Identification of Extremely Premature Infants at Low Risk for Early-Onset Sepsis
BACKGROUND: Premature infants are at high risk of early-onset sepsis (EOS) relative to term infants, and most are administered empirical antibiotics after birth. We aimed to determine if factors evident at birth could be used to identify premature infants at lower risk of EOS.
METHODS: Study infants were born at 22 to 28 weeks’ gestation in Neonatal Research Network centers from 2006 to 2014. EOS was defined by isolation of pathogenic species from blood or cerebrospinal fluid culture at ≤72 hours age. Infants were hypothesized as “low risk” for EOS when delivered via cesarean delivery, with membrane rupture at delivery, and absence of clinical chorioamnionitis. Frequency of prolonged antibiotics (≥5 days) was compared between low-risk infants and all others. Risks of mortality, EOS, and other morbidities were assessed by using regression models adjusted for center, race, antenatal steroid use, multiple birth, sex, gestation, and birth weight.
RESULTS: Of 15 433 infants, 5759 (37%) met low-risk criteria. EOS incidence among infants surviving >12 hours was 29 out of 5640 (0.5%) in the low-risk group versus 209 out of 8422 (2.5%) in the comparison group (adjusted relative risk = 0.24 [95% confidence interval, 0.16–0.36]). Low-risk infants also had significantly lower combined risk of EOS or death ≤12 hours. Prolonged antibiotics were administered to 34% of low-risk infants versus 47% of comparison infants without EOS.
CONCLUSIONS: Delivery characteristics of extremely preterm infants can be used to identify those with significantly lower incidence of EOS. Recognition of differential risk may help guide decisions to limit early antibiotic use among approximately one-third of these infants.
- aRR —
- adjusted relative risk
- BPD —
- bronchopulmonary dysplasia
- BW —
- birth weight
- CD —
- cesarean delivery
- CONS —
- coagulase-negative staphylococci
- CSF —
- cerebrospinal fluid
- EOS —
- early-onset sepsis
- GA —
- gestational age
- LOS —
- late-onset sepsis
- NEC —
- necrotizing enterocolitis
- NRN —
- Neonatal Research Network
- PMA —
- postmenstrual age
- PVL —
- periventricular leukomalacia
- ROM —
- rupture of membranes
- SGA —
- small for gestational age
- SIP —
- spontaneous intestinal perforation
- VLBW —
- very low birth weight
What’s Known on This Subject:
Characteristics known at birth including gestational age identify infants at highest risk of early-onset sepsis (EOS). It is unknown if delivery characteristics can be used to identify premature infants at lowest risk of EOS to guide empirical antibiotic therapy.
What This Study Adds:
Specific criteria can identify premature infants with a 76% lower adjusted risk for EOS. A substantial proportion of these infants received prolonged antibiotics despite their lower a priori risk. Recognition of this differential risk may reduce early antibiotic exposures.
Accurately estimating individual risk of early-onset sepsis (EOS) among very premature infants is challenging because of the relatively high incidence of clinical instability among these infants and the associated concern for sepsis as a treatable cause of such instability.1,2 Antibiotics are initiated in the majority of extremely preterm infants and are frequently continued despite sterile blood cultures.3–5 Of concern, prolonged early antibiotic exposure has been associated with increased subsequent risk of late-onset sepsis (LOS), necrotizing enterocolitis (NEC), severe retinopathy of prematurity, and death.3,6–9 Identification of premature infants at low risk of EOS may help guide decisions for initiating and/or discontinuing empirical antibiotic treatments in the first days of life and would be a critical first step in promoting antibiotic stewardship among these infants.
