Matthew J. Bizzarro

Early Onset Neonatal Sepsis: The Burden of Group B Streptococcal and E. coli Disease Continues

BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

Seventy-Five Years of Neonatal Sepsis at Yale: 1928–2003

Objective. Yale-New Haven Hospital (Y-NHH) has maintained the longest running, single-center longitudinal database of neonatal sepsis, started in 1928. The objective of this study was to update this database with review of neonatal sepsis cases at Y-NHH to identify longitudinal trends in demographics, pathogens, and outcome. Methods. Records of infants with positive blood cultures obtained while they were inpatients in the NICU at Y-NHH from 1989 to 2003 were reviewed retrospectively. Records of infants who were ≤30 days of age, had positive blood cultures, and were hospitalized at Y-NHH outside the NICU from the same period were also reviewed, and all findings were compared with 60 years of preexisting data. Results. A total of 862 organisms were identified in 755 episodes of sepsis from 647 infants. The percentage of cases of early-onset sepsis decreased and late-onset sepsis increased compared with the previous 10-year study period. A marked increase in cases as a result of commensal species was observed, particularly in preterm infants who had indwelling central vascular catheters, were receiving parenteral nutrition, and required prolonged mechanical ventilation. The overall percentage of sepsis caused by group B streptococcus and Escherichia coli decreased. No episodes of sepsis from Streptococcus pneumoniae or S pyogenes, common in the early years of the survey, were observed. The sepsis-related mortality rate steadily decreased, from 87% in 1928 to 3% in 2003. Conclusions. The demographics, pathogens, and outcome associated with neonatal sepsis continue to change. The increase in late-onset sepsis in preterm infants who required prolonged intensive care indicates that strategies to prevent infection are urgently needed for this population of infants.

Familial and Genetic Susceptibility to Major Neonatal Morbidities in Preterm Twins

BACKGROUND. Intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia remain significant causes of morbidity and mortality in preterm newborns. OBJECTIVES. Our goal was to assess the familial and genetic susceptibility to intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia. METHODS. Mixed-effects logistic-regression and latent variable probit model analysis were used to assess the contribution of several covariates in a multicenter retrospective study of 450 twin pairs born at ≤32 weeks of gestation. To determine the genetic contribution, concordance rates in a subset of 252 monozygotic and dizygotic twin pairs were compared. RESULTS. The study population had a mean gestational age of 29 weeks and birth weight of 1286 g. After controlling for effects of covariates, the twin data showed that 41.3%, 51.9%, and 65.2%, respectively, of the variances in liability for intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia could be accounted for by genetic and shared environmental factors. Among the 63 monozygotic twin pairs, the observed concordance for bronchopulmonary dysplasia was significantly higher than the expected concordance; 12 of 18 monozygotic twin pairs with ≥1 affected member had both members affected versus 3.69 expected. After controlling for covariates, genetic factors accounted for 53% of the variance in liability for bronchopulmonary dysplasia. CONCLUSIONS. Twin analyses show that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin. These data demonstrate, for the first time, the significant genetic susceptibility for bronchopulmonary dysplasia in preterm infants.

Changing Patterns in Neonatal Escherichia coli Sepsis and Ampicillin Resistance in the Era of Intrapartum Antibiotic Prophylaxis

OBJECTIVE. The goal was to determine current trends in Escherichia coli-related early- and late-onset sepsis and patterns of ampicillin resistance in relation to institutional changes in the use of intrapartum antibiotic prophylaxis. METHODS. A retrospective review of data for all infants with E coli sepsis at Yale-New Haven Hospital from 1979 to 2006 was performed. Study periods were based on predominant intrapartum antibiotic prophylaxis practices at Yale-New Haven Hospital, that is, (1) 1979 to 1992 (no formal intrapartum antibiotic prophylaxis), (2) 1993 to 1996 (risk factor-based), and (3) 1997 to 2006 (screening-based). Sepsis rates and patterns of ampicillin resistance were compared. RESULTS. Fifty-three cases of E coli early-onset sepsis and 129 cases of E coli late-onset sepsis were identified over 3 eras. In very low birth weight (<1500 g) infants, increases in E coli early-onset sepsis (period 1: 2.83 cases per 1000 very low birth weight admissions; period 2: 7.12 cases per 1000 very low birth weight admissions; period 3: 10.22 cases per 1000 very low birth weight admissions), intrapartum ampicillin exposure, and ampicillin-resistant E coli were observed. Intrapartum ampicillin exposure was determined to be an independent risk factor for ampicillin-resistant E coli early-onset sepsis. For the first time, a significant increase in E coli late-onset sepsis was observed in preterm infants (period 1: 10.39 cases per 1000 very low birth weight admissions; period 2: 16.01 cases per 1000 very low birth weight admissions; period 3: 21.66 cases per 1000 very low birth weight admissions) and term infants (period 1: 4.07 cases per 1000 admissions; period 2: 4.22 cases per 1000 admissions; period 3: 8.23 cases per 1000 admissions). CONCLUSIONS. Studies to provide a better understanding of potential consequences of intrapartum antibiotic exposure and its contribution to evolving trends in neonatal sepsis are urgently needed.

