Cord serum ferritin levels, fetal iron status, and neurodevelopmental outcomes: Correlations and confounding variables

Abstract

Both the medical literature1Grantham-McGregor S Ani C A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-666SCrossref PubMed Google Scholar, 2Logan S Commentary: iron deficiency and developmental deficit—the jury is still out.BMJ. 1999; 318: 697-698PubMed Google Scholar, 3Lozoff B Jimenez E Hagen J Mollen E Wolf AW Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy.Pediatrics. 2000; 105: E51Crossref PubMed Scopus (649) Google Scholar and popular press4Lord M Of algebra and anemia: a link between iron defciency and math woes?.US News World Rep. 2001; 130: 47PubMed Google Scholar have given considerable attention to a possible relationship between iron status in childhood and cognitive development. A correlation between iron deficiency anemia early in life and poor neurodevelopmental outcome is well established. Furthermore, iron deficiency has been shown to affect brain development in animal models.5Lozoff B Perinatal iron deficiency and the developing brain.Pediatr Res. 2000; 48: 137-139Crossref PubMed Scopus (92) Google Scholar Whether there is sufficient evidence to establish a causal link between iron deficiency and cognitive deficits, however, remains controversial.1Grantham-McGregor S Ani C A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-666SCrossref PubMed Google Scholar, 2Logan S Commentary: iron deficiency and developmental deficit—the jury is still out.BMJ. 1999; 318: 697-698PubMed Google Scholar It has also been unclear whether the correlation between the two implicates iron deficiency per se or the accompanying anemia. The recent report that children with iron deficiency—including children without anemia—score lower on standardized math tests6Halterman JS Kaczorowski JM Aligne CA Auinger P Szilagyi PG Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States.Pediatrics. 2001; 107: 1381-1386Crossref PubMed Scopus (403) Google Scholar suggests that the developing brain may be vulnerable to iron deficiency of insufficient severity to affect erythropoiesis. Although iron deficiency anemia in the newborn is unusual, the range of iron stores (as measured by cord serum ferritin levels) at birth is quite wide. In this context, it is reasonable to ask whether iron status at birth correlates with neurodevelopmental outcome. In this issue of The Journal, Tamura et al report an association between relatively low umbilical cord serum ferritin levels and lower scores on certain mental and psychomotor tests at 5 years of age.7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar The authors conclude that a poor intrauterine iron status (low ferritin) is associated with less favorable mental and psychomotor development. They also noted an apparent association between See related article, p 165. relatively high cord ferritin levels and lower test scores. These important observations draw due attention to issues regarding neurodevelopment and the intrauterine iron milieu. Before definitively implicating the fetal iron status, however, it is worthwhile to review several aspects of this study.The authors determined fetal iron status by using a single measure, the cord serum ferritin level. In the absence of inflammation (see following), cord ferritin levels provide a good measurement of fetal tissue iron storage concentration.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar Ferritin levels increase throughout gestation9Carpani G Marini F Ghisoni L Buscaglia M Sinigaglia E Moroni G Red cell and plasma ferritin in a group of normal fetuses at different ages of gestation.Eur J Haematol. 1992; 49: 260-262Crossref PubMed Scopus (16) Google Scholar and reach levels at birth higher than levels during most of postnatal life.10Dallman PR Siimes MA Stekel A Iron deficiency in infancy and childhood.Am J Clin Nutr. 1980; 33: 86-118Crossref PubMed Scopus (357) Google Scholar In the absence of a clear basis for defining abnormal ferritin levels at this age, Tamura et al divided their population into 4 quartiles and compared the quartiles with the lowest (and highest) ferritin levels independently with the middle 2 quartiles. The 25th percentile level (76 μg/L) is above levels generally associated with noticeable effects on erythropoiesis in children. However, central nervous system iron falls before changes in red cell production.11Yehuda S Youdim MB Brain iron: a lesson from animal models.Am J Clin Nutr. 1989; 50: 618-625Crossref PubMed