Tarah T. Colaizy

Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants

BACKGROUND Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.).

Nasal high‐frequency ventilation for premature infants

Aim: To assess the use of nasal high‐frequency ventilation (HFV) to provide noninvasive ventilatory support for very low birthweight (VLBW) infants.

Growth in VLBW infants fed predominantly fortified maternal and donor human milk diets: a retrospective cohort study.

BackgroundTo determine the effect of human milk, maternal and donor, on in-hospital growth of very low birthweight (VLBW) infants. We performed a retrospective cohort study comparing in-hospital growth in VLBW infants by proportion of human milk diet, including subgroup analysis by maternal or donor milk type. Primary outcome was change in weight z-score from birth to hospital discharge.MethodsRetrospective cohort study.Results171 infants with median gestational age 27 weeks (IQR 25.4, 28.9) and median birthweight 899 g (IQR 724, 1064) were included. 97% of infants received human milk, 51% received > 75% of all enteral intake as human milk. 16% of infants were small-for-gestational age (SGA, < 10th percentile) at birth, and 34% of infants were SGA at discharge. Infants fed >75% human milk had a greater negative change in weight z-score from birth to discharge compared to infants receiving < 75% (−0.6 vs, -0.4, p = 0.03). Protein and caloric supplementation beyond standard human milk fortifier was related to human milk intake (p = 0.04). Among infants receiving > 75% human milk, there was no significant difference in change in weight z-score by milk type (donor −0.84, maternal −0.56, mixed −0.45, p = 0.54). Infants receiving >75% donor milk had higher rates of SGA status at discharge than those fed maternal or mixed milk (56% vs. 35% (maternal), 21% (mixed), p = 0.08).ConclusionsVLBW infants can grow appropriately when fed predominantly fortified human milk. However, VLBW infants fed >75% human milk are at greater risk of poor growth than those fed less human milk. This risk may be highest in those fed predominantly donor human milk.

Genetic Contributions to the Development of Retinopathy of Prematurity

There is growing support for the role of genetic factors in the development of retinopathy of prematurity (ROP), a serious visual morbidity resulting from preterm birth. We used both candidate gene and data-mining approaches to investigate the role of genetic polymorphisms in the development of ROP. Our study population consisted of 330 infants, less than 32 wk gestation, and their parents. We initially studied 24 single nucleotide polymorphisms (SNPs) in 11 candidate genes. Using a family-based analysis strategy, we found an association between SNPs in the EPAS1 gene and the development of ROP (p = 0.007). Logistic regression analysis showed three SNPs associated with development of ROP, two in the CFH gene (p = 0.01) and one in the EPAS1 gene (p = 0.001). Extending this analysis to include genotyping data from a larger genetic study of prematurity (455 SNPs in 153 genes), we found SNPs in five genes associated with the development of ROP: IHH (p = 0.003), AGTR1 (p = 0.005), TBX5 (p = 0.003), CETP (p = 0.004), and GP1BA (p = 0.005). Our data suggest that genetic risk factors contribute to the development of ROP.

Detection of Ureaplasma DNA in Endotracheal Samples Is Associated With Bronchopulmonary Dysplasia After Adjustment for Multiple Risk Factors

Microorganisms are hypothesized to contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW) infants. This hypothesis remains controversial. We sought to determine whether endotracheal colonization with Ureaplasma sp., adenovirus, or Chlamydia sp. increases the risk of BPD. Intubated VLBW infants were included. Polymerase chain reaction (PCR) analysis was used to detect Ureaplasma sp., adenovirus, and Chlamydia sp. The outcome measure was BPD or death due to lung disease. Detection of microorganisms was compared between subjects with and without BPD. Logistic regression was used to control for covariates. Of 139 subjects, 33 (25%) screened positive for Ureaplasma sp., 22 of 136 (16%) were positive for adenovirus; eight of 133 (6%) were positive for Chlamydia sp. At 36 wk postmenstrual age, 14 patients had died, 68 (57%) had BPD. Detection of Ureaplasma sp. was associated with BPD or death (p < 0.001); adenovirus (p = 0.52) and Chlamydia sp. (p = 0.33) were not. Controlling confounding factors, the odds ratio for Ureaplasma sp. and BPD or death was 4.2 (95% CI 1.03, 17). In our population, detection of Ureaplasma sp., but not adenovirus or Chlamydia sp. was associated with BPD or death due to lung disease.

Maternal intention to breast-feed and breast-feeding outcomes in term and preterm infants: Pregnancy Risk Assessment Monitoring System (PRAMS), 2000–2003

OBJECTIVE To determine the effect of intention to breast-feed on short-term breast-feeding outcomes in women delivering term and preterm infants. DESIGN Data from the US Centers for Disease Control and Preventions Pregnancy Risk Assessment Monitoring System (PRAMS) for three states, Ohio, Michigan and Arkansas, during 2000-2003 were analysed. SAS 9·1·3 and SUDAAN 10 statistical software packages were used for analyses. SETTING Arkansas, Michigan and Ohio, USA. SUBJECTS Mothers of recently delivered infants, selected by birth certificate sampling. RESULTS Of 16,839 mothers included, 9·7% delivered preterm. Some 52·2% expressed definite intention to breast-feed, 16·8% expressed tentative intention, 4·3% were uncertain and 26·8% had no intention to breast-feed. Overall 65·2% initiated breast-feeding, 52·0% breast-fed for ≥4 weeks and 30·8% breast-fed for ≥10 weeks. Women with definite intention were more likely to initiate (OR = 24·3, 95% CI 18·4, 32·1), to breast-feed for ≥4 weeks (OR = 7·12, 95% CI 5·95, 8·51) and to breast-feed for ≥10 weeks (OR = 2·75, 95% CI 2·20, 3·45) compared with women with tentative intention. Levels of intention did not differ between women delivering preterm and term. Women delivering at <34 weeks were more likely to initiate breast-feeding (OR = 2·24, 95% CI 1·64, 3·06) and to breast-feed for ≥4 weeks (OR = 2·58, 95% CI 1·96, 3·41), but less likely to breast-feed for ≥10 weeks (OR = 0·55, 95% CI 0·44, 0·68), compared with those delivering at term. Women delivering between 34 and 36 weeks were less likely to breast-feed for ≥10 weeks than those delivering at term (OR = 0·63, 95% CI 0·49, 0·81). CONCLUSIONS Prenatal intention to breast-feed is a powerful predictor of short-term breast-feeding outcomes in women delivering both at term and prematurely.

Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study

Background Single-center studies suggest that neonatal acute kidney injury (AKI) is associated with poor outcomes. However, inferences regarding the association between AKI, mortality, and hospital length of stay are limited due to the small sample size of those studies. In order to determine whether neonatal AKI is independently associated with increased mortality and longer hospital stay, we analyzed the Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) database. Methods All neonates admitted to 24 participating neonatal intensive care units from four countries (Australia, Canada, India, United States) between January 1 and March 31, 2014, were screened. Of 4273 neonates screened, 2022 (47·3%) met study criteria. Exclusion criteria included: no intravenous fluids ≥48 hours, admission ≥14 days of life, congenital heart disease requiring surgical repair at <7 days of life, lethal chromosomal anomaly, death within 48 hours, inability to determine AKI status or severe congenital kidney abnormalities. AKI was defined using a standardized definition —i.e., serum creatinine rise of ≥0.3 mg/dL (26.5 mcmol/L) or ≥50% from previous lowest value, and/or if urine output was <1 mL/kg/h on postnatal days 2 to 7. Findings Incidence of AKI was 605/2022 (29·9%). Rates varied by gestational age groups (i.e., ≥22 to <29 weeks =47·9%; ≥29 to <36 weeks =18·3%; and ≥36 weeks =36·7%). Even after adjusting for multiple potential confounding factors, infants with AKI had higher mortality compared to those without AKI [(59/605 (9·7%) vs. 20/1417 (1·4%); p< 0.001; adjusted OR=4·6 (95% CI=2·5–8·3); p=<0·0001], and longer hospital stay [adjusted parameter estimate 8·8 days (95% CI=6·1–11·5); p<0·0001]. Interpretation Neonatal AKI is a common and independent risk factor for mortality and longer hospital stay. These data suggest that neonates may be impacted by AKI in a manner similar to pediatric and adult patients. Funding US National Institutes of Health, University of Alabama at Birmingham, Cincinnati Children’s, University of New Mexico.

Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study

Introduction Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. Methods and analysis The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly “snapshots”; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. Ethics and dissemination AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. Discussion The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few “lessons learned.” The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.

NOX2 Protects against Prolonged Inflammation, Lung Injury, and Mortality following Systemic Insults

The systemic inflammatory response syndrome (SIRS) is a clinical condition occurring in intensive care unit patients as a consequence of both infectious and noninfectious insults. The mechanisms underlying resolution of SIRS are not well characterized. NOX2 (NADPH oxidase 2)-derived reactive oxygen species are critical for killing of certain pathogens by polymorphonuclear leukocytes (PMN). Patients with chronic granulomatous disease who lack functional NOX2 are not only prone to serious infections, they also exhibit chronic inflammatory conditions, suggesting a local anti-inflammatory role for NOX2. We hypothesized that NOX2 is required for the resolution of sterile systemic inflammation. Using a murine model of sterile generalized inflammation, we observed dramatically increased mortality of gp91phox-/y (NOX2-deficient) as compared to wild-type (WT) mice. Both genotypes developed robust SIRS with hypothermia, hypotension, and leukopenia; however, WT mice recovered within 48 h whereas NOX2-deficient mice did not. Although both groups displayed rapid peritoneal PMN recruitment, the recruited NOX2-deficient PMN demonstrated an enhanced inflammatory phenotype. Moreover, NOX2-deficient mice exhibited a hemorrhagic inflammatory response in the lungs with rapid and persistent recruitment of neutrophils to the alveolar space, whereas WT mice had minimal lung pathology. Several proinflammatory cytokines remained elevated in NOX2-deficient mice. The persistent inflammatory environment observed in NOX2-deficient mice resulted from continued peritoneal chemokine secretion and not delayed apoptosis of PMN. These data suggest a requirement for NOX2 in the resolution of systemic inflammation.

Long-chain polyunsaturated fatty acid levels in US donor human milk: meeting the needs of premature infants?

Objective:To determine fatty acid levels in the US donor milk supply.Study Design:Donor human milk samples from Iowa (n=62), Texas (n=5), North Carolina (n=5) and California (n=5) were analyzed by gas chromatography. Levels in the Iowa donor milk were compared before and after pasteurization using Students t-test. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were compared among all milk banks using analysis of variance.Result:ARA (0.4 pre, 0.4 post, P=0.18) and DHA (0.073 pre, 0.073 post, P=0.84) were not affected by pasteurization. DHA varied between banks (P<0.0001), whereas ARA did not (P=0.3). DHA levels from all banks were lower than published values for maternal milk and infant formula (P<0.0001).Conclusion:Pasteurization of breastmilk does not affect DHA or ARA levels. However, DHA content in US donor milk varies with bank location and may not meet the recommended provision for preterm infants.