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OBJECTIVE. Healthy very-low-birth-weight neonates (VLBW, < or = 1500 g) exhibit a high incidence of neutropenia according to Manroe's reference ranges for neutrophil indices. Since these reference ranges may be inappropriate for VLBW neonates, we determined the reference ranges for circulating peripheral neutrophils in VLBW neonates between birth and 28 days of age. METHODS. Serial, timed peripheral white blood cell counts (n = 1788) were prospectively obtained between birth and 28 days from 193 inborn, VLBW neonates delivered between January 1 and December 31, 1990. Data were divided into neutrophil counts obtained prior to (n = 630) and after (n = 1158) 60 hours of age. After excluding counts from neonates with perinatal and/or neonatal complications, values from 'normal' neonates were compared to Manroe's reference ranges. Where indicated new ranges were developed. RESULTS. Although immature neutrophil (ATI) and immature:total neutrophil (I:T) values were within Manroe's reference ranges (P > .1) throughout the neonatal period, 67% of total neutrophil values (ATN) obtained prior to 60 hours of age were outside (P < .001) and 95% were considered neutropenic. Newly developed ATN reference ranges for VLBW neonates have a wider range of distribution compared to Manroe's results, primarily reflecting a decrease in the lower boundary. ATN values between 61 hours and 28 days also differed (P < .001), and new ranges had upper and lower boundaries of 6000 and 1100/mm3, respectively. Maternal hypertension was associated with neonatal neutropenia (P < .001) without abnormalities of ATI or I:T prior to day 3 of life; however, neutrophilia predominated after day 7. Between birth and 28 days > 70% of ATN values were abnormal in neonates with apnea, neutrophilia occurring in > 90% of counts; I:T values, however, were normal between 61 hours and 28 days. CONCLUSIONS. Normal preterm VLBW neonates have ATN reference ranges that differ significantly from that for larger, older neonates, demonstrating the effects of development on neutrophil dynamics. The predictability of neonatal infection using these new reference ranges requires additional study. [ABSTRACT FROM AUTHOR]

The importance of a Neonatal Intensive Care Unit (NICU) database lies in its critical role in improving the quality of care for very preterm neonates and other high-risk newborns. These databases contain extensive information regarding maternal exposures, pregnancy complications, and neonatal care. They support quality improvement (QI) initiatives, facilitate clinical research, and track health outcomes in order to identify best practices and improve clinical guidelines. The Parkland Memorial Hospital NICU database was originally part of the Maternal and Neonatal Data Acquisition, Transmission and Evaluation project funded by the Robert Wood Johnson Foundation to assess perinatal-neonatal care in Dallas County Texas, 1977-1982. Clinical data points were defined, transcribed and validated in 1977; revalidation has occurred multiple times. Data are prospectively extracted from health records of high-risk neonates among >11,000 births annually. The database contains clinical information on >50,000 neonates, including all initially admitted to the NICU regardless of gestational age or birthweight and since 10/03/2011, all neonates admitted for observation and transferred to the term newborn nursery. The database has provided the basis for QI studies and research designed to assess and improve neonatal care. We discuss the history, evolution, administration, impact on neonatal outcomes, and future directions of our database. IMPACT: A single neonatal intensive care unit (NICU) database was designed for prospective data collection, validated and maintained for 46yrs. This database has supported quality improvement assessment, original clinical research, education and administrative requirements and impacted clinical neonatal care., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: The aim of this study was to determine which late-preterm (35-36 weeks' gestational age [GA]) and term neonates with early-onset hypoglycemia in the first 72 hours postnatal required a continuous glucose infusion to achieve and successfully maintain euglycemia., Study Design: This is a retrospective cohort study of late preterm and term neonates born in 2010-2014 and admitted to the Mother-Baby Unit at Parkland Hospital who had laboratory-proven blood glucose concentration < 40 mg/dL (2.2 mmol/L) during the first 72 hours of life. Among the subgroup needing intravenous (IV) glucose infusion, we analyzed which factors predicted a maximum glucose infusion rate (GIR) ≥ 10 mg/kg/min. The entire cohort was randomly divided into a derivation cohort ( n  = 1,288) and a validation cohort ( n  = 1,298)., Results: In multivariate analysis, the need for IV glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection, and other perinatal variables in both cohorts. A GIR ≥ 10 mg/kg / min was required in 14% of neonates with blood glucose value < 20 mg/dL during the first 3 hours of observation. The likelihood of a GIR ≥ 10 mg/kg/min was associated with lower initial blood glucose value and lower umbilical arterial pH., Conclusion: Need for IV glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection, and variables associated with perinatal hypoxia-asphyxia. The likelihood of a maximum GIR ≥ 10 mg/kg/min was greater in neonates with lower blood glucose value during the first 3 hours of observation and lower umbilical arterial pH., Key Points: · We studied 51,973 neonates ≥ 35 weeks' GA.. · We established a model predicting the need for IV glucose.. · We also predicted the need for a high rate of IV glucose.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: A ventricle-to-brain index (VBI) >0.35 is associated with low scores on the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) in preterm infants with birth weight <1,250 g. However, VBI obtained at the third ventricle has only moderate interobserver reliability. The objective of this study was to test (1) reliability of VBI measured at the foramen of Monro on the latest ultrasonogram (US) before discharge using the intraclass correlation coefficient (ICC) and (2) the relationship between VBI and BSID-III scores at ≥18 months corrected age., Study Design: The present study is a single-center retrospective cohort study., Results: The study included 270 preterm infants born at 23 0/7 to 28 6/7 weeks of gestational age. The ICC of VBI between independent measurements by two study radiologists on the first 50 patients was 0.934. Factors associated with the value of VBI included severe intraventricular hemorrhage, bronchopulmonary dysplasia, and systemic steroid administration for BPD but not postmenstrual age. In multivariate analysis, VBI was negatively and independently associated with cognitive ( p  = 0.002), language ( p  = 0.004), and motor ( p  < 0.001) BSID-III scores. The association between VBI and BSID-III scores was observed even in infants in whom the latest US was obtained before term equivalent age. The association between VBI and BSID-III scores was also observed after excluding those with severe intraventricular hemorrhage., Conclusion: In this very preterm cohort the measurement of VBI had excellent reliability. Moreover, VBI measurements were negatively associated with motor, language, and cognitive BSID-III scores., Key Points: · Mean values of VBI are stable with postmenstrual age.. · Values at the foramen of Monro are reliable and reproducible.. · VBI is negatively associated with Bayley scores.. · The association is observed even before term age.., Competing Interests: None declared, (Thieme. All rights reserved.)