Scopus (102) Google Scholar Thus levels higher than those used to diagnose iron deficiency in childhood (10-15 μg/L)12Looker AC Dallman PR Carroll MD Gunter EW Johnson CL Prevalence of iron deficiency in the United States.JAMA. 1997; 277: 973-976Crossref PubMed Google Scholar, 13CDC Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention.MMWR Morb Mortal Wkly Rep. 1998; 47: 1-29PubMed Google Scholar could theoretically affect the developing central nervous system (CNS). By using this approach, Tamura et al demonstrated that infants in the lowest and highest quartiles for cord ferritin levels performed worse on tests of neurodevelopment at 5 years of age.It is important to recognize that ferritin levels reflect tissue iron stores (primarily hepatic), rather than overall iron status. Iron stores are influenced by both iron supply (placental transport) and iron use (primarily erythropoiesis). Thus, changes in ferritin levels may reflect changes in the relative distribution of iron between sites of storage and use. In a previous study, MacPhail et al8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar compared a number of parameters of iron status in healthy term infants having cord serum ferritin levels <34 μg/L (one SD below the mean) with those >34 μg/L.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar They found that although serum iron levels and transferrin saturations were lower in the infants with low ferritin levels, hemoglobin levels were actually greater (16.6 ± 1.5 vs 15.1 ± 1.1, P <.001). These results suggested that iron had shifted from stores to use in this group of infants. Furthermore, cord serum ferritin concentrations and cord blood hemoglobin levels were inversely correlated in their patient population overall, suggesting that the relative distribution of iron between tissue stores and erythrocytes is determined by the level of erythropoietic activity. This conclusion is further supported by the negative correlation between umbilical cord serum ferritin levels and erythropoietin levels observed in another study by Milman et al14Milman N Graudal N Nielsen OJ Agger AO Cord serum erythropoietin in 90 healthy newborn term infants: relationship to blood gases and iron status markers.Int J Hematol. 1996; 64: 197-201Crossref PubMed Scopus (4) Google Scholar of healthy term infants. It appears then that low cord ferritin levels may indicate a redistribution of iron from stores to hemoglobin synthesis, rather than a decrease in placental transport or overall fetal iron accumulation.The combination of low cord ferritin levels and increased erythropoiesis has been observed in pregnancies complicated by placental insufficiency or maternal diabetes. Placental insufficiency from a variety of causes is associated with birth of small for gestational age (SGA) infants. Increased fetal erythropoiesis,15Finne PH Erythropoietin levels in cord blood as an indicator of intrauterine hypoxia.Acta Paediatr Scand. 1966; 55: 478-489Crossref PubMed Scopus (78) Google Scholar increased hemoglobin levels at birth,16Bard H The effect of placental insufficiency on fetal and adult hemoglobin synthesis.Am J Obstet Gynecol. 1974; 120: 67-72Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 17Weiner CP Williamson RA Evaluation of severe growth retardation using cordocentesis—hematologic and metabolic alterations by etiology.Obstet Gynecol. 1989; 73: 225-229PubMed Google Scholar and decreased cord ferritin levels18Chockalingam UM Murphy E Ophoven JC Weisdorf SA Georgieff MK Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.J Pediatr. 1987; 111: 283-286Abstract Full Text PDF PubMed Scopus (115) Google Scholar have been demonstrated in association with placental insufficiency. The erythropoietic stimulus in this situation is thought to be relative fetal hypoxemia. A similar picture (increased hemoglobin synthesis and decreased fetal iron stores) is seen at birth in the infant of the diabetic mother.19Georgieff MK Landon MB Mills MM Hedlund BE Faassen AE Schmidt RL et al.Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents.J Pediatr. 1990; 117: 455-461Abstract Full Text PDF PubMed Scopus (134) Google Scholar Increased risk for poor long-term neurodevelopmental outcome has been reported for SGA infants born20Liao QK Kong PA Gao J Li FY Qian ZM Expression of ferritin receptor in placental microvilli membrane in pregnant women with different iron status at mid-term gestation.Eur J Clin Nutr. 2001; 55: 651-656Crossref PubMed Scopus (26) Google Scholar, 21Larroque B Bertrais S Czernichow P Leger J School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study.Pediatrics. 