Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm.

OBJECTIVES: Evidence-based care of extremely preterm infants (<28 weeks' gestation) depends heavily on research in which a primary outcome is infant neurodevelopmental impairment (NDI), yet it is unclear how well NDI in infancy predicts long-term NDI. In this study, we aim to assess the relationship between 2- and 10-year neurodevelopment using a well-known 2-year definition and a 10-year definition developed by an expert panel. METHODS: Using data from the Extremely Low Gestational Age Newborn Study cohort, we classified 2-year NDI using definitions developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. We classified 10-year NDI using definitions developed by an expert panel, which added epilepsy and ASD at 10 years. RESULTS: Of 1506 infants, 80% survived. Data sufficient to classify severity of NDI at both 2 and 10 years were available for 67% of survivors (n = 802). Among children classified as having moderate to severe NDI at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. Cohen's κ statistic indicated minimal to fair agreement between NDI at 2 and 10 years (0.34, P < .001). CONCLUSIONS: NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.

Teamwork, communication and resident leadership at resident-attended, neonatal delivery room resuscitations.

OBJECTIVE: Determine if a NICU resident delivery room (DR) skills educational curriculum is associated with changes in neonatal resuscitation team characteristics, including teamwork, communication and leadership. STUDY DESIGN: This prospective, observational study of resident-attended neonatal resuscitations utilized team questionnaire, video assessment and chart review. Each resident NICU block included a curriculum consisting of two educational programs focusing on NRP knowledge and skills with additional emphasis on teamwork and communication strategies. RESULTS: Ninety-nine resuscitations met inclusion criteria. Comparing behaviors at the beginning versus end of a NICU block, residents demonstrated increased frequency of initiating leadership (31% vs. 93%, p < 0.001) and maintaining leadership (19% vs. 79%, p < 0.001) at low-risk, resident-attended DR resuscitations. Overall measurements of teamwork and communication were unchanged. CONCLUSIONS: A NICU DR skills educational curriculum is associated with increased resident leadership at low-risk DR resuscitations over the course of NICU blocks, without compromising measurements of teamwork or communication.

Effect of Routine, Screening Head Ultrasounds on Clinical Interventions for Premature Infants.

OBJECTIVE: This article assesses whether routine, screening head ultrasound (HUS) studies performed at 7 to 14 postnatal days for premature infants are followed by clinical interventions. STUDY DESIGN: This retrospective cohort study included all inborn infants delivered at < 30 weeks' gestational age (GA) between January 1, 2012 and December 31, 2015 at a single center who had a routine, screening HUS performed between 7 and 14 postnatal days (n = 303). We defined "clinical intervention" as a 7 to 14 postnatal day HUS that was followed by neurosurgical intervention prior to a 36- to 40-week postmenstrual age (PMA) HUS or elective withdrawal of critical care within 30 days of a positive HUS finding. RESULTS: Four infants (1.3%) had neurosurgical intervention prior to a 36- to 40-week PMA HUS; all four had a diagnostic HUS performed prior to postnatal day 7 to assess for an intraventricular hemorrhage (IVH) due to clinical instability. No infant had critical care electively withdrawn following a 7 to 14 postnatal day HUS. CONCLUSION: Clinical intervention rarely followed routine, screening HUS studies performed at 7 to 14 postnatal days for inborn infants delivered at < 30 weeks' GA. In no case did clinical intervention related to HUS results occur when a 7 to 14 postnatal day HUS was the initial HUS performed.

Development and validation of the Proxy-Reported Pulmonary Outcomes Scale for premature infants.

OBJECTIVE: Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures. STUDY DESIGN: Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool. RESULT: We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies. CONCLUSION: The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

Factors Influencing the Accuracy of Noninvasive Blood Pressure Measurements in NICU Infants.

