Persistent high blood pressure and renal dysfunction in preterm infants during childhood.

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 m2]-1). Notably, 57% of reenrolled PT-VLBW Cases had low eGFRcysC 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 eGFRCr 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.

Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis.

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-1ß, 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), UmA¼UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA¼UmV. 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.

Factors Associated with Need for Intravenous Glucose Infusion for the Treatment of Early Neonatal Hypoglycemia in Late Preterm and Term Neonates.

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..

Relationship between Ventricular Size on Latest Ultrasonogram and the Bayley Scores ≥ 18 Months in Extremely Low Gestational Age Neonates: A Retrospective Cohort Study.

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 230/7 to 286/7 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..

Association of Placental Pathologic Findings with the Severity of Necrotizing Enterocolitis in Preterm infants - A Matched Case-Control Study.

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.

Discontinuing Nasal Continuous Positive Airway Pressure in Infants ≤32 Weeks of Gestational Age: A Randomized Control Trial.

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 230-326 weeks of gestational age. NCPAP was stopped either at 5 cm H2O (control) or 3 cm H2O 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 H2O did not decrease the duration of NCPAP therapy compared with stopping from 5 cm H2O 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.

Autism spectrum disorders in extremely preterm infants and placental pathology findings: a matched case-control study.

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.

Impact of multiple placental pathologies on neonatal death, bronchopulmonary dysplasia, and neurodevelopmental impairment in preterm infants.

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.

Screening and Serial Neutrophil Counts Do Not Contribute to the Recognition or Diagnosis of Late-Onset Neonatal Sepsis.

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.

Placental clearance/synthesis of neurobiomarkers GFAP and UCH-L1 in healthy term neonates and those with moderate-severe neonatal encephalopathy.

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.

Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation.

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.

Fetal Sheep Mesenteric Resistance Arteries: Functional and Structural Maturation.

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.

Biomarkers of adiposity are elevated in preterm very-low-birth-weight infants at 1, 2, and 3 y of age.

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-LZ) 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 (SSZ), and measured serum adipokines. RESULTS: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-LZ, AC, and SSZ 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 SSZ (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.

Maternal high-fat diet is associated with impaired fetal lung development.

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.

Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia.

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.

Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy.

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.

Serial neutrophil values facilitate predicting the absence of neonatal early-onset sepsis.

OBJECTIVE: To validate established neonatal neutrophil reference ranges (RRs) and determine the utility of serial measurements of neutrophil values in the first 24 hours to predict the absence of neonatal early-onset sepsis (EOS). STUDY DESIGN: Retrospective study of 2073 admissions to the neonatal intensive care unit (2009-2011). Neonates were classified as blood culture-positive, proven EOS (n = 9), blood culture-negative but clinically suspect EOS (n = 292), and not infected (n = 1292). Neutrophil values from 745 not-infected neonates without perinatal complications were selected to validate RR distributions. Positive and negative predictive values were calculated; area under receiver operating characteristic curves (AUCs) were constructed to predict the presence or absence of EOS. Neutrophil value scores were established to determine whether serial neutrophil values predict the absence of EOS. RESULTS: Seventy-seven percent of admissions to the neonatal intensive care unit were evaluated for EOS: 9 (0.56%) had proven EOS with positive blood culture ≤ 37 hours; 18% had clinically suspect EOS. Neutropenia occurred in preterm neonates, and nonspecific neutrophilia was common in uninfected neonates. The distribution of neutrophil values differed significantly between study groups. The specificity for absolute total immature neutrophils and immature to total neutrophil proportions was 91% and 94%, respectively, with negative predictive value of 99% for proven and 78% for proven plus suspect EOS. Absolute total immature neutrophils and immature to total neutrophil proportions had the best predictability for EOS >6 hours postnatal with an AUC ∼ 0.8. Neutrophil value scores predicted the absence of EOS with AUC of 0.9 and 0.81 for proven and proven plus suspect EOS, respectively. CONCLUSION: Age-dependent neutrophil RRs remain valid. Serial neutrophil values at 0, 12, and 24 hours plus blood culture and clinical evaluation can be used to discontinue antimicrobial therapy at 36-48 hours.

Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy.

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.

Follow-up of a randomized trial optimizing neonatal nutrition in preterm very low birthweight infants: growth, serum adipokines, renal function and blood pressure.

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.

Double-blinded randomized controlled trial of optimizing nutrition in preterm very low birth weight infants: Bayley scores at 18-38 months of age.

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.