Maternal executive function, infant feeding responsiveness and infant growth during the first 3 months.

BACKGROUND: There is limited research in young infants, particularly <3 months of age, on maternal feeding practices in spite of increasing evidence that early weight gain velocity is a determinant of later obesity risk. OBJECTIVE: To examine associations between maternal executive function (cognitive control over one's own behaviour), maternal feeding decisions and infant weight and adiposity gains. METHODS: We used a checklist to assess cues mothers use to decide when to initiate and terminate infant feedings at 2 weeks and 3 months of age (N = 69). Maternal executive function was assessed using the NIH Toolbox Cognition Battery subtests for executive function and infant body composition using air displacement plethysmography. RESULTS: Mothers with higher executive function reported relying on fewer non-satiety cues at 2 weeks of age (ß = -0.29, p = 0.037) and on more infant hunger cues at 3 months of age (ß = 0.31, p = 0.018) in their decisions on initiating and terminating feedings. Responsive feeding decisions, specifically the use of infant-based hunger cues at 3 months, in turn were associated with lower gains in weight-for-length (ß = -0.30, p = 0.028) and percent body fat (ß = -0.2, p = 0.091; non-covariate adjusted ß = -0.27, p = 0.029). CONCLUSIONS: These findings show both an association between maternal executive function and responsive feeding decisions and an association between responsive feeding decisions and infant weight and adiposity gains. The causal nature and direction of these associations require further investigation.

Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development.

Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use. SUMMARY: Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14 DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 µm ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 µm ELT, but not 2 µm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6 µm ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions Eltrombopag treatment during development may impair neuronal structure as a result of neuronal ID. Preclinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development.

Temporal manipulation of transferrin-receptor-1-dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment.

Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2-3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long-term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain-derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID.

Antenatal betamethasone treatment has a persisting influence on infant HPA axis regulation.

OBJECTIVE: To examine the consequences of antenatal betamethasone (AB) exposure on postnatal stress regulation. STUDY DESIGN: Fourteen AB exposed infants born at 28-30 weeks' gestation were assessed in the NICU during postnatal week 1 and at 34 weeks postconception. Nine infants born at 34 weeks gestation without AB treatment were evaluated as a postconceptional age comparison group. Salivary cortisol, heart rate, and behavior were measured at baseline and in response to a heelstick blood draw. RESULTS: Repeated measures ANOVAs revealed that both groups displayed an increase in heart rate and behavioral distress in response to the stressor. The cortisol response, however, was blunted in AB-treated infants at both assessments. CONCLUSION: AB treatment has consequences for hypothalamic-pituitary-adrenal (HPA) axis regulation that persist for at least four to six weeks after birth, indicating that studies of long-term effects are warranted.

Perinatal aspects of iron metabolism.

UNLABELLED: Iron sufficiency is critical for rapidly developing fetal and neonatal organ systems. The majority of iron in the third trimester fetus and the neonate is found in the red cell mass (as hemoglobin), with lesser amounts in the tissues as storage iron (e.g. ferritin) or functional iron (e.g. myoglobin, cytochromes). Iron is prioritized to hemoglobin synthesis in red cells when iron supply does not meet iron demand. Thus, non-heme tissues such as the skeletal muscle, heart and brain will become iron deficient before signs of iron-deficiency anemia. Gestational conditions that result in lower newborn iron stores include severe maternal iron deficiency, maternal hypertension with intrauterine growth retardation and maternal diabetes mellitus. Stable, very low birthweight premature infants are also at risk for early postnatal iron deficiency because they accrete less iron during gestation, grow more rapidly postnatally, are typically undertreated with enteral iron and receive fewer red cell transfusions. Conversely, iron overload remains a significant concern in multiply transfused sick preterm infants because they have low levels of iron-binding proteins and immature antioxidant systems. CONCLUSION: The highly variable iron status of preterm infants combined with their risk for iron deficiency and toxicity warrants careful monitoring and support in the newborn and postdischarge periods.