2001; 108: 111-115Crossref PubMed Scopus (152) Google Scholar and infants of diabetic mothers.22Rizzo TA Dooley SL Metzger BE Cho NH Ogata ES Silverman BL Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers.Am J Obstet Gynecol. 1995; 173: 1753-1758Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 23Ornoy A Ratzon N Greenbaum C Peretz E Soriano D Dulitzky M Neurobehaviour of school age children born to diabetic mothers.Arch Dis Child Fetal Neonatal Ed. 1998; 79: F94-F99Crossref PubMed Scopus (90) Google Scholar It should be noted that the patient population studied by Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar included a disproportionate number of SGA infants (22%). Although the distribution of these SGA infants across the study groups was not reported, the group of infants in the lowest quartile for cord ferritin levels had a significantly lower mean birth weight compared with the other 2 groups (despite a similar mean gestational age). Thus the correlation between low ferritin levels and neurodevelopmental outcome reported by Tamura et al might actually reflect a correlation between placental insufficiency and neurodevelopmental outcome.Whether the adverse neurodevelopmental outcomes associated with low ferritin levels are because, in whole or in part, of decreased availability of iron for the developing CNS is an important question. The redistribution of iron from stores to the erythron could in theory restrict iron availability to the CNS. Supporting this concept is an autopsy study of infants of diabetic mothers that demonstrated a 40% decrease in brain nonheme iron concentrations, despite normal hemoglobin levels.24Petry 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: 109-114Abstract Full Text PDF PubMed Scopus (158) Google Scholar Several biochemical changes in the CNS have been reported in response to iron deficiency.25Youdim MB Yehuda S The neurochemical basis of cognitive deficits induced by brain iron deficiency: involvement of dopamine-opiate system.Cell Mol Biol. 2000; 46: 491-500PubMed Google Scholar An experimental animal model of perinatal iron deficiency demonstrated changes in brain iron distribution and cytochrome c oxidase activity (a marker for neuronal metabolic activity).26de Deungria M Rao R Wobken JD Luciana M Nelson CA Georgieff MK Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.Pediatr Res. 2000; 48: 169-176Crossref PubMed Scopus (222) Google Scholar Nonetheless, there may be alternative explanations unrelated to iron status for the neurodevelopmental problems associated with placental insufficiency and in the infant of the diabetic mother.Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar demonstrated that relatively high (as well as low) cord ferritin levels were associated with poorer neurodevelopmental outcomes. Because ferritin is an acute-phase protein, levels increase in response to a number of inflammatory stimuli. The authors suggest that undiagnosed infection may have raised ferritin levels in some of the patients. Perhaps subclinical chorioamnionitis, which has been associated with adverse neurologic outcomes,27De Felice C Toti P Laurini RN Stumpo M Picciolini E Todros T et al.Early neonatal brain injury in histologic chorioamnionitis.J Pediatr. 2001; 138: 101-104Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar was a confounding variable. However, implicating inflammation does not exclude the possibility that changes in iron homeostasis are involved. Inflammation influences iron distribution, leading to an increase in reticuloendothelial cell storage and a decrease in circulating iron levels.28Jurado RL Iron, infections, and anemia of inflammation.Clin Infect Dis. 1997; 25: 888-895Crossref PubMed Scopus (321) Google Scholar One could speculate that the sequestering of iron in storage tissues might decrease availability to the central CNS.The findings of this study draw attention to the issue of maternal iron supplementation during pregnancy. The fetus can, in cases other than severe maternal iron deficiency, achieve normal ironstatus, including hemoglobin levels, transferrin saturations, and ferritin concentrations, despite a wide variation in maternal iron status.29Blot I Diallo D Tchernia G Iron deficiency in pregnancy: effects on the newborn.Curr Opin Hematol. 1999; 6: 65-70Crossref PubMed Scopus (51) Google Scholar, 30Rios E Lipschitz DA Cook JD Smith NJ Relationship of maternal and infant iron stores as assessed by determination of plasma ferritin.Pediatrics. 