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1.
Neoreviews ; 21(2): e80-e88, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32005718

RESUMO

Prematurity, maternal diabetes, maternal smoking, being medically underserved, and small size for gestational age are common characteristics of neonates in the NICU and can predispose them to develop congenital iron deficiency. Iron is critical for organ development. In the fetus and newborn, iron is prioritized for red blood cell production, sometimes at the expense of other tissues, including the brain. It is critical to optimize iron levels in newborns to support erythropoiesis, growth, and brain development. Available studies support improved neurodevelopmental outcomes with either iron supplementation or delayed umbilical cord clamping at birth. Erythropoietic doses of erythropoietin/erythrocyte-stimulating agents may also improve neurocognitive outcomes. However, the literature on the effect of liberal red blood cell transfusions on long-term neurodevelopment is mixed. Understanding age-specific normal values and monitoring of iron indices can help individualize and optimize the iron status of patients in the NICU.

2.
J Nutr ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722400

RESUMO

BACKGROUND: Iron deficiency is the most common nutrient deficiency in human infants aged 6 to 24 mo, and negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. There can be persistent influences on long-term metabolic health beyond its acute effects. OBJECTIVES: The objective was to determine how iron deficiency in infancy alters the serum metabolomic profile and to test whether these effects persist after the resolution of iron deficiency in a nonhuman primate model of spontaneous iron deficiency. METHODS: Blood was collected from naturally iron-sufficient (IS; n = 10) and iron-deficient (ID; n = 10) male and female infant rhesus monkeys (Macaca mulatta) at 6 mo of age. Iron deficiency resolved without intervention upon feeding of solid foods, and iron status was re-evaluated at 12 mo of age from the IS and formerly ID monkeys using hematological and other indices; sera were metabolically profiled using HPLC/MS and GC/MS with isobaric standards for identification and quantification at both time points. RESULTS: A total of 413 metabolites were measured, with differences in 40 metabolites identified between IS and ID monkeys at 6 mo (P$\le $ 0.05). At 12 mo, iron-related hematological parameters had returned to normal, but the formerly ID infants remained metabolically distinct from the age-matched IS infants, with 48 metabolites differentially expressed between the groups. Metabolomic profiling indicated altered liver metabolites, differential fatty acid production, increased serum uridine release, and atypical bile acid production in the ID monkeys. CONCLUSIONS: Pathway analyses of serum metabolites provided evidence of a hypometabolic state, altered liver function, differential essential fatty acid production, irregular uracil metabolism, and atypical bile acid production in ID infants. Many metabolites remained altered after the resolution of ID, suggesting long-term effects on metabolic health.

3.
Alcohol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31734307

RESUMO

Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated if maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron-fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an ID (2-6 ppm), iron-sufficient (IS; 100 ppm), or IF (500 ppm) diet. Alcohol (5g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (P < 0.0001), placental weight (P = 0.0324), and placental efficiency (P = 0.0043). PAE downregulated placental transferrin receptor (P = 0.0032); it also altered placental Il1b and Tnf expression and Il6:Il10 ratio (P = 0.0337, 0.0300 and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of variability in fetal weight and 20% of variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

4.
Nutrients ; 11(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623079

RESUMO

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, ß = 1.75, p = 0.02). In contrast, BDNF levels inversely correlated with ferritin (ß = -1.20, p = 0.03), with stronger association in female neonates (n = 37, ß = -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, ß = -0.69, p = 0.02), female IDMs showed a positive correlation (n = 37, ß = 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, ß = -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.

5.
Alcohol Clin Exp Res ; 43(11): 2332-2343, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31524964

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production-EPO/BMP6/SMAD and IL-6/JAK2/STAT3. METHODS: Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron-sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5. RESULTS: PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (p = 0.03) and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.02). PAE modestly elevated maternal Il-1ß, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (p = 0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (p < 0.001) in maternal liver and a 10-fold decrease (p < 0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver. CONCLUSIONS: These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.

