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

OBJECTIVE: To determine the prevalence of C-reactive protein (CRP) use in early-onset sepsis (EOS) evaluations in neonatal intensive care units (NICUs) across the US 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 < .001), and those with low CRP use increased (47.9% vs 64.8%, P < .001). Compared with low-use NICUs, high-use NICUs more frequently continued antibiotics > 3 days (10% vs 25%, P < .001). This association persisted in multivariable-adjusted regression analyses (adjusted risk ratio 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.

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.

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.

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.

Prenatal treatment of ornithine transcarbamylase deficiency.

PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Covariation of Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Management and In-Neonatal Intensive Care Unit Outcomes Following Preterm Birth.

OBJECTIVE: To test the hypothesis that neonatal intensive care unit (NICU)-specific changes in patent ductus arteriosus (PDA) management are associated with changes in local outcomes in preterm infants. STUDY DESIGN: This retrospective repeated-measures study of aggregated data included infants born 400-1499 g admitted within 2 days of delivery to NICUs participating in the California Perinatal Quality Care Collaborative. The period 2008-2015 was divided into four 2-year epochs. For each epoch and NICU, we calculated proportions of infants receiving cyclooxygenase inhibitor (COXI) or PDA ligation and determined NICU-specific changes in these therapies between consecutive epochs. Generalized estimating equations were used to examine adjusted relationships between NICU-specific changes in PDA management and contemporaneous changes in local outcomes. RESULTS: We included 642 observations of interepoch change at 119 hospitals summarizing 32 094 infants. NICU-specific changes in COXI use and ligation showed significant dose-response associations with contemporaneous changes in adjusted local outcomes. Each percentage point decrease in NICU-specific proportion treated with either COXI or ligation was associated with a 0.21 percentage point contemporaneous increase in adjusted local in-hospital mortality (95% CI 0.06, 0.33; P = .005) among infants born 400-749 g. In contrast, decreasing NICU-specific ligation rate among infants 1000-1499 g was associated with decreasing adjusted local bronchopulmonary dysplasia (P = .009) and death or bronchopulmonary dysplasia (P = .01). CONCLUSIONS: NICU-specific outcomes of preterm birth co-vary with local PDA management. Treatment for PDA closure may benefit some infants born 400-749 g. Decreasing NICU-specific rates of COXI use or ligation were not associated with increases in local adjusted rates of examined adverse outcomes in larger preterm infants.

Temporal Relationship of Onset of Necrotizing Enterocolitis and Introduction of Enteric Feedings and Powdered Milk Fortifier.

OBJECTIVE: This article evaluates temporal relationships between onset of necrotizing enterocolitis (NEC) in preterm infants and introduction of enteral feedings or powdered human milk fortifier (HMF). STUDY DESIGN: This is a Poisson regression analysis of NEC cases at a single children's hospital between 1999 and 2009, using the self-controlled case series method to estimate adjusted daily event rate ratios (DERR) during postexposure intervals. RESULTS: Of 139 patients with a clinical diagnosis of NEC, 26 had early disease onset prior to initiation of feeding and were considered to be cases of spontaneous intestinal perforation (SIP). For the remaining 113 infants, the DERR for NEC onset were significantly greater on days for which infants were <14 days of age (DERR, 2.15; 95% confidence interval [CI], 1.22-3.79) or ≥31 weeks postmenstrual age (2.94; 95% CI, 1.51-5.83) or which fell within 14 days after initiation of enteric feeding (8.29; 95% CI, 4.73-14.53) or 4 days after introduction of HMF (12.32; 95% CI, 7.13-21.29). CONCLUSION: There are strong temporal associations between onset of NEC and initiation of enteral feeding or powdered HMF in preterm infants.

Changing Management of the Patent Ductus Arteriosus: Effect on Neonatal Outcomes and Resource Utilization.

Objective This historical cohort study investigated how a shift toward a more conservative approach of awaiting spontaneous closure of the patent ductus arteriosus (PDA) in preterm infants has affected neonatal outcomes and resource utilization. Methods We retrospectively studied very low birth weight infants diagnosed with a PDA by echocardiogram (ECHO) in 2006-2008 (era 1), when medical or surgical PDA management was emphasized, to those born in 2010-2012 (era 2) when conservative PDA management was encouraged. Multiple regression analyses adjusted for gestational age were performed to assess differences in clinical outcomes and resource utilization between eras. Results More infants in era 2 (35/89, 39%) compared with era 1 (22/120, 18%) had conservative PDA management (p < 0.01). Despite no difference in surgical ligation rate, infants in era 2 had ligation later (median 24 vs. 8 days, p < 0.0001). There was no difference in clinical outcomes between eras, while number of ECHOs per patient was the only resource measure that increased in era 2 (median 3 vs. 2 ECHOs, p = 0.003). Conclusion In an era of more conservative PDA management, no increase in adverse clinical outcomes or significant change in resource utilization was found. Conservative PDA management may be a safe alternative for preterm infants.

