Neonatal Iron Deficiency Research Articles

Latent Iron Deficiency in Neonates With and Without Risk Factors for Poor In-Utero Iron Status

Latent Iron Deficiency in Neonates With and Without Risk Factors for Poor In-Utero Iron Status

Comparison of Molecular Potential for Iron Transfer across the Placenta in Domestic Pigs with Varied Litter Sizes and Wild Boars.

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter.

Cord Blood Hemoglobin Levels in Full Term Neonates of Mothers with Iron Deficiency Anemia

Abstract Background Iron is a critical micronutrient for tissue oxygenation, cellular metabolism, energy generation, and the metabolism of toxins. Iron transfer from mother to fetus is a regulated process involving iron status in the maternal circulation, its transport across the placenta and subsequent transfer into the fetal circulation. Objective To evaluate cord blood Hemoglobin (Hb) levels in neonates of mothers with iron deficiency anemia (IDA). Patients and Methods This prospective case-control study was conducted at Ain Shams University Hospitals. It included 60 full terms newborn who were born at Obstetrics and Gynecology Hospital. The study population included full term neonates delivered at ≥ completed 37 weeks of gestation which was divided into two groups according to maternal risk factor: Case: full term neonates with maternal risk factor. Control: full term neonates without maternal risk factor. Thorough clinical examination and investigations were performed including cord blood samples collected for measurement of the level of complete blood count (CBC; (Hb, MCV and MCH). For the mothers, venous blood samples were withdrawn with standard precautions and strict sterile conditions for CBC, transferrin saturation and serum ferritin. Results In comparison between cases and controls as regard RBCS parameter, there was no significant difference between cases and controls regarding neonatal hemoglobin( 14.93±1.14 vs 15.44 ±1.35(g/dL), p = 0.12) and MCH (32.51±2.9 vs33.57 ±1.9 (pg), p = 0.10), but there was significantly lower MCV in cases compared to controls (104.07± 7.36 vs 109.60±4.93 (fL), p = 0.001). There was no significant difference between cases and controls as regard maternal clinical characteristics including (age, weight, height, maternal diseases, gravidity, consanguinity and mode of delivery, p > 0.05 for all). Also, there was no significant difference between cases and controls regarding neonatal weight, Z score for weight, length (cm), head circumference (cm) and gestational age by Ballord Score and Apgar Score in 1-minute and 5-minute score p > 0.05 for all). Conclusion There was no relation between the maternal Hb deficient levels and neonatal Hb. The first sign of iron deficiency in neonates reflected in lower MCV in cases, but not reached to decrease Hb levels in neonates.

Iron deficiency in pregnant women: effect on offspring neuropsychic development

Increasing evidence indicates that adversities in utero and early childhood can have long-lasting effects on physiological and mental health not only in childhood but also in adulthood. Micronutrient deficiency, and in particular iron deficiency, is one of the most significant factors. Based on literature data, to determine the effect of iron deficiency in pregnant women on the neuropsychological development of infants, as well as to determine a cohort of pregnant women who need iron supplements. The search was conducted in MEDLINE (from PubMed), EMBASE (from OVID), Cochrane Library and ClinicalTrials.gov from 2010 to December 2023 without language restrictions. Data were extracted. Primary outcomes included iron deficiency, serum ferritin less than 15 μg/L in pregnant women, perinatal outcomes, and development of children in infancy. The data of serum ferritin in umbilical cord blood in newborns were compared with the serum ferritin of mothers. Data on iron supplementation and its effect on perinatal outcomes were assessed. Daily oral iron supplementation during pregnancy in women without IDA or ID reduces the incidence of iron deficiency anemia at the woman’s due date, reduces the incidence of iron deficiency in fullterm neonates, and reduces the incidence of morbidity in low-birth-weight infants. Iron supplementation during pregnancy and the postpartum period is a strategy for timely replenishment of ID and prevention of IDA to reduce cerebral iron deficiency in the fetus and newborn. The absence of side effects and high bioavailability, enhanced by ascorbic acid, allow us to recommend SunActive®Fe Bonoferlat as a daily supplement for pregnant and lactating women, according to WHO recommendations.