The pathogenesis of EOS is predominantly that of ascending colonization of the uterine and fetal compartments with maternal recto-vaginal flora, progressing to inflammation and infection.10,11 Preterm onset of labor and preterm rupture of amniotic membranes are both significantly associated with risk of EOS.12,13 However, a proportion of preterm deliveries occur because of maternal medical indications (such as preeclampsia) or for chronic fetal conditions (such as growth restriction).14 In the absence of labor or rupture of membranes (ROM), the risk of EOS in preterm infants delivered via cesarean delivery (CD) should be substantially lower compared with preterm infants delivered because of preterm labor or premature ROM. We accessed data collected by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) and used delivery characteristics to define a group of extremely preterm infants we hypothesized would be at lower risk for EOS. Our objectives were to compare the incidence of culture-confirmed EOS and the prevalence of prolonged early antibiotic treatment among infants with and without low EOS risk criteria.
Infants were born at NRN centers between January 1, 2006, and December 31, 2014, and enrolled in a registry maintained by the NRN. Inclusion criteria for the cohort studied were: gestational age (GA) 22 weeks, 0 days to 28 weeks, 6 days; birth weight (BW) 401 to 1500 g; inborn; and no major congenital anomaly. Registry data included prospectively collected maternal pregnancy and delivery information; infant data from birth until death, hospital discharge or transfer, or 120 days of age; and if hospitalized at 120 days, final discharge or transfer date or death up to 1 year of age.15 Participation in the registry was approved at most sites by the local institutional review board under a waiver of consent; 3 sites required parental consent.
Delivery Criteria for Categorizing Infants as Hypothetically “Low Risk” for EOS
Preterm labor was not recorded in the registry during the study period. Delivery characteristics likely to capture infants delivered for maternal health indications without preterm onset of labor were used to define a hypothesized low-risk group for EOS. Low-risk infants had all of the following characteristics: delivery by CD, ROM at delivery, and no documentation of maternal clinical chorioamnionitis in the obstetrical record. Infants without low-risk criteria were denoted as the “comparison” group for description of study results. In a secondary analysis, the low-risk group was further defined to also exclude infants of mothers with histologic diagnosis of chorioamnionitis on the basis of placental pathologic examination.
Hospital Outcomes and Clinical Interventions
Hospital morbidities and clinical interventions were recorded for infants who survived >12 hours. EOS (≤72 hours of age) and LOS (>72 hours of age) were defined by blood or cerebrospinal fluid (CSF) cultures positive for pathogenic bacteria or fungi and antibiotic therapy ≥5 days or intent to treat and death within 5 days. Micrococcus, Propionibacterium, Corynebacterium, Bacillus, and coagulase-negative staphylococci (CONS) grown on cultures of blood or CSF ≤72 hours of age were considered contaminants for the primary outcome of EOS incidence. Cultures growing ≥1 species of which at least 1 was considered a true pathogen were counted as EOS cases. For a secondary analysis, infants with CONS were included as EOS cases. CONS grown from LOS cultures were included as true pathogens. Other morbidities included respiratory distress syndrome defined by clinical features in the first 24 hours, pneumothorax, pulmonary hemorrhage, pulmonary interstitial emphysema, patent ductus arteriosus, NEC stage 2 to 3,16,17 spontaneous intestinal perforation (SIP), severe intracranial hemorrhage (ICH) grade 3 or 418 based on a cranial sonogram taken within 28 days of birth, periventricular leukomalacia (PVL), and bronchopulmonary dysplasia (BPD) defined as need for supplemental oxygen at 36 weeks postmenstrual age (PMA). Surviving infants discharged or transferred before 36 weeks PMA were classified on the basis of their status at 36 weeks, if known, or on the basis of oxygen use at discharge or transfer. Small for gestational age (SGA) was defined as BW <10th percentile for sex and GA.19
Prolonged early antibiotic therapy was defined as receipt of antibiotics for ≥5 days starting <72 hours of age (or intent to treat for ≥5 days in an infant who died within 5 days and was receiving antibiotics). Those who did not receive prolonged antibiotics were either not started on antibiotics <72 hours, or had antibiotics initiated but discontinued before 5 days. Other interventions recorded included receipt of surfactant, nitric oxide, treatment of hypotension, and duration and type of respiratory support.