6.
J Pediatric Infect Dis Soc ; 8(4): 310-316, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-29846666

RESUMO

BACKGROUND: Meeting antibiotic stewardship goals in the neonatal intensive care unit (NICU) is challenging because of the unique nature of newborns and the lack of specificity of clinical signs of sepsis. Antibiotics are commonly continued for 48 hours pending culture results and clinical status. The goal of this study was to examine if the implementation of a 48-hour automatic stop (autostop) order during NICU admissions would decrease antibiotic use at UnityPoint Health-Meriter. METHODS: An observational double-cohort study was performed in a level 3 NICU. Antibiotic use was evaluated before and after the autostop initiative. The admission order set included 48 hours of ampicillin and gentamicin coverage. RESULTS: After the autostop initiation, total doses given per patient decreased by 35% and doses per patient-day decreased by 25% (P < .0001). The greatest effect was a 66% decrease in the use of vancomycin, an antibiotic not included in the admission order set. Providers proactively continued antibiotics for infants in whom they had high suspicion for sepsis and in those with positive blood or cerebral spinal fluid culture results. CONCLUSIONS: An admission-order autostop was highly effective at decreasing antibiotic usage with no doses intended for a pathogen missed. Fewer doses of certain antibiotics outside of the admission order set were administered, particularly vancomycin, which results in our speculation that provider awareness of the antibiotic stewardship initiative might have altered prescribing practices.

7.
Am J Perinatol ; 36(5): 511-516, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30193381

RESUMO

OBJECTIVE: Obesity during pregnancy impedes fetal iron endowment. In adults, both iron depletion and hypoxia stimulate erythropoietin (Epo) production, while hepcidin, the primary iron regulator, is inhibited by Epo and stimulated by obesity. To understand this relationship in fetuses, we investigated obesity, inflammation, and fetal iron status on fetal Epo and hepcidin levels. STUDY DESIGN: Epo, hepcidin, C-reactive protein (CRP), and ferritin levels were measured in 201 newborns of 35 to 40 weeks' gestation with historical risk factors for a low fetal iron endowment, including half with maternal obesity. RESULTS: Epo was unrelated to fetal size, but Epo was directly related to maternal body mass index (BMI; kg/m2) (p < 0.03) and CRP (p < 0.0005) at delivery. Epo levels were twice as likely to be elevated (≥50 IU/L) while comparing the lowest quartile of ferritin with the upper three quartiles (p < 0.01). Hepcidin was directly related to ferritin (p < 0.001) and indirectly related to maternal BMI (p < 0.015), but BMI became nonsignificant when undergoing multivariate analysis. Hepcidin was unrelated to Epo. CONCLUSION: Although some of the fetal responses involving Epo were similar to adults, we did not find a hepcidin-Epo relationship like that of adults, where fetal liver is the site of both hepcidin and Epo production.

8.
J Pediatr ; 200: 166-173.e2, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908648

RESUMO

OBJECTIVE: To investigate the impact of maternal stress during pregnancy on newborn iron and stage 1 iron deficiency at 1 year of age. STUDY DESIGN: In total, 245 mothers and their newborn infants (52% male; 72% white) were recruited at the Meriter Hospital Birthing Center on the basis of known risk factors for iron deficiency. Umbilical cord blood hemoglobin and zinc protoporphyrin/heme (ZnPP/H) were determined to evaluate erythrocyte iron and plasma ferritin was determined to reflect storage iron. Mothers retrospectively reported stress experienced previously during pregnancy on a 25-item questionnaire. Blood was also was collected from 79 infants who were breastfed at 1 year of age. RESULTS: Maternal recall of distress and health concerns during pregnancy correlated with cord blood ZnPP/H indices (r = 0.21, P < .01), even in the absence of major traumatic events. When concurrent with other known risks for iron deficiency, including maternal adiposity, socioeconomic status, and race, maternal stress had a summative effect, lowering cord blood iron. At 1 year, 24% of infants who were breastfed had moderate iron deficiency (plasma ferritin <12 µg/L). Higher cord blood ZnPP/H was predictive of this moderate iron deficiency (95% CI 0.26-1.47, P = .007). When coincident with maternal reports of gestational stress, the likelihood of low plasma ferritin at 1 year increased 36-fold in breastfed infants as compared with low-stress pregnancies (95% CI 1.33-6.83, P = .007). CONCLUSIONS: Maternal recall of stress during pregnancy was associated with lower iron stores at birth. High cord blood ZnPP/H, reflecting low erythrocyte iron, was correlated with the likelihood of stage 1 iron deficiency at 1 year, when rapid growth can deplete storage iron in breastfed infants.