Objective: The primary objectives were to compare body mass index (BMI) Z-score (Z), systolic blood pressure (SBP), serum leptin:adiponectin (L:A) ratio and estimated glomerular filtration rate (eGFR) at ~3 years adjusted age between two arms of a randomized controlled trial (RCT) comparing two modes of human milk fortification for very low-birthweight infants in the neonatal intensive care unit., Study Design: Follow-up of RCT at 33-48 months., Results: Follow-up data are available in 82/120 infants. Infants in the experimental arm have anthropometric data consistent with central obesity and higher serum L:A ratio (sensitivity analysis adjusting for sex and using all available data), but have similar eGFR and SBP at follow-up compared with controls. Serum L:A ratio is strongly correlated with anthropometric measurements suggesting central obesity., Conclusions: Infants in the experimental arm have central obesity and higher serum L:A ratio compared with controls. Notably, serum L:A ratio is strongly correlated with weight gain., Trial Registration: This randomized controlled trial was registered at ClinicalTrials.gov NCT02372136., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To determine the association of placental pathology with the severity of necrotizing enterocolitis (NEC) in preterm infants., Methods: This single-center matched case-control study included infants with NEC ( n  = 107) and gestational age and birth weight-matched controls ( n  = 130), born between 2013 and 2020. Placentas were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement., Results: Acute histologic chorioamnionitis with the fetal response was significantly more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p  = 0.02). On regression model, infants with multiple placental pathologies (OR 2.16; 95% CI 1.01 - 4.73; p  = 0.04) and maternal vascular malperfusion (OR 2.2; 95% CI 1.12 - 4.51; p  = 0.02) had higher odds of either medical or surgical NEC than controls., Conclusion: Infants with multiple placental lesions, including placental inflammatory and vascular lesions, were at higher risk of medical or surgical NEC in the postnatal period.

Background: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia., Methods: Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1β, IL-2, IL-6, IL-8, TNFα, and IL-10., Results: IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA»UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA»UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis., Conclusions: Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects., Impact: The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Infants born very preterm (≤32 weeks gestational age, GA) and very-low birth weight (≤1500 g; PT-VLBW) demonstrate high systolic blood pressure (SBP), renal dysfunction, and obesity at 6 months-3 years and in early adulthood. Their parallel measurement and progression during childhood is unclear., Methods: We reenrolled 62/120 patients originally seen at 1-3 years at 10-13 years and remeasured anthropometric indices, SBP, and serum creatinine (Cr) and cystatin C (cysC) to determine estimated glomerular filtration rate (eGFR). We selected Term-matched Controls at 10-13 years from the 2015-2016 NHANES database at a ratio of 2 Controls:1 Case (124:62)., Results: Reenrolled patients were predominantly Hispanic, birth weight 1073 ± 251 g, and GA at birth 28 ± 2 weeks. At 10-13 years, 45% were classified overweight/obese, 48% had SBP ≥ 90th centile (77% considered hypertensive), and 34% had low eGFR (<90 mL min -1  [1.73 m 2 ] -1 ). Notably, 57% of reenrolled PT-VLBW Cases had low eGFR cysC at both 1-3 and 10-13 years, P < 0.03. Compared to Controls, Cases had four times the adjusted odds for having an elevated SBP and low eGFR Cr despite similar proportions with overweight/obesity among Cases and Controls., Conclusions: PT-VLBW infants seen at 1-3 years exhibit obesity, elevated SBP, and low eGFR in infancy and 10-13 years. Although the small sample size may limit conclusions, pediatricians should consider serial evaluations of PT-VLBW throughout childhood., Impact: The association between preterm birth and elevated blood pressure, renal dysfunction, and obesity in young adults begins as early as 1 year and persists at 10-13 years of age. This is the first study reporting serial measurements of blood pressure, renal function, and obesity from infancy to preadolescence in children born very preterm. Fifty-seven percent of preterm 1-3 year olds have persistent low estimated glomerular filtration rate associated with hypertension at 10-13 years. Clinicians should consider serial evaluations of blood pressure, renal function, and obesity throughout infancy and childhood in all preterm births., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: To determine the association of placental pathologic lesions with postoperative outcomes, survival, and white matter injury (WMI) in preterm infants with NEC., Methods: A retrospective chart review of 107 neonates with NEC (Bell stage > IIa) from Jan 2013- June 2020 was completed. Demographic, clinical, and outcome data were compared between infants with or without placental pathologic lesions., Results: In this cohort, 59/107 (55%) infants had medical NEC, and 48 (45%) had surgical NEC. The infants had a mean gestational age of 28.1±3.7 weeks and a birth weight of 1103±647 g. Maternal vascular malperfusion (82/107, 76.6%) and acute histological chorioamnionitis (42, 39.3%) were the most common pathological placental lesions. Acute histologic chorioamnionitis with fetal inflammatory response was more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p = 0.02). The NEC Infants with WMI on brain MRI scans had a significantly higher incidence of acute histological chorioamnionitis (52% vs. 27.8%; P = 0.04). No significant differences in mortality, length of stay and postoperative outcomes in neonates with and without acute histologic chorioamnionitis with fetal inflammatory response were noted. On unadjusted logistic regression, acute histologic chorioamnionitis without fetal inflammatory response was also associated with higher odds of WMI (OR 2.81; 95% CI 1.05-7.54; p = 0.039)., Conclusion: Acute histological chorioamnionitis without fetal inflammatory response was associated with higher odds of WMI in infants with NEC, with no significant impact on mortality and other postoperative outcomes.

Background: Human milk supplementation for preterm infants in the neonatal intensive care unit (NICU) can be based on optimized nutrition (feeding adjustments based on growth and measurements of serum nutrients) or individualized nutrition (measurements of macronutrients in mother's own milk)., Objective: To compare Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18-38mo adjusted age in infants who had been randomly allocated to individualized+optimized nutrition (experimental group) vs optimized nutrition alone (control) in the NICU., Methods: Double-blinded randomized controlled trial in neonates <29wks gestational age (GA) and those <34wks GA and small for GA., Results: Bayley scores were assessed in 91/114 (80%) infants. The two study groups had similar frequencies of low cognitive, motor and language Bayley scores and similar age-adjusted Bayley scores in bivariate and multivariate analyses., Conclusions: The type of human milk supplementation provided had no significant effect on Bayley scores assessed at 18-38mo., Trial Registration: This randomized controlled trial was registered at ClinicalTrials.gov NCT02372136., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Environmental justice and health research demonstrate unequal exposure to environmental hazards at the neighborhood-level. We use an innovative method-eco-intersectional multilevel (EIM) modeling-to assess intersectional inequalities in industrial air toxics exposure across US census tracts in 2014. Results reveal stark inequalities in exposure across analytic strata, with a 45-fold difference in average exposure between most and least exposed. Low SES, multiply marginalized (high % Black, high % female-headed households) urban communities experienced highest risk. These inequalities were not described by additive effects alone, necessitating the use of interaction terms. We advance a critical intersectional approach to evaluating environmental injustices., Competing Interests: Declaration of competing interest Not applicable., (Published by Elsevier Ltd.)