Muscle proteolysis and weight loss in a neonatal rat model of sepsis syndrome.

Our hypothesis is that nitrogen loss in septic neonates is caused by increased muscle proteolysis. Sprague-Dawley rat pups (P7) were injected intraperitoneally with NaCl or 4 mg/kg/BW lipopolysaccharide (LPS) and then sacrificed at 2, 4, 24, and 48 hr. Sepsis syndrome was confirmed by elevated serum tumor necrosis factor (24.6 ng/mL +/- 18.4 [LPS] and < 1.0 ng/mL [controls]; p < .05). Proteolysis in gastrocnemius/soleus muscle was analyzed by quantitation of tissue tyrosine loss. The neonatal rats injected with LPS had significant media tyrosine release at 24 hr compared to the controls (0.39 +/- 0.14 versus 0.25 +/- 0.11 micromol tyrosine/g muscle; p < .05). At 48 hr, LPS-induced muscle tyrosine release ceased (0.24 +/- 0.04 [control] versus 0.23 +/- 0.03 micromol tyrosine/g muscle [LPS]). After 48 hr, gastrocnemius/soleus weight was less in the LPS-injected rats (50.5 +/- 4.8 to 31.2 +/- 4.0 g; p < .0001). Similar changes were not seen in the extensor digitorum longus, suggesting that some muscles were relatively preserved. Also, LPS resulted in significant weight loss. We conclude that selective muscle proteolysis contributes to nitrogen loss in neonatal sepsis. Although proteolysis abates by 48 hr, short-term injury results in significant muscle-mass deficit.

Impact of Genetic potential and prematurity on growth outcomes.

PURPOSE: To explore the relationship between genetic potential and catch-up growth in school-age children who were born prematurely. STUDY DESIGN AND METHOD: This descriptive correlational study compared three groups of children who were born prematurely, sorted by birthweight groups into low, very low, and extremely low birthweight on measures of catch-up growth and body composition at school age (n = 45). Height and weight were compared to established norms for children of normal birthweight. Growth at school age and parental heights were also correlated. RESULTS: Children in all birthweight groups achieved growth within normal ranges (two standard deviations from the mean) by school age. The growth of the extremely low birthweight group was in the lower range of normal. Maternal height was the best predictor of children's heights at 8 to 10 years of age. CLINICAL IMPLICATIONS: Parents and providers can be reassured that many children overcome the adverse effects of prematurity on childhood growth. Throughout childhood, growth should be closely monitored using appropriate grids, and correcting for prematurity.

Neonatal iron nutrition.

Preterm infants are prone to iron deficiency. Their total body iron content at birth is low and gets further depleted by clinical practices such as uncompensated phlebotomy losses and exogenous erythropoietin administration during the neonatal period. Early iron deficiency appears to adversely affect cognitive development in human infants. To maintain iron sufficiency and meet the iron demands of catch-up postnatal growth, iron supplementation is prudent in preterm infants. A dose of 2-4 mg/kg/day is recommended for preterm infants who are fed exclusively human milk. A dose of 6 mg/kg/day or more is needed with the use of exogenous erythropoietin or to correct preexisting iron deficiency. However, due to the poor antioxidant capabilities of preterm infants and the potential role of iron in several oxidant-related perinatal disorders, indiscriminate iron supplementation should be avoided.

Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers.