Characteristics and outcomes were compared between infants in the low-risk and comparison groups. Additionally, we compared outcomes for low-risk infants with and without early prolonged antibiotics, excluding infants with any of the following at <7 days of age: positive blood or CSF culture results (including isolates considered contaminants in this study) and/or a diagnosis of NEC or SIP. Statistical significance for unadjusted comparisons between groups was determined by χ2 test for categorical variables and Wilcoxon test for continuous variables. Poisson regression models with robust variance estimators20 were used to assess risk of mortality, the primary outcome EOS, and other binary outcomes in comparison groups while adjusting for study center, maternal race and/or ethnicity, antenatal steroid use, multiple birth, sex, GA (categorical by week), and BW (continuous). Adjusted relative risks (aRRs), 95% confidence intervals (CIs), and P values by the score or Wald χ2 test from these models were reported. Morbidity outcomes were compared between low-risk and comparison infants surviving >12 hours, accounting for the age at which assessment took place. Combined death or morbidity outcomes were also examined to account for the competing risk of death before evaluation. For analyses of low-risk infants with and without early prolonged antibiotics, morbidities were examined among infants who survived >7 days to allow for exposure to prolonged antibiotics to have occurred. For these analyses, combined death or morbidity outcomes included all deaths after 7 days and before discharge to examine risk of death in addition to morbidity before discharge. A P value < .05 was considered significant; no adjustment was made for multiple comparisons. Analyses were performed by using SAS version 9.4 (SAS Institute, Cary, NC).
Between January 1, 2006, and December 31, 2014, 16 185 infants with GA 22 to 28 weeks and BW 401 to 1500 g were born at NRN centers. Of these, 640 (4%) infants with a major congenital anomaly, 111 (0.7%) infants with insufficient information (maternal clinical chorioamnionitis, 54; ROM, 43; EOS or antibiotic information, 10; delivery type, 4), and 1 infant with congenital syphilis were excluded. Thus, 15 433 infants were studied, of whom 5759 (37.3%) were classified into the low-risk group and 9674 (62.7%) into the comparison group.
Maternal and Infant Characteristics
By definition, all infants in the low-risk group were delivered by CD, without ROM before delivery, and none had maternal clinical chorioamnionitis (Table 1). Maternal histologic chorioamnionitis was reported for a smaller proportion of infants in the low-risk group versus the comparison group (21% vs 66%). Mothers in the low-risk group were more likely to suffer complications such as hypertension, more likely to receive antenatal corticosteroids, and less likely to receive antenatal antibiotics. Median gestation was higher in the low-risk group, as was the proportion of female infants, multiple births, and SGA infants. In all measures except 1 (nitric oxide therapy), a significantly greater proportion of infants in the low-risk group had markers of illness and clinical intervention (Table 1).
Mortality and Early-Onset Infection
The proportion of infants who died in the first 12 hours after birth was smaller in the low-risk group than in the comparison group (Table 2). Risk of the composite outcome of death within 12 hours or EOS was also reduced for infants in the low-risk group (2.6% vs 15.1%; aRR [95% CI]: 0.36 [0.30–0.43]). Among infants surviving >12 hours, 29 out of 5640 (0.5%) in the low-risk group and 209 out of 8422 (2.5%) in the comparison group had EOS (aRR [95% CI]: 0.24 [0.16–0.36]). The risk of EOS in the low-risk group was consistently lower than in the comparison group for infants born at each GA, as well as when CONS cases were included. Escherichia coli was the most frequent pathogen isolated in both the low-risk group (9 out of 29 cases) and the comparison group (103 out of 209 cases) (Supplemental Tables 8 and 9). The predictive performance of risk categorization by study criteria is shown in Supplemental Table 10. The likelihood of not having EOS was 3 times greater for low-risk infants than for infants in the comparison group.
Placental pathology was available for 4802 out of 5622 (85.4%) low-risk infants and 7202 out of 8394 (85.7%) comparison infants surviving >12 hours (excluding those with no information). The proportion of infants with EOS was similar for those with and without placental pathology (with versus without pathology, low-risk group: 0.5% vs 0.4%; comparison group: 2.5% vs 2.5%; P = .86 for overall difference). Among low-risk infants surviving >12 hours and born to mothers without a histologic diagnosis of chorioamnionitis on placental pathology, 10 out of 3771 (0.3%) infants had EOS (Table 3).
