Among episodes for which organism data were available, 2657 of 3624 (73%) were caused by Gram-positive organisms only, 603 of 3624 (17%) were caused by Gram-negative organisms only, 241 of 3624 (7%) were caused by fungal organisms only and 123 of 3624 (3%) were polymicrobial, with multiple types of organisms (Table 3). The proportion of episodes of LOS caused by Gram-positive organisms and Gram-negative organisms did not change between the 2 study periods, but the proportion of episodes caused by fungal organisms was lower in era 2 [111/1728 (6%) vs. 188/1896 (10%); P < 0.001]. The proportion of polymicrobial infections was significantly lower in era 2 when compared with era 1 [44/1728 (2.6%) vs. 79/1896 (4.2%); P = 0.007].
Of the 12 centers, 7 showed a significantly lower incidence of LOS in era 2 when compared with era 1 (Fig. 2A). On multivariable regression, 9 of 11 centers had significantly higher odds of LOS in era 2 than the reference center, which had the lowest incidence (P < 0.05; Fig. 2B). Gestational age of 23, 24, 25 and 26 weeks (compared with reference, 28 weeks), birth weight and male sex were significant predictors of LOS (P < 0.05). Multiple birth, SGA, race and exposure to antenatal steroids were not significant covariates in the model. Similar center variation was also noted in era 1, with all centers showing significantly higher odds of LOS than the reference center (data not shown).
This study demonstrates a decline in LOS over time among extremely preterm infants cared for at 12 academic centers that participated in the National Institute of Child Health and Human Development NRN over a 12-year period, 2000–2011. A reduced incidence of infection was found in 7 of 12 study centers, with no centers showing significantly higher incidence of LOS in era 2 when compared with era 1. The decrease in LOS associated with increasing birth year remained significant after adjustment for center and other risk factors. The 7% absolute change (17% relative change) in incidence of LOS represents a clinically significant finding and validates the efforts that NICUs across the United States and other countries have made to reduce infection. The relative decrease in incidence of LOS was even higher (29%) when CoNS and other potential contaminants were excluded. Our findings are consistent with other studies that have suggested a decrease in LOS over time. A single-center study showed an improvement in LOS incidence in premature infants 1 year after relocation of a nursery to a different facility.5 Another single-center study reported decreased rates of nosocomial infection of 26%–29% in the first 3 years after several catheter care interventions, including improved training and education in addition to implementation of a specialty nursing team for catheter care.15 Twenty-four NICUs in Ohio instituted a quality improvement collaborative to improve catheter care and demonstrated a 20% reduction in the incidence of LOS over 16 months,6 while another study of 2 hospitals in Minnesota achieved 50% reduction in nosocomial infection after the institution of quality improvement efforts.9 Quality improvement interventions were also associated with decreased rates of nosocomial infection between 1994 and 1996 in 6 NICUs in the Vermont Oxford Network, between 2007 and 2013 among 330 NICUs in the Pediatrix Network and between 2004 and 2013 at Yale-New Haven Children’s Hospital’s NICU.10,16,17 These studies demonstrated that quality improvement interventions can lead to decreased incidence of infection.