Assuntos
Anemia Ferropriva/sangue , Recém-Nascido Prematuro/sangue , Exposição Materna/efeitos adversos , Complicações na Gravidez , Estresse Psicológico/sangue , Adolescente , Adulto , Anemia Ferropriva/epidemiologia , Anemia Ferropriva/etiologia , Feminino , Ferritinas/sangue , Seguimentos , Idade Gestacional , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Wisconsin/epidemiologia , Adulto Jovem
9.
Alcohol Clin Exp Res ; 42(6): 1022-1033, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29672865

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis. METHODS: Pregnant Long-Evans rats, fed iron-sufficient (100 ppm iron) or iron-fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5. RESULTS: PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol-mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol-exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF-PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron. CONCLUSIONS: Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol-exposed pregnancies.


Assuntos
Feto/irrigação sanguínea , Hepcidinas/biossíntese , Ferro na Dieta/farmacologia , Ferro/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Índices de Eritrócitos/efeitos dos fármacos , Feminino , Ferritinas/metabolismo , Desenvolvimento Fetal , Feto/efeitos dos fármacos , Hematócrito , Hemoglobinas/efeitos dos fármacos , Homeostase , Fígado/metabolismo , Masculino , Gravidez , Ratos , Receptores da Transferrina/biossíntese , Transferrina/metabolismo
10.
J Neurosci Res ; 96(9): 1586-1599, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29696692

RESUMO

Erythropoietin (Epo) drives iron (Fe) utilization for erythropoiesis, but the potentially resultant tissue iron deficiency (ID) can also impede brain development. Conversely, Epo binds to Epo receptors (EpoR) on immature brain oligodendrocytes and neurons, promoting growth and differentiation. The objective of the study was to examine the interaction between Epo and Fe on myelination in brain development during daily Epo treatment. Male and female Sprague-Dawley rats from postnatal day (P) P4-P12 modeled premature newborns. Dam-fed Fe-sufficient (IS) or postnatal ID groups were given daily subcutaneous sham or erythropoietic Epo injections (425 U. kg-1. d-1 ), ± oral Fe (6 mg. kg-1. d-1 ). Tissues and blood were collected and studied at P12. Epo in the ID groups, in the absence of oral Fe, stimulated microcytic ID anemia along with raising inflammatory markers. Both the microcytic anemia and inflammation improved in the ID + Epo + Fe group. Fe treatment positively impacted erythropoiesis and body Fe (µg/g) in all groups. Relative brain Fe (µg/g rat) was improved in the IS + Epo + Fe group. Brain Fe was not worsened in +Epo groups. Brain weight and brain Fe were related to plasma Epo levels. Amount of myelination was impacted by feeding type, but was not inhibited by Epo. Expression of a protein in myelin, mylein basic protein, was greater in all +Fe groups than -Fe groups. With therapeutic Epo, available body Fe was prioritized for erythropoiesis instead of brain, but Epo did not worsen brain Fe and potentially Epo improved myelination and maturation in the brain.


Assuntos
Cerebelo/fisiologia , Eritropoetina/metabolismo , Hipocampo/fisiologia , Ferro/metabolismo , Animais , Animais Recém-Nascidos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Eritropoese , Eritropoetina/administração & dosagem , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ferro/administração & dosagem , Masculino , Proteína Básica da Mielina/metabolismo , Bainha de Mielina , Ratos Sprague-Dawley
11.
J Vet Diagn Invest ; 30(2): 238-244, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29291683

