of the oligosaccharides present in the binding domain.15
Furthermore, placental vascular disease might be present in mothers with longstanding, poorly controlled diabetes mellitus, further limiting iron transport across the placenta. Tissue iron is depleted to support the iron needs of augmented erythropoiesis under these situations. Nearly 65% of infants of diabetic mothers (IDM) have perinatal iron deficiency, as suggested by cord serum ferritin concentration <60 μg/L. In approximately 25% of these infants cord serum ferritin is <35 μg/L, suggesting significant depletion of tissue iron, including brain iron.16,17
Preterm birth is another important cause of iron deficiency during the perinatal period. Between 25% and 85% of preterm infants with a birth weight <1500 g are at risk of iron deficiency during infancy, depending on their diet and iron supplementation.18
Preterm birth deprives the fetus of the significant iron accretion that occurs beyond 32 weeks of gestation. The total body and tissue iron contents, Hb and serum ferritin concentration are lower in the preterm infant.2,19,20
Early onset of postnatal erythropoiesis, greater postnatal growth velocity, uncompensated phlebotomy losses, exclusive use of breast milk and delayed or inadequate iron supplementation predispose the preterm infant to iron deficiency until 24 months of age. Birth weight <1000 g (extremely low birth weight, ELBW), associated IUGR and use of recombinant human erythropoietin (rHuEpo) without adequate iron supplementation are additional risk factors. Without an external source of iron, iron stores in non-transfused preterm infants will sustain effective erythropoiesis only until they have doubled their birth weight, i.e. until approximately 2 months of age.21
Without iron supplementation, ELBW infants might be in negative iron balance during the first month.22
Effects of perinatal iron deficiency
The most well-described effect of iron deficiency is anemia. However, anemia as a consequence of iron deficiency is extremely rare during the perinatal period. Before the appearance of anemia, the storage form of iron in the reticuloendothelial system, specifically in the placenta and liver, is depleted, followed by decreased tissue iron in the heart and brain. Autopsy studies have demonstrated that liver iron is decreased by 90%, heart iron by 55% and brain iron by 40% in infants of mothers with poorly controlled diabetes mellitus.17
Serum ferritin concentration <35 μg/L at birth suggest a >70% decrease of storage pools in the liver and the likelihood of brain iron deficiency (see Siddappa et al.23
for details). Such low serum ferritin concentrations at birth are present in approximately 25% of IDM and 14% of infants born to mothers with iron deficiency.6,16
Perinatal iron deficiency adversely affects the growth and functioning of multiple organ systems, including heart, skeletal muscle, the gastrointestinal tract and brain.24-27
Altered immune function and temperature instability are also attributed to perinatal iron deficiency.28
The most significant adverse effects of perinatal iron deficiency are neurodevelopmental impairments and predisposition to earlier onset of postnatal iron deficiency.
Effects of perinatal iron deficiency on neurodevelopment
Iron deficiency between 6 and 24 months of age is associated with long-term neurocognitive abnormalities that are not reversed, despite adequate iron supplementation.29
Iron is essential for neurotransmission, energy metabolism and myelination in the developing brain. The exact mechanisms through which iron deficiency affects brain development and function are not completely understood, although both direct and indirect mechanisms have been proposed.29
Iron deficiency during the perinatal period also appears to be detrimental to the developing brain. Research from our laboratory has demonstrated neurometabolic, structural, electrophysiological and behavioral alterations in developing rats subjected to perinatal iron deficiency.30-32
Brain regions involved with cognitive processing, such as the hippocampus and striatum, appear to be particularly vulnerable. Although iron rehabilitation corrects some deficits, structural and functional abnormalities persist into adulthood.
In contrast to the literature on postnatal iron deficiency, few studies have assessed the role of perinatal iron deficiency on neurodevelopment in human infants. Newborn infants with low cord blood Hb and iron have altered temperament during the first week of life.33
Preterm infants with iron-deficiency anemia have abnormal reflexes at 36 weeks postconceptional age.34
Electrophysiological studies from our laboratory have demonstrated that IDM with serum ferritin concentration <35 μg/L at birth have abnormal recognition memory processing soon after birth,23
which persists in infancy,35
despite complete repletion of iron stores by 9 months.36
Tamura et al.37
have described impaired language ability, fine-motor skills and tractability at 5 years in children born with cord serum ferritin concentration <76 μg/L. Thus, perinatal iron deficiency appears to have immediate and long-term adverse effect on neurodevelopment.
Predisposition to future iron deficiency
Infants with perinatal iron deficiency are at risk of iron deficiency during infancy. Use of cow's milk and inadequate iron supplementation can increase the risk. In developing countries, full-term infants with lower Hb and serum ferritin concentration at birth are at risk of developing iron deficiency at 6 months of age—3 months earlier than those with adequate iron endowment at birth.5
Even in developed countries, full-term infants with low cord ferritin concentrations have low serum ferritin concentration at 9 months of age.36
Infants born to mothers who smoked during gestation are at risk for iron deficiency at 12 and 24 months.38
However, whether these infants had poor iron endowment at birth is not known. Finally, preterm birth as a risk factor for postnatal iron deficiency has been discussed above.