Antibiotic Exposure in the Newborn Intensive Care Unit and the Risk of Necrotizing Enterocolitis

OBJECTIVE To determine whether duration of antibiotic exposure is an independent risk factor for necrotizing enterocolitis (NEC). STUDY DESIGN A retrospective, 2:1 control-case analysis was conducted comparing neonates with NEC to those without from 2000 through 2008. Control subjects were matched on gestational age, birth weight, and birth year. In each matched triad, demographic and risk factor data were collected from birth until the diagnosis of NEC in the case subject. Bivariate and multivariate analyses were used to assess associations between risk factors and NEC. RESULTS One hundred twenty-four cases of NEC were matched with 248 control subjects. Cases were less likely to have respiratory distress syndrome (P = .018) and more likely to reach full enteral feeding (P = .028) than control subjects. Cases were more likely to have culture-proven sepsis (P < .0001). Given the association between sepsis and antibiotic use, we tested for and found a significant interaction between the two variables (P = .001). When neonates with sepsis were removed from the cohort, the risk of NEC increased significantly with duration of antibiotic exposure. Exposure for >10 days resulted in a nearly threefold increase in the risk of developing NEC. CONCLUSIONS Duration of antibiotic exposure is associated with an increased risk of NEC among neonates without prior sepsis.

Necrotizing enterocolitis in newborns: pathogenesis, prevention and management.

Necrotizing enterocolitis (NEC) is primarily a disease process of the gastrointestinal (GI) tract of premature neonates that results in inflammation and bacterial invasion of the bowel wall. Despite advances in the care of premature infants, NEC remains one of the leading causes of morbidity and mortality in this population. It occurs in 1–5% of all neonatal intensive care admissions and 5–10% of all very low birthweight (<1500 g) infants. Although research has presented an interesting array of potential contributing factors, the precise aetiology of this multifactorial disease process remains elusive. Historically, it was believed that NEC arose predominantly from ischaemic injury to the immature GI tract, yet alternate plausible hypotheses indicate that many factors are likely to be involved. These may include issues related to the introduction and advancement of enteric feeding, alterations in the normal bacterial colonization of the GI tract, bacterial translocation and activation of the cytokine cascade, decreased epidermal growth factor, increased platelet activating factor, and mucosal damage from free radical production.Clinical manifestations of NEC may be vague, including increased episodes of apnoea, desaturations, bradycardia, lethargy and temperature instability. There may also be GI-specific symptoms such as feeding intolerance, emesis, bloody stools, abdominal distention and tenderness, and abdominal wall discolouration. Laboratory values may be indicative of infection, coagulation abnormalities and fluid retention. Radiographic signs may include ileus, dilated or fixed intestinal loops, air in the intestinal wall or free air in the abdomen. Medical treatment typically consists of bowel rest and decompression, antibacterial therapy, and management of other haematological or electrolyte imbalances. Increased respiratory and cardiovascular support is sometimes needed. In neonates who do not respond adequately to medical management, or if pneumoperitoneum is present, surgical intervention may occur with either use of a peritoneal drain or laparotomy.Advances in antenatal and neonatal care have resulted in increased survival of extremely preterm neonates. As this at-risk population continues to increase, an effective preventative strategy for NEC is needed. One preventative strategy is the use of antenatal corticosteroids to enhance maturation of the fetus if preterm delivery is likely. Recommendation of use of breast milk, early initiation of trophic feeds and judicoius advancement of enteric feeds are current postnatal strategies. Other preventative strategies that have been investigated include the use of oral antibacterials, antioxidants, supplementation of arginine and epidermal growth factor, none of which have changed clinical practice. Recent promising data indicate that prophylactic use of probiotics may play a role in preventing the onset of NEC. However, more large-scale, definitive studies are needed.

A quality improvement initiative to reduce central line-associated bloodstream infections in a neonatal intensive care unit.

OBJECTIVE To reduce the rate of late-onset sepsis in a neonatal intensive care unit (NICU) by decreasing the rate of central line-associated bloodstream infection (CLABSI). METHODS We conducted a quasi-experimental study of an educational intervention designed to improve the quality of clinical practice in an NICU. Participants included all NICU patients with a central venous catheter (CVC). Data were collected during the period from July 1, 2005, to June 30, 2007, to document existing CLABSI rates and CVC-related practices. A multidisciplinary quality improvement committee was established to review these and published data and to create guidelines for CVC placement and management. Educational efforts were conducted to implement these practices. Postintervention CLABSI rates were collected during the period from January 1, 2008, through March 31, 2009, and compared with preintervention data and with benchmark data from the National Healthcare Safety Network (NHSN). RESULTS The rate of CLABSI in the NICU decreased from 8.40 to 1.28 cases per 1,000 central line-days (adjusted rate ratio, 0.19 [95% confidence interval, 0.08-0.45]). This rate was lower than the NHSN benchmark rate for level III NICUs. The overall rate of late-onset sepsis was reduced from 5.84 to 1.42 cases per 1,000 patient-days (rate difference, -4.42 cases per 1,000 patient-days [95% confidence interval, -5.55 to -3.30 cases per 1,000 patient-days]). CONCLUSIONS It is possible to reduce the rate of CLABSI, and therefore the rate of late-onset sepsis, by establishing and adhering to evidence-based guidelines. Sustainability depends on continued data surveillance, knowledge of medical and nursing literature, and timely feedback to the staff. The techniques established are applicable to other populations and areas of inpatient care.

Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults.

Objective: To determine current rates, risk factors, and causal organisms related to infections acquired during extracorporeal membrane oxygenation (ECMO). Design: A descriptive and retrospective case-control study. Setting: ECMO centers belonging to the Extracorporeal Life Support Organization. Patients: The Extracorporeal Life Support Organization Registry was queried for data related to all ECMO cases from 1998 through 2008. All culture-proven infections obtained from any site during ECMO support and not believed preexisting were included. Infection rates were analyzed by age category (i.e., neonatal, pediatric, adult), indication for ECMO (i.e., respiratory, cardiac, cardiopulmonary resuscitation), mode of ECMO (e.g., venovenous), and duration of ECMO support. Infected and noninfected ECMO patients were compared. Interventions: None. Measurements and Main Results: A total of 2,418 infections were reported during 20,741 (11.7%) ECMO cases for a rate of 15.4 per 1,000 ECMO days. Rates were highest in the adult vs. the pediatric and neonatal populations (30.6 vs. 20.8 vs. 10.1 infections per 1,000 ECMO days, respectively) and in those necessitating extracorporeal cardiopulmonary resuscitation (24.7 infections per 1,000 ECMO days). In each age category, venoarterial ECMO was the mode of support associated with the highest rate of infection. Prevalence of infection increased with duration of ECMO support from 6.1% of those requiring bypass for ≤7 days to 30.3% of those requiring ECMO for >14 days (p < .001). Coagulase-negative staphylococci (15.9%) were the most common organisms cultured followed by species of Candida (12.7%), and Pseudomonas (10.5%). Those with an infection acquired during ECMO support were significantly older, had a longer duration of ECMO, a longer duration of post-ECMO ventilatory support, and a higher prevalence of death than those without. Conclusions: Infections acquired during ECMO are common and can have significant associated consequences. Knowledge of high-risk patients and common causal organisms may improve strategies for treatment and prevention, but further work to develop strategies and guidelines for prevention of these infections is urgently needed.

Genetic susceptibility to retinopathy of prematurity.

OBJECTIVES. The goals were to isolate and to estimate the genetic susceptibility to retinopathy of prematurity. METHODS. A retrospective study (1994–2004) from 3 centers was performed with zygosity data for premature twins who were born at a gestational age of ≤32 weeks and survived beyond a postmenstrual age of 36 weeks. Retinopathy of prematurity was diagnosed and staged by pediatric ophthalmologists at each center. Data analyses were performed with mixed-effects logistic regression analysis and latent variable probit modeling. RESULTS. A total of 63 monozygotic and 137 dizygotic twin pairs were identified and analyzed. Data on gestational age, birth weight, gender, respiratory distress syndrome, retinopathy of prematurity, bronchopulmonary dysplasia, duration of ventilation and supplemental oxygen use, and length of stay were comparable between monozygotic and dizygotic twins. In the mixed-effects logistic regression analysis for retinopathy of prematurity, gestational age and duration of supplemental oxygen use were significant covariates. After controlling for known and unknown nongenetic factors, genetic factors accounted for 70.1% of the variance in liability for retinopathy of prematurity. CONCLUSION. In addition to prematurity and environmental factors, there is a strong genetic predisposition to retinopathy of prematurity.

A Decline in the Frequency of Neonatal Exchange Transfusions and Its Effect on Exchange-Related Morbidity and Mortality

OBJECTIVE. Our goal was to identify trends in patient demographics and indications for and complications related to neonatal exchange transfusion over a 21-year period in a single institution using a uniform protocol for performing the procedure. METHODS. A retrospective chart review of 107 patients who underwent 141 single- or double-volume exchange transfusions from 1986–2006 was performed. Patients were stratified into 2 groups, 1986–1995 and 1996–2006, on the basis of changes in clinical practice influenced by American Academy of Pediatrics management guidelines for hyperbilirubinemia. RESULTS. There was a marked decline in the frequency of exchange transfusions per 1000 newborn special care unit admissions over the 21-year study period. Patient demographics and indications for exchange transfusion were similar between groups. A significantly higher proportion of patients in the second time period received intravenous immunoglobulin before exchange transfusion. There was a higher proportion of patients in the 1996–2006 group with a serious underlying condition at the time of exchange transfusion. During that same time period, a lower proportion of patients experienced an adverse event related to the exchange transfusion. Although a similar percentage of patients in both groups experienced hypocalcemia and thrombocytopenia after exchange transfusion, patients treated from 1996–2006 were significantly more likely to receive calcium replacement or platelet transfusion. No deaths were related to exchange transfusion in either time period. CONCLUSIONS. Improvements in prenatal and postnatal care have led to a sharp decline in the number of exchange transfusions performed. This decline has not led to an increase in complications despite relative inexperience with the procedure.