Several older studies failed to demonstrate a reduction in LOS over time, suggesting that more recent interventions have been more beneficial. An older report from Yale-New Haven Children’s Hospital showed that from 1989 to 2003, the number of LOS episodes increased significantly.3 Two previous studies from the NRN have evaluated the incidence of LOS in infants <1500 g and <25 weeks of gestational age at birth.13,18 The incidence was increased in 2002–2004 (59%) when compared with 1991–2001 (50%). These proportions are both increased from 1991–1994 (45%) and 1995–1998 (44%). The incidence of LOS in the most recent era (2006–2011) of the current study was 38%, which is lower than these previous reports from the NRN. However, it should be noted that the current study represents a slightly different population of infants (those <1000 g and <28 weeks of gestational age at birth). Of note, older NRN studies were performed before the introduction of central line bundles, antibiotic stewardship and antifungal prophylaxis. Lack of antibiotic stewardship (ie, broad-spectrum antibiotics and longer initial empiric antibiotic courses) has been associated with increased risk of sepsis.19–21 The most recent NRN Generic Database report confirmed an increased incidence of LOS through 2004 and a decreased incidence from 2005 to 2012, although this report did not quantify center differences or examine pathogens.16
We found that despite the association of LOS with adverse outcomes in ELBW infants, the decrease in LOS over time was not accompanied by a decrease in mortality or length of hospital stay. The explanation for this finding is unclear. A slightly higher percentage of infants with LOS died in era 2 compared with era 1. While more infants with Gram-positive infections died in era 2, there was no difference in infection-associated death among infants with Gram-positive infections between eras 1 and 2. It is possible that the episodes of LOS prevented in the more recent era would have been milder episodes, and thus, the elimination of these episodes had no impact on overall mortality or length of stay. Infants with Gram-positive infections may also represent a group of infants at higher risk of death with a longer exposure to invasive devices, such as catheters, and the Gram-positive organisms were not the cause of death. In addition, although the difference was not significant, the median gestational age was 1 week lower in era 2 than in era 1, which may account for the lack of impact on mortality and the longer length of stay. When we adjusted for gestational age, there was no significant difference in length of hospital stay or postmenstrual age at discharge among infants with LOS.
Multiple previous studies have shown variation in the risk of infection across NICUs.19,22 The incidence of LOS in era 2 of our study varied markedly across centers, with a maximum odds ratio of 4.8 compared with the reference center. We elected to use the low incidence center as the reference center rather than comparing all sites with a central tendency because we thought that after risk adjustment, if there were truly no significant differences or potential for a best practice to be identified, no center would be statistically different from the low center. We found that the odds of LOS at 9 of 11 sites to be statistically significantly higher than the reference center after risk adjustment; we believe this strengthens the case that “best practices” could be identified and that LOS may be preventable in many cases. The reason why some centers were able to demonstrate a more robust improvement in infection risk over time remains unclear. We postulate that multiple factors contribute to infection risk at a given center, including hand hygiene policies, differences in central line bundle practices and staff training, antibiotic regimens typically used at a particular center (type and duration), nursery design and staffing, use of antifungal prophylaxis and underlying differences in genetic risk of infection. Previous studies on human milk in low birth weight infants have also shown a dose-related impact on neonatal outcomes.23,24 Unfortunately, our study was limited in that our database contains no information about the timing and duration of quality improvement projects. In addition, information across the entire study period about centers’ antimicrobial use practices and details about human milk feeding were not available, which represents an additional limitation. Given the growing body of literature on the role of lactoferrin and probiotics in infection prevention, further study is warranted on the effect of varying feeding and medication practices across institutions.25,26
The strengths of our study include the large sample size of extremely preterm infants, uniform definitions and data collection over time and ability to observe the incidence of LOS across time and across centers in multiple regions in the United States. Our study was limited by its design in that it was a retrospective analysis of a prospective observational study cohort. Regression models in retrospective cohort studies may omit variables that could influence the outcomes. Because death associated with infection was defined according to clinician diagnosis, this variable could have been subject to reporting bias. In addition, data on some organisms were not available in era 1, which may have affected our analysis of the organism distribution. The number of positive cultures for CoNS in each episode was also not available, and therefore, we relied on a clinical definition for infection that has been used previously within our network.1 Use of this definition may have overestimated the true incidence of LOS in our cohort. We also did not collect information on one of the most significant risk factors for LOS, the presence of central catheters. Knowledge of a change in the use or duration of central catheters in this population could impact our understanding of the change in incidence of LOS over time. We observed a lower incidence of fungal infections in era 2, but we cannot speculate on the cause for this change, as we did not have data on the use of antifungal prophylaxis at participating centers. We also did not have data regarding the timing of infection prevention processes or programs that may have been associated with the variation in the incidence of LOS across different centers. Finally, although the NRN overall mortality among ELBW infants has been dropping over time,16 we did not note a difference in death associated with infection.
Data collected at participating sites of the NICHD NRN (Appendix) were transmitted to RTI International, the data coordinating center for the network, which stored, managed and analyzed the data for this study. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.
1. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2, pt 1):285–291.
2. Stoll BJ, Hansen NI, Adams-Chapman I, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292:2357–2365.
3. Bizzarro MJ, Raskind C, Baltimore RS, et al. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics. 2005;116:595–602.
4. Bizzarro MJ, Dembry LM, Baltimore RS, et al. Changing patterns in neonatal Escherichia coli
sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics. 2008;121:689–696.
5. Jones AR, Kuschel C, Jacobs S, et al. Reduction in late-onset sepsis on relocating a neonatal intensive care nursery. J Paediatr Child Health. 2012;48:891–895.
6. Kaplan HC, Lannon C, Walsh MC, et al; Ohio Perinatal Quality Collaborative. Ohio statewide quality-improvement collaborative to reduce late-onset sepsis in preterm infants. Pediatrics. 2011;127:427–435.
7. Trijbels-Smeulders M, de Jonge GA, Pasker-de Jong PC, et al. Epidemiology of neonatal group B streptococcal disease in the Netherlands before and after introduction of guidelines for prevention. Arch Dis Child Fetal Neonatal Ed. 2007;92:F271–F276.
8. van den Hoogen A, Gerards LJ, Verboon-Maciolek MA, et al. Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents. Neonatology. 2010;97:22–28.
9. Payne NR, Barry J, Berg W, et al; Stop Transmission of Pathogens (STOP) team of the St. Paul Campus; Prevent Infection Team (PIT) of the Minneapolis Campus of Children’s Hospitals and Clinics of Minnesota. Sustained reduction in neonatal nosocomial infections through quality improvement efforts. Pediatrics. 2012;129:e165–e173.
10. Horbar JD, Rogowski J, Plsek PE, et al. Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network. Pediatrics. 2001;107:14–22.
11. Wilson-Costello D, Friedman H, Minich N, et al. Improved neurodevelopmental outcomes for extremely low birth weight infants in 2000-2002. Pediatrics. 2007;119:37–45.
12. Hintz SR, Kendrick DE, Vohr BR, et al; National Institute of Child Health and Human Development Neonatal Research Network. Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993-1999. Pediatrics. 2005;115:1645–1651.
13. Hintz SR, Kendrick DE, Wilson-Costello DE, et al; NICHD Neonatal Research Network. Early-childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks’ gestational age. Pediatrics. 2011;127:62–70.
14. Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126:443–456.
15. Schelonka RL, Scruggs S, Nichols K, et al. Sustained reductions in neonatal nosocomial infection rates following a comprehensive infection control intervention. J Perinatol. 2006;26:176–179.
16. Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314:1039–1051.
17. Bizzarro MJ, Shabanova V, Baltimore RS, et al. Neonatal sepsis 2004-2013: the rise and fall of coagulase-negative Staphylococci
. J Pediatr. 2015;166:1193–1199.
18. Hintz SR, Poole WK, Wright LL, et al. Changes in mortality and morbidities among infants born at less than 25 weeks during the post-surfactant era. Arch Dis Child Fetal Neonatal Ed. 2005;90:F128–F133.
19. Benjamin DK Jr, Stoll BJ, Gantz MG, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126:e865–e873.
20. Cotten CM, Taylor S, Stoll B, et al; NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009;123:58–66.
21. Cotten CM, McDonald S, Stoll B, et al; National Institute for Child Health and Human Development Neonatal Research Network. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics. 2006;118:717–722.
22. Chien LY, Macnab Y, Aziz K, et al; Canadian Neonatal Network. Variations in central venous catheter-related infection risks among Canadian neonatal intensive care units. Pediatr Infect Dis J. 2002;21:505–511.
23. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol. 2009;29:57–62.
24. Patel AL, Johnson TJ, Engstrom JL, et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatol. 2013;33:514–519.
25. Rao SC, Athalye-Jape GK, Deshpande GC, et al. Probiotic supplementation and late-onset sepsis in preterm infants: a meta-analysis. Pediatrics. 2016;137:e20153684.