RESUMO

Normative data for plasma chemistry values in pregnant and non-pregnant reproductive age ewes are scant. Availability of data would aid monitoring of ewe health for both research and veterinary medicine. We determined specific plasma chemistry 95% confidence reference intervals (RIs) in non-pregnant and pregnant ewes. Mixed Western-breed ewes were grouped based on phase of ovarian cycle: luteal ( n = 15), follicular ( n = 17), or late-gestation pregnant ( n = 102). Plasma samples were collected for analysis on a commercial biochemical analyzer. For RIs, chemistry panels for the 3 groups of ewes included nutrients and metabolites (glucose, triglycerides, cholesterol, urea, creatinine, total protein, albumin, and bilirubin), enzymes (lactate dehydrogenase, aspartate transaminase, gamma-glutamyl transferase, alanine aminotransferase, and alkaline phosphatase [ALP]), and micronutrients (calcium, phosphorus, iron, sodium, potassium, and chloride). Sample chemistry values for glucose and total protein in pregnant ewes were lower than in follicular ewes; cholesterol was lower in pregnant and luteal ewes than in follicular ewes. In addition, total bilirubin in pregnant ewes differed from that in luteal ewes, and that in follicular ewes also differed from luteal ewes. ALP in pregnant ewes was higher than other groups; phosphorus in pregnant ewes was lower than in luteal ewes. Iron was higher in pregnant ewes than in luteal ewes, with iron in luteal ewes lower than in follicular ewes. These data provide clinical RIs comparing pregnant and non-pregnant ewes for use in monitoring ewe health in both human research and veterinary medicine.


Assuntos
Alanina Transaminase/sangue , Ciclo Estral/fisiologia , Prenhez/fisiologia , Ovinos/sangue , Albuminas/metabolismo , Animais , Bilirrubina/sangue , Análise Química do Sangue/veterinária , Glicemia , Colesterol/sangue , Ciclo Estral/sangue , Feminino , Micronutrientes/sangue , Gravidez , Prenhez/sangue , Valores de Referência , Triglicerídeos/sangue
12.
Biochem Cell Biol ; 96(2): 204-212, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29017023

RESUMO

Alcohol consumption during pregnancy places the fetus at risk for permanent physical, cognitive, and behavioral impairments, collectively termed fetal alcohol spectrum disorder (FASD). However, prenatal alcohol exposure (PAE) outcomes vary widely, and growing evidence suggests that maternal nutrition is a modifying factor. Certain nutrients, such as iron, may modulate FASD outcomes. Untreated gestational iron deficiency (ID) causes persistent neurodevelopmental deficits in the offspring that affect many of the same domains damaged by PAE. Although chronic alcohol consumption enhances iron uptake and elevates liver iron stores in adult alcoholics, alcohol-abusing premenopausal women often have low iron reserves due to menstruation, childbirth, and poor diet. Recent investigations show that low iron reserves during pregnancy are strongly associated with a worsening of several hallmark features in FASD including reduced growth and impaired associative learning. This review discusses recent clinical and animal model findings that maternal ID worsens fetal outcomes in response to PAE. It also discusses underlying mechanisms by which PAE disrupts maternal and fetal iron homeostasis. We suggest that alcohol-exposed ID pregnancies contribute to the severe end of the FASD spectrum.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/metabolismo , Ferro , Micronutrientes/uso terapêutico , Neurogênese , Animais , Modelos Animais de Doenças , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Ferro/sangue , Ferro/deficiência , Ferro/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Gravidez
13.
Clin Pediatr (Phila) ; 57(9): 1064-1068, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29183146

RESUMO

In 2010, the American Academy of Pediatrics recommended universal screening for anemia at approximately 1 year of age. This quality improvement study sought to improve anemia screening in an ambulatory setting. In a large university-based setting, a best practice alert (BPA) was placed within the electronic health record. The primary outcome was overall screening rate in ambulatory family medicine (DFM) and pediatrics (PEDS) clinics. From 2545 pre-BPA clinic visits over a 12-month period, the screening rate was 48.2%. Among 2186 post-BPA clinic visits over an 8-month period, the screening rate improved to 72.7%, P < .0001. Follow-up over a second 7-month period demonstrated sustained improvements (70.8%) but was not higher after educational sessions between the periods. Screening rates were higher in PEDS than DFM at each time point; P < .0001. This technology-based intervention increased and maintained higher screening rates for anemia at 1 year, with higher rates in PEDS.