Background: Randomized trials of antenatal steroid administration (ANS) for extreme or moderate preterm pregnancies excluded women with diabetes mellitus (DM) and included few with preeclampsia., Methods: Cohort study (n = 1,813) including moderate preterm births [29 0/7 -33 6/7 wks' gestational age GA)] before (Epoch-1) and after (Epoch-2) expansion of ANS administration to women with hypertensive disorders (HTN) and/or DM. We compared surfactant administration in Group-1 (neither HTN nor DM), Group-2a (HTN not DM), Group-2b (DM not HTN) and Group-2c (DM and HTN)., Results: Surfactant administration was less frequent after ANS in Group-1 [adjusted odds ratio (aOR) 0.54, 95% confidence interval (CI) 0.31, 0.93, P = 0.03], Group-2a (aOR 0.36, CI 0.22, 0.58, P < 0.001) and Group-2c (aOR 0.29, CI 0.12, 0.71, P = 0.007) but not Group-2b (P = 0.64)., Conclusions: ANS administration was independently associated with less surfactant administration in moderately preterm neonates whose mothers had neither HTN nor DM, and those with HTN, but not those with DM without HTN., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Severe burns result in cardiovascular dysfunction, but responses in the peripheral vasculature are unclear. We hypothesize that severe burns disturb arterial contractility through acute changes in adrenergic and cholinergic receptor function. To address this, we investigated the changes in carotid artery contractility and relaxation following a severe burn. Thirty-four adult Sprague-Dawley male rats received a 40% total body surface area (TBSA) scald burn and fluid resuscitation using the Parkland formula. Control animals received sham burn procedure. Animals were serially euthanized between 6 h and 14 days after burn and endothelium-intact common carotid arteries were used for ex vivo force/relaxation measurements. At 6 h after burn, carotid arteries from burned animals demonstrated a > 50% decrease in cumulative dose-responses to norepinephrine (p < 0.05) and to 10 -7  M angiotensin II (p < 0.05). Notably, pre-constricted carotid arteries also demonstrated reduced relaxation responses to acetylcholine (p < 0.05) 6 h after burn, but not to sodium nitroprusside. Histologic examination of cross-sectional planes revealed significant increases in carotid artery wall thickness in burned rats at 6 h versus 3 days, with increased collagen expression in tunica media at 3 days (p < 0.05). Carotid artery dysfunction occurs within 6 h after severe burn, demonstrating decreased sensitivity to adrenergic- and angiotensin II-induced vasoconstriction and acetylcholine-induced relaxation., (© 2021. The Author(s).)

Background: Randomized trials of antenatal steroids (ANS) included women at 24-33 weeks gestational age (GA); however, few women had preeclampsia and women with diabetes mellitus (DM) were excluded., Methods: Cohort study including preterm births at 23 0/7 -28 6/7 weeks GA before (Epoch-1) and after (Epoch-2) expansion of ANS administration to women with DM and hypertensive disorders (HTN). We compared Group-A (neither DM nor HTN) and Group-B (DM and/or HTN)., Results: Among 747 neonates the adjusted odds ratio (aOR) for surfactant administration, in-hospital mortality, severe intraventricular hemorrhage (IVH) and death or severe IVH were lower in ANS-exposed neonates than unexposed neonates. In Group-B, ANS administration was independently associated with less severe IVH and less death or severe IVH, but not less surfactant use or mortality., Conclusions: Increased ANS administration in women with DM and/or HTN was independently associated with less severe IVH and less death or severe IVH but without decrease in surfactant administration., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The prevalence of autism spectrum disorders (ASD) is 5-fold higher in preterm (PT) infants born ≤28 weeks gestational age (GA) as compared to the general population. The relationship between placental pathologic lesions and ASD in PT infants has not been studied., Objectives: The objective of this study was to determine the association of placental pathology with the occurrence of ASD in PT infants born ≤28 weeks GA., Study Design: A matched case-control study to identify confirmed ASD cases (n = 16) and matched controls (n = 48) born at Parkland Hospital between January 2012 and December 2015. Patients were matched using known variables associated with increased risk of ASD in PT infants. Placental histology from all births was reviewed., Results: Children with ASD had 2-fold greater incidence of multiple placental pathologic lesions vs. matched controls [11/16 (69%) vs.16/48 (33%), respectively; P = 0.01]. In contrast, single placental pathologic lesions were not associated with ASD [5/16 (31%) vs. 21/48 (43%), respectively; P = 0.1]., Conclusions: In this study, we have demonstrated an association between the increasing complexity of histologic placental lesions and the later risk for ASD in infants born ≤28 weeks GA. Thus, placental pathology findings may be valuable in further understanding the prenatal pathologic processes underlying ASD in PT infants., Impact: PT infants with ASD have a 2-fold greater incidence of multiple placental pathologies. This is the first study to report an association between the complexity of histologic placental lesions and later risk of ASD in infant born extremely PT (i.e., ≤28 weeks GA). This study reiterates the importance of examining placental pathologic lesions, since placental evidence of antenatal insults correlates with postnatal morbidities and mortality in PT infants.

Objective: To assess if the adjusted odds of low composite cognitive Bayley-III scores changed after implementing a single-institution quality improvement (QI) project designed to decrease discharge Z-scores for weight, body mass index (BMI), and weight-for-length, but not length or fronto-occipital circumference (FOC) in infants 23-28 weeks gestational age (GA)., Methods: Compare Bayley-III outcomes at ≥18 months corrected age (postnatal age adjusted for prematurity) in infants tested before (Epoch-1) and after (Epoch-2) QI implementation., Results: Bayley testing was available in 134/156 infants (86%) in Epoch-1 and 139/175 (79%) in Epoch-2. There was no change in frequency of low (<85) cognitive score (p = 0.5) or in median cognitive scores (80 in Epoch-1 vs. 85 Epoch-2, p = 0.35). The adjusted odds of low cognitive scores was not different between Epochs., Conclusion: No change in cognitive outcome at ≥18 months corrected age was observed after implementing a QI project designed to reduce discharge weight-for-length disproportion in very preterm infants.