Impact of litter size on the hematological and iron status of gilts, sows and newborn piglets: a comparative study of domestic pigs and wild boars

BackgroundThe critically low hepatic iron stores of newborn piglets are considered to be a major cause of neonatal iron deficiency in modern breeds of domestic pig (Sus domestica). The main factor believed to contribute to this phenomenon is large litter size, which has been an objective of selective breeding of pigs for decades. As consequence, iron transferred from the pregnant sow has to be distributed among a greater number of fetuses.ResultsHere, we investigated whether litter size influences red blood cell (RBC) indices and iron parameters in Polish Large White (PLW) piglets and gilts. Small and large litters were produced by the transfer of different numbers of embryos, derived from the same superovulated donor females, to recipient gilts. Piglets from large litters obtained following routine artificial insemination were also examined. Our results clearly demonstrated that varying the number of piglets in a litter did not affect the RBC and iron status of 1-day-old piglets, with all showing iron deficiency anemia. In contrast, gilts with small litters displayed higher RBC and iron parameters compared to mothers with large litters. A comparative analysis of the RBC status of wild boars (having less than half as many piglets per litter as domestic pigs) and PLW pigs, demonstrated higher RBC count, hemoglobin level and hematocrit value of both wild boar sows and piglets, even compared to small-litter PLW animals.ConclusionsThese findings provide evidence that RBC and iron status in newborn PLW piglets are not primarily determined by litter size, and indicate the need to study the efficiency of iron transport across the placenta in domestic pig and wild boar females.

Early-life iron deficiency persistently disrupts affective behaviour in mice

Background/Objective Iron deficiency (ID) is the most common nutrient deficiency, affecting two billion people worldwide, including about 30% of pregnant women. During gestation, the brain is particularly vulnerable to environmental insults, which can irrevocably impair critical developmental processes. Consequently, detrimental consequences of early-life ID for offspring brain structure and function have been described. Although early life ID has been associated with an increased long-term risk for several neuropsychiatric disorders, the effect on depressive disorders has remained unresolved. Materials and methods A mouse model of moderate foetal and neonatal ID was established by keeping pregnant dams on an iron-deficient diet throughout gestation until postnatal day 10. The ensuing significant decrease of iron content in the offspring brain, as well as the impact on maternal behaviour and offspring vocalization was determined in the first postnatal week. The consequences of early-life ID for depression- and anxiety-like behaviour in adulthood were revealed employing dedicated behavioural assays. miRNA sequencing of hippocampal tissue of offspring revealed specific miRNAs signatures accompanying the behavioural deficits of foetal and neonatal ID in the adult brain. Results Mothers receiving iron-deficient food during pregnancy and lactation exhibited significantly less licking and grooming behaviour, while active pup retrieval and pup ultrasonic vocalizations were unaltered. Adult offspring with a history of foetal and neonatal ID showed an increase in depression- and anxiety-like behaviour, paralleled by a deranged miRNA expression profile in the hippocampus, specifically levels of miR200a and miR200b. Conclusion ID during the foetal and neonatal periods has life-long consequences for affective behaviour in mice and leaves a specific and persistent mark on the expression of miRNAs in the brain. Foetal and neonatal ID needs to be further considered as risk factor for the development of depression and anxiety disorders later in life. Key Messages Marginal reduction of gestational alimentary iron intake decreases brain iron content of the juvenile offspring. Early-life ID is associated with increased depression- and anxiety-like behaviour in adulthood. Reduction of maternal alimentary iron intake during pregnancy is reflected in an alteration of miRNA signatures in the adult offspring brain.

