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Background Malaria in pregnancy has been associated with worse cognitive outcomes in children, but its association with behavioral outcomes and the effectiveness of malaria chemoprevention on child neurodevelopment are not well characterized. Methods To determine if more effective malaria chemoprevention in mothers and their children results in better neurodevelopment, 305 pregnant women were randomly assigned to 3 doses of sulfadoxine-pyrimethamine, 3 doses of dihydroartemisinin-piperaquine (DP), or monthly DP during pregnancy, and their 293 children were assigned to DP every 3 months or monthly DP from 2 to 24 months of age. Cognition, language, and motor function were assessed at 12, 24. and 36 months of age, and attention, memory, behavior, and executive function were assessed at 24 and 36 months of age. Results Children of mothers with versus without malaria in pregnancy had worse scores on cognitive, behavioral, and executive function outcomes at 24 months. Clinical malaria in children within the first 12 months was similarly associated with poorer scores in behavior and executive function at 24 months, language at 24 and 36 months, and motor function scores at 36 months. However, more effective malaria chemoprevention in the mothers and children was not associated with better outcomes. Conclusions Malaria in pregnancy was associated with worse cognitive, behavioral, and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children. Clinical Trials Registration. NCT02557425.

The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD).A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization.Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD.We find no support for an increased risk of BPD with iron supplementation.NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

The role of early life nutrition's impact on relevant health outcomes across the lifespan laid the foundation for the field titled the developmental origins of health and disease. Studies in this area initially concentrated on nutrition and the risk of adverse cardio-metabolic and cancer outcomes. More recently the role of nutrition in early brain development and the subsequent influence of later mental health has become more evident. Scientific breakthroughs have elucidated two mechanisms behind long-term nutrient effects on the brain, including the existence of critical periods for certain nutrients during brain development and nutrient-driven epigenetic modifications of chromatin. While multiple nutrients and nutritional conditions have the potential to modify brain development, iron can serve as a paradigm to understand both mechanisms. New horizons in nutritional medicine include leveraging the mechanistic knowledge of nutrient–brain interactions to propose novel nutritional approaches that protect the developing brain through better timing of nutrient delivery and potential reversal of negative epigenetic marks. The main challenge in the field is detecting whether a change in nutritional status truly affects the brain's development and performance in human subjects. To that end, a strong case can be made to develop and utilise bioindicators of a nutrient's effect on the developing brain instead of relying exclusively on biomarkers of the nutrient's status.

BackgroundFetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies have shown that early-life ID produces sex-specific effects. However, little is known about the molecular mechanisms underlying these early-life ID-induced sex-specific effects on neural gene regulation.ObjectiveTo illustrate sex-specific transcriptome alteration in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment.MethodsPregnant rats were fed an iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11-18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression.ResultsBoth early-life ID and choline treatment induced transcriptional changes in adult female and male rat hippocampus. Both sexes showed ID-induced alterations in gene networks leading to enhanced neuroinflammation. In females, ID-induced changes indicating enhanced activity of oxidative phosphorylation and fatty acid metabolism, which are contrary to the ID effect in males. Prenatal choline supplementation induced the most robust changes in gene expression, particularly in the iron-deficient animals where it partially rescued ID-induced dysregulations. Choline supplementation also altered hippocampal transcriptome in the iron-sufficient rats with indications for both beneficial and adverse effects.ConclusionsThis study provided unbiased global assessments of gene expression regulated by iron and choline status in a sex-specific manner, with greater effects in female than male rats. Our new findings highlight potential sex-specific gene networks regulated by iron and choline status for further investigation.

Iron deficiency during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive and widespread hippocampal gene dysregulation. Globally, fetal-neonatal iron deficiency produces both long-term activation and repression of hundreds of loci in the adult rat hippocampus. Prenatal choline (a methyl donor) supplementation can partially reverse these effects, suggesting an interaction between iron and choline in regulating the hippocampal transcriptome. To gain insights into the underlying epigenetic signatures, we integrate hippocampal transcriptomes and epigenetic marks of active (transposase accessible chromatin/ATAC) and repressed (H3K9me3 enrichment) genes in adult rats that had been exposed to fetal-neonatal iron deficiency with or without prenatal choline supplementation. Rats were made iron-deficient during fetal and neonatal period by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Choline (5.5 g/kg) was given to half of the pregnant dams during G11-18. This paradigm produced four comparison groups (Iron-sufficient [IS], Iron-deficient [ID], IS+choline [ISch], and ID+choline [IDch]). Hippocampi were collected from P65 males and analyzed for changes in chromatin conformation and histone H3K9me3 enrichment. ATAC-seq results accounted for 22% and 24%, whereas H3K9me3 enrichment accounted for 1.7% and 13% of differences in ID- and IDch-altered gene expression. These epigenetic changes were annotated onto gene networks regulating synaptic structure and plasticity, neuroinflammation, and reward circuits. The low correlation between gene dysregulation and changes in ATAC or H3K9me3 signatures indicate involvements of other epigenetic modifications. This study provides a genome-wide findings of stable epigenetic changes and lays a foundation for further analyses to elucidate more fully iron-dependent epigenetic mechanisms that underlie iron deficiency, choline supplementation, and their interactions in mediating long-term neural gene dysregulation.SIGNIFICANCE STATEMENTEarly-life iron deficiency can lead to long-term neurocognitive dysfunction and persistent neural gene dysregulation, despite prompt iron replenishment, suggesting that iron deficiency results in long-term neuroepigenomic changes. This study combined RNA-seq, ATAC-seq, and ChIP-seq to provide the epigenetic basis for gene dysregulation due to fetal-neonatal iron deficiency and prenatal choline supplementation. We found that early-life iron deficiency alters epigenetic regulation of genes involved in neuronal development, cell signaling, neuroinflammation, and reward-related cognition. While choline supplementation to iron-deficient animals partially reverses these effects, it also leads to dysregulation of genes in iron-sufficient animals. The patterns of gene dysregulation were positively correlated with differences in chromatin accessibility and negatively correlated with repressive histone H3K9me3 modification. Our results indicate that these changes at the epigenetic level partially account for the long-term hippocampal gene dysregulation.

Altered body composition in preterm infants is associated with risks to cognitive development, but the effect specific to prefrontal cortex (PFC) development is unknown. We were interested in the impact of fat mass (FM) and fat free mass (FFM) gains out to 4 months corrected gestational age (CGA) on PFC development, as indexed by working memory and temperament. This is a prospective observational pilot study recruiting 100 preterm (33 weeks gestation), appropriate for gestational age, and very low birth weight infants, of which 49 infants met inclusion criteria. Body composition was measured using air displacement plethysmography at hospital discharge and 4 months CGA. Questionnaire based temperament assessments were completed at 12 and 24 months CGA and a working memory assessment was completed at 24 months CGA. Associations between developmental tests and body composition obtained at term and 4 months were analyzed. Increased FM at discharge was associated with increased fear and decreased soothability at 12 months. Increased FM at 4 months was associated with increased activity level, increased distress from limitations at 12 months and decreased attentional shifting, decreased frustration, and decreased inhibitory control at 24 months. Increased FFM at 4 months was associated with increased activity level at 12 months and increased impulsivity and decreased low intensity pleasure at 24 months. In this exploratory pilot study, increased FM out to 4 months and increased FFM after discharge are associated with negative markers of infant temperament. Infant temperament may be sensitive to body composition status at least to 4 months CGA.

The effects of early-life iron deficiency anemia (IDA) extend past the blood and include both short- and long-term adverse effects on many tissues including the brain. Prior to IDA, iron deficiency (ID) can cause similar tissue effects, but a sensitive biomarker of iron-dependent brain health is lacking. To determine serum and CSF biomarkers of ID-induced metabolic dysfunction we performed proteomic and metabolomic analysis of serum and CSF at 4- and 6- months from a nonhuman primate model of infantile IDA. LC/MS/MS analyses identified a total of 227 metabolites and 205 proteins in serum. In CSF, we measured 210 metabolites and 1,560 proteins. Data were either processed from a Q-Exactive (Thermo Scientific, Waltham, MA) through Progenesis QI with accurate mass and retention time comparisons to a proprietary small molecule database and Metlin or with raw files imported directly from a Fusion Orbitrap (Thermo Scientific, Waltham, MA) through Sequest in Proteome Discoverer 2.4.0.305 (Thermo Scientific, Waltham, MA) with peptide matches through the latest Rhesus Macaque HMDB database. Metabolite and protein identifiers, p-values, and q-values were utilized for molecular pathway analysis with Ingenuity Pathways Analysis (IPA). We applied multiway distance weighted discrimination (DWD) to identify a weighted sum of the features (proteins or metabolites) that distinguish ID from IS at 4-months (pre-anemic period) and 6-months of age (anemic).

To assess sex-specific differences in early brain structure and function of preterm infants after red blood cell (RBC) transfusions.A single-center subset of infants with a birth weight1000 g and gestational age 22-29 weeks were enrolled from the National Institute of Child Health and Human Development's Neonatal Research Network Transfusion of Prematures Trial. Hemoglobin (Hb) concentration obtained directly before each transfusion (pretransfusion Hb [ptHb]) was obtained longitudinally throughout each infant's neonatal intensive care unit stay and used as a marker of degree of anemia (n = 97). Measures of regional brain volumes using magnetic resonance imaging were obtained at ∼40 weeks postmenstrual age or at hospital discharge, if earlier (n = 29). Measures of brain function were obtained at 12 months corrected age using the Bayley Scales of InfantToddler Development, 3rd Edition (n = 34).PtHb was positively correlated with neonatal cerebral white matter volume in males (B = +0.283; P = .006), but not females (B = -0.099; P = .713), resulting in a significant sex interaction (P = .010). Bayley-III gross motor scores and a pooled mean score were significantly lower in association with higher ptHb in females (gross motor score: B = -3.758; P = .013; pooled mean score: B = -1.225; P = .030), but not males (gross motor score: B = +1.758; P = .167; pooled mean score: B = +0.621; P = .359). Higher ptHb was associated with descriptively lower performance on multiple Bayley-III subscales in females, but not in males.This study demonstrates sex-specific associations between an early marker of anemia and RBC transfusion status (ie, ptHb) with both neonatal white matter volume and early cognitive function at age 12 months in preterm infants.

Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective problems in attention, executive functioning, memory, visual–perceptual/motor skills, social cognition, and academics. One potential intervention for the cognitive impairments associated with FASD is the essential nutrient choline, which is known to have numerous direct effects on brain and cognition in both typical and atypical development. We provide a summary of the literature supporting the use of choline as a neurodevelopmental intervention in those affected by prenatal alcohol. We first discuss how alcohol interferes with normal brain development. We then provide a comprehensive overview of the nutrient choline and discuss its role in typical brain development and its application in the optimization of brain development following early insult. Next, we review the preclinical literature that provides evidence of choline’s potential as an intervention following alcohol exposure. Then, we review a handful of existing human studies of choline supplementation in FASD. Lastly, we conclude with a review of practical considerations in choline supplementation, including dose, formulation, and feasibility in children.