Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies.

Importance: Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies. Objective: To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants. Design, Setting, and Participants: This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020. Main Outcomes and Measures: Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death. Results: A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008). Conclusions and Relevance: In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.

Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial.

OBJECTIVE: To assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight. STUDY DESIGN: This trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight <1600 g, and in an incubator were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. The infants were weaned to the crib following stable temperature at 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was length of hospital stay from birth to discharge; secondary outcomes included length of stay and growth velocity from weaning to discharge. Adverse events were monitored. RESULTS: Of 1565 infants screened, 885 were eligible, and 366 enrolled-187 to the 1600-g and 179 to the 1800-g group. Maternal and neonatal characteristics did not differ among weight groups. Length of hospital stay was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). Growth velocity from completion of weaning to discharge was higher in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/day (P = .005). Groups did not differ in adverse events. CONCLUSIONS: Among moderately preterm neonates, weaning from incubator to crib at a lower weight did not decrease length of stay, but was safe and was accompanied by higher weight gain after weaning. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02160002.

Vitamin D deficiency and respiratory morbidity among African American very low birth weight infants.

BACKGROUND: Very low birth weight infants (VLBWI) have unexplained variation in respiratory morbidity, including respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). We examined a potential association to serum 25-hydroxyvitamin D (s-25OHD) on day one. STUDY DESIGN: Prospective, observational study on 89 VLBWI (≤1250 g). S-25OHD (day one and 21) and respiratory severity score (RSS) (day one) were examined. Other respiratory morbidities including BPD were compared between infants with s-25OHD ≤ 10 ng/ml (deficient) versus >10 ng/ml (adequate). RESULTS: Eighty one neonates (91%) were African Americans. The mean (SD) birthweight was 868 (229) g, gestational age 27 (2) weeks. On day one, mean (SD) s-25OHD was 15.48 (8.31) ng/ml, with 32 (37%) being vitamin D deficient. The deficiency and adequate VLBWI groups had similar birthweight; 860 (262) vs 873 (210) g, and gestational age; 27 (2) vs 27 (2) weeks. In 78 survivors, s-25OHD rose from 15.48 (8.31) ng/ml day one to 52.36 (22.49) ng/ml day 21 after supplementation, p < 0.001. On day one, increasing RSS was inversely related to s-25OHD, trend p = 0.054. Compared to the adequate group, the deficiency group had higher RSS (5.0 ±â€¯2.7 vs 3.6 ±â€¯1.9), required surfactant therapy more frequently (91% vs 72%), and needed home oxygen therapy more often (48% vs 26%), p ≤ 0.05 for all. Among infants with BPD, the severity of disease was inversely related to s-25OHD, trend p < 0.09. CONCLUSION: Lower levels of s-25OHD were associated with increased severity of RDS and BPD among a cohort of mostly African American VLBWI.

Does vitamin D deficiency affect placental inflammation or infections among very low birth weight infants?

OBJECTIVE: Examine the association between placental inflammation and neonatal infections, and 25OH vitamin D (25OH D) levels at birth among very low birth weight infants (VLBWI). STUDY DESIGN: Serum 25OH D levels were measured in 89 VLBWI (≤1250 g) and 47 mothers on day one, and in 78 infants on day 21. Placentas were examined for maternal and fetal inflammation. Infants were divided into deficient (≤10 ng/ml) and adequate (>10 ng/ml) groups based on 25OH D levels on day 1. RESULTS: Mean ± SD maternal levels of 25OH D (21 ± 9 ng/ml) correlated with infants' levels (15 ± 8 ng/ml), (p < .001). 25OH D levels were lower in deficient (32/89) than in adequate group (8 ± 2 versus 20 ± 7 ng/ml, p = .011). Infants' 25OH D levels rose significantly by day 21 (p < .001). Univariate analyses showed no differences between infant groups in maternal or fetal inflammation, or neonatal infections (p > .05). Logistic regression analyses revealed no association between deficient 25OH D levels and the odds of maternal or fetal inflammation or other infections. Levels of 25OH D did not correlate with severity of placental inflammation. CONCLUSIONS: Deficient levels of 25OH D at birth are not associated with the occurrence of placental inflammation or neonatal infections among VLBWI.

Role of spontaneous breathing trial in predicting successful extubation in premature infants.

