The Obstetrical Care and Delivery Experience of Women with Epilepsy in the MONEAD Study.

OBJECTIVE: We examined mode of delivery among pregnant women with epilepsy (PWWE) versus pregnant controls (PC). We hypothesize that PWWE are more likely to deliver by cesarean. STUDY DESIGN: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an observational, prospective, multicenter investigation of pregnancy outcomes funded by the National Institute of Health (NIH). MONEAD enrolled patients from December 2012 through January 2016. PWWE were matched to PC in a case:control ratio of 3:1. This analysis had 80% power to detect a 36% increase in cesarean frequency assuming a baseline rate of 30% among PC at an α = 0.05. RESULTS: This report analyzed 331 PWWE (76%) and 102 PC (24%) who gave birth while enrolled in the study. PWWE and PC had similar rates of cesarean delivery (34.7 vs. 28.6%; p = 0.27). Of women with cesarean, rates of cesarean without labor were similar between groups for those delivering in recruitment hospitals (48.2 vs. 50.0%) but in nonrecruitment hospitals, cesarean rates without labor were over two-fold higher among PWWE than those of PC (68.8 vs. 30.8%; p = 0.023). Receipt of a cesarean after labor did not differ for PWWE compared to PC or by type of antiepileptic drug among the PWWE. CONCLUSION: These findings suggest that the obstetrical experiences of PWWE and PC are similar. An interesting deviation from this observation was the mode of delivery with higher unlabored cesarean rates occurring among PWWE in nonrecruitment hospitals. As the study recruitment hospitals were tertiary academic centers and nonrecruitment hospitals tended to be community-based institutions, differences in perinatal expertise might contribute to this difference. KEY POINTS: · Unlabored cesarean rates higher among women with epilepsy.. · Provider preference may influence delivery mode among women with epilepsy.. · Type and amount of antiepileptic drug was not associated with mode of delivery..

Urine Proteomics for Noninvasive Monitoring of Biomarkers in Bronchopulmonary Dysplasia.

INTRODUCTION: Current techniques to diagnose and/or monitor critically ill neonates with bronchopulmonary dysplasia (BPD) require invasive sampling of body fluids, which is suboptimal in these frail neonates. We tested our hypothesis that it is feasible to use noninvasively collected urine samples for proteomics from extremely low gestational age newborns (ELGANs) at risk for BPD to confirm previously identified proteins and biomarkers associated with BPD. METHODS: We developed a robust high-throughput urine proteomics methodology that requires only 50 µL of urine. We utilized the methodology with a proof-of-concept study validating proteins previously identified in invasively collected sample types such as blood and/or tracheal aspirates on urine collected within 72 h of birth from ELGANs (gestational age [26 ± 1.2] weeks) who were admitted to a single Neonatal Intensive Care Unit (NICU), half of whom eventually developed BPD (n = 21), while the other half served as controls (n = 21). RESULTS: Our high-throughput urine proteomics approach clearly identified several BPD-associated changes in the urine proteome recapitulating expected blood proteome changes, and several urinary proteins predicted BPD risk. Interestingly, 16 of the identified urinary proteins are known targets of drugs approved by the Food and Drug Administration. CONCLUSION: In addition to validating numerous proteins, previously found in invasively collected blood, tracheal aspirate, and bronchoalveolar lavage, that have been implicated in BPD pathophysiology, urine proteomics also suggested novel potential therapeutic targets. Ease of access to urine could allow for sequential proteomic evaluations for longitudinal monitoring of disease progression and impact of therapeutic intervention in future studies.

Neonatal Outcomes in the MONEAD Study of Pregnant Women with Epilepsy.

Objective: To determine whether growth measures at birth differ between offspring of pregnant women with epilepsy and healthy pregnant women. Study design: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a National Institutes of Health-funded, prospective, observational, multicenter investigation of pregnancy outcomes for mothers and their infants. Between 2012 and 2016, pregnant women with epilepsy and healthy pregnant women were enrolled at 20 US epilepsy centers. Pregnant women with epilepsy were exposed to various antiepileptic drugs. The main outcome measure was small for gestational age at birth. Principal univariate and multivariate analyses compared outcomes between pregnant women with epilepsy and healthy pregnant women. Secondary analyses focused on outcomes among mothers receiving different antiepileptic drug therapies. Results: In total, 345 infants were born to 331 pregnant women with epilepsy and 106 infants were born to 102 healthy pregnant women. No differences were seen between infants born to pregnant women with epilepsy vs healthy pregnant women in preterm births, major congenital malformations, 5-minute Apgar <6, special care nursery or neonatal intensive care unit admission, gestational age, or any growth measure. There was no difference in the rates of small for gestational age status among infants born to pregnant women with epilepsy vs healthy pregnant women; however, infants born to mothers receiving topiramate had lower birth weight z scores and lamotrigine higher birth weight z scores compared with other monotherapies. The greatest rate of special care nursery or neonatal intensive care unit admission was observed among those on oxcarbazepine monotherapy. Conclusions: Maternal treatment with antiepileptic drugs, overall, appears unassociated with adverse early neonatal outcomes. However, specific monotherapies appear to affect fetal growth with, on average, the greatest reduction in birth weight z score observed among infants born to pregnant women with epilepsy exposed to topiramate monotherapy.

