Neonatal Iron Research Articles

Fetal and Neonatal Iron Deficiency Exacerbates Mild Thyroid Hormone Insufficiency Effects on Male Thyroid Hormone Levels and Brain Thyroid Hormone-Responsive Gene Expression

Fetal/neonatal iron (Fe) and iodine/TH deficiencies lead to similar brain developmental abnormalities and often coexist in developing countries. We recently demonstrated that fetal/neonatal Fe deficiency results in a mild neonatal thyroidal impairment, suggesting that TH insufficiency contributes to the neurodevelopmental abnormalities associated with Fe deficiency. We hypothesized that combining Fe deficiency with an additional mild thyroidal perturbation (6-propyl-2-thiouracil [PTU]) during development would more severely impair neonatal thyroidal status and brain TH-responsive gene expression than either deficiency alone. Early gestation pregnant rats were assigned to 7 different treatment groups: control, Fe deficient (FeD), mild TH deficient (1 ppm PTU), moderate TH deficient (3 ppm PTU), severe TH deficient (10 ppm PTU), FeD/1 ppm PTU, or FeD/3 ppm PTU. FeD or 1 ppm PTU treatment alone reduced postnatal day 15 serum total T4 concentrations by 64% and 74%, respectively, without significantly altering serum total T3 concentrations. Neither treatment alone significantly altered postnatal day 16 cortical or hippocampal T3 concentrations. FeD combined with 1 ppm PTU treatment produced a more severe effect, reducing serum total T4 by 95%, and lowering hippocampal and cortical T3 concentrations by 24% and 31%, respectively. Combined FeD/PTU had a more severe effect on brain TH-responsive gene expression than either treatment alone, significantly altering Pvalb, Dio2, Mbp, and Hairless hippocampal and/or cortical mRNA levels. FeD/PTU treatment more severely impacted cortical and hippocampal parvalbumin protein expression compared with either individual treatment. These data suggest that combining 2 mild thyroidal insults during development significantly disrupts thyroid function and impairs TH-regulated brain gene expression.

Effect Of Maternal Cigarette Smoking On Newborn Iron Stores

Objective Previous small-scale studies suggest that maternal smoking lowers neonatal body iron. Our objective was to study and compare the relationship between maternal and infants’ body iron in smokers and non-smokers in a large matched-pair cohort. Method This was a prospective cohort study involving 144 mothers – 72 smokers and 72 non-smokers and their respective infants. Samples were obtained from maternal blood and infants’ cord blood at delivery for serum transferrin receptor (sTfR) and ferritin levels. Serum TfR and ferritin levels were measured by RAMCO ELISA and RIA assays. The total body iron (TBI) was calculated using the sTfR/ferritin ratio. Results Maternal total body iron and smoking status Women who smoked had lower sTfR, higher ferritin and higher body iron compared to nonsmoking women. Infant’s total body iron, measurements at birth and smoking status In contrast to their respective mothers, we found a small but statistically significant negative correlation between smoking and infants’ total body iron. The number of PPD smoked was negatively correlated with infants’ ferritin and total body iron. The number of days smoked during pregnancy was also negatively correlated with infants’ ferritin and total body iron and positively correlated with infants' sTfR. Birth weight was lower in babies of smokers compared to nonsmokers (mean /- SD =3270 +/-475 vs. 3393 g +/- 475 g, p=0.03). Correlation studies revealed that birth weight in infants of smokers was negatively correlated with PPD smoked and number of days smoked. Birth length in the same infants was also negatively correlated with PPD smoked and number of days smoked. Conclusion Mothers who smoked during pregnancy had higher iron stores but their newborn infants had lower iron stores than those of non-smoking mothers. There may be a negative dose-dependent response between fetal smoke exposure and infant iron stores. Disclosures: No relevant conflicts of interest to declare.

Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

Fetal and neonatal iron deficiency results in cognitive impairments in adulthood despite prompt postnatal iron replenishment. To systematically determine whether abnormal expression and localization of proteins that regulate adult synaptic efficacy are involved, we used a quantitative proteomic approach (isobaric tags for relative and absolute quantitation, iTRAQ) and pathway analysis to identify dysregulated proteins in hippocampal synapses of fetal iron deficiency model. Rat pups were made iron deficient (ID) from gestational day 2 through postnatal day (P) 7 by providing pregnant and nursing dams an ID diet (4 ppm Fe) after which they were rescued with an iron-sufficient diet (200 ppm Fe). This paradigm resulted in a 40% loss of brain iron at P15 with complete recovery by P56. Synaptosomes were prepared from hippocampi of the formerly iron-deficient (FID) and always iron-sufficient controls rats at P65 using a sucrose gradient method. Six replicates per group that underwent iTRAQ labeling and LC-MS/MS analysis for protein identification and comparison elucidated 331 differentially expressed proteins. Western analysis was used to confirm findings for selected proteins in the glutamate receptor signaling pathway, which regulates hippocampal synaptic plasticity, a cellular process critical for learning and memory. Bioinformatics were performed using knowledge-based Interactive Pathway Analysis. FID synaptosomes show altered expression of synaptic proteins-mediated cellular signalings, supporting persistent impacts of fetal iron deficiency on synaptic efficacy, which likely cause the cognitive dysfunction and neurobehavioral abnormalities. Importantly, the findings uncover previously unsuspected pathways, including neuronal nitric oxide synthase signaling, identifying additional mechanisms that may contribute to the long-term biobehavioral deficits.

Multigenerational effects of fetal-neonatal iron deficiency on hippocampal BDNF signaling.

Fetal-neonatal iron deficiency induces adult learning impairments concomitant with changes in expression of key genes underlying hippocampal learning and memory in spite of neonatal iron replenishment. Notably, expression of brain-derived neurotrophic factor (BDNF), a gene critical for neuronal maturation and synaptic plasticity, is lowered both acutely and in adulthood following early-life iron deficiency. Although the mechanism behind its long-term downregulation remains unclear, epigenetic modification in BDNF, as seen in other models of early-life adversity, may play a role. Given that early iron deficiency occurs during critical periods in both hippocampal and gonadal development, we hypothesized that the iron-sufficient offspring (F2 IS) of formerly iron-deficient (F1 FID) rats would show a similar suppression of the BDNF gene as their parents. We compared hippocampal mRNA levels of BDNF and functionally related genes among F1 IS, F1 ID, and F2 IS male rats at postnatal day (P) 15 and P65 using RT-qPCR. As expected, the F1 ID group showed a downregulation of BDNF and associated genes acutely at P15 and chronically at P65. However, the F2 IS group showed an upregulation of these genes at P15, returning to control levels at P65. These results demonstrate that adverse effects of early iron deficiency on hippocampal gene expression observed in the F1 are not present in the F2 generation, suggesting differential effects of nutritionally induced epigenetic programing during the critical periods of hippocampal and gonadal development.

Associations of maternal and neonatal serum trace element concentrations with neonatal birth weight.

BackgroundTrace elements play important nutritional roles in neonates. Our objective was to examine whether there are differences in maternal/neonatal serum trace element concentrations between mature infants and premature infants.MethodsDuring 2012, 44 infants born at National Center for Global Health and Medicine, Tokyo, Japan, were enrolled. Serum samples were collected to measure serum iron, zinc, copper, and selenium concentrations 5 days after birth. Maternal serum samples were obtained before delivery and cord blood was taken at delivery to measure the same trace elements. We compared the results between term group whose birth weight were ≥2500 g and gestational age were ≥37 weeks and premature group whose birth weight were <2500 g or gestational age were <37 weeks. Variables significantly different between two groups were included in linear regression models to identify significant predictors of birth weight. Values of P<0.05 were considered statistically significant.ResultsSerum selenium concentrations were lower in premature group than in term group (43.3±7.0 µg/L vs. 52.0±8.9 µg/L, P = 0.001). Maternal serum selenium concentrations were also significantly lower in the mothers of premature group than in the mothers of term group (79.3±19.3 µg/L vs. 94.1±18.1 µg/L, P = 0.032). There were no significant differences in neonatal or maternal iron, zinc, or copper concentrations between two groups. Multivariate linear regression analysis showed that, except for gestational age, only maternal serum selenium was significantly associated with birth weight (P = 0.015).ConclusionsSerum selenium concentrations were lower in premature group and their mothers compared with the term group. The maternal serum selenium concentration was positively correlated with birth weight. These results suggest that maternal serum selenium concentration may influence neonatal birth weight.