Objectives: To compare immediate cessation of nasal continuous positive airway pressure (NCPAP) vs a stepwise decrease in pressure on the duration of NCPAP therapy in infants born prematurely., Study Design: A single center study in infants 23 0 -32 6  weeks of gestational age. NCPAP was stopped either at 5 cm H 2 O (control) or 3 cm H 2 O after a stepwise pressure wean (wean) using defined stability and failure criteria. Primary outcome is total NCPAP days., Results: We enrolled 226 infants; 116 were randomly assigned to control and 110 to the wean group. There was no difference in the total NCPAP days between groups (median [25th, 75th percentiles] 16 [5, 36] vs 14 [7, 33] respectively). There were no differences between groups in secondary outcomes, including duration of hospital stay, critical care days, and oxygen supplementation. A higher proportion of control infants failed the initial attempt to discontinue NCPAP (43% vs 27%, respectively; P < .01) and required ≥2 attempts (20% vs 5%, respectively; P < .01). In addition, infants 23-27 weeks of gestational age in the wean group were 2.4-times more likely to successfully stop NCPAP at the first attempt (P = .02) vs controls., Conclusions: Discontinuation of NCPAP after a gradual pressure wean to 3 cm H 2 O did not decrease the duration of NCPAP therapy compared with stopping from 5 cm H 2 O in infants ≤32 weeks of gestational age. However, weaning decreased failed initial attempts to stop NCPAP, particularly among infants <28 weeks of gestational age., Trial Registration: Clinicaltrials.gov: NCT02064712., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Drawing on the traditions of environmental justice, intersectionality, and social determinants of health, and using data from the EPA's NATA 2014 estimates of cancer risk from air toxics, we demonstrate a novel quantitative approach to evaluate intersectional environmental health risks to communities: Eco-Intersectional Multilevel (EIM) modeling. Results from previous case studies were found to generalize to national-level patterns, with multiply marginalized tracts with a high percent of Black and Latinx residents, high percent female-headed households, lower educational attainment, and metro location experiencing the highest risk. Overall, environmental health inequalities in cancer risk from air toxics are: (1) experienced intersectionally at the community-level, (2) significant in magnitude, and (3) socially patterned across numerous intersecting axes of marginalization, including axes rarely evaluated such as gendered family structure. EIM provides an innovative approach that will enable explicit consideration of structural/institutional social processes in the social production of intersectional and geospatial inequalities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To assess whether in very preterm infants (1) body mass index (BMI) Z-score and weight-for-length (WtFL) Z-score at 1 year of age and (2) head growth from discharge to 1 year are associated with breastfeeding at discharge and the age of onset and type of complementary foods., Study Design: Observational cohort study., Results: Infants started on only ready-made complementary (RMC) feedings at ≤26 weeks adjusted age had the highest adjusted BMI Z-score and WtFL Z-score at 1 year of age. Adjusted change in fronto-occipital circumference was highest in infants either discharged on breastmilk or receiving home-made complementary food with/without RMC (HMM) at ≤26 weeks adjusted age., Conclusions: Infants started on RMC ≤26 weeks adjusted age had the highest BMI Z-score and WtFL Z-score at 1 year. Head growth from discharge to 1 year was highest in infants either discharged on breastmilk or receiving HMM at ≤26 weeks adjusted age.

Objective: In preterm neonates fed human milk, fortification may be adjusted by (1) optimization, based on growth rate and serum nutrient analyses, or (2) individualization, based on serial milk nutrient analyses. The primary aim was to determine whether individualized plus optimized nutrition (experimental) improves velocity of weight gain and linear growth from birth to endpoint (36 weeks postmenstrual age or discharge) when compared with optimized nutrition alone (controls)., Study Design: Double-blinded parallel group randomized trial in 120 neonates <29 weeks gestational age (GA) or <35 weeks and small for GA (birth weight < 10th centile)., Result: Weight-gain velocity (13.1 ± 2.1, n = 57 controls, vs. 13.0 ± 2.6 g kg -1  day -1 , n = 59 experimental, P = 0.87), linear growth (0.9 ± 0.2, n = 55, vs. 0.9 ± 0.2 cm week -1 , n = 52, P = 0.90) and frequency of weight/length disproportion (2% vs. 2%, P = 0.98) were similar in both groups., Conclusions: Individualized plus optimized nutrition does not improve weight gain, linear growth, or weight/length disproportion at endpoint versus optimized nutrition alone.

Background: To determine the association of placental pathology, including multiple placental lesions, with the occurrence and severity of bronchopulmonary dysplasia (BPD), death, and neurodevelopmental impairment (NDI) in preterm infants., Method: A retrospective cohort study of neonates <29 weeks gestational age (GA) born at Parkland Hospital from 08/2009 to 08/2012. Infants were stratified as follows: Group 1: no significant placental pathology; Group 2: single significant placental lesion; and Group 3: ≥2 placental lesions (multiple lesions). Primary outcome was death and/or BPD. Two-year neurodevelopmental follow-up was compared., Results: In all, 42% (100/241) of infants had one placental lesion, and 34% (82/241) ≥2 lesions. As the number of the pathologic lesions increased (no lesions vs. 1 vs. ≥2), the occurrence of death or BPD increased (25%, 37%, and 52%, respectively; P = 0.004). Moreover, infants with multiple pathologic lesions were more likely to have NDI (29%, 29%, and 46%, respectively; P = 0.03). After logistic regression, infants with multiple pathologic lesions were more likely to develop moderate-to-severe BPD [P < 0.01; OR 3.9 (1.5-10.1)] but not NDI., Conclusion(s): Neonates <29 weeks GA with multiple placental pathologic lesions have an increased risk for developing BPD, suggesting an interaction between placental inflammation and vascular pathology and the pathogenesis of BPD; however, the risk of NDI is not increased.

Background: V-Go is a wearable, patch-like, 24-h insulin delivery device that delivers both a continuous preset basal rate and on-demand bolus dosing. The aim of this study was to observe glycemic control, insulin dosing, and hypoglycemia risk in patients switched to V-Go in a real-world setting. The primary objective was to compare change in mean hemoglobin A1c (HbA1c) from baseline to the end of V-Go use., Methods: This prospective, open-label, multicenter study recruited patients with type 2 diabetes (T2D) and suboptimal glycemic control (HbA1c ≥ 7%) across 28 centers. Efficacy analyses were conducted for all patients with a post-baseline HbA1c and results stratified based on prior antihyperglycemic medication therapies. Insulin dosing was at the discretion of the health care provider and the protocol did not mandate glycemic targets. Treatment satisfaction surveys were utilized to gain patient feedback on the use of V-Go., Results: One hundred eighty-eight patients were enrolled in the study, among whom 140 patients had a valid post-baseline HbA1c and were included in the primary efficacy analysis. Use of V-Go resulted in a change of - 0.64%; (P = 0.003) in HbA1c from baseline, and in those prescribed insulin, the total daily dose of insulin was decreased by 12 units/day (P < 0.0001). Twenty-two patients (12%) reported hypoglycemic events (≤ 70 mg/dL), with an event rate of 1.51 events/patient/year., Conclusion: In a T2D population with suboptimal HbA1c, initiating V-Go therapy in a real-world setting significantly improved glycemic control and led to significant insulin dose reductions. ClinicalTrial.gov registry identifier: NCT01326598.