Other Morbidities Before Discharge
Among infants who survived >12 hours, the adjusted risks of respiratory distress syndrome, pulmonary hemorrhage, and patent ductus arteriosus were higher in the low-risk group compared with the comparison group (Table 4). The composite risks of death within 12 hours and each of pneumothorax, pulmonary interstitial emphysema, NEC, and SIP, were lower in the low-risk group, as was the risk of LOS or death within 3 days, and the risk of intraventricular hemorrhage and/or PVL or death within 28 days without evaluation (data not shown).
Prolonged Early Antibiotic Therapy in the Absence of Positive Culture Results
Among infants surviving >12 hours without EOS, 34.1% of infants in the low-risk group received prolonged early antibiotics compared with 47.4% in the comparison group, P < .001 (Table 5). This difference persisted when infants with standard indications for antibiotic use (positive culture results, NEC, and/or SIP ≤7 days of life) were excluded. For each EOS case, 66 low-risk infants received prolonged early antibiotics compared with 19 infants in the comparison group, P < .001. Among low-risk and comparison infants, the proportion of infants who received prolonged early antibiotics varied by center (Fig 1). In comparison with the incidence of EOS cases, the proportion of infants treated with prolonged antibiotics was many times higher at all centers in both groups.
Comparing Low-Risk Group Infants With and Without Prolonged Early Antibiotic Therapy
Maternal and delivery characteristics did not differ significantly between the 1771 infants in the low-risk group who received prolonged early antibiotics without a positive culture result and/or a diagnosis of NEC or SIP ≤7 days of life and the 3563 who did not (Supplemental Table 11). However, the low-risk infants who received prolonged early antibiotics were significantly younger and smaller at birth, more likely to be boys, SGA, and have 5 minute Apgar score <5, and more likely to have received surfactant and other interventions (Table 6). After adjustment for GA and other covariates, the adjusted risk of death after 7 days and before discharge and the composite outcomes of death and/or either NEC, SIP, or LOS were increased for low-risk infants who received prolonged early antibiotics compared with low-risk infants who did not (Table 7). Risks of pulmonary outcomes were also higher among low-risk infants who received prolonged early antibiotics, including the risk of BPD among survivors to 36 weeks PMA (aRR [95% CI]: 1.28 [1.20–1.36]).
In this NRN cohort of extremely low gestation infants, characteristics evident at birth were able to be used to identify a group of infants with significantly lower risk of EOS. A third of the infants in the study cohort fulfilled the defined low-risk delivery criteria. The lower incidence of EOS in this group was, however, not associated with a proportional reduction in prolonged early antibiotic therapy, presenting an opportunity to revisit current antibiotic prescribing practices.
The lower incidence of EOS in the low-risk cohort confirmed our hypothesis that the absence of factors that might reflect (eg, preterm labor) or promote (eg, membrane rupture) the pathogenesis of ascending infection would be associated with a reduced occurrence of infection. However, 29 cases of EOS were identified in the low-risk group. These cases may be due to imprecision in our definition of these risk factors. The NRN database does not record presence of preterm labor, unexplained fetal distress, or criteria leading to a diagnosis of clinical chorioamnionitis. Therefore, we used CD with ROM at delivery and absence of clinical chorioamnionitis as indirect estimators. It is likely that we included some mothers who labored before being taken for a CD delivery before ROM, providing opportunity for ascending infection. Prospective collection of delivery criteria in real-time practice could improve capture of EOS risk factors and subsequently the precision of identifying infants at low risk for EOS. Hematogenous spread of infection across the placenta and infection after invasive intrauterine procedures can also rarely cause fetal infection.21 Emerging evidence also points to a placental and amniotic fluid microbiome whose disturbance may be associated with preterm labor.22
Despite these limitations, the 76% lower risk of EOS among low-risk infants compared with the comparison group is substantial and warrants consideration in making management decisions. We recently reported a similar single-center study that included detailed maternal chart review of EOS cases among very low birth weight (VLBW) infants (BW <1500 g). In that study, we found a 92% lower unadjusted risk for EOS among VLBW infants delivered by CD to mothers with a diagnosis of preeclampsia and without diagnoses of preterm ROM or chorioamnionitis, compared with VLBW infants born without these characteristics (1 out of 605 [0.17%] vs 45 out of 2143 [2.1%], P = .001).23 The incidence of EOS in the current study was even lower (0.3% vs 0.5%) among low-risk infants when the definition was refined to exclude infants born in the setting of histologic as well as clinical chorioamnionitis. Placental histopathology results obtained shortly after delivery may further aid in decisions to continue early empirical antibiotic therapy beyond the first few days of age.