OBJECTIVES: We evaluated the integrity of neural pathways for auditory recognition memory in normal newborn infants (n = 32) and infants of diabetic mothers (IDMs, n = 25). IDMs are at risk for fetal metabolic abnormalities that potentially damage recognition memory pathways. We hypothesized that newborn IDMs would have recognition memory deficits that would be correlated with later cognitive development. STUDY DESIGN: Recognition memory was assessed with event-related potentials (ERPs). Neonatal ERPs elicited by the maternal voice were compared with those elicited by a stranger's voice. The Bayley Scales of Infant Development were administered at 1 year of age. RESULTS: Infants in both the control and IDM groups demonstrated recognition of the maternal voice, but their ERP patterns differed. Both groups demonstrated increased amplitude and latency for the "P2" peak elicited by the maternal voice compared with the stranger's voice. In the control group the stranger's voice also elicited a negative slow wave, which was attenuated in the IDMs. The negative slow wave correlated significantly with the 1-year Mental Developmental Index. CONCLUSIONS: The presence of a specific neonatal ERP pattern indicated better 1-year cognitive development in infants in the control and IDM groups. ERPs from IDMs demonstrated subtle evidence of recognition memory impairments.

Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta.

The mechanism by which iron is transported from mother to fetus is incompletely understood. Whereas transferrin receptor (TfR) is responsible for iron uptake from maternal serum by the syncytiotrophoblast, the proteins responsible for intracytoplasmic transport and for delivery to the fetal serum remain unknown. The aim of this study was to determine whether the recently characterized endosomal membrane iron transporter, divalent metal ion transporter-1 (DMT-1), is expressed in human syncytiotrophoblast, and whether its cellular localization would support roles for cytoplasmic and placental-fetal iron transport. Six micron sections of frozen, term human placenta were assessed immunohistochemically using a polyclonal antibody to rat DMT-1 and a monoclonal antibody to human TfR. DMT-1 was found both in the cytoplasm and at the junction of the fetal (basal) membrane and fetal vessels, while TfR was localized predominantly to the maternal (apical) side of the syncytiotrophoblastic membrane. Double staining demonstrated no overlap between the two proteins on the apical membrane and minimal areas of overlap in the cytoplasm. We postulate that the syncytiotrophoblast takes up diferric transferrin from serum via TfR, subsequently incorporating the transferrin : TfR complex via endosomes. Subsequent transport of iron out of the endosome and across the basal membrane to the fetus may occur via DMT-1.

Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.

Intrauterine growth retardation and diabetes mellitus during human gestation result in significant losses of fetal and neonatal brain iron. Brain iron deficiency is associated with impaired cognitive processes including memory and attention. The regional distribution of iron staining and cytochrome c oxidase (CytOx) activity have not been mapped in the iron-sufficient or -deficient neonatal rat. CytOx is the iron-containing terminal enzyme in oxidative phosphorylation; its activity reflects neuronal metabolism. We hypothesized that neonatal brain iron deficiency differentially decreases iron and CytOx activity in brain regions, with more pronounced losses in structures involved in recognition memory. Pregnant Sprague Dawley rats were fed either an iron-deficient or -fortified diet from gestational d 1 until postnatal d 10. Iron staining and CytOx activity of 20 brain structures were mapped histochemically in 25 rats from each group. Brain iron staining was reduced from 75% to 100% and CytOx staining was decreased from 0% to 42% in the iron deficient group (p < 0.001). Areas with significantly reduced CytOx activity (p < 0.001) included all measured subareas of the hippocampus (CA1: 42%, CA3ab: 34%, CA3c: 33%, and dentate gyrus: 32%), the piriform cortex (17%), the medial dorsal thalamic nucleus (28%), and the cingulate cortex (41%). In contrast, the anterior thalamic nucleus, the lateral amygdaloid nucleus, and the medial habenula, areas not involved in higher cognitive functions, did not have significantly reduced CytOx activity (0%, 10%, and 16%, respectively). We conclude that perinatal iron deficiency differentially reduces neuronal metabolic activity, specifically targeting areas of the brain involved in memory processing.

Explicit memory in low-risk infants aged 19 months born between 27 and 42 weeks of gestation.