Studying the Effect of Maternal Anemia and Neonatal Hematological Indices on Auditory Brainstem Responses of Newborn Babies

Purpose: Animal studies have shown the effect of maternal anemia (MA) and neonatal iron deficiency (ID) on the auditory system of young ones. However, the evidence supporting the same in human infants is inconclusive. Hence, the present study aims to investigate the effect of MA and neonatal iron status on the auditory brainstem responses (ABRs) of newborn babies. Materials and Methods: A total of 100 babies (gestational age ≥34 weeks) were divided into “Normal” group-57 babies without MA, “Mild” group-22 mild MA babies, and “Moderate” group-21 moderate MA babies. The ABR was recorded using 80 dBnHL click stimuli at 10 and 90 Hz repetition rates. Results: The results based on MA showed a significantly better presence of ABR peaks for the normal group than mild and moderate groups at a higher rate and no significant difference for latency and amplitude measures across the groups. The results based on neonatal hematological indices showed that the ABR measures were better in babies with probable ID which could be attributed to neural hyperactivity and an increase in axonal diameter leading to faster nerve conduction velocity. Conclusion: The auditory system maturation in newborn babies is influenced by maternal as well as neonatal iron status.

18 Prevalence of iron deficiency among extreme preterm neonates based on Reticulocyte-Hemoglobin levels: a single center cross-sectional study

Abstract Background Extreme preterm neonates are at risk of developing iron deficiency due to multiple factors including lack of third trimester placental iron accretion and frequent blood sampling. The true prevalence of iron deficiency in this cohort is not known due to lack of valid markers. Compared to Hemoglobin (Hb) derived from the entire red blood cell population (lifespan 120 days), Hb derived for reticulocytes (lifespan 3 days) is a real-time indicator of functional iron available for erythropoiesis during the previous 3-4 days. Reticulocyte-Hemoglobin (Ret-Hb) levels lower than 29pg can indicate iron deficiency in preterm neonates < 32 weeks gestation with 85% sensitivity and 73% specificity. Objectives This study aims to measure the prevalence and risk factors of iron deficiency at term equivalent age among extreme preterm neonates based on Ret-Hb levels. Design/Methods A single center retrospective chart review of neonates born at <= 29 weeks gestation between June 2016 to December 2019. All neonates received routine iron supplementation from 2 weeks postnatal age at 3-4mg/kg/day (birth weight <1Kg) or 2-3mg/kg/day (birth weight>1Kg) to a maximum of 15mg elemental iron as ferrous sulfate or iron fortified formula. Hb, Reticulocyte count, Ret-Hb, Immature reticulocyte fraction (IRF) and mean corpuscular volume (MCV) was measured at 4 weeks postnatal age, 36 weeks corrected gestation, and at discharge. Iron deficiency at term equivalent age was defined as Ret-Hb levels <= 29pg. Results Among 387 eligible neonates, 187 who had hematological parameters available at term equivalent age were included. The study cohort had a mean gestation of 25.7 (1.6) weeks, birth weight of 863 (220) g, mean SNAPPEII score of 29.2 (19), and gestational age at discharge of 42.7 (7.2) weeks. The prevalence of iron deficiency among neonates < 24 weeks, 24-25 + 6 weeks, 26-27 + 6 weeks, and >=28 weeks was 35.7%, 18.4%, 27.7%, and 15.6% respectively. Male infants were more likely to have iron deficiency at term equivalent [Table 1]. The neonates with iron deficiency had higher rates of necrotising enterocolitis [14% versus 8%], laparotomy [14% versus 10%] and postnatal steroids [69% versus 57%] compared to neonates without iron deficiency, however not statistically significant. Ret-Hb levels at 4 weeks postnatal age showed a positive correlation with Ret-Hb levels [Slope 0.58, R2 squared 0.02] and MCV levels [Slope 0.75, R2 0.11] at discharge [Figure 1]. Contrary to changes in Hb levels and reticulocyte counts, Ret-Hb levels, MCV and IFR progressively decrease from 4 wks postnatal age to discharge. Conclusion Despite routine standardized iron supplementation, extreme preterm neonates may have iron-limited erythropoiesis indicated by low Ret-Hb levels at term equivalent age. Lower levels of Ret-Hb at 4 weeks postnatal age was associated with low IRF and low MCV at discharge although Hb levels may remain within acceptable range. Future studies would need to elucidate the impact of iron deficiency at corrected term on long-term outcome. Guidelines should consider incorporating Ret-Hb levels in the workup of anemia of prematurity.