OBJECTIVE: Compare invasive blood pressure (IBP) and noninvasive blood pressure (NIBP) measurement methods in the neonatal intensive care unit (NICU) across various gestational age and postmenstrual age (PMA), and determine the effect of gestational age and PMA on accuracy of NIBP measurements. STUDY DESIGN: Retrospective chart review of paired mean IBP and NIBP measurements from infants admitted to a single NICU from January 2008 through December 2010. Infants with congenital anomalies or receiving therapeutic hypothermia were excluded. Difference between paired measurements was analyzed using Bland-Altman method. We examined the association between PMA, sex, race, mechanical ventilation, medications, and axillary temperature, and the difference in measurements using a mixed effects linear regression model. RESULTS: Eighty-seven infants had 243 observations. The mean (range) gestational age at birth was 31.9 (23-41) weeks and PMA at time of measurement ranged from 26 to 52 weeks. We found poor agreement between IBP and NIBP measurements, with mean difference (95% limits of agreement) of -8.8 (11, -28.7) mm Hg. The mean blood pressure percent difference ( ± SD) was -28.3 ( ± 35.6%). A greater blood pressure percent difference between the two measurement techniques was associated with lower PMA and lower mean IBP. CONCLUSION: NIBP measurements overestimate IBP measurements particularly in smaller, sicker infants at lower IBP measurements.

Influence of neonatal practice variation on outcomes of late preterm birth.

OBJECTIVE: Examine variation in short-term outcomes of late preterm births (34(0/7)-36(6/7) weeks) between a university teaching hospital, teaching community hospital, and nonteaching community hospital. STUDY DESIGN: Review of maternal and newborn data from a random sample of late preterm births at three hospitals in North Carolina from 2008 to 2009. Outcomes included length of stay, neonatal intensive care unit (NICU) admission, respiratory support, antibiotic exposure, phototherapy exposure, and hypoglycemia. RESULTS: We analyzed data from 331 singleton late preterm newborns: 93 (28.1%) from a university teaching hospital, 110 (33.2%) from a teaching community hospital, and 128 (38.7%) from a nonteaching community hospital. Mean gestational age did not vary between hospitals. NICU admission, exposure to antibiotics, and phototherapy were more common at the university teaching hospital after controlling for risk factors, yet length of stay was shortest at the university teaching hospital and longest at the teaching community hospital after adjustment. CONCLUSION: Practice variation contributes to differences in length of stay, NICU admission, and exposure to antibiotics and phototherapy among late preterm newborns. Differences in practice during the birth hospitalization may affect outcomes and health care utilization (e.g., readmission) after discharge.

Regional variation in late preterm births in North Carolina.

Late preterm (LPT) neonates (34 0/7th-36 6/7th weeks' gestation) account for 70% of all premature births in the United States. LPT neonates have a higher morbidity and mortality risk than term neonates. LPT birth rates vary across geographic regions. Unwarranted variation is variation in medical care that cannot be explained by sociodemographic or medical risk factors; it represents differences in health system performance, including provider practice variation. The purpose of this study is to identify regional variation in LPT births in North Carolina that cannot be explained by sociodemographic or medical/obstetric risk factors. We searched the NC State Center for Health Statistics linked birth-death certificate database for all singleton term and LPT neonates born between 1999 and 2006. We used multivariable logistic regression analysis to control for socio-demographic and medical/obstetric risk factors. The main outcome was the percent of LPT birth in each of the six perinatal regions in North Carolina. We identified 884,304 neonates; 66,218 (7.5%) were LPT. After multivariable logistic regression, regions 2 (7.0%) and 6 (6.6%) had the highest adjusted percent of LPT birth. Analysis of a statewide birth cohort demonstrates regional variation in the incidence of LPT births among NC's perinatal regions after adjustment for sociodemographic and medical risk factors. We speculate that provider practice variation might explain some of the remaining difference. This is an area where policy changes and quality improvement efforts can help reduce variation, and potentially decrease LPT births.

Development of a proxy-reported pulmonary outcome scale for preterm infants with bronchopulmonary dysplasia.

