Trends in C-Reactive Protein Use in Early-Onset Sepsis Evaluations and Associated Antibiotic Use.

OBJECTIVES: To determine the prevalence of C-reactive protein (CRP) use in early-onset sepsis (EOS) evaluations in neonatal intensive care units (NICUs) across the United States over time and to determine the association between CRP use and antibiotic use. STUDY DESIGN: A retrospective cohort study of NICUs contributing data to Premier Healthcare Database from 2009 through 2021. EOS evaluation was defined as a blood culture charge <3 days after birth. CRP use for each NICU was calculated as the proportion of infants with a CRP test obtained <3 days after birth among those undergoing an EOS evaluation and categorized as, low (<25%); medium-low (25 to <50%), medium-high (50 to <75%), and high (≥75%). Outcomes included antibiotic use and mortality ≤7 days after birth. RESULTS: Among 572 NICUs, CRP use varied widely and was associated with time. The proportion of NICUs with high CRP use decreased from 2009 to 2021 (24.7% vs. 17.4%, P <0.001), and low CRP use NICUs increased (47.9% vs. 64.8%, P <0.001). Compared with low use NICUs, high use NICUs more frequently continued antibiotics >3 days (10% vs. 25%, P<0.001). This association persisted in multivariable-adjusted regression analyses (aRR 1.95, 95%CI 1.54, 2.48). Risk of mortality was not different in high use NICUs (adjusted risk difference -0.02%, 95%CI -0.04%, 0.0008%). CONCLUSIONS: CRP use in EOS evaluations varied widely across NICUs. High CRP use was associated with prolonged antibiotic therapy but not mortality ≤7 days after birth. Reducing routine CRP use in EOS evaluations may be a target for neonatal antibiotic stewardship efforts.

At a crossroads for early medical treatment of persistent patent ductus arteriosus in preterm infants.

Administration of early medical therapy for the patent ductus arteriosus has ebbed and flowed through the years, with a multitude of studies failing to demonstrate a reduction in morbidity or mortality from ductal closure in the preterm population. Concerningly, an increasing number of studies have demonstrated an increase in morbidity, such as bronchopulmonary dysplasia and mortality with the use of early medical therapy to close the ductus. Considering information regarding potential risk without clear benefit in an overall cohort of preterm patients with a patent ductus, use of early medical therapy is increasingly challenging to justify and necessitates studies that will aid in identifying a patient population that would benefit from ductal closure and timing of therapy.

28 NICUs participating in a quality improvement collaborative targeting early-onset sepsis antibiotic use.

OBJECTIVE: There is widespread overuse of antibiotics in neonatal intensive care units (NICUs). The objective of this study was to safely reduce antibiotic use in participating NICUs by targeting early-onset sepsis (EOS) management. STUDY DESIGN: Twenty-eight NICUs participated in this statewide multicenter antibiotic stewardship quality improvement collaborative. The primary aim was to reduce the total monthly mean antibiotic utilization rate (AUR) by 25% in participant NICUs. RESULT: Aggregate AUR was reduced by 15.3% (p < 0.001). There was a wide range in improvement among participant NICUs. There were no increases in EOS rates or nosocomial infection rates related to the intervention. CONCLUSION: Participation in this multicenter NICU antibiotic stewardship collaborative targeting EOS was associated with an aggregate reduction in antibiotic use. This study informs efforts aimed at sustaining improvements in NICU AURs.

Data-driven longitudinal characterization of neonatal health and morbidity.

Although prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here, we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly before conception and ending months after birth. By linking the EHRs of the Lucile Packard Children's Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. Maternal and newborn EHRs were extracted and used to train a multi-input multitask deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional cohort of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to validate the model. Areas under the receiver operating characteristic curve at delivery exceeded 0.9 for 10 of the 24 neonatal outcomes considered and were between 0.8 and 0.9 for 7 additional outcomes. Moreover, comprehensive association analysis identified multiple known associations between various maternal and neonatal features and specific neonatal outcomes. This study used linked EHRs from more than 30,000 mother-newborn dyads and would serve as a resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.

Ductus arteriosus and the preterm brain.

As the approach to the patent ductus arteriosus (PDA) in the preterm infant remains controversial, the potential consequences of a significant ductal shunt on the brain should be evaluated. In this population at high risk of adverse outcomes, including intraventricular haemorrhage and white matter injury, as well as longer-term neurodevelopmental impairment, it is challenging to attribute sequelae to the PDA. Moreover, individual patient characteristics including gestational age and timing of PDA intervention factor into risks of brain injury. Haemodynamic assessment of the ductus combined with bedside neuromonitoring techniques improve our understanding of the role of the PDA in neurological injury. Effects of various PDA management strategies on the brain can similarly be investigated. This review incorporates current understanding of how the PDA impacts the developing brain of preterm infants and examines modalities to measure these effects.

Diagnostic Performance and Patient Outcomes With C-Reactive Protein Use in Early-Onset Sepsis Evaluations.

OBJECTIVES: To determine performance of C-reactive protein (CRP) in the diagnosis of early-onset sepsis, and to assess patient outcomes with and without routine use of CRP. STUDY DESIGN: This was a retrospective cohort study of infants admitted to 2 neonatal intensive care units. CRP was used routinely in early-onset sepsis evaluations during 2009-2014; this period was used to determine CRP performance at a cut-off of ≥10 mg/L in diagnosis of culture-confirmed early-onset sepsis. Routine CRP use was discontinued during 2018-2020; outcomes among infants admitted during this period were compared with those in 2012-2014. RESULTS: From 2009 to 2014, 10 134 infants were admitted; 9103 (89.8%) had CRP and 7549 (74.5%) had blood culture obtained within 3 days of birth. CRP obtained ±4 hours from blood culture had a sensitivity of 41.7%, specificity 89.9%, and positive likelihood ratio 4.12 in diagnosis of early-onset sepsis. When obtained 24-72 hours after blood culture, sensitivity of CRP increased (89.5%), but specificity (55.7%) and positive likelihood ratio (2.02) decreased. Comparing the periods with (n = 4977) and without (n = 5135) routine use of CRP, we observed lower rates of early-onset sepsis evaluation (74.5% vs 50.5%), antibiotic initiation (65.0% vs 50.8%), and antibiotic prolongation in the absence of early-onset sepsis (17.3% vs 7.2%) in the later period. Rate and timing of early-onset sepsis detection, transfer to a greater level of care, and in-hospital mortality were not different between periods. CONCLUSIONS: CRP diagnostic performance was not sufficient to guide decision-making in early-onset sepsis. Discontinuation of routine CRP use was not associated with differences in patient outcomes despite lower rates of antibiotic administration.

Patent Ductus Arteriosus: A Contemporary Perspective for the Pediatric and Adult Cardiac Care Provider.

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer-term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence-based medicine.

The Term Newborn: Early-Onset Sepsis.

The changing epidemiology of early-onset neonatal sepsis among term infants has required reappraisal of approaches to management of newborn infants at potential risk. As this is now a rare disease, new strategies for reduction in diagnostic testing and empirical treatment have been developed. Adoption and refinement of these strategies should be a priority for all facilities where babies are born.

Regional Variation of Early-onset Neonatal Group B Streptococcal Disease Prevention Strategies in Mainland China.

BACKGROUND: Prevention strategies can reduce the incidence of early-onset group B Streptococcus (GBS) neonatal sepsis (EOGBS). Rates of GBS colonization and infection vary among regions within China. China has not adopted a unified prevention strategy. METHODS: To assess strategies to reduce EOGBS in China, models were developed to quantify residual EOGBS rates with intrapartum antibiotic prophylaxis in infants ≥ 35 weeks' gestation in risk factor-based and antepartum screening-based strategies. Maternal GBS colonization rates and EOGBS incidence in 3 regions of China (A: Xiamen of Fujian province, B: Shanghai and C: Liuzhou of Guangxi province) were estimated from published data. RESULTS: Estimates for GBS colonization and attack rates were 21.6%, 11.7% and 6.1% and 1.79, 1.79 and 0.58 per 1000 live births for regions A, B and C, respectively. Modeling predicted that strategies including screening cultures beginning at 36 weeks' gestation and intrapartum antibiotic prophylaxis in 90% of eligible parturients could reduce EOGBS incidence to 0.44, 0.50 and 0.16 per 1000 live births in these regions. In region C, the expected EOGBS rate could be reduced to 0.28 per 1000 using a risk factor-based strategy. CONCLUSIONS: Different strategies for preventing EOGBS may be needed in different regions of mainland China. Screening strategies may be most appropriate in regions with higher attack rates, even with moderate levels of maternal GBS colonization. In areas with low attack rates, risk factor strategies that reduce morbidity by at least one-third may suffice.

Vignettes Identify Variation in Antibiotic Use for Suspected Early Onset Sepsis.

BACKGROUND AND OBJECTIVES: There is widespread unwarranted antibiotic use and large individual provider variation in antibiotic use in NICUs. Vignette-based research methodology offers a unique method of studying variation in individual provider decisions. The objective with this study was to use a vignette-based survey to identify specific areas of provider antibiotic use variation in newborns being evaluated for early onset sepsis. METHODS: This study was undertaken as part of a statewide multicenter neonatal antibiotic stewardship quality improvement project led by a perinatal quality improvement collaborative. A web-based vignette survey was administered to identify variation in decisions to start and discontinue antibiotics in cases of early onset sepsis. RESULTS: The largest variation was noted in 3 of the 6 vignette cases. These cases highlighted variation in (1) decisions to start antibiotics in a case describing a well-appearing newborn with risk factors and an elevated C-reactive protein, (2) decisions to start antibiotics in the case of a newborn with risk factors plus mild respiratory signs at birth, and (3) decisions to stop antibiotics in the case of the newborn with a history of sepsis risk factors and mild clinical respiratory signs that resolved after 72 hours. CONCLUSIONS: Clinical vignette assessment identified specific areas of variation in individual provider antibiotic use decisions in cases of suspected early onset sepsis. Vignettes are a valuable method of describing individual provider variation and highlighting antibiotic stewardship improvement opportunities in NICUs.

Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis.

OBJECTIVES: To provide a comprehensive assessment of case stratification by the Neonatal Early-Onset Sepsis (EOS) Calculator, a novel tool for reducing unnecessary antibiotic treatment. STUDY DESIGN: A systematic review with individual patient data meta-analysis was conducted, extending PROSPERO record CRD42018116188. Cochrane, PubMed/MEDLINE, EMBASE, Web of Science, Google Scholar, and major conference proceedings were searched from 2011 through May 1, 2020. Original data studies including culture-proven EOS case(s) with EOS Calculator application, independent from EOS Calculator development, and including representative birth cohorts were included. Relevant (individual patient) data were extracted from full-text and data queries. The main outcomes were the proportions of EOS cases assigned to risk categories by the EOS Calculator at initial assessment and within 12 hours. Evidence quality was assessed using Newcastle-Ottawa scale, Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies, and GRADE tools. RESULTS: Among 543 unique search results, 18 were included, totaling more than 459 000 newborns. Among 234 EOS cases, EOS Calculator application resulted in initial assignments to (strong consideration of) empiric antibiotic administration for 95 (40.6%; 95% CI, 34.2%-47.2%), more frequent vital signs for 36 (15.4%; 95% CI, 11.0%-20.7%), and routine care for 103 (44.0%; 95% CI, 37.6%-50.6%). By 12 hours of age, these proportions changed to 143 (61.1%; 95% CI, 54.5%-67.4%), 26 (11.1%; 95% CI, 7.4%-15.9%), and 65 (27.8%; 95% CI, 22.1%-34.0%) of 234 EOS cases, respectively. CONCLUSIONS: EOS Calculator application assigns frequent vital signs or routine care to a substantial proportion of EOS cases. Clinical vigilance remains essential for all newborns.

Technical assessment of the neonatal early-onset sepsis risk calculator.

The use of the neonatal early-onset sepsis risk calculator, developed by Kaiser Permanente Northern California (CA, USA), is increasing for the management of late preterm and full term newborn babies at risk for early-onset sepsis. The calculator is based on a robust logistic regression model that provides quantitative individualised estimates of early-onset sepsis risk. Low sensitivity for prediction of sepsis at birth shows that standard perinatal risk factors alone are insufficient for ascertainment of neonatal early-onset sepsis. Performance is improved by the addition of physical examination findings at birth, but the sensitivity of combined findings remains limited. The present implementation of the calculator integrates risk factors and examination findings. A methodological error in adapting the regression for application in the population (rather than the development sample) and several subsequent modifications compromise the accuracy of quantitative predictions of the absolute risk of sepsis, but these factors are not expected to seriously undermine the use of the calculator for risk stratification. The calculator has served as an instrument of change away from previously recommended categorical risk ascertainment strategies, and its implementation reduces the need for diagnostic testing and empirical antibiotic treatment without apparent ill effects. However, the calculator should not be relied on to provide accurate estimates for individuals with regard to absolute risk of early-onset sepsis in newborn babies.

Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?

Optimal management of patent ductus arteriosus (PDA) in extremely preterm infants remains controversial. There is paucity of evidence on the benefits of PDA treatment in reducing mortality and morbidities in extremely preterm infants. Failure of randomized clinical trials to demonstrate beneficial effects of PDA treatment on outcomes has often been attributed to open treatment of control subjects. This perspective examines the PDA treatment trials to date, with specific focus on rates of and ages of subjects at open rescue treatment. Although these trials demonstrate that ductal closure is significantly increased with treatment, that does not translate to a significant decrease in major morbidities or mortality in premature infants, even when trials with high rates of rescue treatment of controls are excluded. Trials in which enrollment occurred after 7 days of age include insufficient numbers of subjects to evaluate this relationship.

Sustainability of a Clinical Examination-Based Approach for Ascertainment of Early-Onset Sepsis in Late Preterm and Term Neonates.

We demonstrated the sustained impact over a 5-year period of a clinical examination-based approach to identification of early-onset sepsis in late preterm and term neonates at our hospital. To date, more than 20 000 neonates have been safely managed using this approach, resulting in a 63% reduction in antibiotic use.