Frequency of fetal iron deficiency anemia at the time of birth in obese mothers.

Objectives: To determine frequency of fetal iron deficiency anemia at the time of birth in obese mothers. Study Design: Cross-sectional Descriptive study. Setting: Department of Obstetrics and Gynecology, Nishtar Hospital Multan. Period: September 2018 to February 2019. Material & Methods: A total of 368 obese pregnant women with singleton pregnancy between 37 -40 weeks of gestation were included in the study after informed consent. Cord blood was collected after delivery via syringe aspiration from the umbilical vein. Fetal Iron status in the form of serum iron, hemoglobin, transferrin saturation was measured with calorimetric endpoint assay. Obesity in pregnancy is defined as BMI equal and more than 30kg/m2. Fetal iron deficiency anemia was defined as fetal hemoglobin less than 14.5g/dl, fetal iron 97.3micro gram/dl and transferrin saturation 39.6% at birth. Results: Among 368 cases, 87.8% of cases were having their BMI 30kg/m2 to 34.9kg/m2. BMI between35kg/m2 to 39.9kg/m2 was noted in 10% of cases and in 2.2% of cases BMI was equal to or more than 40kg/m2. Frequency of neonatal iron deficiency anemia was 22.8%. Conclusion: There is a increase prevalence of obesity in women of childbearing age however maternal obesity has no significant correlation of fetal iron deficiency anemia.

Behavioral consequences at 5 y of neonatal iron deficiency in a low-risk maternal–infant cohort

Iron is critical to the developing brain, but fetal iron accretion is compromised by several maternal and pregnancy-related factors. Little consideration has been given to the long-term neurologic consequences of neonatal iron deficiency, especially in generally healthy, low-risk populations. We aimed to investigate the association between neonatal iron deficiency and neurologic development at 2 and 5 y of age. We measured umbilical cord serum ferritin concentrations in the prospective maternal-infant Cork BASELINE (Babies after SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints) Birth Cohort. Lifestyle and clinical data were collected from 15 weeks of gestation to 5 y of age. Standardized neurologic assessments were performed at 2 y [Bayley Scales of Infant Development/Child Behavior Checklist (CBCL)] and 5 y (Kaufman Brief Intelligence Test/CBCL). Among 697 maternal-infant pairs, median (IQR) cord ferritin concentrations were 200.9 (139.0, 265.8) µg/L; 8% had neonatal iron deficiency (ferritin<76 µg/L). Using fully adjusted models, there was no association between neonatal iron deficiency and cognitive or behavioral outcomes at 2 or 5 y. We conducted an a priori sensitivity analysis in 306 high-risk children, selected using known risk factors for neonatal iron deficiency (smoking/obesity/cesarean section delivery/small-for-gestational age birth). In this high-risk subgroup, children with iron deficiency at birth (12%) had similar cognitive outcomes, but the behavioral assessments showed higher internalizing [9.0 (5.3, 12.0) compared with 5.0 (3.0, 10.0), P=0.006; adjusted estimate (95% CI): 2.8 (0.5, 5.1), P=0.015] and total [24.5 (15.3, 40.8) compared with 16.0 (10.0, 30.0), P=0.009; adjusted estimate (95% CI): 6.6 (0.1, 13.1), P=0.047] problem behavior scores at 5 y compared with those born iron sufficient. We have demonstrated lasting behavioral consequences of neonatal iron deficiency in high-risk children from our generally healthy, low-risk maternal-infant cohort. Although larger investigations are warranted, this study provides strong association data to suggest that interventions and strategies targeting the fetal and neonatal period should be prioritized for the prevention of iron deficiency and associated neurologic consequences.