The aim of this study was to determine whether there are primary effects of prematurity on the development of explicit memory. Elicited imitation of action sequences was used to compare immediate and 15-minute delayed memory in term and preterm infants (19 months corrected age; n=48) who were at low risk: none had experienced the medical or social risk factors often associated with preterm birth. Relative to infants born at term (38 to 40 weeks' gestation), children who had been born at 27 to 34 weeks' gestation showed lower levels of ordered recall; performance of healthy infants born at 35 to 37 weeks' gestation was intermediate and did not differ significantly from that of the other groups. These results suggest that specific cognitive deficits can occur as a function of preterm birth even in low-risk infants.

Effect of sepsis syndrome on neonatal protein and energy metabolism.

OBJECTIVE: It was our hypothesis that septic illness would alter both protein and energy metabolism in neonates, with elevations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) serving as markers for these effects. STUDY DESIGN: A total of 31 infants with suspected sepsis were enrolled into four groups: septic, sick-nonseptic, healthy-nonseptic, and recovered septic infants. Degree of illness, oxygen consumption, nitrogen balance, urine 3-methylhistidine/creatinine (MeH/Cr), and TNF-alpha, IL-6, IL-1 beta, and C-reactive protein (CRP) were measured. RESULTS: Oxygen consumption increased, while nitrogen balance decreased and MeH/Cr increased with increasing degree of illness. Nitrogen balance improved on recovery from sepsis. IL-6 and CRP levels were elevated in septic infants compared with sick-nonseptic and healthy infants. CONCLUSION: Neonates experience a hypermetabolic response with increased nitrogen loss during septic illness, proportional to the degree of illness. Increased delivery of protein substrate may be nutritionally advantageous to the septic neonate.

American Academy of Pediatrics. Committee on Nutrition. Calcium requirements of infants, children, and adolescents.

This statement is intended to provide pediatric caregivers with advice about the nutritional needs of calcium of infants, children, and adolescents. It will review the physiology of calcium metabolism and provide a review of the data about the relationship between calcium intake and bone growth and metabolism. In particular, it will focus on the large number of recent studies that have identified a relationship between childhood calcium intake and bone mineralization and the potential relationship of these data to fractures in adolescents and the development of osteoporosis in adulthood. The specific needs of children and adolescents with eating disorders are not considered.

Increased placental iron regulatory protein-1 expression in diabetic pregnancies complicated by fetal iron deficiency.

Placental transferrin receptor (TfR) protein expression is increased in diabetic pregnancies that are complicated by low fetal iron stores, suggesting regulation of placental iron transport by fetoplacental iron status. In cell culture, iron homeostasis is regulated by coordinate stabilization of TfR mRNA and translation inactivation of ferritin mRNA by iron regulatory proteins (IRP-1 and -2) which bind to iron-responsive elements (IREs) on the respective mRNAs. Concentrations of IRP-1, IRP-2 and TfR mRNA were measured in 10 placentae obtained from diabetic and non-diabetic human pregnancies with a wide range of fetoplacental iron status. IRP-1 activity was present in human placenta and correlated closely with TfR mRNA concentration (r=0.82; P=0.007). IRP-2 activity and protein were not detected. In a second experiment, placentae were collected from 12 diabetic pregnancies, six with low fetal cord serum ferritin and placental non-heme iron concentrations, and six with normal iron status. IRP-1 activity and TfR Bmax for diferric transferrin were greater in the iron-deficient group (P<0.05). IRP-1 activity correlated inversely with cord serum ferritin (r=0.75; P<0.01) and placental non-heme iron (r=0.61; P=0.05) concentration. Placental IRP-1 activity is directly related to TfR mRNA concentration and is more highly expressed in iron-deficient placentae. The study provides direct in vivo evidence for IRP regulation of TfR expression in the human placenta.

Perinatal brain iron deficiency increases the vulnerability of rat hippocampus to hypoxic ischemic insult.

Fetal brain iron deficiency occurs in human pregnancies complicated by diabetes mellitus or intrauterine growth retardation. Because neurocognitive deficits are more common in the offspring of these pregnancies, we tested the hypothesis that perinatal brain iron deficiency predisposes the neonatal hippocampus, a structure important for memory processing, to injury. Brain iron concentration was reduced by 45% in 45 neonatal rats by maternal dietary iron restriction during gestation. Right-sided neuronal injury in four hippocampal subareas was induced by hypoxic-ischemic insult (ipsilateral carotid artery ligation and subsequent hypoxia on postnatal d 7) and was quantified histochemically on d 8 by cytochrome c oxidase activity (n = 30), and on d 14 by Nissl staining (n = 15). Acute right-sided cytochrome c oxidase activity loss occurred in CA1 (P = 0.02), CA3c (P < 0.001) and dentate gyrus (P < 0.001) in the iron-deficient group, whereas only CA1 (P = 0. 003) was affected in the iron-sufficient group. Long-term right-sided Nissl substance loss occurred in CA1 (P = 0.001), CA3a,b (P < 0.001) and dentate gyrus (P = 0.008) in the iron-deficient group, but only in CA1 (P = 0.004) in the iron-sufficient group. No increase in right-sided free-iron staining was present in either group. Perinatal iron deficiency predisposes the neonatal hippocampus to a greater acute loss of neuronal metabolic activity after an hypoxic-ischemic event, suggesting compromised cellular energetics. The subsequently greater loss of hippocampal neuronal integrity suggests poorer recoverability after injury in the perinatal iron-deficient brain.

Intracardiac iron distribution in newborn guinea pigs following isolated and combined fetal hypoxemia and fetal iron deficiency.

Myocardial iron deficiency complicates chronic intrauterine hypoxemia during diabetic pregnancies. To understand the effect of both conditions during fetal life on intracardiac iron prioritization, we measured heart myoglobin, cytochrome c, and elemental iron concentrations in six iron-deficient, hypoxic, five iron-sufficient, hypoxic, six iron-deficient, normoxic, and six iron-sufficient, normoxic newborn guinea pigs. The iron-deficient, hypoxic group had lower heart iron (p = 0.03) but higher myoglobin concentration (p < 0.0001) when compared with the iron-sufficient, normoxic group. The percentage of iron incorporated into myoglobin was higher than control in the iron-deficient, hypoxic group (23.2+/-7.2% vs. 5.2+/-0.8%; p < 0.001) and increased as total heart iron decreased (r = 0.97; p < 0.001). In contrast, heart cytochrome c concentration was lower than control in the iron-deficient, hypoxic group (p = 0.01), with equal percentages of heart iron incorporated into cytochrome c. This intracellular prioritization of myocardial iron to myoglobin and away from cytochrome c following combined fetal hypoxemia and iron deficiency may represent an adaptive mechanism to preserve myocardial tissue oxygenation, although at the expense of oxidative phosphorylative capability.

Health, growth, and use of community services in NICU graduates at early school age.

PURPOSE: To examine outcomes related to health, growth, and use of community health and education services in children ages 6 to 8 years who received newborn intensive care because of prematurity or perinatal complications. METHOD: Parents of 81 children who had received neonatal intensive care at a Midwest US tertiary care center completed a mailed questionnaire. Three birth weight groups (very low birth weight [VLBW] < 1500 g, n = 35; low birth weight [LBW] 1501-2500 g, n = 24, and normal birth weight [NBW] > 2500 g, n = 22) were compared regarding growth, health, and use of community-based services using descriptive statistics and one-way analysis of variance. FINDINGS: VLBW and NBW groups had more ongoing health concerns. Growth patterns were similar in all groups. VLBW and NBW groups demonstrated greater use of community-based services, and service use increased at school age. CONCLUSIONS: Comprehensive systems are needed for follow-up of high-risk infants to detect and refer problems early. Neonatal histories must be tracked throughout childhood. Seriously ill term NBW infants are at risk for later morbidity and require follow-up similar to that provided for VLBW children.