Background: Patent ductus arteriosus (PDA) management varies widely among neonatologists., Local Problem: Lack of institution-specific evidence-based guidelines for therapeutic closure of PDA., Methods: Quality improvement project among infants <30 weeks gestational age (GA) designed to determine whether the odds of therapy for closing the PDA, adjusted for GA, decreased after implementing evidence-based guidelines., Intervention: Implementation of guidelines with conservative approach to PDA management., Results: The frequency of PDA treatment decreased from 446/1125 (40%) in Epoch 1 to 96/482 (20%) in Epoch 2. PDA treatment was more frequent in neonates 23-26 weeks GA than those of 27-29 weeks GA (43% vs. 28%, respectively). Among 542 infants receiving indomethacin for PDA, 25% had subsequent ligation; the odds of ligation after indomethacin were lower in neonates 27-29 weeks GA and decreased during Epoch 2., Conclusions: The frequency of medical and surgical treatment for therapeutic closure of PDA decreased after implementing evidence-based treatment guidelines.

Background: Fetal concentrations of GFAP and UCH-L1 are elevated in umbilical arterial (UmA) blood of neonates with birth asphyxia plus neonatal encephalopathy (NE), but their source and role of placental clearance/synthesis is unknown., Methods: Prospective cohort study of term neonates to (a) determine UmA and venous (UmV) blood concentrations of GFAP and UCH-L1 in term uncomplicated pregnancies and their placental synthesis and/or clearance and (b) compare UmA concentrations in uncomplicated pregnancies with those complicated by fetal hypoxia-asphyxia+NE. Three term groups were studied: uncomplicated cesarean delivery without labor (Group 1, n = 15), uncomplicated vaginal delivery with labor (Group 2, n = 15), and perinatal hypoxia-asphyxia+NE (Group 3, n = 8)., Results: UmA GFAP concentrations were lower in Group 1 vs. 2 (P = 0.02) and both demonstrated 100% placental clearance. In contrast, UmA and UmV UCH-L1 concentrations were not unaffected by labor. Group 3 UmA GFAP concentrations were 30- and 8-fold higher than Groups 1 and 2, respectively, P = 0.02, whereas UmA UCH-L1 concentrations were similar in all groups., Conclusions: UmA GFAP is derived from the fetus, and circulating levels, which are modulated by placental clearance, increase during uncomplicated labor and more so in the presence of fetal hypoxia-asphyxia+NE, providing a better biomarker than UCH-L1 for hypoxia-asphyxia+NE.

Background: Preterm very-low-birth-weight (≤1500 g) infants exhibit disproportionate weight-for-length growth in the Neonatal Intensive Care Unit., Local Problem: High frequency of body mass index (BMI) > 90th centile at discharge and 1-year postnatal age associated with elevated blood pressure and serum leptin in infancy and adolescence., Methods: Single-institution quality improvement project in appropriately grown infants born at 23 0/7 -28 6/7 weeks gestational age and discharged home., Intervention: Adjustable feeding protocol based on valid serial length measurements (board or caliper)., Results: The average monthly percentage of weight-for-length disproportion at discharge decreased from 13% in Epoch 1 to 0% in Epoch 2 (P < 0.05). Although the average Z-score for BMI at discharge was lower in Epoch 2 versus Epoch 1 (P < 0.01), this was absent by 1 year follow-up (P = 0.91)., Conclusions: Adjustable feedings plus use of accurate serial length measurements decreases weight-for-length disproportion at hospital discharge but not at 1 year.

Objectives: Determine incidence of preoperative adrenal insufficiency in neonates >35 weeks gestation with congenital heart disease undergoing cardiothoracic surgery with bypass and effects of prophylactic methylprednisolone on postoperative hypothalamic-pituitary-adrenal function and hemodynamic stability., Design: Prospective observational study in 36 neonates with preoperative adrenocorticotrophic hormone stimulation tests and serial total cortisol and adrenocorticotrophic hormone measurements before and after surgery. Data analyses: analysis of variance and regression., Results: Baseline circulating adrenocorticotrophic hormone and cortisol were unchanged 4-20 days postnatal (P > 0.1); however, cortisol levels rose with increasing adrenocorticotrophic hormone, P = 0.02. Ten neonates (29%) demonstrated preoperative adrenal insufficiency (∆cortisol ≤9 µg/dl); one had postoperative hemodynamic instability. Growth-restricted neonates had lower baseline cortisol, but normal stimulation tests and responded well to surgical stresses. Seventy-five percent of neonates receiving perioperative methylprednisolone demonstrated postoperative hypothalamic-pituitary-adrenal inhibition., Conclusion: Adrenal insufficiency appears common in neonates >35 weeks gestation with congenital heart disease, but did not contribute to postoperative hemodynamic instability despite hypothalamic-pituitary-adrenal inhibition.

Objectives: Determine sources of error in electronically extracted data from electronic health records., Study Design: Categorical and continuous variables related to early-onset neonatal hypoglycemia were preselected and electronically extracted from records of 100 randomly selected neonates within 3479 births with laboratory-proven early-onset hypoglycemia. Extraction language was written by an information technologist and data validated by blinded manual chart review. Kappa coefficient assessed categorical variables and percent validity continuous variables., Results: 8/23 (35%) categorical variables had acceptable Κappa (1-0.81); 5/23 (22%) had fair-slight agreement, Κappa < 0.40. Notably, "hypoglycemia" had poor agreement, Κappa 0.16. In contrast, 6/8 continuous variables had validity ≥ 94%. After correcting extraction language, 6/9 variables were corrected and inter-rater validation improved. However, "hypoglycemia" was not corrected, remaining an issue., Conclusions: Data extraction without validation procedures, especially categorical variables using International Classification of Diseases-9 (ICD-9) codes, often results in incorrect data identification. Electronically extracted data must incorporate built-in validating processes.