Assuntos
Anemia Ferropriva/diagnóstico , Serviços de Saúde da Criança/organização & administração , Registros Eletrônicos de Saúde/estatística & dados numéricos , Programas de Rastreamento/estatística & dados numéricos , Melhoria de Qualidade , Fatores Etários , Anemia Ferropriva/epidemiologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Masculino , Programas de Rastreamento/métodos , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Estados Unidos
14.
Biol Reprod ; 96(1): 211-220, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395333

RESUMO

In ovine pregnancy, uterine space restriction (USR) resulting from decreased space for placental attachment caused intrauterine growth restriction and impaired nephrogenesis. The fetal kidney renin-angiotensin system (RAS) is involved in nephrogenesis, fluid balance, and iron deposition. Angiotensin II exerts its effects via multiple receptors: angiotensin II 1-8 receptor type 1 (AT 1 R) and type 2 (AT 2 R), and angiotensin II 1-7 Mas receptor (MASR). Objective: : To test the hypothesis that ovine USR is associated with dysregulation of the fetal renal RAS. Methods: : Multiparous pregnant ewes (n = 32), 16 with surgical bifurcated disconnection of one uterine horn to further reduce placental attachment sites, were studied. USR (n = 31) ovine fetuses were compared to nonspace restricted (NSR) singleton controls (n = 22) on gestational day (GD) 120 or GD130, term GD147. Fetal plasma was collected to evaluate plasma renin activity and iron indices. Fetal kidney AT 1 R, AT 2 R, and MASR proteins were assessed by Western immunoblotting and immunohistochemistry. Results: : AT 1 R, AT 2 R, and MASR protein expression was higher in USR at GD130 than aged-matched NSR and USR at GD120, ( P < 0.05 all). AT 1 R and AT 2 R localization was homogenous throughout proximal and distal tubules in both USR and NSR at both gestational dates. MASR localization was punctate throughout renal cortical structures including tubules and glomeruli in both USR and NSR, shifted to intranuclear at GD130. Plasma renin activity was inversely related to plasma osmolarity ( P < 0.02) and was downregulated in USR at GD130 ( P < 0.05). Conclusions: : By late gestation, USR upregulated renal angiotensin receptor expression, an effect with potential functional implications.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Córtex Renal/metabolismo , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Animais , Creatinina/sangue , Modelos Animais de Doenças , Feminino , Ferro/metabolismo , Concentração Osmolar , Gravidez , Renina/sangue , Ovinos
15.
Physiol Rep ; 4(16)2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27565903

RESUMO

Intrauterine growth restriction (IUGR) is interconnected with developmental programming of lifelong pathophysiology. IUGR is seen in human multifetal pregnancies, with stepwise rises in fetal numbers interfering with placental nutrient delivery. It remains unknown whether fetal blood analyses would reflect fetal nutrition, liver, and excretory function in the last trimester of human or ovine IUGR In an ovine model, we hypothesized that fetal plasma biochemical values would reflect progressive placental, fetal liver, and fetal kidney dysfunction as the number of fetuses per gestation rose. To determine fetal plasma biochemical values in singleton, twin, triplet, and quadruplet/quintuplet ovine gestation, we investigated morphometric measures and comprehensive metabolic panels with nutritional measures, liver enzymes, and placental and fetal kidney excretory measures at gestational day (GD) 130 (90% gestation). As anticipated, placental dysfunction was supported by a stepwise fall in fetal weight, fetal plasma glucose, and triglyceride levels as fetal number per ewe rose. Fetal glucose and triglycerides were directly related to fetal weight. Plasma creatinine, reflecting fetal renal excretory function, and plasma cholesterol, reflecting placental excretory function, were inversely correlated with fetal weight. Progressive biochemical disturbances and growth restriction accompanied the rise in fetal number. Understanding the compensatory and adaptive responses of growth-restricted fetuses at the biochemical level may help explain how metabolic pathways in growth restriction can be predetermined at birth. This physiological understanding is important for clinical care and generating interventional strategies to prevent altered developmental programming in multifetal gestation.


Assuntos
Sangue Fetal/química , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/fisiopatologia , Feto/fisiologia , Placenta/fisiologia , Prenhez , Gravidez Múltipla/fisiologia , Carneiro Doméstico/crescimento & desenvolvimento , Animais , Química Clínica , Feminino , Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Idade Gestacional , Tamanho do Órgão , Placenta/metabolismo , Gravidez , Ovinos , Carneiro Doméstico/fisiologia
16.
J Nutr ; 146(6): 1180-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27146918

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes neurodevelopmental disabilities, and gestational iron deficiency (ID) selectively worsens learning and neuroanatomical and growth impairments in PAE. It is unknown why ID worsens outcomes in alcohol-exposed offspring. OBJECTIVE: We hypothesized that PAE alters maternal-fetal iron distribution or its regulation. METHODS: Nulliparous, 10-wk-old, Long-Evans rats were mated and then fed iron-sufficient (100 mg Fe/kg) or iron-deficient (≤4 mg Fe/kg) diets. On gestational days 13.5-19.5, dams received either 5.0 g ethanol/kg body weight (PAE) or isocaloric maltodextrin by oral gavage. On gestational day 20.5, maternal and fetal clinical blood counts, tissue mineral and iron transport protein concentrations, and hepatic hepcidin mRNA expression were determined. RESULTS: In fetal brain and liver (P < 0.001) and in maternal liver (P < 0.005), ID decreased iron (total and nonheme) and ferritin content by nearly 200%. PAE reduced fetal bodyweight (P < 0.001) and interacted with ID (P < 0.001) to reduce it by an additional 20%. Independent of maternal iron status, PAE increased fetal liver iron (30-60%, P < 0.001) and decreased brain iron content (total and nonheme, 15-20%, P ≤ 0.050). ID-PAE brains had lower ferritin, transferrin, and transferrin receptor content (P ≤ 0.002) than ID-maltodextrin brains. PAE reduced fetal hematocrit, hemoglobin, and red blood cell numbers (P < 0.003) independently of iron status. Unexpectedly, and also independent of iron status, PAE increased maternal and fetal hepatic hepcidin mRNA expression >300% (P < 0.001). CONCLUSIONS: PAE altered fetal iron distribution independent of maternal iron status in rats. The elevated iron content of fetal liver suggests that PAE may have limited iron availability for fetal erythropoiesis and brain development. Altered fetal iron distribution may partly explain why maternal ID substantially worsens growth and behavioral outcomes in PAE.


Assuntos
Transtornos do Espectro Alcoólico Fetal/sangue , Hepcidinas/metabolismo , Ferro/sangue , Ferro/deficiência , Anemia Ferropriva/sangue , Animais , Peso Corporal , Encéfalo/metabolismo , Dieta , Modelos Animais de Doenças , Feminino , Ferritinas/genética , Ferritinas/metabolismo , Hematócrito , Hemoglobinas/metabolismo , Hepcidinas/genética , Ferro/administração & dosagem , Fígado/metabolismo , Troca Materno-Fetal , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
17.
J Pediatr ; 172: 20-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26970931

RESUMO

OBJECTIVE: To determine the impact of maternal obesity and gestational weight gain across pregnancy on fetal indices of inflammation and iron status. STUDY DESIGN: Eighty-five healthy term newborns delivered via elective cesarean were categorized by 2 maternal body mass index (BMI) thresholds; above or below 30 kg/m(2) or above or below 35 kg/m(2). Umbilical cord plasma levels of C-reactive protein, interleukin (IL)-6, tumor necrosis factor (TNF)-α, ferritin, and hepcidin were assayed. Cytokines released by phytohemagglutinin-stimulated umbilical cord mononuclear cells (MNCs) were assayed. RESULTS: Maternal class II obesity, defined as BMI of 35 kg/m(2) and above, predicted higher C-reactive protein and TNF-α in umbilical cord plasma (P < .05 for both), and also proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) from stimulated MNC (P < .05 for all). The rise in plasma TNF-α and MNC TNF-α was not linear but occurred when the threshold of BMI 35 kg/m(2) was reached (P < .005, P < .06). Poorer umbilical cord iron indices were associated with maternal obesity. When ferritin was low, IL-6 was higher (P < .04), but this relationship was present primarily when maternal BMI exceeded 35 kg/m(2) (P < .03). Ferritin was correlated with hepcidin (P < .0001), but hepcidin was unrelated to either maternal BMI or inflammatory indices. CONCLUSIONS: Class II obesity and above during pregnancy is associated with fetal inflammation in a threshold fashion. Although maternal BMI negatively impacted fetal iron status, hepcidin, related to obesity in adults, was related to iron status and not obesity in fetuses. Pediatricians should be aware of these relationships.