Neonatal Iron Deficiency Causes Abnormal Phosphate Metabolism by Elevating FGF23 in Normal and ADHR Mice

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.

Effect of Delayed Versus Early Umbilical Cord Clamping on Neonatal Outcomes and Iron Status at 4 Months

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Pregnancy and iron homeostasis: an update

It has been nearly 15 years since the first review on pregnancy and iron deficiency was published in Nutrition Reviews. Many unresolved issues raised in that seminal review have been addressed. New proteins involved in nonheme and heme iron transport have been identified in the enterocyte, and information on the roles of these proteins in the placenta is evolving. The systemic iron regulatory hormone, hepcidin, has since been identified as a key regulator of iron homeostasis. Additional data on the efficacy and consequences of prenatal iron supplementation are available. Emerging data on developmental changes in iron absorption across early infancy have further emphasized the need to ensure that the iron endowment of the neonate at birth is optimal. This is especially important, given growing evidence linking neonatal iron status with subsequent cognitive and neurobehavioral outcomes. Along with the many advances, new questions and gaps in knowledge have been identified. This review summarizes new data on maternal iron utilization across pregnancy as it impacts the pregnant woman and the iron status of the neonate at birth.

Effects of iron injection at birth on neonatal iron status in young pigs from first-parity sows fed delta-aminolevulinic acid

A total of 40 gilts (Landrace×Yorkshire) fed delta-aminolevulinic acid (ALA) or inorganic iron (FeSO4) and their 392 progeny were used to determine the iron status of sows and piglets at birth and nursing. The experiment was a 2×2 factorial arrangement with two different additive [90mg of iron/kg (as FeSO4) and 90mg ALA/kg (ALA90)] and 2 levels of injection with iron-dextran (0 and 200mg) to neonatal pigs within litter. Dietary treatments were fed during entire gestation and lactation period. Sows fed ALA90 diet had larger (P<0.05) litter size born alive and piglets with higher (P<0.01) body weight at birth and weaning compared with sows fed FeSO4 diet. Plasma hemoglobin (Hb) and iron concentration at d 21, and milk iron concentration of sows were higher (P<0.05) when sows fed ALA90 vs. FeSO4. Feeding ALA90 to sows and iron injection to piglets increased body weight at d 0, 7 and 21 after birth and average daily gain from d 0–7. During d 0–7 the increase in average daily gain due to iron injection was higher in piglets of sows fed FeSO4 compared to sows fed ALA90 (ALA×iron injection; P<0.04). Feeding ALA90 to sows and iron injection increased (P<0.05) plasma iron and Hb concentration and hematocrit values of piglets throughout the nursing phase. At d 2 the increase in plasma iron and Hb concentration and hematocrit values of piglets due to iron injection was higher in piglets of sows fed FeSO4 compared sows fed ALA90 (ALA×iron injection; P<0.05). At d 7 and 21, plasma ceruloplasmin oxidase activity of piglets was reduced (P<0.05) by ALA supplementation to sows and iron injection. In conclusion, this study indicates that dietary supplementation of ALA to sows and iron injection to neonatal piglets can result in increased iron concentration in milk, which may have a beneficial effect on the plasma iron status of sucking pigs.