BACKGROUND: To develop an accurate, proxy-reported bedside measurement tool for assessment of the severity of bronchopulmonary dysplasia (also called chronic lung disease) in preterm infants to supplement providers' current biometric measurements of the disease. METHODS: We adapted Patient-Reported Outcomes Measurement Information System (PROMIS) methodology to develop the Proxy-Reported Pulmonary Outcomes Scale (PRPOS). A multidisciplinary group of registered nurses, nurse practitioners, neonatologists, developmental specialists, and feeding specialists at five academic medical centers participated in the PRPOS development, which included five phases: (1) identification of domains, items, and responses; (2) item classification and selection using a modified Delphi process; (3) focus group exploration of items and response options; (4) cognitive interviews on a preliminary scale; and (5) final revision before field testing. RESULTS: Each phase of the process helped us to identify, classify, review, and revise possible domains, questions, and response options. The final items for field testing include 26 questions or observations that a nurse assesses before, during, and after routine care time and feeding. CONCLUSIONS: We successfully created a prototype scale using modified PROMIS methodology. This process can serve as a model for the development of proxy-reported outcomes scales in other pediatric populations.

Neurodevelopmental outcome of infants with unilateral or bilateral periventricular hemorrhagic infarction.

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05-0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64-1.00] vs 11% [95% CI: 0.01-0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

Insulin-like growth factor and interleukin-1beta levels and subsequent fetal size in response to chronic Porphyromonas gingivalis exposure in the pregnant rabbit.

OBJECTIVE: The purpose of this study was to describe maternal insulin-like growth factor, interleukin-1beta, and fetal size in a rabbit model of Porphyromonas gingivalis exposure. STUDY DESIGN: With the use of a previously described model, 8 New Zealand White rabbits were exposed to either P gingivalis or media during pregnancy and killed at term. Kit and placenta weight were compared between groups. Doe serum insulin-like growth factor system protein and interleukin-1beta levels were compared by analysis of variance for repeated measures; a probability value of <.05 was considered to be significant. RESULTS: No significant differences in kit and placental weights between exposed and unexposed groups were observed. Insulin-like growth factor system proteins increased significantly as pregnancy progressed, but there were no significant differences in insulin-like growth factor system proteins or interleukin-1beta between exposed and unexposed does. CONCLUSION: Chronic P gingivalis exposure does not disrupt insulin-like growth factor system proteins or systemic inflammation and does not impair fetal growth in the pregnant rabbit. Gestational age changes in doe insulin-like growth factor system proteins occur, and the timing of exposure to oral pathogens may influence fetal growth.

Regulation of insulin-like growth factor (IGF)-binding protein expression by growth factors and cytokines alters IGF-mediated proliferation of postnatal lung fibroblasts.

Postnatal day 5 is the beginning of septation and the peak of postnatal fibroblast proliferation. The author and colleagues studied fibroblasts from this developmental time period to determine factors that regulate cell proliferation. Exposure of cells to insulin-like growth factor (IGF)-I for 48 hours increased cell number whereas exposure to epithelial growth factor (EGF), platelet-derived growth factor (PDGF)-BB, fibroblast growth factor (FGF)-7, FGF-2, tumor necrosis factor-alpha (TNF-alpha), or interleukin (L)-1beta did not alter cell number. Long[R3]IGF-I (a synthetic IGF analog with reduced affinity for IGF-binding proteins [IGFBPs]) was more potent than IGF-I, with half-maximal stimulation at a dose of 0.6 nM for long[R3]IGF-I compared to 1.5 nM for IGF-I, suggesting that IGFBPs in the conditioned medium (CM) inhibit IGF activity. Addition of exogenous IGFBP-3 inhibited the IGF-stimulated increase in cell number. Addition of IGFBP-4 did not alter IGF activity because IGF-I stimulated proteolysis of IGFBP-4. The expression of mRNA for PAPP-A (a known IGFBP-4 protease) suggests that the clearance of IGFBP-4 is mediated by pregnancy-associated plasma protein (PAPP)-A. Exposure of cells to TNF-alpha or IL-1beta increased IGFBP-3 mRNA abundance and IGFBP-3 protein in CM. PDGF-BB and IL-1beta increased IGFBP-4 protein abundance and PDGF-BB and dibutyryl cAMP increased IGFBP-4 mRNA. The increase in CM IGFBP-3 following TNF-alpha exposure blocked IGF-mediated cell proliferation, suggesting that the growth factor- and cytokine-mediated changes in IGFBP abundance regulate postnatal fibroblast cell proliferation.

Dexamethasone changes the composition of insulin-like growth factor binding proteins in the newborn mouse ileum.