Fetal loss and malformations in the MONEAD study of pregnant women with epilepsy.

OBJECTIVE: To examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016. RESULTS: The 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04-19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65-12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046). CONCLUSIONS: The findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.

Role of Genetic Susceptibility in the Development of Bronchopulmonary Dysplasia.

OBJECTIVE: To assess heritable contributions to bronchopulmonary dysplasia (BPD) risk in a twin cohort restricted to gestational age at birth <29 weeks. STUDY DESIGN: A total of 250 twin pairs (192 dichorionic, 58 monochorionic) born <29 weeks gestational age with known BPD status were identified. Three statistical methods applicable to twin cohorts (χ2 test, intraclass correlations [ICCs], and ACE modeling [additive genetic or A, common environmental or C, and unique environmental or E components]) were applied. Heritability was estimated as percent variability from A. Identical methods were applied to a subcohort defined by zygosity and to an independent validation cohort. RESULTS: χ2 analyses comparing whether neither, 1, or both of monochorionic (23, 19, 16) and dichorionic (88, 56, 48) twin pairs developed BPD revealed no difference. Although there was similarity in BPD outcome within both monochorionic and dichorionic twin pairs by ICC (monochorionic ICC = 0.34, 95% CI [0.08, 0.55]; dichorionic ICC = 0.39, 95% CI [0.25, 0.51]), monochorionic twins were not more likely than dichorionic twins to have the same outcome (P = .70). ACE modeling revealed no contribution of heritability to BPD risk (% A = 0.0%, 95% CI [0.0%, 43.1%]). Validation and zygosity based cohort results were similar. CONCLUSIONS: Our analysis suggests that heritability is not a major contributor to BPD risk in preterm infants <29 weeks gestational age.

Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.

UNLABELLED: Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero, and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities. CONCLUSION: There is a rationale for clinical trials to evaluate the potential benefits of IGF-1 replacement in very preterm infants.

Automatic measurement of interburst interval in premature neonates using range EEG.

OBJECTIVE: To explore the direct measure of EEG amplitude (range EEG, rEEG) for detection of interburst intervals (IBIs) and bursts in neonates. METHODS: Previously described 177 two-channel EEG recordings 3-6h long from 26 preterm infants (median gestational age of 26 weeks) at 23-38 weeks post-menstrual age (PMA) without major abnormalities were used to test four definitions of IBI detection algorithms with various settings of the parameters. RESULTS: As the basis for all four algorithms we developed the aggregation of rEEG signal over the channels by taking its maximum, and method of EEG trace selection at different phases of sleep-wake cycle (with different degree of discontinuity). The two less restrictive algorithms - with one and two amplitude thresholds - turned to be the most promising definitions. There were enough IBI detections for analysis, with no substantial difference in mean and maximum values of intervals. The longest IBI were measured at the location of greater discontinuity. Values of bursts and IBI indices as well as association with PMA were close to the published normative values derived manually. CONCLUSIONS: rEEG as a direct measure of EEG amplitude can be used for detection of bursts and IBI. SIGNIFICANCE: The automatic measurement of IBI based on rEEG provides a basis for improvements in neonatal brain monitoring.

Hemopexin in severe inflammation and infection: mouse models and human diseases.

INTRODUCTION: Cell-free plasma hemoglobin is associated with poor outcome in patients with sepsis. Extracellular hemoglobin and secondarily released heme amplify inflammation in the presence of microbial TLR ligands and/or endogenous mediators. Hemopexin, a plasma protein that binds heme with extraordinary affinity, blocks these effects and has been proposed as a possible treatment approach to decrease inflammation in critically ill patients. METHODS: We studied mouse models of endotoxemia, burn wound infections and peritonitis in order to assess if a repletion strategy for hemopexin might be reasonable. We also measured hemopexin in small numbers of three patient populations that might be logical groups for hemopexin therapy: patients with sepsis and ARDS, patients with severe burns, and premature infants. RESULTS: Despite severe disease, mean plasma hemopexin levels were increased above baseline in each murine model. However, plasma hemopexin levels were decreased or markedly decreased in many patients in each of the three patient populations. CONCLUSIONS: Potentially different behavior of hemopexin in mice and humans may be important to consider when utilizing murine models to represent acute human inflammatory diseases in which heme plays a role. The findings raise the possibility that decreased hemopexin could result in insufficiently neutralized or cleared heme in some patients with ARDS, burns, or in premature infants who might be candidates to benefit from hemopexin administration.