BACKGROUND: The ability of clinicians to predict successful extubation in mechanically ventilated premature neonates is limited. Identifying objective criteria for predicting successful extubation may reduce the incidence of failed extubation and the duration of mechanical ventilation. OBJECTIVE: To evaluate the validity of objective measures of lung function and spontaneous breathing trial (SBT) in predicting successful extubation among premature neonates with attempted extubations within the first 3 weeks of life. METHODS: Respiratory compliance (Crs) along with SBT was performed prior to elective extubations within 3 weeks of age in premature infants ≤ 32 weeks. Extubation was considered successful if patients remained extubated for > 72 hr. Ventilator settings including mean airway pressure (MAP), set rate, and fraction of inspired oxygen (FiO2) 24 hr after re-intubation were compared with pre-extubation settings, in patients requiring re-intubation. RESULTS: Thirty-nine of 49 infants (80%) were successfully extubated. Of 41 babies who passed SBT, only 5 infants failed extubation. SBT had 92% sensitivity, 50% specificity, 88% positive predictive, and 63% negative predictive value for successful extubation. Crs was comparable between infants who were successfully extubated and those who were not. CONCLUSIONS: A SBT prior to extubation may be a practical objective adjunct in predicting successful extubation in ventilated premature infants.

Role of angiotensin-converting enzyme gene polymorphism in persistent pulmonary hypertension of the newborn.

AIM: To evaluate the association of angiotensin-converting enzyme (ACE) gene polymorphism with risk/severity of persistent pulmonary hypertension of the newborn (PPHN) among at risk infants. METHODS: Infants ≥ 34 weeks with respiratory distress at birth were recruited. PPHN was diagnosed clinically and by cardiac echocardiogram. Control group consisted of infants with respiratory distress who did not develop PPHN. ACE genotyping (DD, II, DI genotypes) and serum ACE levels were determined. RESULTS: A total of 120 infants were included (PPHN = 44; control = 76). Frequency of ACE DD genotype was not different between the two groups of infants (25% versus 33%). Among PPHN infants, severity of illness did not differ between genotypes. Mean (SD) serum ACE levels [15 (9) versus 24 (13) versus 29 (14) U/L] were positively associated with the number of D alleles and inversely associated with infants' gestational age (GA) and level of cardiovascular support. CONCLUSION: Angiotensin-converting enzyme gene polymorphism did not impact the risk or severity of PPHN among infants ≥ 34 weeks GA.

Haplotypes of tumor necrosis factor gene and tracheal aspirate fluid levels of tumor necrosis factor-alpha in preterm infants.

Individual variability in the production of tumor necrosis factor-alpha (TNF-alpha) has been attributed to genetic factors. We examined whether alleles of TNF gene (lymphotoxin-alpha+250, TNF-alpha-308, and TNF-alpha-238) affect tracheal aspirate fluid (TAF) levels of TNF-alpha among preterm infants at risk of bronchopulmonary dysplasia. TAF samples were collected within 48 h of birth and 7, 14, 21, and 28 d later. Haplotypes [designated using the nucleotide bases in the chromosome order (lymphotoxin-alpha+250, TNF-alpha-308, TNF-alpha-238)] of TNF were correlated with levels of TNF-alpha. Diplotypes of TNF (genotypes of haplotypes) classified as high, intermediate, or low based on their relation to TAF TNF-alpha levels were also correlated with TNF-alpha levels. The most frequent (and reference haplotype) was AGG. The GGG haplotype was associated with the lowest TAF TNF-alpha levels on day 7 among African American infants (p < 0.008). Sequential changes in levels of TNF-alpha correlated with infants' diplotype status [high (HH), intermediate (HL), low (LL)]. Fetal chorioamnionitis but not bronchopulmonary dysplasia was associated with infants' diplotypes (p < 0.005). Haplotypes of the TNF gene influence TAF levels of TNF-alpha. Diplotypes of TNF are associated with fetal chorioamnionitis.

Auditory brainstem response abnormalities and hearing loss in children with craniosynostosis.

OBJECTIVES: Craniosynostosis is a devastating disorder characterized by premature closure of the cranial plates before or shortly after birth. This results in an abnormally shaped skull, face, and brain. Little is known about hearing disorders in such patients, and nothing has been published about their auditory brainstem responses. Our objective was to evaluate such patients for auditory brainstem response and hearing disorders with the long-term goal of improving patient evaluation and management. PATIENTS AND METHODS: We evaluated the auditory brainstem responses, hearing, and brain images of children with fibroblast growth factor receptor 2 craniosynostosis (n = 11). RESULTS: Prolongation of the auditory brainstem response I-to-III interpeak latency was a frequent characteristic of fibroblast growth factor receptor 2 craniosynostosis, occurring in 91% of our patients. Prolongation of the III-to-V interpeak latency was an occasional characteristic, occurring in 27% of our patients. Whenever the I-to-III interpeak latency was prolonged, wave II was always abnormal. Associated morbidities included sensorineural hearing loss (27%), recurrent otitis media (100%), and Arnold-Chiari malformation (27%). Cranial decompression improved the interpeak latencies of 2 children. CONCLUSIONS: These previously undocumented auditory brainstem response abnormalities reflect abnormal neural transmission, which could cause peripheral and central auditory processing disorders. We speculate that the major pathogenic basis of the I-to-III interpeak latency and wave II abnormalities is compression of the auditory nerve as it passes through the internal auditory meatus and posterior fossa, which would explain the auditory nerve hearing loss, tinnitus, and vertigo that affect these children. Awareness of these abnormalities could lead to important advancements in the auditory and neurosurgical assessment and management of this overlooked patient group. We provide recommendations for the improved assessment and management of these patients. In particular, we recommend that auditory brainstem response diagnostics become standard clinical care for this patient group as the best way to detect auditory nerve compression.

A cluster-randomized trial of benchmarking and multimodal quality improvement to improve rates of survival free of bronchopulmonary dysplasia for infants with birth weights of less than 1250 grams.

OBJECTIVE: We tested whether NICU teams trained in benchmarking and quality improvement would change practices and improve rates of survival without bronchopulmonary dysplasia in inborn neonates with birth weights of <1250 g. METHODS: A cluster-randomized trial enrolled 4093 inborn neonates with birth weights of <1250 g at 17 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Three centers were selected as best performers, and the remaining 14 centers were randomized to intervention or control. Changes in rates of survival free of bronchopulmonary dysplasia were compared between study year 1 and year 3. RESULTS: Intervention centers implemented potentially better practices successfully; changes included reduced oxygen saturation targets and reduced exposure to mechanical ventilation. Five of 7 intervention centers and 2 of 7 control centers implemented use of high-saturation alarms to reduce oxygen exposure. Lower oxygen saturation targets reduced oxygen levels in the first week of life. Despite these changes, rates of survival free of bronchopulmonary dysplasia were all similar between intervention and control groups and remained significantly less than the rate achieved in the best-performing centers (73.3%). CONCLUSIONS: In this cluster-randomized trial, benchmarking and multimodal quality improvement changed practices but did not reduce bronchopulmonary dysplasia rates.

Cumulative index of exposure to hypocarbia and hyperoxia as risk factors for periventricular leukomalacia in low birth weight infants.

BACKGROUND: Hypocarbia and hyperoxia are risk factors for periventricular leukomalacia in low birth weight infants. The association of a cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia has not been evaluated. OBJECTIVE: Our goal was to examine the relationship between cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia during the first 7 days of life in low birth weight infants. METHODS: Blood gas results were recorded in 6-hour intervals among low birth weight infants in a prospective data registry. Cumulative index of exposure to hypocarbia was calculated as the difference between arterial carbon dioxide level and 35 mmHg multiplied by the time interval in hours for each 6-hour block in a 24-hour day for the first 7 days of life. Cumulative index of exposure to hyperoxia was calculated in the same manner for arterial oxygen level >80 mm Hg. The relationship between exposure to hypocarbia, hyperoxia, and periventricular leukomalacia was examined in 778 infants with blood gas and cranial sonography data. RESULTS: Twenty-one infants had periventricular leukomalacia. Hypocarbia occurred in 489 infants and hyperoxia in 502 infants. Infants with periventricular leukomalacia were more likely to have a lower gestational age and to require delivery room resuscitation than those without periventricular leukomalacia. More infants in the highest quartile of exposure to hypocarbia had periventricular leukomalacia compared to those with no hypocarbia. Risk of periventricular leukomalacia was increased in infants with the highest quartile of exposure to hypocarbia after adjusting for maternal and neonatal variables, none to be associated with periventricular leukomalacia. Cumulative index exposure to hyperoxia was not related to periventricular leukomalacia. CONCLUSIONS: Cumulative exposure to hypocarbia and not hyperoxia was independently related to risk of periventricular leukomalacia in low birth weight infants.

Deletion allele of angiotensin-converting enzyme is associated with increased risk and severity of bronchopulmonary dysplasia.

OBJECTIVE: To explore whether the deletion (D) allele of angiotensin-converting enzyme (ACE) is associated with the risk or severity of bronchopulmonary dysplasia (BPD) among very low birth weight (BW) infants. STUDY DESIGN: Infants with a BW < or = 1250 g were prospectively recruited. The D and I (insertion) alleles of ACE were determined using a polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: Infants with DD/DI genotype of ACE had a (mean +/- SD) birth weight (938 +/- 204 g vs 925 +/- 196 g) and gestational age (28 +/- 3 weeks vs 28 +/- 2 weeks), similar to infants with II genotype of ACE (P > .05). Infants with DD/DI genotype of ACE were more likely to have BPD than infants with II genotype (47% vs 22%, P = .025). Among infants with BPD, ACE DD/DI genotype was more common among infants with moderate or severe BPD compared with infants with mild BPD (74% vs 26%, P = .012). The number of D alleles of ACE correlated directly and positively with the severity of BPD (R = 0.23, P = .045). CONCLUSION: The D allele of ACE is associated with an increased risk and severity of BPD among preterm infants.

Oxygen delivery through nasal cannulae to preterm infants: can practice be improved?

OBJECTIVE: Oxygen delivery through nasal cannulae to convalescent preterm infants is a common but largely unstudied practice. To learn more about current nasal cannula oxygen delivery practices, we examined the variations in oxygen delivery through nasal cannulae among the centers of the Neonatal Research Network, the frequency of prescription of low levels of oxygen, and the success of weaning to room air. We hypothesized that some infants treated with oxygen through nasal cannulae were receiving oxygen levels equivalent to those of room air. METHODS: This was a descriptive, nested, cohort study of nasal cannula oxygen prescription among 187 infants with birth weights of <1250 g. All infants were studied at a postmenstrual age of 36 weeks, with a timed oxygen reduction challenge to establish their ability to be weaned to room air. The results of this challenge were compared with the fraction of inspired oxygen (FIO2) delivered, calculated as effective FIO2. Infants who maintained oxygen saturation values of > or =90% during oxygen weaning and during a 30-minute period in room air were defined as passing the challenge. RESULTS: Fifty-two infants (27.8%) were receiving oxygen concentrations and flow rates through nasal cannulae that delivered an effective FIO2 of <0.23, of whom 16 were receiving oxygen concentrations and flow rates that delivered an effective FIO2 of 0.21. In addition, 22 infants (11.8%) were prescribed room air through nasal cannulae intentionally. Seventy-two percent of those prescribed an effective FIO2 of <0.23 passed the room air challenge. CONCLUSIONS: Prescription of oxygen with combinations of flow rates and oxygen concentrations that delivered a low effective FIO2 was common. We speculate that some of this, including the inadvertent prescription of an effective FIO2 equivalent to that of room air, is related to lack of knowledge of the effective FIO2. Routine calculation of effective FIO2 values may prompt earlier trials of room air and thus reduce unnecessary days of oxygen therapy.

Polymorphism of tumor necrosis factor-alpha and risk and severity of bronchopulmonary dysplasia among very low birth weight infants.

BACKGROUND: Preterm infants with bronchopulmonary dysplasia (BPD) exhibit prolonged elevation of inflammatory indices in their tracheal aspirates. Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of the inflammatory response. The adenine-containing alleles of TNF-alpha-308 and lymphotoxin-alpha+250 have been associated with increased levels of TNF-alpha, whereas the adenine allele of TNF-alpha-238 produces lower levels of TNF-alpha after stimulation. High levels of TNF-alpha may promote chronic inflammation by overwhelming counter-regulatory mechanisms and may lead to the development of BPD. Low levels of TNF-alpha may decrease the risk and/or severity of BPD. OBJECTIVE: To determine whether alleles of TNF-alpha play a role in the susceptibility and/or severity of BPD among very low birth weight infants. METHODS: Infants with birth weights of < or =1250 g were included. Genotypic analyses (polymerase chain reaction-restriction fragment length polymorphism assays) were performed with DNA extracted from whole-blood samples. RESULTS: Infants who developed BPD (fraction of inspired oxygen at postconceptional age of 36 weeks of >0.21, n = 51) had a younger gestational age (mean +/- SD: 27 +/- 4 vs 29 +/- 2 weeks) and lower birth weight (853 +/- 184 vs 997 +/- 193 g) than did infants without BPD (n = 69). The genotypic distributions of lymphotoxin-alpha+250 and TNF-alpha-308 were comparable among the groups of infants. However, the AA and GA TNF-alpha-238 genotypes were much less likely to occur among infants with BPD than among infants without BPD. The adenine allele of TNF-alpha-238 was absent among infants with severe BPD and occurred significantly less often among infants with moderate or severe BPD, compared with infants with mild BPD. The number of adenine alleles of TNF-alpha-238 was correlated inversely with the severity of BPD (r = -.341). CONCLUSION: The adenine allele of TNF-alpha-238 may reduce the risk and severity of BPD.

Tumor necrosis factor-alpha allele lymphotoxin-alpha+250 is associated with the presence and severity of placental inflammation among preterm births.

Histologic inflammation of placenta has been associated with increased risk for bronchopulmonary dysplasia and periventricular leukomalacia among preterm infants. Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the regulation of inflammation. Some alleles of TNF (LT-alpha+250, TNF-alpha-308, and TNF-alpha-238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or involving the immune system. To determine whether alleles of TNF-alpha affect the risk and/or the severity of chorioamnionitis, we examined the placentas of 101 preterm births (birth weight