Our findings suggest that clinicians did not recognize the differential incidence of EOS among low-risk infants or failed to account for it in their antibiotic management decisions. Although prolonged empirical antibiotic use was lower among low-risk infants than among the comparison infants, the ratio of prolonged antibiotics to number of EOS cases was 3 times higher in the low-risk group. Fewer low-risk infants died at ≤12 hours, but those who survived were as sick as or sicker than comparison infants. Maternal morbidity, SGA status, and a stressed in utero environment in infants delivered for maternal indications are associated with greater respiratory morbidity and may explain the greater initial morbidity observed in the low-risk infants.24–26 Administration of antibiotics for increasing clinical instability and attribution of such instability to culture negative sepsis is well-documented in neonatal care.4,27,28 A previous study revealed that >90% of all infants in an earlier NRN cohort were treated with antibiotics at birth.3 We speculate that the greater need for intensive care interventions in the low-risk cohort and persistence of illness beyond 48 hours led to a reluctance to stop antibiotic treatment. These decisions are likely driven by clinical uncertainties and provider preference more than biology because we observed marked variation around prolonged antibiotic administration across study centers that did not correlate with variation in the incidence of EOS at these centers.
Clinicians make antibiotic and other treatment decisions to protect sick newborns, yet multiple reports now suggest harm from early and prolonged empirical antibiotics.3,6–9 We addressed this issue with an analysis restricted to the low-risk group. To focus on potentially modifiable use of antibiotics, we limited this analysis to low-risk infants who received prolonged early antibiotics despite negative blood culture results and/or NEC or SIP in the first week of life. After adjusting for baseline characteristics associated with increased risk of morbidity and mortality, we still found higher subsequent mortality and increased incidence of BPD and other pulmonary outcomes among the low-risk infants who received prolonged early antibiotics. The decision to extend early empirical therapy may reflect a severity of initial illness that strongly influences subsequent morbidity and mortality in a manner for which we could not adequately account in our risk-adjusted analyses. However, there is evidence for the critical role of the early life microbiome in the development of neonatal immune responses and for the significant disruption of that microbiome induced by antibiotic exposure.29–33 Although with this study we cannot determine why it may be, our findings reveal that among infants with a low previous probability of EOS, extended empirical administration of early antibiotics for critical illness may not be beneficial and could potentially be harmful.
Our study is limited by its retrospective design. During the study period, the registry lacked information on the indication for preterm delivery. We have no information on the presence of preterm labor, attempts to induce labor, or unexplained fetal distress. Information about antibiotic therapy was limited to whether antibiotics were started in the first 72 hours after birth and continued for ≥5 days. Types of antibiotics, total duration of antibiotic administration during the NICU admission, and indication for therapy were not recorded.
Delivery characteristics of infants born at 22 to 28 weeks GA were useful in identifying those with significantly lower risk of EOS. Prolonged early antibiotics were administered to a large proportion of these infants despite their lower a priori risk, and this was associated with higher adjusted incidence of death and pulmonary morbidity. Recognition of differential EOS risk may help guide early empirical antibiotic use among approximately one-third of extremely preterm infants.
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the NRN Generic Database through cooperative agreements. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data collected at participating sites of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed, and analyzed the data for this study. On behalf of the NRN, Dr Abhik Das (DCC Principal Investigator) and Ms Nellie Hansen (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chair: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine.
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904): Abbott R. Laptook, MD; Martin Keszler, MD; Andrea M. Knoll; Emilee Little, RN, BSN; Elisa Vieira, RN, BSN; Kristin M. Basso, RN, MaT; Jennifer A. Keller, RN, BSN.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80): Michele C. Walsh, MD, MS; Anna Maria Hibbs, MD; Avroy A. Fanaroff, MD; Nancy S. Newman, BA, RN; Allison H. Payne, MD, MS.
Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284): William E. Truog, MD; Eugenia K. Pallotto, MD, MSCE; Howard W. Kilbride, MD; Cheri Gauldin, RN, BS, CCRC; Anne Holmes, RN, MSN, MBA-HCM, CCRC; Kathy Johnson, RN, CCRC; Allison Knutson, BSN, RNC-NIC.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084): Kurt Schibler, MD; Edward F. Donovan, MD; Cathy Grisby, BSN, CCRC; Kate Bridges, MD; Barbara Alexander, RN; Estelle E. Fischer, MHSA, MBA; Holly L. Mincey, RN, BSN; Jody Hessling, RN; Lenora Jackson, CRC; Kristin Kirker, CRC; Greg Muthig, BS; Stacey Tepe, BS.
Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, UL1 TR1117, M01 RR30, UL1 TR1111): Ronald N. Goldberg, MD; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD, FNP-BC, IBCLC; Joanne Finkle, RN, JD; Matthew M. Laughon, MD, MPH; Carl L. Bose, MD; Janice Bernhardt, MS, RN; Gennie Bose, RN.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39): David P. Carlton, MD; Ellen C. Hale, RN, BS, CCRC; Yvonne Loggins, RN, BSN; Diane I. Bottcher, RN, MSN; Colleen Mackie, BS, RT.
Eunice Kennedy Shriver National Institute of Child Health and Human Development: Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750): Brenda B. Poindexter, MD, MS; Gregory M. Sokol, MD; Dianne E. Herron, RN, CCRC; Lucy Miller, BSN, CCRC; Leslie Dawn Wilson, BSN, CCRC.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, Memorial Hermann Southwest Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373): Kathleen A. Kennedy, MD, MPH; Jon E. Tyson, MD, MPH; Georgia E. McDavid, RN; Julie Arldt-McAlister, RN, BSN; Katrina Burson, RN, BSN; Carmen Garcia, RN, CCRP; Beverly Foley Harris, RN, BSN; Anna E. Lis, RN, BSN; Karen Martin, RN; Sara C. Martin, RN, BSN; Shawna Rodgers, RN; Maegan C. Simmons, RN; Patti L. Pierce Tate, RCP.
Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center (U10 HD68278): Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Patricia Luzader, RN; Christine A. Fortney, PhD, RN; Nehal A. Parikh, MD.
RTI International (U10 HD36790): Dennis Wallace, PhD; Marie G. Gantz, PhD; W. Kenneth Poole, PhD (deceased); Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS, CCRP; Carolyn M. Petrie Huitema, MS, CCRP; Kristin M. Zaterka-Baxter, RN, BSN, CCRP.
Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70): David K. Stevenson, MD; Marian M. Adams, MD; M. Bethany Ball, BS, CCRC; Magdy Ismail, MD, MPH; Andrew W. Palmquist, RN; Melinda S. Proud, RCP.
Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54): Ivan D. Frantz III, MD; John M. Fiascone, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN, BSN.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32): Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN, BSN, MaEd; Shirley S. Cosby, RN, BSN.
University of California Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270): Uday Devaskar, MD; Meena Garg, MD; Teresa Chanlaw, MPH; Rachel Geller, RN, BSN.
University of California San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461): Neil N. Finer, MD; David Kaegi, MD; Maynard R. Rasmussen, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Wade Rich, BSHS, RRT.