Early Life Iron Deficiency Impairs Spatial Cognition in Neonatal Piglets ,2

Iron deficiency is common throughout the world and has been linked to cognitive impairments. Using neonatal piglets to model human infants, we assessed the impact of iron deficiency on spatial learning and memory. Artificially reared piglets were fed 1 of 3 liquid diets with varying concentrations of iron: control (CON), mildly deficient (MID), or severely deficient (SID; 100, 25.0, or 10.0 mg iron/kg milk solids, respectively) for 4 wk. Relative to CON, SID and MID piglets had reduced hemoglobin (P< 0.05) as well as magenta skin color (P< 0.001), which correlated with hematocrit (R2= 0.76;P< 0.001). SID and MID hemoglobin differed at wk 3 and 4 (P< 0.05). In a hippocampal-dependent, spatial, T-maze task, SID piglets were unable to acquire the task (post hoc contrast: first vs. last day of acquisition), while MID piglets demonstrated deficits in reversal learning (P= 0.032). Iron concentrations in the liver (P< 0.001), serum (P= 0.003), and hippocampus (P= 0.004), but not prefrontal cortex, were lower in MID and SID compared with CON piglets. The level of the transferrin receptor mRNA (TFR) was greater in the prefrontal cortex of CON piglets than in MID and SID piglets (P= 0.001) but not the hippocampus. Gene expression of several neurotrophic factors and proinflammatory cytokines, as well as whole-brain and hippocampal volume, were not affected by dietary treatment. In conclusion, neonatal iron deficiency leads to cognitive impairment, which may be due in part to a reduced iron concentration in the hippocampus.

Maternal Serum Ferritin Concentration Is Positively Associated with Newborn Iron Stores in Women with Low Ferritin Status in Late Pregnancy1–3

Iron deficiency (ID) is common in pregnant women and infants, particularly in developing countries. The relation between maternal and neonatal iron status remains unclear. This study considered the issue in a large sample of mother-newborn pairs in rural southeastern China. Hemoglobin (Hb) and serum ferritin (SF) were measured in 3702 pregnant women at ≥37 wk gestation and in cord blood of their infants born at term (37–42 wk gestation). Maternal anemia (Hb <110 g/L) was present in 27.5% and associated with maternal SF <20 μg/L in 86.9%. Only 5.6% of neonates were anemic (Hb <130 g/L) and 9.5% had cord-blood SF <75μg/L. There were low-order correlations between maternal and newborn iron measures (r= 0.07–0.10 for both Hb and SF;P≤ 0.0001 due to the large number). We excluded 430 neonates with suggestion of inflammation [cord SF >370μg/L,n= 208 and/or C-reactive protein (CRP) >5 mg/L,n= 233]. Piecewise linear regression analyses identified a threshold for maternal SF at which cord-blood SF was affected. For maternal SF below the threshold of 13.6μg/L (α=2.4;P= 0.001), cord SF was 0.17 SD lower than in neonates whose mothers had SF above the threshold (167 α 75 vs. 179 α 80μg/L). The study confirmed that ID anemia remains common during pregnancy in rural southeastern China. Despite widespread maternal ID, however, iron nutrition seemed to meet fetal needs except when mothers were very iron deficient. The impact of somewhat lower cord SF on iron status later in infancy warrants further study.

Fetal and Neonatal Iron Deficiency Reduces Thyroid Hormone-Responsive Gene mRNA Levels in the Neonatal Rat Hippocampus and Cerebral Cortex

Copper (Cu), iron (Fe), and thyroid hormone (TH) deficiencies produce similar defects in late brain development including hypomyelination of axons and impaired synapse formation and function, suggesting that these micronutrient deficiencies share a common mechanism contributing to these derangements. We previously demonstrated that fetal/neonatal Cu and Fe deficiencies lower circulating TH concentrations in neonatal rats. Fe deficiency also reduces whole-brain T(3) content, suggesting impaired TH action in the developing Fe-deficient brain. We hypothesized that fetal/neonatal Cu and Fe deficiencies will produce mild or moderate TH deficiencies and will impair TH-responsive gene expression in the neonatal cerebral cortex and hippocampus. To test this hypothesis, we rendered pregnant Sprague Dawley rats Cu-, Fe-, or TH-deficient from early gestation through postnatal d 10 (P10). Mild and moderate TH deficiencies were induced by 1 and 3 ppm propylthiouracil treatment, respectively. Cu deficiency did not significantly alter serum or tissue TH concentrations or TH-responsive brain mRNA expression. Fe deficiency significantly lowered P10 serum total T(3) (45%), serum total T(4) (52%), whole brain T(3) (14%), and hippocampal T(3) (18%) concentrations, producing a mild TH deficiency similar to 1 ppm propylthiouracil treatment. Fe deficiency lowered Pvalb, Enpp6, and Mbp mRNA levels in the P10 hippocampus. Fe deficiency also altered Hairless, Dbm, and Dio2 mRNA levels in the P10 cerebral cortex. These results suggest that some of the brain defects associated with Fe deficiency may be mediated through altered thyroidal status and the concomitant alterations in TH-responsive gene transcription.