Innovative oral sucrosomial ferric pyrophosphate-based supplementation rescues suckling piglets from iron deficiency anemia similarly to commonly used parenteral therapy with iron dextran

Abstract Iron deficiency is the most common mammalian nutritional deficiency during the neonatal period. However, among mammalian species neonatal iron deficiency anemia (IDA), the most severe consequence of iron scarcity, occurs regularly in pigs. Although intramuscular supplementation of piglets with high amounts of iron dextran (FeDex) is largely considered an appropriate preventive therapy for IDA prophylaxis, an increasing evidence shows that it negatively affects pig physiology. The aim of our study was to evaluate the efficacy of non-invasive supplementation of piglets with sucrosomial ferric pyrophosphate (SFP), a highly bioavailable dietary iron supplement in preventing IDA, in humans and mice. Results of our study show that SFP given to piglets per os in the amount of 6 mg Fe daily efficiently counteracts IDA at a rate comparable with the traditional FeDex-based supplementation (100 mgFe/kG b.w.; i.m. injection). This was indicated by physiological values of red blood cell indices and plasma iron parameters measured in 28-day old piglets. Moreover, SFP-supplemented piglets showed significantly lower (P ≤0.05) plasma level of 8-isoprostane, a biomarker for oxidative stress compared to FeDex-treated animals, implying lesser toxicity of this order of iron replenishment. Finally, supplementation with SFP does not increase considerably the blood plasma hepcidin, a peptide that acts to inhibit iron absorption from the diet. SFP emerges as a promising nutritional iron supplement, with a high potential to be adopted in the postnatal period.

Relationship between Down-Regulation of Copper-Related Genes and Decreased Ferroportin Protein Level in the Duodenum of Iron-Deficient Piglets.

In mammals, 2 × 1012 red blood cells (RBCs) are produced every day in the bone marrow to ensure a constant supply of iron to maintain effective erythropoiesis. Impaired iron absorption in the duodenum and inefficient iron reutilization from senescent RBCs by macrophages contribute to the development of anemia. Ferroportin (Fpn), the only known cellular iron exporter, as well as hephaestin (Heph) and ceruloplasmin, two copper-dependent ferroxidases involved in the above-mentioned processes, are key elements of the interaction between copper and iron metabolisms. Crosslinks between these metals have been known for many years, but metabolic effects of one on the other have not been elucidated to date. Neonatal iron deficiency anemia in piglets provides an interesting model for studying this interplay. In duodenal enterocytes of young anemic piglets, we identified iron deposits and demonstrated increased expression of ferritin with a concomitant decline in both Fpn and Heph expression. We postulated that the underlying mechanism involves changes in copper distribution within enterocytes as a result of decreased expression of the copper transporter—Atp7b. Obtained results strongly suggest that regulation of iron absorption within enterocytes is based on the interaction between proteins of copper and iron metabolisms and outcompetes systemic regulation.

Reticulocyte hemoglobin concentration for screening iron deficiency in very low birth weight preterm neonates