1975; 55: 694-699Crossref PubMed Google Scholar, 31Hussain MA Gaafar TH Laulicht M Hoffebrand AV Relation of maternal and cord blood serum ferritin.Arch Dis Child. 1977; 52: 782-784Crossref PubMed Scopus (52) Google Scholar, 32Milman N Ibsen KK Christensen JM Serum ferritin and iron status in mothers and newborn infants.Acta Obstet Gynecol Scand. 1987; 66: 205-211Crossref PubMed Scopus (76) Google Scholar, 33Kelly AM MacDonald DJ McDougall AN Observations on maternal and fetal ferritin concentrations at term.Br J Obstet Gynaecol. 1978; 85: 338-343Crossref PubMed Scopus (55) Google Scholar This is accomplished by the ability of the placental syncytiotrophoblast cells to modulate the expression of certain iron transport proteins.34Gambling L Danzeisen R Gair S Lea RG Charania Z Solanky N et al.Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro.Biochem J. 2001; 356: 883-889Crossref PubMed Scopus (148) Google Scholar Nonetheless, some studies have demonstrated a correlation (albeit a weak one) between maternal and fetal ferritin levels.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar, 32Milman N Ibsen KK Christensen JM Serum ferritin and iron status in mothers and newborn infants.Acta Obstet Gynecol Scand. 1987; 66: 205-211Crossref PubMed Scopus (76) Google Scholar The observations that severe maternal iron deficiency can affect newborn hemoglobin levels and hepatic iron content35Singla PN Gupta VK Agarwal KN Storage iron in human foetal organs.Acta Paediatr Scand. 1985; 74: 701-706Crossref PubMed Scopus (48) Google Scholar suggest fetal iron accrual can be limited by availability. There are conflicting data addressing whether maternal iron supplementation during pregnancy leads to increased cord serum ferritin levels.36Milman N Agger AO Nielsen OJ Iron status markers and serum erythropoietin in 120 mothers and newborn infants: effect of iron supplementation in normal pregnancy.Acta Obstet Gynecol Scand. 1994; 73: 200-204Crossref PubMed Scopus (76) Google Scholar, 37Preziosi P Prual A Galan P Daouda H Boureima H Hercberg S Effect of iron supplementation on the iron status of pregnant women: consequences for newborns.Am J Clin Nutr. 1997; 66: 1178-1182Crossref PubMed Scopus (225) Google Scholar As outlined above, fetal iron requirements appear to be increased in situations where fetal erythropoiesis is increased (eg, pregnancies complicated by maternal diabetes or placental insufficiency). Whether maternal iron supplementation can influence fetal ferritin levels or alter neurodevelopmental outcome in these settings is unknown. Independent of any affect on neurodevelopmental outcome, there are bases for adhering to current recommendations for either universal iron supplementation or universal screening for iron deficiency in pregnant women.13CDC Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention.MMWR Morb Mortal Wkly Rep. 1998; 47: 1-29PubMed Google Scholar, 29Blot I Diallo D Tchernia G Iron deficiency in pregnancy: effects on the newborn.Curr Opin Hematol. 1999; 6: 65-70Crossref PubMed Scopus (51) Google ScholarIn summary, the study by Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar describes a provocative association between ferritin level at birth and neurodevelopmental outcome, but does not definitively implicate the fetal iron status. The association of ferritin levels in the lowest quartile with worse outcomes might reflect the inclusion of infants with placental insufficiency. The association of ferritin levels in the highest quartile with worse neurodevelopmental outcomes might reflect the inclusion of infants with perinatal inflammatory conditions. Whether alterations in intrauterine ferritin levels, regardless of cause, reflect alterations in iron availability to the developing CNS is unknown. A better understanding of this issue awaits additional research on fetal iron homeostasis and mechanisms of iron entry into the developing brain. Both the medical literature1Grantham-McGregor S Ani C A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-666SCrossref PubMed Google Scholar, 2Logan S Commentary: iron deficiency and developmental deficit—the jury is still out.BMJ. 1999; 318: 697-698PubMed Google Scholar, 3Lozoff B Jimenez E Hagen J Mollen E Wolf AW Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy.Pediatrics. 