26. Pammi M, Abrams SA. Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2015:CD007137.
The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chairs: Alan H. Jobe, MD, PhD, University of Cincinnati (2003–2006) and Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006–2011); Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904): William Oh, MD, Angelita M. Hensman, RN, BSN and Kristin Basso, RN, MaT; Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80): Avroy A. Fanaroff, MD; Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084): Kurt Schibler, MD, Edward F. Donovan, MD, Barbara Alexander, RN, Kate Bridges, MD, Cathy Grisby, BSN, CCRC, Marcia Worley Mersmann, RN, Holly L. Mincey, RN, BSN, Jody Hessling, RN, Lenora Jackson, CRC, Kristin Kirker, CRC, Estelle E. Fischer, MHSA, MBA and Greg Muthig, BS; Duke University School of Medicine, University Hospital, Alamance Regional Medical Center and Durham Regional Hospital (U10 HD40492, M01 RR30): Ronald N. Goldberg, MD, C. Michael Cotten, MD, MHS, Kathy J. Auten, MSHS, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Melody B. Lohmeyer, RN, MSN, Sandra Grimes, RN, BSN, BSN and Katherine A. Foy, RN; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital and Emory University Hospital Midtown (U10 HD27851, M01 RR39): David P. Carlton, MD; NICHD: Linda L. Wright, MD, Elizabeth M. McClure, Med and 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, James A. Lemons, MD, Dianne E. Herron, RN, Lucy C. Miller, RN, BSN, CCRC and Leslie Dawn Wilson, BSN, CCRC; RTI International (U10 HD36790): W. Kenneth Poole, PhD, Dennis Wallace, PhD, Jeanette O’Donnell Auman, BS, Margaret Crawford, BS, CCRP, Betty K. Hastings, Carolyn M. Petrie Huitema, MS, CCRP and Kristin M. Zaterka-Baxter, RN, BSN, CCRP; Stanford University, California Pacific Medical Center, Dominican Hospital, El Camino Hospital and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70): David K. Stevenson, MD, Marian M. Adams, MD, Charles E. Ahlfors, MD, Andrew W. Palmquist, RN, Melinda S. Proud, RCP and Robert D. Stebbins, MD; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32): Namasivayam Ambalavanan, MD, Monica V. Collins, RN, BSN, MaEd and Shirley S. Cosby, RN BSN; University of Iowa and Mercy Medical Center (U10 HD53109, M01 RR59): Karen J. Johnson, RN, BSN, Donia B. Campbell, RNC-NIC, John A. Widness, MD, Dan L. Ellsbury, MD and Tarah T. Colaizy, MD, MPH; University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System and Children’s Medical Center Dallas (U10 HD40689, M01 RR633): Charles R. Rosenfeld, MD, Walid A. Salhab, MD, Luc P. Brion, MD, P. Jeannette Burchfield, RN, BSN, Alicia Guzman, Gaynelle Hensley, RN, Melissa H. Leps, RN, Susie Madison, RN, Nancy A. Miller, RN, Diana M. Vasil, RNC-NIC, Lizette E. Torres, RN and Lijun Chen, PhD RN; University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373): Jon E. Tyson, MD, MPH, Kathleen A. Kennedy, MD, MPH, Esther G. Akpa, RN, BSN, Patricia Ann Orekoya, RN, BSN, Beverly Foley Harris, RN, BSN, Claudia I. Franco, RNC, MSN, Anna E. Lis, RN, BSN, Sara Martin, RN, BSN, Georgia E. McDavid, RN, Patti L. Pierce Tate, RCP and Maegan C. Simmons, RN; Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385): Rebecca Bara, RN, BSN, Mary E. Johnson, RN, BSN and Kara Sawaya, RN, BSN; and Yale University, Yale-New Haven Children’s Hospital and Bridgeport Hospital (U10 HD27871, UL1 RR24139, M01 RR125, M01 RR6022): Richard A. Ehrenkranz, MD, Harris Jacobs, MD, Patricia Cervone, RN, Patricia Gettner, RN, Monica Konstantino, RN, BSN, JoAnn Poulsen, RN and Janet Taft, RN, BSN.
late-onset sepsis; extremely premature infants; neonatal intensive care unit