Background Preterm and low birth weight infants are at risk of iron deficiency. Reticulocyte hemoglobin concentration may be useful as a screening test to diagnose iron deficiency in preterm neonates. Objective To evaluate the accuracy and establish the reticulocyte hemoglobin concentration cutoff value for iron deficiency diagnosis in very low birth weight preterm neonates. Method This study was conducted between May 2018 and March 2019 at Chiang Mai University Hospital. Preterm infants born at gestational age ≤34 weeks and birth weight ≤1500 g were enrolled. Blood samplings were obtained within the first 48 h of life. Iron deficiency was defined by using two or more of these following parameters: mean corpuscular volume <100 fL, transferrin saturation <16% and serum ferritin <30 µg/L. Neonatal anemia was defined as hemoglobin <15 g/dL. The optimum reticulocyte hemoglobin concentration cutoff values were performed by using predictive values and receiving operation characteristic analysis. Result Fifty-seven preterm neonates were enrolled. Nine (15.7%) and three (5.3%) neonates had iron deficiency and iron deficiency anemia, respectively. The reticulocyte hemoglobin concentration cutoff value of <29 pg showed the optimum accuracy to diagnose iron deficiency in very low birth weight preterm neonates with sensitivity, specificity, positive and negative predictive values of 89%, 79%, 42% and 97%, respectively. Conclusion Reticulocyte hemoglobin concentration can be used as a screening parameter to diagnose iron deficiency for VLBW preterm neonates. The optimum cutoff value which provided the acceptable accuracy was <29 pg.

Long-lasting behavioural consequences of neonatal iron deficiency in high-risk children

AbstractLittle consideration has been given to the long-term consequences of iron deficiency in new-born infants. Fetal iron accretion is compromised by multiple pregnancy complications including preterm birth, gestational diabetes mellitus and fetal growth restriction, while our work has identified increased risks from maternal lifestyle factors such as smoking and obesity for low iron stores at birth. Early-life events, including C-section delivery, also add to this cumulative risk of neonatal iron deficiency, predisposing infants to iron deficiency later in infancy and early childhood. This study aimed to investigate the effect of neonatal iron deficiency on neurological development up to 5 years of age in term-born participants of a maternal-infant birth cohort in Ireland. In the Cork BASELINE Birth Cohort, 697 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks’ gestation had umbilical cord serum ferritin concentrations measured. Neurological assessments were performed at 2 (Bayley Scales of Infant Development and Child Behaviour Checklist [CBCL]) and 5 (Kaufman Brief Intelligence Test and CBCL) years of age. In the cohort, median [IQR] cord ferritin concentrations were 200.9 [139.0,265.8] μg/L; 7.5% had neonatal iron deficiency (&lt; 76μg/L). Using the risk factors for neonatal iron deficiency that we previously identified (smoking, obesity, C-section delivery, SGA) in this cohort, as selection criteria, we conducted an a priori sensitivity analysis in 306 children. Of the 306 children identified as high-risk, 12.4% had neonatal iron deficiency. Those with neonatal iron deficiency had higher median [IQR] CBCL internal (9.0 [5.3,12.0] vs. 5.0 [3.0,10.0]), external (7.5 [4.0,14.8] vs. 5.0 [2.0,10.0]) and total problem (24.5 [15.3,40.8] vs. 16.0 [10.0,30.0], all P &lt; 0.05) scores at 5 years compared to those without neonatal deficiency. This adverse effect was especially apparent in children of obese mothers (n = 85) who were iron deficient at birth, with a total problem score at 5 years of 42.0 [24.5,54.5] compared to 16.0 [8.8,29.3] in those not deficient (P = 0.008). Associations were robust to adjustment for confounding factors. No effect on cognition or intelligence at 2 or 5 years was observed in this cohort. This study has identified behavioural consequences of neonatal iron deficiency. Interventions targeting the fetal/neonatal period could, therefore, represent a key opportunity for prevention of iron deficiency and its associated long-term neurological consequences. A dual approach is required, comprising public health strategies targeting prevention, through improving nutrition and health in women, and the development of screening strategies for early detection of iron deficiency in new-borns.

The neonatal period: A missed opportunity for the prevention of iron deficiency and its associated neurological consequences?