Early Versus Delayed Cord Clamping in Term and Preterm Births

Abstract The optimal timing for cord clamping, early versus delayed, in the third stage of labour is a controversial subject. Issues surrounding the timing of cord clamping include gestational age and maternal and neonatal considerations. Delayed cord clamping (DCC) has been shown to increase placental transfusion, leading to an increase in neonatal blood volume at birth of approximately 30%. In the term infant, although this may result in an increase in iron stores, thereby decreasing the risk of anemia, it may adversely increase the risk of jaundice and the need for phototherapy. In the preterm infant, DCC (or even milking of the cord) decreases the need for blood transfusions for anemia, the number of such transfusions, and the risks of intraventricular hemorrhage and late-onset sepsis. Advantages of DCC also include a reduction in alloimmunization in Rh-negative women, although this advantage is theoretical and unproven. We searched multiple databases including PubMed Clinical Queries, Trip Database, Cochrane Systematic Reviews, and UpToDate, as well as published guidelines from the Society of Obstetricians and Gynaecologists of Canada, the American Congress of Obstetricians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists. We preferentially selected systematic reviews and randomized controlled trials for this literature review. Overall, the available evidence appears to suggest that DCC is likely to result in better neonatal outcomes in both term and preterm infants, even in areas where neonatal iron deficiency anemia is rare. However, there is insufficient evidence to date to support a recommendation to delay cord clamping in non-vigorous infants requiring resuscitation.

Treatment of iron deficiency anemia in pregnancy and postpartum

SUMMARYIron deficiency (ID), iron deficiency anemia (IDA) and the resulting reduction in blood reserves are one the most common problems in pregnancy. Both oral iron – the traditional treatment – and blood transfusion involve significant drawbacks. High doses of oral iron frequently cause side effects, and noncompliance is common. Therefore, intravenous iron, alone or in association with recombinant human erythropoietin (rHuEPO), has been evaluated as an alternative in the management of ID in this setting. There is increasing evidence that iron sucrose is effective for treating IDA and safe for the mother and the fetus, using the recommended dosages and treatment regimens. In the postpartum period, both iron sucrose and ferric carboxymaltose have been shown to be efficacious, alone or in combination with rHuEPO. In pregnancy and in the postpartum period, the expected hemoglobin increase and treatment times are predictable according to the present data; therefore, in the presence of moderate‐to‐severe anemia, it can be questioned whether it is reasonable to wait for a response to oral iron. Indications for the use of iron sucrose and ferric carboxymaltose are preexisting moderate‐to‐severe anemia, no effect of oral iron, side effects of oral iron, refusal of blood transfusion, limited time until delivery, coexisting risk factors (e.g. inflammatory bowel disease, renal disease), the preoperative and postoperative periods and postpartum anemia. Future fields of research include the impact of intravenous iron therapy on patient satisfaction and quality of life, costs, hospital length of stay, blood transfusion rate, mortality rate, and other outcomes such as breastfeeding behavior and neonatal outcomes (e.g. birth weight, prematurity and neonatal iron stores).

Early Versus Delayed Cord Clamping in Term and Preterm Births: A Review

The optimal timing for cord clamping, early versus delayed, in the third stage of labour is a controversial subject. Issues surrounding the timing of cord clamping include gestational age and maternal and neonatal considerations. Delayed cord clamping (DCC) has been shown to increase placental transfusion, leading to an increase in neonatal blood volume at birth of approximately 30%. In the term infant, although this may result in an increase in iron stores, thereby decreasing the risk of anemia, it may adversely increase the risk of jaundice and the need for phototherapy. In the preterm infant, DCC (or even milking of the cord) decreases the need for blood transfusions for anemia, the number of such transfusions, and the risks of intraventricular hemorrhage and late-onset sepsis. Advantages of DCC also include a reduction in alloimmunization in Rh-negative women, although this advantage is theoretical and unproven.We searched multiple databases including PubMed Clinical Queries, Trip Database, Cochrane Systematic Reviews, and UpToDate, as well as published guidelines from the Society of Obstetricians and Gynaecologists of Canada, the American Congress of Obstetricians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists. We preferentially selected systematic reviews and randomized controlled trials for this literature review.Overall, the available evidence appears to suggest that DCC is likely to result in better neonatal outcomes in both term and preterm infants, even in areas where neonatal iron deficiency anemia is rare. However, there is insufficient evidence to date to support a recommendation to delay cord clamping in non-vigorous infants requiring resuscitation.

Molecular insights into the regulation of iron metabolism during the prenatal and early postnatal periods

Molecular iron metabolism and its regulation are least well understood in the fetal and early postnatal periods of mammalian ontogenic development. The scope of this review is to summarize recent progress in uncovering the molecular mechanisms of fetal iron homeostasis, introduce the molecules involved in iron transfer across the placenta, and briefly explain the role of iron transporters in the absorption of this microelement during early postnatal life. These issues are discussed and parallels are drawn with the relatively well-established system for elemental and heme iron regulation in adult mammals. We conclude that detailed investigations into the regulatory mechanisms of iron metabolism at early stages of development are required in order to optimize strategies to prevent neonatal iron deficiency. We propose that newborn piglets represent a suitable animal model for studies on iron deficiency anemia in neonates.

Randomised controlled trial: effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months

The paper “Randomised controlled trial: effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months” by Ola Andersson and colleagues ( BMJ 2011;343:d7157, doi:10.1136/bmj.d7157) Abstract Objective— To investigate the effects of delayed umbilical cord clamping, compared with early clamping, on infant iron status at 4 months of age in a European setting. Design— Randomised controlled trial. Setting—Swedish county hospital. Participants— 400 full term infants born after a low risk pregnancy. Intervention— Infants were randomised to delayed umbilical cord clamping (≥180 seconds after delivery) or early clamping (≤10 seconds after delivery). Main outcome measures— Haemoglobin and iron status at 4 months of age with the power estimate based on serum ferritin levels. Secondary outcomes included neonatal anaemia, early respiratory symptoms, polycythaemia, and need for phototherapy. Results— At 4 months of age, infants showed no significant differences in haemoglobin concentration between the groups, but infants subjected to delayed cord clamping had 45% (95% confidence interval 23% to 71%) higher mean ferritin concentration (117 μg/L v 81 μg/L, P<0.001) and a lower prevalence of iron deficiency (1 (0.6%) v 10 (5.7%), P=0.01, relative risk reduction 0.90; number needed to treat=20 (17 to 67)). As for secondary outcomes, the delayed cord clamping group had lower prevalence of neonatal anaemia at 2 days of age (2 (1.2%) v 10 (6.3%), P=0.02, relative risk reduction 0.80, number needed to treat 20 (15 to 111)). There were no significant differences between groups in postnatal respiratory symptoms, polycythaemia, or hyperbilirubinaemia requiring phototherapy. Conclusions— Delayed cord clamping, compared with early clamping, resulted in improved iron status and reduced prevalence of iron deficiency at 4 months of age, and reduced prevalence of neonatal anaemia, without demonstrable adverse effects. As iron deficiency in infants even without anaemia has been associated with impaired development, …

Neonatal and maternal iron status, but not serum folate, is related to placental expression of the proton coupled folate transporter (PCFT)

The proton coupled folate transporter (PCFT) has been identified as a major tissue folate transporter but this protein also exhibits a low‐affinity for heme iron (Fe). This study aimed to characterize placental PCFT expression in relation to maternal and neonatal folate and Fe status in 104 pregnant adolescents (ages 13–18y) enrolled in a prospective study examining effects of maternal nutrition on neonatal health. Fe status indicators (hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), total body Fe) were assessed at mid‐gestation (wks 23.4±3.4), delivery (wks 39.9±1.3) and in cord blood. Expression of PCFT, heme oxygenase (HO)‐1 and HO‐2 were assessed by Western blot in placental tissue collected at delivery. Placental PCFT was associated with neonatal sTfR (p=0.01, n=91, R2=0.07) and hepcidin (p=0.04, n=83, R2=0.05). Significant relationships were found between expression of PCFT with HO‐1 (p=0.009, n=55, R2=0.12) and HO‐ 2 (p=0.006, n=50, R2=0.15). Adolescents with depleted Fe stores (SF&lt;12μg/L) at delivery had elevated PCFT expression compared to Fe sufficient adolescents (p=0.03, n=91). Placental PCFT was not related to folate levels in maternal mid‐gestation sera or in cord sera. A multivariate model that included neonatal sTfR and placental HO‐1 explained 20% variation in placental PCFT (n=48, p=0.0027). Placental PCFT expression was related to neonatal and maternal Fe status and placental HO‐1 expression, suggesting an involvement of PCFT in placental Fe utilization and transport. The lack of relationship of PCFT with maternal and cord serum folate suggests a folate‐independent regulation of PCFT expression in the human placenta. Funded by USDA: 2005‐35200 &amp; 2008‐0857Grant Funding Source : USDA

Control of iron metabolism – Lessons from neonatal hemochromatosis

When hepatologists begin their investigations at the scene of liver damage, iron is certainly on the list of ‘‘usual suspects’’ to be rounded up. Hemochromatosis, a well-known cause of chronic liver disease, is the most prevalent genetic disorder in adults [1]. Serum iron parameters are therefore included in most guidelines on how to investigate patients with elevated transaminases or chronic liver disease [2]. The hemochromatosis (HFE) genotype is an important piece of evidence in patients with liver disease and elevated transferrin saturation with hyperferritinemia, because homozygosity for the C282Y allele of HFE is considered sufficient to diagnose hemochromatosis under these circumstances [1]. Compound heterozygosity for C282Y and H63D has been almost removed from the watch-list and is currently considered a mere risk factor for liver diseases – sufficient to cause hemochromatosis or even cirrhosis only in combination with other health burdens. Hence, a partner in crime for HFE mutation must be found in patients with liver disease and C282Y/H63D compound heterozygosity [3]. If there is evidence for iron overload in the absence of hemochromatosis-associated HFE genotypes and the hepatopathologist finds iron confined to hepatocytes, sharp investigators are well advised to search for the culprit in the genes encoding transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) or even to hunt for combined mutations in these genes if a patient presents with severe iron overload or early-onset disease [4]. If the patient is adolescent or before the 3rd decade of life and presents with heart failure or hypogonadism in addition to – often overlooked – liver disease, other genes will be committed in custody. Mutations in HJV and HAMP, which respectively encode hemojuvelin and hepcidin, will be sufficient to identify juvenile hemochromatosis [5]. Through the power of genetics, iron-related diseases are now subject to close scrutiny. In addition, genetic studies have greatly advanced our understanding of hemochromatosis. This progress is reflected in the proposed re-classification of human iron

Association between neonatal iron overload and early human brain development in premature infants

BackgroundEmerging evidence suggests that excess iron may be detrimental for brain development. However, little is known regarding the association between neonatal iron overload and subsequent neurodevelopment during infancy in vulnerable premature infants. AimsTo evaluate the association between neonatal iron overload and neurodevelopment in premature infants. Study designProspective cohort study. Subjects24–32weeks gestational age infants who had serum ferritin (SF) measured at 34–35weeks post-menstrual age (PMA) and did not meet exclusion criteria: SF<76ng/ml, toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes infections, chromosomal disorders, or craniofacial anomalies were eligible. In addition, infants with sepsis or elevated C-reactive protein within 10days before their SF measurement were excluded. Outcome measuresInfants were evaluated for neurodevelopmental outcome at 8–12months of age and were deemed to have neurodevelopmental impairment if they had one or more of the following: mental developmental index<70, abnormal neurological examination, bilateral blindness, bilateral deafness, or required occupational, physical, or speech therapy. Results95 infants were studied. 70 had normal iron status (SF 76–400ng/ml) while 25 were deemed to have iron overload (SF >400ng/ml) at 34–35weeks PMA. There was a marginal increase in neurodevelopmental impairment among infants with iron overload compared to infants with normal iron status (64% vs. 41%, p=0.05). However, after controlling for confounders, iron overload was not associated with neurodevelopmental impairment (Adjusted OR 0.71, 95% CI, 0.21–2.5). ConclusionModest neonatal iron overload is not associated with neurodevelopmental impairment during infancy in premature infants.