Stooling pattern and early nutritional exposures associated with necrotizing enterocolitis in premature infants.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency affecting premature infants. A better understanding of the clinical signs and symptoms associated with the disease may result in an improved ability to more effectively intervene in patient care. One of the clinical signs that have not been fully explored is the stooling pattern of preterm infants. This retrospective case-control study included 258 premature infants born prior to 29 weeks of gestation: 129 infants with NEC and 129 gestational age-matched controls. Data were collected from the medical record for the first 28 postnatal days. The relationships between the stooling pattern of premature infants and NEC were assessed via nonparametric techniques and linear mixed models. We identified few differences in the stooling pattern among infants with NEC and their unaffected counterparts. During the first week following birth, infants with NEC passed stool more frequently than controls. However, we found that these infants were taking nothing by mouth for fewer days in the first week following birth compared with controls. We also found that infants who developed NEC were fed smaller proportions of breast milk than healthy controls. Aberrant gut motility has been associated with prematurity and inflammatory bowel disease. However, our analyses did not identify any major differences in the stooling pattern among NEC case patients and controls. While further analyses may be needed, clinical suspicion for NEC should not be overwhelmingly influenced by the stooling pattern observed during the early neonatal period.

The relationship between TSH and systemic inflammation in extremely preterm newborns.

Elevated thyrotropin (TSH) levels in critically ill extremely premature infants have been attributed to transient hypothyroidism of prematurity or non-thyroidal illness syndrome. We evaluated the hypothesis that relatively high TSH levels in the first 2 postnatal weeks follow recovery from systemic inflammation, similar to non-thyroidal illness syndrome. The study was conducted in 14 Neonatal Intensive Care Units and approved by each individual Institutional Review Board. We measured the concentrations of TSH and 25 inflammation-related proteins in blood spots obtained on postnatal days 1, 7, and 14. We then evaluated the temporal relationships between hyperthyrotropinemia (HTT), defined as a TSH concentration in the highest quartile for gestational age and postnatal day, and elevated levels of inflammation-related proteins. 880 newborns less than 28 weeks of gestation were included. Elevated concentrations of inflammation-related proteins during the first or second week did not precede day-14 HTT. Systemic inflammation on day 7 was associated with day-14 HTT only if inflammation persisted through the end of the 2 week period. HTT frequently accompanied elevated concentrations of inflammation-related proteins on the same day. The hypothesis that HTT follows recovery from severe illness, defined as preceding systemic inflammation, is weakly supported by our study. Our findings more prominently support the hypothesis that TSH conveys information about concomitant inflammation in the extremely premature newborn.

Early blood gas predictors of bronchopulmonary dysplasia in extremely low gestational age newborns.

Aim. To determine among infants born before the 28th week of gestation to what extent blood gas abnormalities during the first three postnatal days provide information about the risk of bronchopulmonary dysplasia (BPD). Methods. We studied the association of extreme quartiles of blood gas measurements (hypoxemia, hyperoxemia, hypocapnea, and hypercapnea) in the first three postnatal days, with bronchopulmonary dysplasia, among 906 newborns, using multivariable models adjusting for potential confounders. We approximated NIH criteria by classifying severity of BPD on the basis of the receipt of any O2 on postnatal day 28 and at 36 weeks PMA and assisted ventilation. Results. In models that did not adjust for ventilation, hypoxemia was associated with increased risk of severe BPD and very severe BPD, while infants who had hypercapnea were at increased risk of very severe BPD only. In contrast, infants who had hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated the associations with hypoxemia and with hypercapnea and made the decreased risk of very severe BPD statistically significant. Conclusions. Among ELGANs, recurrent/persistent blood gas abnormalities in the first three postnatal days convey information about the risk of severe and very severe BPD.

Urinary intestinal fatty acid binding protein predicts necrotizing enterocolitis.

Necrotizing enterocolitis, characterized by sudden onset and rapid progression, remains the most significant gastrointestinal disorder among premature infants. In seeking a predictive biomarker, we found intestinal fatty acid binding protein, an indicator of enterocyte damage, was substantially increased within three and seven days before the diagnosis of necrotizing enterocolitis.

Vitamin D status among preterm and full-term infants at birth.

BACKGROUND: Risk factors for maternal vitamin D deficiency and preterm birth overlap, but the distribution of 25-hydroxyvitamin D (25(OH)D) levels among preterm infants is not known. We aimed to determine the associations between 25(OH)D levels and gestational age. METHODS: We measured umbilical cord plasma levels of 25(OH)D from 471 infants born at Brigham and Women's Hospital in Boston. We used generalized estimating equations to determine whether preterm (<37 wks' gestation) or very preterm (<32 wks' gestation) infants had greater odds of having 25(OH)D levels below 20 ng/ml than more mature infants. We adjusted for potential confounding by season of birth, maternal age, race, marital status, and singleton or multiple gestation. RESULTS: Mean cord plasma 25(OH)D level was 34.0 ng/ml (range: 4.1-95.3 and SD: 14.1). Infants born before 32 wks' gestation had increased odds of having 25(OH)D levels below 20 ng/ml in unadjusted (odds ratio (OR): 2.2; 95% confidence interval (CI): 1.1-4.3) and adjusted models (OR: 2.4; 95% CI: 1.2-5.3) as compared with more mature infants. CONCLUSION: Infants born in <32 wks' gestation are at higher risk than more mature infants for low 25(OH)D levels. Further investigation of the relationships between low 25(OH)D levels and preterm birth and its sequelae is thus warranted.

Low urine vascular endothelial growth factor levels are associated with mechanical ventilation, bronchopulmonary dysplasia and retinopathy of prematurity.

BACKGROUND: Organ-specific vascular endothelial growth factor (VEGF) expression is decreased during the pathogenesis of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) several weeks before either disease can be diagnosed. Early measurement of organ-specific tissue VEGF levels might allow identification of infants at high risk for these diseases, but is not clinically feasible. Urine VEGF is easily measured and useful in early diagnosis of several diseases. OBJECTIVES: Our aims were to assess the correlation of urine VEGF levels measured in the first postnatal month with subsequent BPD or ROP diagnosis and to determine whether various infant characteristics influence urine VEGF levels. METHODS: 106 subjects born at <29 weeks' gestation and surviving to 36 weeks' postmenstrual age were selected from an existing database and biorepository. Urine VEGF and total protein were measured in 2-3 samples per subject. RESULTS: Urine VEGF/protein levels increased by 72% per week (p < 0.0001) during the first postnatal month. In multivariable analysis controlling for postnatal age, lower VEGF/protein was associated with higher levels of mechanical respiratory support (p = 0.006), male gender (p = 0.001) and early sepsis (p = 0.003) but not with fraction of inspired oxygen. Lower urine VEGF/protein and mechanical ventilation were each associated with BPD and ROP. In analyses adjusted for respiratory support, lower urine VEGF/protein and ROP remained associated but urine VEGF/protein and BPD did not. CONCLUSIONS: Low urine VEGF/protein levels in the first postnatal month are associated with mechanical ventilation, BPD, and ROP.

Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborn.

OBJECTIVE: Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome of late-preterm and full-term infants associated with failure of the normal fetal-to-neonatal circulatory transition. This study was designed to test the hypothesis that risk for PPHN is increased after antenatal exposure to nonsteroidal antiinflammatory drugs (NSAIDs), with particular emphasis on late gestational exposures. METHODS: Between 1998 and 2003, we interviewed 377 women whose infants had PPHN and 836 control mothers of infants matched to cases by hospital and birth date. Interviews captured information on prescription and over-the-counter medication use in pregnancy as well as a variety of potential confounding factors. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for third-trimester maternal NSAID use were estimated by using multivariate conditional logistic regression. RESULTS: During the third trimester of gestation, 33 infants (8.8%) with PPHN were exposed to any NSAID compared with 80 (9.6%) controls (OR 0.8; 95% CI 0.5-1.3). We observed an elevated OR for PPHN risk among infants whose mothers consumed aspirin during the third-trimester; however, the lower 95% CI included the null. Neither nonaspirin NSAIDs at any time during pregnancy nor ibuprofen use during the third trimester was associated with an elevated risk of PPHN. Similarly, no association was observed between a mother's third-trimester acetaminophen use and the occurrence of PPHN in her newborn. CONCLUSIONS: This large multicenter epidemiologic study of PPHN risk revealed no evidence to support the hypothesis that maternal consumption during pregnancy of NSAIDs overall or ibuprofen in particular is associated with PPHN risk.

Systemic inflammation associated with mechanical ventilation among extremely preterm infants.

Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1ß, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1ß), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that 2 weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.

Innate immune activation in neonatal tracheal aspirates suggests endotoxin-driven inflammation.

BACKGROUND: Tracheal aspirates (TAs) from critically ill neonates accumulate bacterial endotoxin and demonstrate mobilization of endotoxin-binding proteins, but the potential bioactivity of endotoxin in TAs is unknown. We characterized innate immune activation in TAs of mechanically ventilated neonates. METHODS: Innate immune activation in TAs of mechanically ventilated neonates was characterized using a targeted 84-gene quantitative real-time (qRT) PCR array. Protein expression of cytokines was confirmed by multiplex assay. Expression and localization of the endotoxin-inducible antimicrobial protein Calgranulin C (S100A12) was assessed by flow cytometry. Endotoxin levels were measured in TA supernatants using the Limulus amoebocyte lysate assay. RESULTS: Analyses by qRT-PCR demonstrated expression of pattern recognition receptors, Toll-like receptor-nuclear factor κB and inflammasome pathways, cytokines/chemokines and their receptors, and anti-infective proteins in TA cells. Endotoxin positivity increased with postnatal age. As compared with endotoxin-negative TAs, endotoxin-positive TAs demonstrated significantly greater tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, and serpin peptidase inhibitor, clade E, member 1 (SERPINE1) mRNA, and IL-10, TNF, and IL-1ß protein. Expression of S100A12 protein was localized to TA neutrophils. CONCLUSION: Correlation of endotoxin with TA inflammatory responses suggests endotoxin bioactivity and the possibility that endotoxin antagonists could mitigate pulmonary inflammation and its sequelae in this vulnerable population.

Peak-to-peak amplitude in neonatal brain monitoring of premature infants.

OBJECTIVE: To assess the strength of association between alternative measures of electroencephalographic (EEG) signal peak-to-peak amplitude (ppA) and postmenstrual age (PMA) among a cohort of extremely premature infants. METHODS: 177 Two-channel EEG recordings 3-6h long were collected from 26 infants born before 29weeks of gestation. The raw EEG was converted into four different continuous measures of ppA: amplitude-integrated EEG (aEEG), range-EEG (rEEG), Gotman and Gloor's half-wave decomposition (HWD), and root of mean squares (RMS). For each ppA-measure EEG indices including mean, median, and 5% margins; indices of spread (width, standard deviation, coefficient of variation), and asymmetry were calculated for each 1min epoch. The medians of each index for the entire recording were tested for association with PMA using linear mixed models. RESULTS: The log-transformed values of aEEG and rEEG indices of spread were highly associated with PMA (fixed effects R(ß)(2)=0.84-0.89). CONCLUSIONS: Indices of spread by aEEG or rEEG can be used as indicators of neonatal brain maturation. However, rEEG produces the absolute values that most closely approximate the raw EEG amplitudes. SIGNIFICANCE: The indices of spread and rEEG as a measure of ppA provide a basis for improvements in neonatal EEG monitoring.

Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation.

Necrotizing enterocolitis (NEC) remains one of the most catastrophic comorbidities associated with prematurity. In spite of extensive research, the disease remains unsolved. The aims of this article are to present the current state of the science on the pathogenesis of NEC, summarize the clinical presentation and severity staging of the disease, and highlight the nursing assessments required for early identification of NEC and ongoing care for infants diagnosed with this gastrointestinal disease. The distributions of systemic and intestinal clinical signs that are most sensitive to nursing assessment and associated with Bell Staging Criteria are presented. These descriptive data are representative of 117 cases of NEC diagnosed in low-gestational-age infants (<29 weeks' gestation). The data highlight the clinical signs most commonly observed in infants with NEC and thus provide NICU nurses an evidence-based guide for assessment and care of infants with NEC.

Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first 2 postnatal weeks.

We examined the association between elevated concentrations of 25 blood proteins in blood spots collected on postnatal d 1, 7, and 14 from infants <28 wk gestation who survived to 24 mo and the risk of two patterns of early lung disease i.e. early and persistent pulmonary dysfunction (EPPD) and normal early pulmonary function followed by pulmonary deterioration (PD). Thirty-eight percent (n = 347) of our cohort had PD, and 43% (n = 383) had EPPD. On postnatal d 14, elevated concentrations of two proteins (RANTES and VEGF) were associated with reduced risk of PD. Similarly, the risk of EPPD was also reduced if three proteins had elevated concentrations on postnatal d 14 (RANTES, MMP-1, and VEGF). In contrast, the risk of EPPD was increased if on d 14 two proteins had elevated concentrations (IL-8 and ICAM-1). Inflammation might influence the risk of EPPD and PD or be a consequence of lung damage or therapies to minimize lung dysfunction.