2000; 105: E51Crossref PubMed Scopus (649) Google Scholar and popular press4Lord M Of algebra and anemia: a link between iron defciency and math woes?.US News World Rep. 2001; 130: 47PubMed Google Scholar have given considerable attention to a possible relationship between iron status in childhood and cognitive development. A correlation between iron deficiency anemia early in life and poor neurodevelopmental outcome is well established. Furthermore, iron deficiency has been shown to affect brain development in animal models.5Lozoff B Perinatal iron deficiency and the developing brain.Pediatr Res. 2000; 48: 137-139Crossref PubMed Scopus (92) Google Scholar Whether there is sufficient evidence to establish a causal link between iron deficiency and cognitive deficits, however, remains controversial.1Grantham-McGregor S Ani C A review of studies on the effect of iron deficiency on cognitive development in children.J Nutr. 2001; 131: 649S-666SCrossref PubMed Google Scholar, 2Logan S Commentary: iron deficiency and developmental deficit—the jury is still out.BMJ. 1999; 318: 697-698PubMed Google Scholar It has also been unclear whether the correlation between the two implicates iron deficiency per se or the accompanying anemia. The recent report that children with iron deficiency—including children without anemia—score lower on standardized math tests6Halterman JS Kaczorowski JM Aligne CA Auinger P Szilagyi PG Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States.Pediatrics. 2001; 107: 1381-1386Crossref PubMed Scopus (403) Google Scholar suggests that the developing brain may be vulnerable to iron deficiency of insufficient severity to affect erythropoiesis. Although iron deficiency anemia in the newborn is unusual, the range of iron stores (as measured by cord serum ferritin levels) at birth is quite wide. In this context, it is reasonable to ask whether iron status at birth correlates with neurodevelopmental outcome. In this issue of The Journal, Tamura et al report an association between relatively low umbilical cord serum ferritin levels and lower scores on certain mental and psychomotor tests at 5 years of age.7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar The authors conclude that a poor intrauterine iron status (low ferritin) is associated with less favorable mental and psychomotor development. They also noted an apparent association between See related article, p 165. relatively high cord ferritin levels and lower test scores. These important observations draw due attention to issues regarding neurodevelopment and the intrauterine iron milieu. Before definitively implicating the fetal iron status, however, it is worthwhile to review several aspects of this study. The authors determined fetal iron status by using a single measure, the cord serum ferritin level. In the absence of inflammation (see following), cord ferritin levels provide a good measurement of fetal tissue iron storage concentration.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar Ferritin levels increase throughout gestation9Carpani G Marini F Ghisoni L Buscaglia M Sinigaglia E Moroni G Red cell and plasma ferritin in a group of normal fetuses at different ages of gestation.Eur J Haematol. 1992; 49: 260-262Crossref PubMed Scopus (16) Google Scholar and reach levels at birth higher than levels during most of postnatal life.10Dallman PR Siimes MA Stekel A Iron deficiency in infancy and childhood.Am J Clin Nutr. 1980; 33: 86-118Crossref PubMed Scopus (357) Google Scholar In the absence of a clear basis for defining abnormal ferritin levels at this age, Tamura et al divided their population into 4 quartiles and compared the quartiles with the lowest (and highest) ferritin levels independently with the middle 2 quartiles. The 25th percentile level (76 μg/L) is above levels generally associated with noticeable effects on erythropoiesis in children. However, central nervous system iron falls before changes in red cell production.11Yehuda S Youdim MB Brain iron: a lesson from animal models.Am J Clin Nutr. 1989; 50: 618-625Crossref PubMed Scopus (102) Google Scholar Thus levels higher than those used to diagnose iron deficiency in childhood (10-15 μg/L)12Looker AC Dallman PR Carroll MD Gunter EW Johnson CL Prevalence of iron deficiency in the United States.JAMA. 1997; 277: 973-976Crossref PubMed Google Scholar, 13CDC Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention.MMWR Morb Mortal Wkly Rep. 1998; 47: 1-29PubMed Google Scholar could theoretically affect the developing central nervous system (CNS). By using this approach, Tamura et al demonstrated that infants in the lowest and highest quartiles for cord ferritin levels performed worse on tests of neurodevelopment at 5 years of age. It is important to recognize that ferritin levels reflect tissue iron stores (primarily hepatic), rather than overall iron status. Iron stores are influenced by both iron supply (placental transport) and iron use (primarily erythropoiesis). Thus, changes in ferritin levels may reflect changes in the relative distribution of iron between sites of storage and use. In a previous study, MacPhail et al8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar compared a number of parameters of iron status in healthy term infants having cord serum ferritin levels <34 μg/L (one SD below the mean) with those >34 μg/L.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar They found that although serum iron levels and transferrin saturations were lower in the infants with low ferritin levels, hemoglobin levels were actually greater (16.6 ± 1.5 vs 15.1 ± 1.1, P <.001). These results suggested that iron had shifted from stores to use in this group of infants. Furthermore, cord serum ferritin concentrations and cord blood hemoglobin levels were inversely correlated in their patient population overall, suggesting that the relative distribution of iron between tissue stores and erythrocytes is determined by the level of erythropoietic activity. This conclusion is further supported by the negative correlation between umbilical cord serum ferritin levels and erythropoietin levels observed in another study by Milman et al14Milman N Graudal N Nielsen OJ Agger AO Cord serum erythropoietin in 90 healthy newborn term infants: relationship to blood gases and iron status markers.Int J Hematol. 1996; 64: 197-201Crossref PubMed Scopus (4) Google Scholar of healthy term infants. It appears then that low cord ferritin levels may indicate a redistribution of iron from stores to hemoglobin synthesis, rather than a decrease in placental transport or overall fetal iron accumulation. The combination of low cord ferritin levels and increased erythropoiesis has been observed in pregnancies complicated by placental insufficiency or maternal diabetes. Placental insufficiency from a variety of causes is associated with birth of small for gestational age (SGA) infants. Increased fetal erythropoiesis,15Finne PH Erythropoietin levels in cord blood as an indicator of intrauterine hypoxia.Acta Paediatr Scand. 1966; 55: 478-489Crossref PubMed Scopus (78) Google Scholar increased hemoglobin levels at birth,16Bard H The effect of placental insufficiency on fetal and adult hemoglobin synthesis.Am J Obstet Gynecol. 1974; 120: 67-72Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 17Weiner CP Williamson RA Evaluation of severe growth retardation using cordocentesis—hematologic and metabolic alterations by etiology.Obstet Gynecol. 1989; 73: 225-229PubMed Google Scholar and decreased cord ferritin levels18Chockalingam UM Murphy E Ophoven JC Weisdorf SA Georgieff MK Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.J Pediatr. 1987; 111: 283-286Abstract Full Text PDF PubMed Scopus (115) Google Scholar have been demonstrated in association with placental insufficiency. The erythropoietic stimulus in this situation is thought to be relative fetal hypoxemia. A similar picture (increased hemoglobin synthesis and decreased fetal iron stores) is seen at birth in the infant of the diabetic mother.19Georgieff MK Landon MB Mills MM Hedlund BE Faassen AE Schmidt RL et al.Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents.J Pediatr. 1990; 117: 455-461Abstract Full Text PDF PubMed Scopus (134) Google Scholar Increased risk for poor long-term neurodevelopmental outcome has been reported for SGA infants born20Liao QK Kong PA Gao J Li FY Qian ZM Expression of ferritin receptor in placental microvilli membrane in pregnant women with different iron status at mid-term gestation.Eur J Clin Nutr. 2001; 55: 651-656Crossref PubMed Scopus (26) Google Scholar, 21Larroque B Bertrais S Czernichow P Leger J School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study.Pediatrics. 2001; 108: 111-115Crossref PubMed Scopus (152) Google Scholar and infants of diabetic mothers.22Rizzo TA Dooley SL Metzger BE Cho NH Ogata ES Silverman BL Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers.Am J Obstet Gynecol. 1995; 173: 1753-1758Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 23Ornoy A Ratzon N Greenbaum C Peretz E Soriano D Dulitzky M Neurobehaviour of school age children born to diabetic mothers.Arch Dis Child Fetal Neonatal Ed. 1998; 79: F94-F99Crossref PubMed Scopus (90) Google Scholar It should be noted that the patient population studied by Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar included a disproportionate number of SGA infants (22%). Although the distribution of these SGA infants across the study groups was not reported, the group of infants in the lowest quartile for cord ferritin levels had a significantly lower mean birth weight compared with the other 2 groups (despite a similar mean gestational age). Thus the correlation between low ferritin levels and neurodevelopmental outcome reported by Tamura et al might actually reflect a correlation between placental insufficiency and neurodevelopmental outcome. Whether the adverse neurodevelopmental outcomes associated with low ferritin levels are because, in whole or in part, of decreased availability of iron for the developing CNS is an important question. The redistribution of iron from stores to the erythron could in theory restrict iron availability to the CNS. Supporting this concept is an autopsy study of infants of diabetic mothers that demonstrated a 40% decrease in brain nonheme iron concentrations, despite normal hemoglobin levels.24Petry 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: 109-114Abstract Full Text PDF PubMed Scopus (158) Google Scholar Several biochemical changes in the CNS have been reported in response to iron deficiency.25Youdim MB Yehuda S The neurochemical basis of cognitive deficits induced by brain iron deficiency: involvement of dopamine-opiate system.Cell Mol Biol. 2000; 46: 491-500PubMed Google Scholar An experimental animal model of perinatal iron deficiency demonstrated changes in brain iron distribution and cytochrome c oxidase activity (a marker for neuronal metabolic activity).26de Deungria M Rao R Wobken JD Luciana M Nelson CA Georgieff MK Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.Pediatr Res. 2000; 48: 169-176Crossref PubMed Scopus (222) Google Scholar Nonetheless, there may be alternative explanations unrelated to iron status for the neurodevelopmental problems associated with placental insufficiency and in the infant of the diabetic mother. Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar demonstrated that relatively high (as well as low) cord ferritin levels were associated with poorer neurodevelopmental outcomes. Because ferritin is an acute-phase protein, levels increase in response to a number of inflammatory stimuli. The authors suggest that undiagnosed infection may have raised ferritin levels in some of the patients. Perhaps subclinical chorioamnionitis, which has been associated with adverse neurologic outcomes,27De Felice C Toti P Laurini RN Stumpo M Picciolini E Todros T et al.Early neonatal brain injury in histologic chorioamnionitis.J Pediatr. 2001; 138: 101-104Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar was a confounding variable. However, implicating inflammation does not exclude the possibility that changes in iron homeostasis are involved. Inflammation influences iron distribution, leading to an increase in reticuloendothelial cell storage and a decrease in circulating iron levels.28Jurado RL Iron, infections, and anemia of inflammation.Clin Infect Dis. 1997; 25: 888-895Crossref PubMed Scopus (321) Google Scholar One could speculate that the sequestering of iron in storage tissues might decrease availability to the central CNS. The findings of this study draw attention to the issue of maternal iron supplementation during pregnancy. The fetus can, in cases other than severe maternal iron deficiency, achieve normal ironstatus, including hemoglobin levels, transferrin saturations, and ferritin concentrations, despite a wide variation in maternal iron status.29Blot I Diallo D Tchernia G Iron deficiency in pregnancy: effects on the newborn.Curr Opin Hematol. 1999; 6: 65-70Crossref PubMed Scopus (51) Google Scholar, 30Rios E Lipschitz DA Cook JD Smith NJ Relationship of maternal and infant iron stores as assessed by determination of plasma ferritin.Pediatrics. 1975; 55: 694-699Crossref PubMed Google Scholar, 31Hussain MA Gaafar TH Laulicht M Hoffebrand AV Relation of maternal and cord blood serum ferritin.Arch Dis Child. 1977; 52: 782-784Crossref PubMed Scopus (52) Google Scholar, 32Milman N Ibsen KK Christensen JM Serum ferritin and iron status in mothers and newborn infants.Acta Obstet Gynecol Scand. 1987; 66: 205-211Crossref PubMed Scopus (76) Google Scholar, 33Kelly AM MacDonald DJ McDougall AN Observations on maternal and fetal ferritin concentrations at term.Br J Obstet Gynaecol. 1978; 85: 338-343Crossref PubMed Scopus (55) Google Scholar This is accomplished by the ability of the placental syncytiotrophoblast cells to modulate the expression of certain iron transport proteins.34Gambling L Danzeisen R Gair S Lea RG Charania Z Solanky N et al.Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro.Biochem J. 2001; 356: 883-889Crossref PubMed Scopus (148) Google Scholar Nonetheless, some studies have demonstrated a correlation (albeit a weak one) between maternal and fetal ferritin levels.8MacPhail AP Charlton RW Bothwell TH Torrance JD The relationship between maternal and infant iron status.Scand J Haematol. 1980; 25: 141-150Crossref PubMed Scopus (48) Google Scholar, 32Milman N Ibsen KK Christensen JM Serum ferritin and iron status in mothers and newborn infants.Acta Obstet Gynecol Scand. 1987; 66: 205-211Crossref PubMed Scopus (76) Google Scholar The observations that severe maternal iron deficiency can affect newborn hemoglobin levels and hepatic iron content35Singla PN Gupta VK Agarwal KN Storage iron in human foetal organs.Acta Paediatr Scand. 1985; 74: 701-706Crossref PubMed Scopus (48) Google Scholar suggest fetal iron accrual can be limited by availability. There are conflicting data addressing whether maternal iron supplementation during pregnancy leads to increased cord serum ferritin levels.36Milman N Agger AO Nielsen OJ Iron status markers and serum erythropoietin in 120 mothers and newborn infants: effect of iron supplementation in normal pregnancy.Acta Obstet Gynecol Scand. 1994; 73: 200-204Crossref PubMed Scopus (76) Google Scholar, 37Preziosi P Prual A Galan P Daouda H Boureima H Hercberg S Effect of iron supplementation on the iron status of pregnant women: consequences for newborns.Am J Clin Nutr. 1997; 66: 1178-1182Crossref PubMed Scopus (225) Google Scholar As outlined above, fetal iron requirements appear to be increased in situations where fetal erythropoiesis is increased (eg, pregnancies complicated by maternal diabetes or placental insufficiency). Whether maternal iron supplementation can influence fetal ferritin levels or alter neurodevelopmental outcome in these settings is unknown. Independent of any affect on neurodevelopmental outcome, there are bases for adhering to current recommendations for either universal iron supplementation or universal screening for iron deficiency in pregnant women.13CDC Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention.MMWR Morb Mortal Wkly Rep. 1998; 47: 1-29PubMed Google Scholar, 29Blot I Diallo D Tchernia G Iron deficiency in pregnancy: effects on the newborn.Curr Opin Hematol. 1999; 6: 65-70Crossref PubMed Scopus (51) Google Scholar In summary, the study by Tamura et al7Tamura T Goldenberg RL Hou J Johnston KE Cliver SP Ramey SL et al.Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age.J Pediatr. 2001; 140: 165-170Abstract Full Text Full Text PDF Scopus (235) Google Scholar describes a provocative association between ferritin level at birth and neurodevelopmental outcome, but does not definitively implicate the fetal iron status. The association of ferritin levels in the lowest quartile with worse outcomes might reflect the inclusion of infants with placental insufficiency. The association of ferritin levels in the highest quartile with worse neurodevelopmental outcomes might reflect the inclusion of infants with perinatal inflammatory conditions. Whether alterations in intrauterine ferritin levels, regardless of cause, reflect alterations in iron availability to the developing CNS is unknown. A better understanding of this issue awaits additional research on fetal iron homeostasis and mechanisms of iron entry into the developing brain. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of ageThe Journal of PediatricsVol. 140Issue 2PreviewObjective: Our purpose was to evaluate the association between fetal iron status and mental and psychomotor development at 5 years of age. Study design: We evaluated the association of fetal iron status (umbilical cord serum ferritin concentrations) with test scores of mental and psychomotor development of 278 children. Six tests were given, including full-scale intelligence quotient (FSIQ), language ability, fine- and gross-motor skills, attention, and tractability. Results: Compared with children with cord ferritin in the 2 median quartiles, those in the lowest quartile scored lower on every test and had significantly worse language ability, fine-motor skills, and tractability. Full-Text PDF