Assuntos
Citocinas/sangue , Sangue Fetal/metabolismo , Inflamação/metabolismo , Ferro/sangue , Obesidade/sangue , Adulto , Índice de Massa Corporal , Feminino , Feto/metabolismo , Humanos , Recém-Nascido , Inflamação/complicações , Masculino , Troca Materno-Fetal , Gravidez
18.
J Pediatr Hematol Oncol ; 38(3): 210-5, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26907656

RESUMO

OBJECTIVE: To determine whether prenatal risk factors (RFs) that predict cord blood iron status in term newborns also predict iron status of premature newborns. STUDY DESIGN: Cord blood iron indices from 80 preterm newborns were compared with historical and demographic RFs for developing iron deficiency if born at term. RESULT: The presence of multiple RFs did not incrementally interfere with cord iron status in preterm newborns. Poorer iron status accompanied being small for gestational age in prematurity, but other RFs, including diabetes, had relatively little impact. CONCLUSION: Growth-restricted preterm newborns are at risk for poor iron endowment, likely due to uteroplacental insufficiency. Other RFs were less impactful on iron status of premature newborns than in term newborns, likely reflecting that disruptive effects of RFs are more impactful in the third trimester. Understanding RFs for poor iron endowment is important for clinical recognition and treatment of premature babies.


Assuntos
Sangue Fetal/química , Retardo do Crescimento Fetal/sangue , Recém-Nascido Prematuro/sangue , Ferro/sangue , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/sangue , Estudos Prospectivos , Fatores de Risco
19.
Reprod Fertil Dev ; 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26876724

RESUMO

Gestational iron deficiency (ID) can alter developmental programming through impaired nephron endowment, leading to adult hypertension, but nephrogenesis is unstudied. Iron status and renal development during dietary-induced gestational ID (<6 mg Fe kg-1 diet from Gestational Day 2 to Postnatal Day (PND) 7) were compared with control rats (198 mg Fe kg-1 diet). On PND2-PND10, PND15, PND30 and PND45, blood and tissue iron status were assessed. Nephrogenic zone maturation (PND2-PND10), radial glomerular counts (RGCs), glomerular size density and total planar surface area (PND15 and PND30) were also assessed. Blood pressure (BP) was measured in offspring. ID rats were smaller, exhibiting lower erythrocyte and tissue iron than control rats (PND2-PND10), but these parameters returned to control values by PND30-PND45. Relative kidney iron (µg g-1 wet weight) at PND2-PND10 was directly related to transport iron measures. In ID rats, the maturation of the active nephrogenic zone was later than control. RGCs, glomerular size, glomerular density, and glomerular planar surface area were lower than control at PND15, but returned to control by PND30. After weaning, the kidney weight/rat weight ratio (mg g-1) was heavier in ID than control rats. BP readings at PND45 were lower in ID than control rats. Altered kidney maturation and renal adaptations may contribute to glomerular size, early hyperfiltration and long-term renal function.

20.
Semin Fetal Neonatal Med ; 21(1): 10-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26712568

RESUMO

Neonatal thrombocytopenia is widespread in preterm and term neonates admitted to neonatal intensive care units, with up to one-third of infants demonstrating platelet counts <150 × 10(9)/L. Thrombocytopenia may arise from maternal, placental or fetal/neonatal origins featuring decreased platelet production, increased consumption, or both mechanisms. Over the past years, innovations in managing neonatal thrombocytopenia were achieved from prospectively obtained clinical data on thrombocytopenia and bleeding events, animal studies on platelet life span and production rate and clinical use of fully automated measurement of reticulated platelets (immature platelet fraction). This review summarizes the pathophysiology of neonatal thrombocytopenia, current management including platelet transfusion thresholds and recent developments in megakaryopoietic agents. Furthermore, we propose a novel index score for bleeding risk in thrombocytopenic neonates to facilitate clinician's decision-making when to transfuse platelets.


Assuntos
Transfusão de Plaquetas , Trombocitopenia/terapia , Benzoatos/uso terapêutico , Tomada de Decisão Clínica , Fármacos Hematológicos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Recém-Nascido , Terapia Intensiva Neonatal , Transfusão de Plaquetas/métodos , Transfusão de Plaquetas/normas , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/diagnóstico , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombopoese/fisiologia , Trombopoetina/uso terapêutico
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