Objective: To determine the validity of screening and serial neutrophil counts in predicting the absence/presence of late-onset sepsis (LOS) in infants with central venous catheters., Study Design: Retrospective study of infants admitted to the neonatal intensive care unit (2009-2013) at Parkland Hospital with a central venous catheter and ≥1 LOS evaluations. Infants were categorized as proven or suspect LOS or uninfected based on results of blood cultures, clinical illness, and duration of antibiotics. Receiver operating curves (ROCs) were constructed to predict the absence or presence of LOS using Manroe reference ranges for total and immature neutrophils and the immature to total neutrophil ratio at 0, 12, and 24 hours after blood culture and the neutrophil value score, which assesses serial values., Results: Of the 497 infants with a central venous catheter, 179 underwent ≥1 LOS evaluations, and 140 of 179 (78%) had ≥1 complete evaluations (2 blood cultures and neutrophil values at 0, 12, and 24 hours), resulting in 188 complete LOS evaluations. The gestational age was 28 ± 4 weeks and LOS evaluation occurred at 29 ± 34 days (SD; 4-197 days). Sixty-one (35%) infants had proven LOS, 48 (23%) were suspect, and 71 (38%) were noninfected. ROC comparing proven vs noninfected was ≤0.56 for total neutrophils, immature neutrophils, and immature to total neutrophil ratio at 0, 12, and 24 hours and similar for proven + suspect vs noninfected. ROC for neutrophil value scores and absence of LOS was 0.56., Conclusions: Screening neutrophil values are poor predictors of LOS in neonates with a central venous catheter, as are serial neutrophils and the neutrophil value score. Alternative biomarkers are needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The lack of a valid and safe method for measuring length in critically ill preterm neonates has led to a primary focus on weight gain., Local Problem: Paucity of valid length measurements, precluding the accurate analysis of growth patterns., Methods: Quality improvement project among infants < 29 weeks or small for gestational age < 35 weeks with embedded validation of (1) a caliper (infantometer) for length measurements and (2) length measurements during the first week to estimate birth length., Intervention: Implementation of valid methods to measure length., Results: We validated infantometer measurements and first week length measurements. The percentage of neonates with valid measurements during the first week rose from 10% to 78%, resulting in increased identification of classifiable growth patterns from < 10% to 89%., Conclusions: By increasing the percentage of neonates with valid length measurements in the first week postnatal, we identified an increased number of neonates with classifiable growth abnormalities.

Objective: To examine the inter-rater reliability for the diagnosis of LSV on cranial ultrasound (cUS), determine the risk factors associated with LSV and its progression, and examine neurodevelopmental outcome., Study Design: Prospective case-control study of neonates ≤32wks of gestation assessed for LSV by serial cUS (n = 1351) between 2012 and 2014 and their neurodevelopment at 18-36mon-corrected age compared to controls., Results: Agreement for LSV on cUS improved from Κappa 0.4-0.7 after establishing definitive criteria and guidelines. BPD was the only variable associated with the occurrence and the progression of LSV. Cytomegalovirus (CMV) infection occurred in one neonate (1.5%). Neurodevelopmental outcome of neonates with LSV did not differ from controls., Conclusions: Establishment of well-defined stages of LSV improves the reliability of the diagnosis and allows identification of neonates with progression of LSV. Although LSV was associated with BPD, it was not associated with congenital CMV infection.

Background: Cytokines modulate fetal well-being and contribute to parturition. Their origin in fetal blood, whether maternal, placental or fetal, at the time of parturition remains unclear., Objective: To determine fetal and placental contributions to circulating fetal cytokines by measuring umbilical arterial (UmA) and venous (UmV) concentration differences in uncomplicated term pregnancies in the absence and presence of labor., Methods: Term uncomplicated pregnancies were assessed: Group 1 were not in labor and delivered by elective cesarean section (n = 20); Group 2 delivered vaginally following uncomplicated pregnancy and labor (n = 30). UmA and UmV blood was collected before delivery of the placenta to measure circulating cytokines. Placental tissue was collected for histology and to determine cytokine contents and localization., Results: Group 1 UmA and UmV IL-10 concentrations were similar (504 ± 15 and 468 ± 16 pg/ml, respectively; P ≥ 0.1); other cytokines were below level of detection. During labor, IL-10 concentrations increased 15-34%, but placental contents decreased. Group 2 UmA IL-6 and IL-8 concentrations increased (P < 0.001) to 16.7 ± 1.6 and 18.4 ± 4.3 pg/ml, respectively, but were less (P < 0.001) in UmV, 0.29 ± 0.2 and 0.74 ± 0.3 pg/ml, respectively, demonstrating placental clearances ≥97%. This was associated with >6-fold increases in placental IL-6/IL-8 contents (P < 0.001) and chorioamniotic infiltration of activated maternal neutrophils. IL-6 and IL-10 were localized to villous syncytiotrophoblasts., Conclusions: In uncomplicated term pregnancies fetal circulating IL-10 is likely of placental origin, whereas IL-6/IL-8 are derived from the fetus, increase during parturition, and circulating levels are modulated by non-saturable placental clearance, revealing a novel pathway for fetal-placental crosstalk and signaling., (Published by Elsevier Ltd.)

Background: Preterm, very-low-birth-weight (PT-VLBW) neonates are at-risk for metabolic syndrome later in life. At 1-3 y, they exhibit excessive weight-for-length z-scores (Wt-L Z ) and elevated systolic blood pressures (SBP). Serum adipokines are biomarkers of adiposity, but expression in PT-VLBW infants is unclear. We examined the correlation between serum adipokine levels, anthropometric measures and SBP in PT-VLBW neonates at follow-up., Methods: This was a cross-sectional cohort study of PT-VLBW infants at 1, 2, and 3 y of age (40/cohort). We measured SBP, abdominal circumference (AC) and anthropometrics; calculated age/gender-specific z-scores for Wt, L, Wt-L and subscapular skin fold (SS Z ), and measured serum adipokines., Results: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-L Z , AC, and SS Z at 1 and 3 y (P < 0.01). Female infants at 1 and 3 y had a more significant relationship than males between serum leptin and SS Z (P < 0.001, R = 0.75 and P < 0.001, R = 0.70, respectively). Adiponectin levels were 16-20% lower at 3 vs. 1-2 y (P = 0.02, ANOVA) and negatively correlated with SBP., Conclusion: Although serum leptin was unrelated to advancing age, gender, and SBP in PT-VLBW infants, levels correlated with measures of adiposity at 1 and 3 y, females > males, suggesting leptin resistance may occur in early infancy.

Limitations of extant research on neighborhood disadvantage and health include general reliance on point-in-time neighborhood measures and sensitivity to residential self-selection. Using data from the US Census and the 1995-2008 National Longitudinal Study of Adolescent to Adult Health, we applied conventional methods and coarsened exact matching to assess how cardiometabolic health varies among those entering, exiting, or remaining in poor and nonpoor neighborhoods. Within the full sample (n = 11,767), we found significantly higher systolic and diastolic blood pressures among those who entered or consistently lived in poor neighborhoods relative to those who never lived in poor neighborhoods. Obesity was similarly more common among those who originated from poor neighborhoods than among those who originated from nonpoor neighborhoods. Having exited poor neighborhoods was associated with lower systolic blood pressure than was consistent residence in low-income communities. Among the matched sample (n = 9,727), results adjusted for confounders and residential self-selection revealed fewer significant contrasts. Compared with peers who had no neighborhood poverty exposure, those who consistently lived in poor neighborhoods had 46% and 52% higher odds of being obese or hypertensive, respectively. Those who exited neighborhood poverty had significantly higher diastolic blood pressures than those who had never lived in poor neighborhoods. These findings underscore the importance of past as well as current residential circumstances for cardiometabolic health., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Endogenous hydrogen sulfide (H2S) synthesized via metabolizing L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) is a potent vasodilator and angiogenic factor. The objectives of this study were to determine if human uterine artery (UA) H2S production increases with augmented expression and/or activity of CBS and/or CSE during the menstrual cycle and pregnancy and whether exogenous H2S dilates UA. Uterine arteries from nonpregnant (NP) premenopausal proliferative (pPRM) and secretory (sPRM) phases of the menstrual cycle and pregnant (P) women were studied. H2S production was measured by the methylene blue assay. CBS and CSE mRNAs were assessed by quantitative real-time PCR, and proteins were assessed by immunoblotting and semiquantitative immunofluorescence microscopy. Effects of H2S on rat UA relaxation were determined by wire myography ex vivo. H2S production was greater in NP pPRM and P than NP sPRM UAs and inhibited by the specific CBS but not CSE inhibitor. CBS but not CSE mRNA and protein were greater in NP pPRM and P than NP sPRM UAs. CBS protein was localized to endothelium and smooth muscle and its levels were in a quantitative order of P >NP UAs of pPRM>sPRM. CSE protein was localized in UA endothelium and smooth muscle with no difference among groups. A H2S donor relaxed P > NP UAs but not mesentery artery. Thus, human UA H2S production is augmented with endothelium and smooth muscle CBS upregulation, contributing to UA vasodilation in the estrogen-dominant physiological states in the proliferative phase of the menstrual cycle and pregnancy., (© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fetal blood pressure increases during late gestation; however, the underlying vascular mechanisms are unclear. Knowledge of the maturation of resistance arteries is important to identify the mechanisms and vulnerable periods for the development of vascular dysfunction in adulthood., Methods: We determined the functional and structural development of fetal sheep mesenteric resistance arteries using wire myography and immunohistochemistry., Results: Media mass and distribution of myosin heavy-chain isoforms showed no changes between 0.7 (100 ± 3 days) and 0.9 (130 ± 3 days) gestation. However, from 0.7 to 0.9 gestation, the resting wall tension increased accompanied by non-receptor-dependent (potassium) and receptor-dependent (noradrenaline; endothelin-1) increases in vasocontraction. Angiotensin II had no contractile effect at both ages. Endothelium-dependent relaxation to acetylcholine and prostaglandin E2 was absent at 0.7 but present at 0.9 gestation. Augmented vascular responsiveness was paralleled by the maturation of sympathetic and sensory vascular innervation. Non-endothelium-dependent relaxation to nitric oxide showed no maturational changes. The expression of vasoregulator receptors/enzymes did not increase between 0.7 and 0.9 gestation., Conclusion: Vascular maturation during late ovine gestation involves an increase in resting wall tension and the vasoconstrictor and vasodilator capacity of the mesenteric resistance arteries. Absence of structural changes in the tunica media and the lack of an increase in vasoregulator receptor/enzyme expression suggest that vasoactive responses are due to the maturation of intracellular pathways at this gestational age., (© 2017 S. Karger AG, Basel.)

Background: It is well known that adolescent body mass index (BMI) shows school-level clustering. We explore whether school-level clustering of BMI persists into adulthood., Methods: Multilevel models nesting young adults in schools they attended as adolescents are fit for 3 outcomes: adolescent BMI, self-report adult BMI and measured adult BMI. Sex-stratified and race/ethnicity-stratified (black, Hispanic, white, other) analyses were also conducted., Results: School-level clustering (wave 1 intraclass correlation coefficient (ICC)=1.3%) persists over time (wave 4 ICC=2%), and results are comparable across stratified analyses of both sexes and all racial/ethnic groups (except for Hispanics when measured BMIs are used). Controlling for BMI in adolescence partially attenuates this effect., Conclusions: School-level clustering of BMI persists into young adulthood. Possible explanations include the salience of school environments in establishing behaviours and trajectories, the selection of adult social networks that resemble adolescent networks and reinforce previous behaviours, and characteristics of school catchment areas associated with BMI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Although neonatal encephalopathy (NE) due to perinatal asphyxia accounts for a notable proportion of brain injury, the causal pathway remains largely unexplained. We sought to determine the association of placental pathology with: (1) severity of NE in the first 6 hours postnatal, and (2) abnormal neurodevelopmental outcomes (NDO) in neonates requiring hypothermia therapy., Study Design: This is a retrospective cohort study of neonates ≥36 weeks' gestation born at Parkland Hospital, Dallas, TX, from January 2006 through November 2011 with NE. Placental histology was reviewed and validated by a pediatric pathologist blinded to outcomes. Abnormal NDO was defined as death or Bayley-III score of <85 at 18-24 months of age., Results: Of 86,274 neonates ≥36 weeks' gestation, 120 had evidence of a combination of perinatal acidosis and NE. In all, 47 had mild NE and received no treatment, while 73 had moderate (n = 70) or severe (n = 3) NE and received systemic hypothermia. Nine neonates died and all survivors receiving hypothermia had a Bayley-III assessment at 22 ± 7 (SD) months of age. Chorioamnionitis with or without fetal response and patchy/diffuse chronic villitis were found to be independently associated with severity of NE (P < .001). Univariate logistic regression revealed an association with a diagnosis of major placental pathology (odds ratio, 3.5; 95% confidence interval, 1.1-11.4) and abnormal outcomes following cooling. Specifically, diffuse chronic villitis (odds ratio, 9.29; 95% confidence interval, 1.11-77.73) was the only individual predictor of abnormal NDO following hypothermia therapy., Conclusion: Placental inflammatory villitis appears to be a harbinger of abnormal outcomes in neonates with NE, spanning to the 18-24 month NDO., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Maternal nutrition has a profound long-term impact on infant health. Poor maternal nutrition influences placental development and fetal growth, resulting in low birth weight, which is strongly associated with the risk of developing chronic diseases, including heart disease, hypertension, asthma, and type 2 diabetes, later in life. Few studies have delineated the mechanisms by which maternal nutrition affects fetal lung development. Here, we report that maternal exposure to a diet high in fat (HFD) causes placental inflammation, resulting in placental insufficiency, fetal growth restriction (FGR), and inhibition of fetal lung development. Notably, pre- and postnatal exposure to maternal HFD also results in persistent alveolar simplification in the postnatal period. Our novel findings provide a strong association between maternal diet and fetal lung development., (Copyright © 2015 the American Physiological Society.)

Lenticulostriate vasculopathy (LSV) is a diagnosis dependent on neonatal cranial ultrasound (US). The diagnosis of LSV requires the presence of linear or branching echogenicities in the area of the basal ganglia and/or thalamus on gray scale cranial US. Although the diagnosis of LSV is dependent on cranial US, there are no convincing correlates observed on either computerized tomography or magnetic resonance imaging. Moreover, the radiographic criteria for LSV on cranial US remain vague, and intra-observer correlations are generally reported to be poor. The purpose of this review is to examine the issues associated with the use of cranial US and the diagnosis of LSV, including alternative imaging, clinical abnormalities and the significance of LSV on cranial US., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Although lenticulostriate vasculopathy (LSV) was recognized nearly 30 years ago, neonatologists and radiologists still question its clinical significance. The diagnosis of LSV may be highly subjective, resulting in many false negatives when the radiologist is not familiar with the lesion or false positive if over-read by those with special interest in this finding. There has been an increase in incidence of LSV since its recognition in 1985 which might reflect nothing more than a growing awareness of this finding on neonatal cranial ultrasound. On the other hand, improved ultrasound imaging technology may have enhanced identification of LSV. Prospective studies evaluating the presence, significance and diagnosis of LSV are limited and have produced conflicting results. Therefore, the associated risk factors and clinical relevance of LSV on cranial ultrasound remain unclear. This review will examine the existing literature., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Estrogens dramatically dilate numerous vascular beds with the greatest response in the uterus. Endogenous hydrogen sulfide (H2S) is a potent vasodilator and proangiogenic second messenger, which is synthesized from L-cysteine by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). We hypothesized that estrogen replacement therapy (ERT) selectively stimulates H2S biosynthesis in uterine artery (UA) and other systemic arteries. Intact and endothelium-denuded UA, mesenteric artery (MA), and carotid artery (CA) were obtained from ovariectomized nonpregnant ewes (n = 5/group) receiving vehicle or estradiol-17β replacement therapy (ERT). Total RNA and protein were extracted for measuring CBS and CSE, and H2S production was determined by the methylene blue assay. Paraffin-embedded UA rings were used to localize CBS and CSE proteins by immunofluorescence microscopy. ERT significantly stimulated CBS mRNA and protein without altering CSE mRNA or protein in intact and denuded UA. Quantitative immunofluorescence microscopic analyses showed CBS and CSE protein localization in endothelium and smooth muscle and confirmed that ERT stimulated CBS but not CSE protein expression in UA endothelium and smooth muscle. ERT also stimulated CBS, but not CSE, mRNA and protein expression in intact and denuded MA but not CA in ovariectomized ewes. Concomitantly, ERT stimulated UA and MA but not CA H2S production. ERT-stimulated UA H2S production was completely blocked by a specific CBS but not CSE inhibitor. Thus, ERT selectively stimulates UA and MA but not CA H2S biosynthesis by specifically up-regulating CBS expression, implicating a role of H2S in estrogen-induced vasodilation and postmenopausal women's health.

Mechanisms regulating uteroplacental blood flow (UPBF) in pregnancy remain unclear, but they likely involve several integrated signaling systems. Endothelium-derived nitric oxide (NO) is considered an important contributor, but the extent of its involvement is unclear. Bolus intra-arterial infusions of nitro-l-arginine methyl ester (l-NAME) modestly decrease ovine basal UPBF; however, the doses and duration of infusion may have been insufficient. We, therefore, examined prolonged uterine artery (UA) NO synthase inhibition with l-NAME throughout the last third of ovine pregnancy by performing either continuous 30-min UA infusion dose responses (n = 4) or 72-h UA infusions (0.01 mg/ml) at 104-108, 118-125, and 131-137 days of gestation (n = 7) while monitoring mean arterial pressure (MAP), heart rate (HR), and UPBF. Uteroplacental vascular resistance (UPVR) was calculated, and uterine cGMP synthesis was measured. Thirty-minute UA l-NAME infusions did not dose dependently decrease UPBF, increase UPVR, or decrease uterine cGMP synthesis (P > 0.1); however, MAP rose and HR fell modestly. Prolonged continuous 72-h UA l-NAME infusions decreased UPBF ∼32%, increased UPVR ∼68% (P ≤ 0.001), and decreased uterine cGMP synthesis 70% at 54-72 h (P ≤ 0.004); the noninfused uterine horn was unaffected. These findings were associated with ∼10% increases in MAP and decreases in HR that were greater at 104-108 than 118-125 and 131-137 days of gestation (P = 0.006). Although uterine and UA NO and cGMP synthesis increase severalfold during ovine pregnancy, they contribute modestly to the maintenance and rise in UPBF in the last third of gestation. Thus, local UA NO may primarily modulate vasoconstrictor responses. Notably, the systemic vasculature appears more sensitive than the uterine vasculature to NO synthase inhibition., (Copyright © 2014 the American Physiological Society.)

The uteroplacental vasculature is refractory to α-adrenergic stimulation, and large conductance Ca(2+)-activated K(+) channels (BK(Ca)) may contribute. We examined the effects of uterine artery (UA) BK(Ca) inhibition with tetraethylammonium (TEA) on hemodynamic responses to phenylephrine (PE) at 101 to 117 days and 135 to 147 days of ovine gestation, obtaining dose responses for mean arterial pressure (MAP), heart rate (HR), and uteroplacental blood flow (UPBF) and vascular resistance (UPVR) before and during UA TEA infusions. The UA α(1)-adrenergic receptors (α1-ARs) were assessed. The PE increased MAP and UPVR and decreased HR and UPBF dose dependently at both gestations (P < .001, analysis of variance). The %▵MAP was less at 135 to 147 days before and during TEA infusions (P ≤ .008); however, responses during TEA were greater (P ≤ .002). The PE increased %▵UPVR>>%▵MAP, thus %▵UPBF fell. The TEA enhanced PE-mediated increases in %▵UPVR at 135 to 147 days (P ≤ .03). The UA α(1)-AR expression was unchanged in pregnancy. Uterine vascular responses to PE exceed systemic vascular responses throughout pregnancy and are attenuated by BK(Ca) activation, suggesting BK(Ca) protect UPBF.

Objective: To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes., Study Design: This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6-24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15-18 months., Results: Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6-24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6-24 hours were associated with abnormal neurological outcomes., Conclusions: The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes., (Copyright © 2014 Mosby, Inc. All rights reserved.)