Red blood cell transfusion is not associated with necrotizing enterocolitis: a review of consecutive transfusions in a tertiary neonatal intensive care unit.

OBJECTIVE: To explore the association between red blood cell transfusion and necrotizing enterocolitis (NEC) in a neonatal intensive care unit with liberal transfusion practices. STUDY DESIGN: A retrospective cohort study was conducted for all infants weighing <1500 g who received at least 1 packed red blood cell transfusion between January 2008 and June 2013 in a tertiary neonatal intensive care unit. The primary outcome was NEC, defined as Bell stage II or greater. The temporal association of NEC and transfusion was assessed using multivariate Poisson regression. RESULTS: The study sample included 414 very low birth weight infants who received 2889 consecutive red blood cell transfusions. Twenty-four infants (5.8%) developed NEC. Four cases of NEC occurred within 48 hours of a previous transfusion event. Using multivariate Poisson regression, we did not find evidence of a temporal association between NEC and transfusion (P = .32). CONCLUSION: There was no association between NEC and red blood cell transfusion. Our results differ from previous studies and suggest that the association between NEC and transfusion may be contextual.

Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus.

BACKGROUND: Preterm infants with a patent ductus arteriosus (PDA) are at risk for death or development of bronchopulmonary dysplasia (BPD). However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD. METHODS: We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1,500 g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree analyses were performed to assess variables associated with the combined outcome of death or BPD. RESULTS: Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgical ligation and 25% were managed conservatively. Death or BPD occurred in 80 (43%) infants. The results of logistic regression analyses showed that lower gestational age (odds ratio (OR): 0.5), earlier year of birth during the study period (OR: 0.9), and larger ductal diameter (OR: 4.3) were associated with the decision to treat the PDA, whereas gestational age was the only variable associated with death or BPD (OR: 0.6; 95% confidence interval: 0.5-0.8). CONCLUSION: Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.

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.

Anti-Ge3 causes late-onset hemolytic disease of the newborn: the fourth case in three Hispanic families.

BACKGROUND: The Gerbich (Ge) blood group system consists of 11 antigens carried on red blood cell (RBC) membrane glycophorins C and D; of these, Ge:3 antigen is of high prevalence, and the anti-Ge3 is found to be clinically significant. CASE REPORT: A 34-week neonate born to a Hispanic mother with anti-Ge3 developed late-onset hemolysis with hyperbilirubinemia and was successfully treated with transfusions from her mother. Relevant clinical findings and laboratory results for this case are summarized and compared to three other previously reported cases; all babies were born from a mother of Hispanic ethnicity. CONCLUSION: Hemolytic disease of the fetus and new born associated with anti-Ge3 is rare but should be considered when working up a broadly reactive RBC antibody screen in women of Hispanic ethnicity. Early identification of pregnant women with anti-Ge3 is recommended for prenatal transfusion planning and close monitoring of the newborn infant for evidence of late-onset anemia.

Prevention of postpartum traumatic stress in mothers with preterm infants: manual development and evaluation.

Premature birth has been associated with multiple adverse maternal psychological outcomes that include depression, anxiety, and trauma as well as adverse effects on maternal coping ability and parenting style. Infants who are premature are more likely to have poorer cognitive and developmental functioning and, thus, may be harder to parent, both as infants and as they get older. In response to these findings, a number of educational and behavioral interventions have been developed that target maternal psychological functioning, parenting, and aspects of the parent-infant relationship. The current study aimed to both develop and evaluate a treatment that integrates, for the first time, effective interventions for reducing symptoms of posttraumatic stress disorder (PTSD) and enhancing maternal-infant interactions. Conclusions from the study indicate that the intervention is feasible, able to be implemented with a high level of fidelity, and is rated as highly satisfactory by participants. Though encouraging, these findings are preliminary, and future studies should strive to reproduce these findings with a larger sample size and a comparison group.

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.

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/.