University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59): Tarah T. Colaizy, MD, MPH; Dan L. Ellsbury, MD; John A. Widness, MD; Karen J. Johnson, RN, BSN; Donia B. Campbell, RNC-NC; Jacky R. Walker, RN; Tracy L. Tud, RN.
University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587): Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN, MSN.
University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997): Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Carol H. Hartenberger, MPH, RN; Sandra Sundquist Beauman, MSN, RNC-NIC, Mary Ruffaner Hanson, RN, BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244): Barbara Schmidt, MD, MSc; Haresh Kirpalani, MB, MSc; Sara B. DeMauro, MD, MSCE; Aasma S. Chaudhary, BS, RRT; Soraya Abbasi, MD; Toni Mancini, RN, BSN, CCRC; Dara M. Cucinotta, RN.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (U10 HD68263, U10 HD40521, M01 RR44, UL1 TR42): Carl T. D’Angio, MD; Dale L. Phelps, MD; Ronnie Guillet, MD, PhD; Satyan Lakshminrusimha, MD; Linda J. Reubens, RN, CCRC; Cassandra A. Horihan, MS; Mary Rowan, RN; Holly I.M. Wadkins, MA; Rosemary Jensen; Melissa Bowman, MSN; Julianne Hunn, BS; Stephanie Guilford, BS; Deanna Maffett, RN; Diane Prinzing; Anne Marie Reynolds, MD, MPH; Ashley Williams, MSEd; Karen Wynn, RN; Erica Burnell, RN; Michael G. Sacilowski, MAT, CCRC.
University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633): Luc P. Brion, MD; Walid A. Salhab, MD; Charles R. Rosenfeld, MD; Diana M. Vasil, MSN, BSN, RNC-NIC; Lijun Chen, PhD, RN; Alicia Guzman; Gaynelle Hensley, RN; Lizette E. Lee, RN; Melissa H. Leps, RN; Nancy A. Miller, RN; Janet S. Morgan, RN; Lara Pavageau, MD.
University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64, UL1 RR25764): Roger G. Faix, MD; Bradley A. Yoder, MD; Karen A. Osborne, RN, BSN, CCRC; Cynthia Spencer, RNC, BSN; Kimberlee Weaver-Lewis, RN, MS; Karie Bird, RN, BSN; Jill Burnett, RNC, BSN; Jennifer J. Jensen, RN, BSN; Karen Zanetti, RN.
Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122): T. Michael O’Shea, MD, MPH; Nancy Peters, RN.
Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385): Seetha Shankaran, MD; Athina Pappas, MD; John Barks, MD; Rebecca Bara, RN, BSN; Girija Natarajan, MD; Mary Christensen, RT; Stephanie A. Wiggins, MS; Diane White, RT.
Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, ULTR142, M01 RR125): Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Patricia Cervone, RN; Monica Konstantino, RN, BSN; JoAnn Poulsen, RN; Janet Taft, RN, BSN.
- Accepted July 31, 2017.
- Address correspondence to Karen M. Puopolo, MD, PhD, The Children’s Hospital of Philadelphia, Newborn Care at Pennsylvania Hospital, 800 Spruce St, Philadelphia, PA 19107. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: The National Institutes of Health: the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Schrag SJ,
- Farley MM,
- Petit S, et al
- Stoll BJ,
- Hansen NI,
- Sánchez PJ, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
- Cotten CM,
- Taylor S,
- Stoll B, et al; NICHD Neonatal Research Network
- Schulman J,
- Dimand RJ,
- Lee HC,
- Duenas GV,
- Bennett MV,
- Gould JB
- Benjamin DK Jr,
- Stoll BJ,
- Gantz MG, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
- Ting JY,
- Synnes A,
- Roberts A, et al; Canadian Neonatal Network Investigators
- Henderson JJ,
- McWilliam OA,
- Newnham JP,
- Pennell CE
- Piantino JH,
- Schreiber MD,
- Alexander K,
- Hageman J
- Olszak T,
- An D,
- Zeissig S, et al
- Copyright © 2017 by the American Academy of Pediatrics