BACKGROUND: Early postnatal glucocorticoid exposure accelerates the maturation of the bowel mucosa but results in bowel wall thinning in the newborn mouse ileum and increases the risk of focal ileal perforation in extremely premature infants. We have previously demonstrated a redistribution of insulin-like growth factor-I (IGF-I) from the submucosa in control animals to the distal villi of those treated with early postnatal dexamethasone, implicating IGF-I as an important mediator of dexamethasone's capacity to alter tissue growth. To investigate the possibility that IGF binding proteins (IGFBPs) might contribute to this process, we characterized the localization and abundance of IGFBP peptides and mRNAs in the same model. METHODS: Newborn mice received daily intraperitoneal injections of dexamethasone (l microg/g) or phosphate-buffered saline and then were euthanized on day 3 of life. Their ileums were harvested and prepared for microscopy. Tissue sections of ileum from both treatment conditions were processed in parallel for immunolocalization of each of the six IGFBP peptides and for in situ hybridization of each of the six IGFBP transcripts. RESULTS: Transcripts for IGFBP-1, -2, and -3 were highly abundant and ubiquitous the ileal mucosa, whereas transcripts for IGFBP-4, -5, and -6 were less abundant in epithelial cells. There were no differences in abundance between control and dexamethasone-treated ileum with regard to mRNA localization or abundance for IGFBP-1, -2, -3, and -6. In contrast, mRNA transcripts for IGFBP-4 and -5 were modestly increased with dexamethasone treatment (although only IGFBP-4 was significant). Strikingly different patterns of IGFBP immunolocalization were observed between control and dexamethasone-treated animals. IGFBP-1, -2, -3, and -5 were not detected in control ileum, whereas IGFBP-4 and -6 were both present in the mucosa. In contrast, dexamethasone treatment resulted in dramatic mucosal increases in IGFBP-2, -3, -4, and -5, paralleling the changing distribution of IGF-I that we previously reported. CONCLUSION: Taken together, these findings further implicate the IGF system as an important participant in dexamethasone-induced maturation in the newborn mouse ileum.

Pro- and anti-inflammatory cytokines regulate insulin-like growth factor binding protein production by fetal rat lung fibroblasts.

The inflammatory response of the lung to noxious factors contributes to the pathogenesis of chronic lung injury. Inflammatory mediators regulate the insulin-like growth factor (IGF) system, a key modulator of lung fibroblast proliferation. The activity of IGFs is regulated by IGF-binding proteins (IGFBPs) secreted by lung cells. To investigate the regulation of lung fibroblast IGFBPs by cytokines, we exposed 19-d fetal rat lung fibroblasts to various pro- and anti-inflammatory mediators. IGFBP abundance in conditioned medium (CM) was measured by ligand blot and RNA transcript abundance by RNase protection assays. Fetal rat lung fibroblasts exposed to interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha for 48 h demonstrated increased abundance of CM IGFBP-3 (5.9- and 4.7-fold increases for IL-1beta and TNF-alpha, respectively) and IGFBP-4 (5.7- and 7.4-fold increases for IL-1beta and TNF-alpha, respectively) that was accompanied by a small increase in IGFBP-4 mRNA and a larger increase in IGFBP-3 mRNA abundance. IGFBP-4 specific proteolysis was examined in CM collected from fetal rat lung fibroblasts after incubation with serum-free medium (SFM), IL-1beta, or TNF-alpha for 48 h. Cell-free aliquots of SFM-CM incubated at 37C for 24 h showed a 65% decrease in IGFBP-4 abundance that was inhibited by 1,10-phenanthroline. In contrast, CM from cells exposed to IL-1beta or TNF-alpha incubated at 37 degrees C for 24 h did not show a significant decrease in IGFBP-4 abundance unless IGF-I was present during the cell-free incubation. Addition of IGFBP-3 to aliquots of SFM-CM reversed the IGF-I-mediated acceleration of IGFBP-4 proteolysis. Similarly, addition of IGFBP-3 to cells in culture increased the accumulation of CM IGFBP-4. These results demonstrate that cytokines regulate IGFBP production and clearance by fetal lung cells and suggest a mechanism by which cytokines regulate cell proliferation following lung injury.