AbstractIron deficiency is the most common micronutrient deficiency worldwide. Iron is essential for the development of multiple organ systems, most especially the developing brain. Iron deficiency, particularly during sensitive periods of brain development, such as in early childhood, is associated with long‐lasting adverse consequences for cognition, motor function and behaviour. Little consideration has been given to iron deficiency in newborn infants and its potential health consequences. Fetal iron accretion is compromised by pregnancy complications such as pre‐term birth and gestational diabetes mellitus, and our work has identified an increased risk of low iron stores at birth from maternal lifestyle factors such as smoking and obesity. Early‐life events, including Caesarean section delivery, further add to the cumulative risk of neonatal iron deficiency, which can persist throughout infancy into early childhood. While investigations into the long‐term neurological consequences of neonatal iron deficiency are limited, there is evidence of poorer memory, motor function and language ability in children born iron deficient. Recently, we also identified significant behavioural consequences of neonatal deficiency persisting from 2 to 5 years of age, with effects particularly apparent in ‘high‐risk’ children born to obese or smoking mothers or delivered by Caesarean section. Interventions targeting the fetal/neonatal period could therefore represent a key opportunity for the prevention of iron deficiency and its associated long‐term health consequences. A dual approach is required, comprising public health strategies targeting prevention, to improve health in women of reproductive age, and the development of screening strategies for the early detection of iron deficiency in newborn infants.

Cord Blood-Derived Exosomal CNTN2 and BDNF: Potential Molecular Markers for Brain Health of Neonates at Risk for Iron Deficiency

Maternal iron deficiency anemia, obesity, and diabetes are prevalent during pregnancy. All are associated with neonatal brain iron deficiency (ID) and neurodevelopmental impairment. Exosomes are extracellular vesicles involved in cell–cell communication. Contactin-2 (CNTN2), a neural-specific glycoprotein, and brain-derived neurotrophic factor (BDNF) are important in neurodevelopment and found in exosomes. We hypothesized that exosomal CNTN2 and BDNF identify infants at risk for brain ID. Umbilical cord blood samples were measured for iron status. Maternal anemia, diabetes, and body mass index (BMI) were recorded. Cord blood exosomes were isolated and validated for the exosomal marker CD81 and the neural-specific exosomal marker CNTN2. Exosomal CNTN2 and BDNF levels were quantified by ELISA. Analysis of CNTN2 and BDNF levels as predictors of cord blood iron indices showed a direct correlation between CNTN2 and ferritin in all neonates (n = 79, β = 1.75, p = 0.02). In contrast, BDNF levels inversely correlated with ferritin (β = −1.20, p = 0.03), with stronger association in female neonates (n = 37, β = −1.35, p = 0.06), although there is no evidence of a sex-specific effect. Analysis of maternal risk factors for neonatal brain ID as predictors of exosomal CNTN2 and BDNF levels showed sex-specific relationships between infants of diabetic mothers (IDMs) and CNTN2 levels (Interaction p = 0.0005). While male IDMs exhibited a negative correlation (n = 42, β = −0.69, p = 0.02), female IDMs showed a positive correlation (n = 37, β = 0.92, p = 0.01) with CNTN2. A negative correlation between BNDF and maternal BMI was found with stronger association in female neonates (per 10 units BMI, β = −0.60, p = 0.04). These findings suggest CNTN2 and BNDF are respective molecular markers for male and female neonates at risk for brain ID. This study supports the potential of exosomal markers to assess neonatal brain status in at-risk infants.

SAT-248 Maternal Iron Deficiency Alters Brain Glucose, Lactate and Thyroxine Transport in Developing Neonatal Rats

Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Published data from our laboratory demonstrate a reduction in circulating and brain thyroid hormone levels in neonatal rats when dams are fed an iron deficient diet. We have also previously reported an observed increase in brain vascular density in iron deficient neonatal rats as a possible compensatory mechanism for increasing oxygen delivery to the developing brain. We now report the effects of gestational and neonatal FeD on glucose, lactate, and thyroxine transport in the neonatal rat brain. Gestational day 2 (G2) Sprague-Dawley rat dams were assigned to two groups. The Control group was fed a standard chow diet with 84 ppm iron while the FeD group was fed an iron deficient diet (10 ppm Fe). All animals were maintained on the defined diets from G2 through weaning. Serum hemoglobin, glucose, lactate and thyroxine levels were measured at postnatal days 7 (P7), 14, and 21. Blood vessel density was assessed by immunohistochemistry. Finally, a brain perfusion method was developed to quantify total brain vascular volume and measure transport rates for substrates glucose, lactate, and thyroxine. Hemoglobin levels were significantly reduced by 40% in FeD P7 up to 60% by P21 indicating a marked reduction in iron stores was achieved at all ages in the FeD group. Consistent with our previously reported findings, we found significant 23% reductions in serum T4 in FeD pups at P14 and 36% increases in cortical blood vessel density. Brain vascular volume was similarly significantly increased at P14 (31%) and P21 (37%). Importantly, we found that glucose, lactate, and thyroxine blood-to-brain transport rates were all increased in the FeD neonates. Glucose transport rates significantly increased by 57% at P14 and 90% by P21. Lactic acid transport rates were significantly elevated by 44% at P14 and 36% at P21. Thyroxine transport rates were significantly increased by 23% at P14 only. Assessment of neonatal hypoxic hypoxia treatment on brain glucose transport is currently in progress. Together our data demonstrate a significant impact of gestational and neonatal iron deficiency on nutrient and thyroid hormone transport in the developing brain. Increased vascular density and vascular volume may explain the magnitude of increased lactate and thyroxine transport. However, the more substantially increased glucose transport rate suggests additional mechanisms of glucose transport regulation are altered during iron deficiency. Alterations in nutrient and hormone transport homeostasis may contribute to the developmental brain pathology associated with neonatal iron deficiency.

Neonatal Growth, Neurotrophine, Zinc, and Ferritin Concentration in Normal and Iron Deficience Pregnancy: An Observational Analitic Study.

BACKGROUND:Anemia in pregnancy was one of the national problems. Insufficient iron deposits before pregnancy and inadequate iron intake during pregnancy could lead to iron deficiency anaemia in pregnancy, followed by iron deficiency in neonates.AIM:This study aimed to assess the molecular relationship of maternal iron deficiency with the function of the neonatal central nervous system to know the cognitive aspects of learning ability of children.METHODS:This study was an observational analytic study with cross-sectional design underwent in RSUP Dr M. Djamil Padang, RSI Ibnu Sina Padang, and RSU BMC Padang. The sample size was 80 pregnant women at term. After a maternal and neonatal physical examination, maternal and umbilical blood samples were obtained to assess maternal ferritin levels and neonates ferritin, neurotrophin and zinc levels using the Enzyme-Linked Immunosorbent Assay (ELISA). Data were analysed using the IBM SPSS Statistics for Windows. The independent sample t-test was performed to assess the relationship for normally distributed data and Mann-Whitney test for abnormal data distribution with significance level p < 0.05.RESULTS:There were differences in mean neonatal ferritin (p < 0.001), neonatal neurotrophin (p < 0.001), and neonatal zinc (p < 0.001) to normal maternal ferritin levels (≥ 15 μg/ml) and low maternal ferritin levels (< 15 μg/ml). The difference in mean neonatal head circumference (0.92; CI95% -0.79-0.98) was associated with neonatal ferritin levels.CONCLUSIONS:The mean neonatal ferritin, neurotrophin, and zinc levels were found lower in iron deficiency maternal. Maternal iron deficiency correlates with neonate growth, iron deficiency, and neurotrophin expression that affected neonate cognition.

Correction: Mateusz, S., et al. Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia. Pharmaceuticals 2018, 11, 128.

The authors wish to make the following corrections to this paper [¹]: the term "liposomal" should be replaced with the term "sucrosomial" in the following places [...].

Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia.

In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements.