Publications by authors named "William Benitz"

63 Publications

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

J Pediatr 2021 Feb 3. Epub 2021 Feb 3.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA.

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.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.065DOI Listing
February 2021

Prolonged Ductal Patency in Preterm Infants: Does It Matter?

J Pediatr 2021 02 30;229:12-14.e1. Epub 2020 Oct 30.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California.

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http://dx.doi.org/10.1016/j.jpeds.2020.10.059DOI Listing
February 2021

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

Lancet Infect Dis 2021 05 29;21(5):e134-e140. Epub 2020 Oct 29.

Department of Pediatrics, Tergooi Hospital, Blaricum, Netherlands; Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands; Amsterdam University Medical Centre, Vrije Universiteit, Amsterdam, Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam, Netherlands; Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, Netherlands.

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.
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http://dx.doi.org/10.1016/S1473-3099(20)30490-4DOI Listing
May 2021

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

J Perinatol 2020 12 6;40(12):1863-1870. Epub 2020 Oct 6.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.

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.
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http://dx.doi.org/10.1038/s41372-020-00848-zDOI Listing
December 2020

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

J Pediatr 2020 10 5;225:263-268. Epub 2020 Jun 5.

Department of Pediatrics, Stanford University, Stanford, CA.

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.
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http://dx.doi.org/10.1016/j.jpeds.2020.05.055DOI Listing
October 2020

Finding a role for the neonatal early-onset sepsis risk calculator.

EClinicalMedicine 2020 Feb 26;19:100255. Epub 2020 Jan 26.

Department of Pediatrics, Tergooi Hospital, Blaricum, the Netherlands.

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http://dx.doi.org/10.1016/j.eclinm.2019.100255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046501PMC
February 2020

Newborn Antibiotic Exposures and Association With Proven Bloodstream Infection.

Pediatrics 2019 11 22;144(5). Epub 2019 Oct 22.

NICU, Lucile Packard Children's Hospital, Stanford, California.

Objectives: To estimate the percentage of hospital births receiving antibiotics before being discharged from the hospital and efficiency diagnosing proven bloodstream infection.

Methods: We conducted a cross-sectional study of 326 845 live births in 2017, with a 69% sample of all California births involving 121 California hospitals with a NICU, of which 116 routinely served inborn neonates. Exposure included intravenous or intramuscular antibiotic administered anywhere in the hospital during inpatient stay associated with maternal delivery. The main outcomes were the percent of newborns with antibiotic exposure and counts of exposed newborns per proven bloodstream infection. Units of observation and analysis were the individual hospitals. Correlation analyses included infection rates, surgical case volume, NICU inborn admission rates, and mortality rates.

Results: The percent of newborns with antibiotic exposure varied from 1.6% to 42.5% (mean 8.5%; SD 6.3%; median 7.3%). Across hospitals, 11.4 to 335.7 infants received antibiotics per proven early-onset sepsis case (mean 95.1; SD 71.1; median 69.5), and 2 to 164 infants received antibiotics per proven late-onset sepsis case (mean 19.6; SD 24.0; median 12.2). The percent of newborns with antibiotic exposure correlated neither with proven bloodstream infection nor with the percent of patient-days entailing antibiotic exposure.

Conclusions: The percent of newborns with antibiotic exposure varies widely and is unexplained by proven bloodstream infection. Identification of sepsis, particularly early onset, often is extremely inefficient. Knowledge of the numbers of newborns receiving antibiotics complements evaluations anchored in days of exposure because these are uncorrelated measures.
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http://dx.doi.org/10.1542/peds.2019-1105DOI Listing
November 2019

Transcatheter patent ductus arteriosus closure-will history repeat itself?

J Perinatol 2019 11 12;39(11):1435-1436. Epub 2019 Sep 12.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.

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http://dx.doi.org/10.1038/s41372-019-0483-xDOI Listing
November 2019

Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis.

JAMA Pediatr 2019 Nov;173(11):1032-1040

Department of Pediatrics, Tergooi Hospital, Blaricum, the Netherlands.

Importance: The neonatal early-onset sepsis (EOS) calculator is a clinical risk stratification tool increasingly used to guide the use of empirical antibiotics for newborns. Evidence on the effectiveness and safety of the EOS calculator is essential to inform clinicians considering implementation.

Objective: To assess the association between management of neonatal EOS guided by the neonatal EOS calculator (compared with conventional management strategies) and reduction in antibiotic therapy for newborns.

Data Sources: Electronic searches in MEDLINE, Embase, Web of Science, and Google Scholar were conducted from 2011 (introduction of the EOS calculator model) through January 31, 2019.

Study Selection: All studies with original data that compared management guided by the EOS calculator with conventional management strategies for allocating antibiotic therapy to newborns suspected to have EOS were included.

Data Extraction And Synthesis: Following PRISMA-P guidelines, relevant data were extracted from full-text articles and supplements. CHARMS (Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies) and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tools were used to assess the risk of bias and quality of evidence. Meta-analysis using a random-effects model was conducted for studies with separate cohorts for EOS calculator and conventional management strategies.

Main Outcomes And Measures: The difference in percentage of newborns treated with empirical antibiotics for suspected or proven EOS between management guided by the EOS calculator and conventional management strategies. Safety-related outcomes involved missed cases of EOS, readmissions, treatment delay, morbidity, and mortality.

Results: Thirteen relevant studies analyzing a total of 175 752 newborns were included. All studies found a substantially lower relative risk (range, 3%-60%) for empirical antibiotic therapy, favoring the EOS calculator. Meta-analysis revealed a relative risk of antibiotic use of 56% (95% CI, 53%-59%) in before-after studies including newborns regardless of exposure to chorioamnionitis. Evidence on safety was limited, but proportions of missed cases of EOS were comparable between management guided by the EOS calculator (5 of 18 [28%]) and conventional management strategies (8 of 28 [29%]) (pooled odds ratio, 0.96; 95% CI, 0.26-3.52; P = .95).

Conclusions And Relevance: Use of the neonatal EOS calculator is associated with a substantial reduction in the use of empirical antibiotics for suspected EOS. Available evidence regarding safety of the use of the EOS calculator is limited, but shows no indication of inferiority compared with conventional management strategies.
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http://dx.doi.org/10.1001/jamapediatrics.2019.2825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724419PMC
November 2019

Is prophylaxis with early low-dose hydrocortisone in very preterm infants effective in preventing bronchopulmonary dysplasia?

J Perinatol 2019 12 30;39(12):1688-1691. Epub 2019 Aug 30.

Department of Pediatrics/Division of Neonatology, Stanford University School of Medicine, 750 Welch Road, Suite 315, Palo Alto, CA, 94304, USA.

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http://dx.doi.org/10.1038/s41372-019-0485-8DOI Listing
December 2019

The Holy Grail of Ascertainment of Early-Onset Neonatal Sepsis.

J Pediatr 2019 10 27;213:10-12. Epub 2019 Jun 27.

Section of Pediatric Infectious Diseases, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.jpeds.2019.05.072DOI Listing
October 2019

Authors' Response.

Pediatrics 2019 05;143(5)

Physician, Children's Hospital of Philadelphia.

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http://dx.doi.org/10.1542/peds.2019-0533BDOI Listing
May 2019

Management of Chorioamnionitis-Exposed Infants in the Newborn Nursery Using a Clinical Examination-Based Approach.

Hosp Pediatr 2019 04 4;9(4):227-233. Epub 2019 Mar 4.

Department of Pediatrics, Stanford University, Stanford, California; and

Background: Antibiotic use in well-appearing late preterm and term chorioamnionitis-exposed (CE) infants was reduced by 88% after the adoption of a care approach that was focused on clinical monitoring in the intensive care nursery to determine the need for antibiotics. However, this approach continued to separate mothers and infants. We aimed to reduce maternal-infant separation while continuing to use a clinical examination-based approach to identify early-onset sepsis (EOS) in CE infants.

Methods: Within a quality improvement framework, well-appearing CE infants ≥35 weeks' gestation were monitored clinically while in couplet care in the postpartum unit without laboratory testing or empirical antibiotics. Clinical monitoring included physician examination at birth and nurse examinations every 30 minutes for 2 hours and then every 4 hours until 24 hours of life. Infants who developed clinical signs of illness were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, and clinical outcomes were collected.

Results: Among 319 initially well-appearing CE infants, 15 (4.7%) received antibiotics, 23 (7.2%) underwent laboratory testing, and 295 (92.5%) remained with their mothers in couplet care throughout the birth hospitalization. One infant had group B EOS identified and treated at 24 hours of age based on new-onset tachypnea and had an uncomplicated course.

Conclusions: Management of well-appearing CE infants by using a clinical examination-based approach during couplet care in the postpartum unit maintained low rates of laboratory testing and antibiotic use and markedly reduced mother-infant separation without adverse events. A framework for repeated clinical assessments is an essential component of identifying infants with EOS.
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http://dx.doi.org/10.1542/hpeds.2018-0201DOI Listing
April 2019

PDA: To treat or not to treat.

Congenit Heart Dis 2019 Jan;14(1):46-51

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California.

Management of patent ductus arteriosus in extremely preterm infants remains a topic of debate. Treatment to produce ductal closure was widely practiced until the past decade, despite lack of evidence that it decreases morbidities or mortality. Meta-analyses of trials using nonsteroidal anti-inflammatory drugs have shown effectiveness in accelerating ductal closure, but no reduction in neonatal morbidities, regardless of agent used, indication, timing, gestational age, or route of administration. Surgical ligation closes the ductus but is associated with adverse effects. Recent experience with conservative approaches to treatment suggest improved neonatal outcomes and a high rate of spontaneous ductal closure after discharge. Careful postdischarge follow-up is important, however, because potential adverse effects of long-standing aortopulmonary shunts may be an indication for catheter-based ductal closure. Identification of extremely preterm infants at greatest risk of potential harm from a persistently patent ductus, who may benefit most from treatment are urgently needed.
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http://dx.doi.org/10.1111/chd.12708DOI Listing
January 2019

Unwinding old habits: deimplementation of treatment regimens for patent ductus arteriosus in preterm infants.

Authors:
William E Benitz

J Pediatr (Rio J) 2020 Mar - Apr;96(2):138-141. Epub 2018 Dec 11.

Stanford University School of Medicine, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Palo Alto, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jped.2018.12.003DOI Listing
September 2020

While waiting for a vaccine: opportunities for optimization of neonatal group B streptococcal (GBS) disease prevention in Israel.

J Perinatol 2019 02 11;39(2):331-338. Epub 2018 Dec 11.

Stanford University School of Medicine, Division of Neonatal & Developmental Medicine, Palo Alto, CA, 94304, USA.

Objective: To quantify effects of different strategies for decreasing neonatal early onset GBS sepsis (EOGBS) in Israel.

Study Design: A risk allocation model for EOGBS among infants ≥ 35w was adapted to Israeli data. Effects of strategies for antepartum (APS) and intrapartum (IPS) screening, and intrapartum (IAP) and/or postpartum antibiotic prophylaxis (PAP) were calculated.

Results: Estimated EOGBS attack rates (AR) with APS in 90%, IAP in 90%, may reduce AR to 0.18/1000. A rapid intrapartum test would further decrease AR to 0.16/1000, while reducing IAP from 21.3 to 12.5% of women. For babies with risk factors and GBS+ who do not receive IAP, further risk reduction could be achieved by PAP.

Conclusion: IAP remains the main intervention to decrease EOGBS. IAP and PAP together may reduce EOGBS present incidence by 40%. Combining rapid intrapartum screening with selective IAP and selective PAP for remaining gaps, would be the most efficient strategy.
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http://dx.doi.org/10.1038/s41372-018-0289-2DOI Listing
February 2019

Management of Neonates Born at ≤34 6/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis.

Pediatrics 2018 12;142(6)

Early-onset sepsis (EOS) remains a serious and often fatal illness among infants born preterm, particularly among newborn infants of the lowest gestational age. Currently, most preterm infants with very low birth weight are treated empirically with antibiotics for risk of EOS, often for prolonged periods, in the absence of a culture-confirmed infection. Retrospective studies have revealed that antibiotic exposures after birth are associated with multiple subsequent poor outcomes among preterm infants, making the risk/benefit balance of these antibiotic treatments uncertain. Gestational age is the strongest single predictor of EOS, and the majority of preterm births occur in the setting of other factors associated with risk of EOS, making it difficult to apply risk stratification strategies to preterm infants. Laboratory tests alone have a poor predictive value in preterm EOS. Delivery characteristics of extremely preterm infants present an opportunity to identify those with a lower risk of EOS and may inform decisions to initiate or extend antibiotic therapies. Our purpose for this clinical report is to provide a summary of the current epidemiology of preterm neonatal sepsis and provide guidance for the development of evidence-based approaches to sepsis risk assessment among preterm newborn infants.
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http://dx.doi.org/10.1542/peds.2018-2896DOI Listing
December 2018

Management of Neonates Born at ≥35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis.

Pediatrics 2018 12;142(6)

The incidence of neonatal early-onset sepsis (EOS) has declined substantially over the last 2 decades, primarily because of the implementation of evidence-based intrapartum antimicrobial therapy. However, EOS remains a serious and potentially fatal illness. Laboratory tests alone are neither sensitive nor specific enough to guide EOS management decisions. Maternal and infant clinical characteristics can help identify newborn infants who are at risk and guide the administration of empirical antibiotic therapy. The incidence of EOS, the prevalence and implications of established risk factors, the predictive value of commonly used laboratory tests, and the uncertainties in the risk/benefit balance of antibiotic exposures all vary significantly with gestational age at birth. Our purpose in this clinical report is to provide a summary of the current epidemiology of neonatal sepsis among infants born at ≥35 0/7 weeks' gestation and a framework for the development of evidence-based approaches to sepsis risk assessment among these infants.
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http://dx.doi.org/10.1542/peds.2018-2894DOI Listing
December 2018

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

J Pediatr 2018 12 20;203:225-233.e1. Epub 2018 Sep 20.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA; California Perinatal Quality Care Collaborative, Stanford University School of Medicine, Stanford, CA.

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.
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http://dx.doi.org/10.1016/j.jpeds.2018.07.025DOI Listing
December 2018

Clinical Monitoring of Well-Appearing Infants Born to Mothers With Chorioamnionitis.

Pediatrics 2018 04;141(4)

Department of Pediatrics, School of Medicine, Stanford University, Stanford, California; and

Background: The risk of early-onset sepsis is low in well-appearing late-preterm and term infants even in the setting of chorioamnionitis. The empirical antibiotic strategies for chorioamnionitis-exposed infants that are recommended by national guidelines result in antibiotic exposure for numerous well-appearing, uninfected infants. We aimed to reduce unnecessary antibiotic use in chorioamnionitis-exposed infants through the implementation of a treatment approach that focused on clinical presentation to determine the need for antibiotics.

Methods: Within a quality-improvement framework, a new treatment approach was implemented in March 2015. Well-appearing late-preterm and term infants who were exposed to chorioamnionitis were clinically monitored for at least 24 hours in a level II nursery; those who remained well appearing received no laboratory testing or antibiotics and were transferred to the level I nursery or discharged from the hospital. Newborns who became symptomatic were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, culture results, and clinical outcomes were collected.

Results: Among 277 well-appearing, chorioamnionitis-exposed infants, 32 (11.6%) received antibiotics during the first 15 months of the quality-improvement initiative. No cases of culture result-positive early-onset sepsis occurred. No infant required intubation or inotropic support. Only 48 of 277 (17%) patients had sepsis laboratory testing. The implementation of the new approach was associated with a 55% reduction (95% confidence interval 40%-65%) in antibiotic exposure across all infants ≥34 weeks' gestation born at our hospital.

Conclusions: A management approach using clinical presentation to determine the need for antibiotics in chorioamnionitis-exposed infants was successful in reducing antibiotic exposure and was not associated with any clinically relevant delays in care or adverse outcomes.
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http://dx.doi.org/10.1542/peds.2017-2056DOI Listing
April 2018

Prenatal treatment of ornithine transcarbamylase deficiency.

Mol Genet Metab 2018 03 16;123(3):297-300. Epub 2018 Jan 16.

Department of Pediatrics, Stanford University, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymgme.2018.01.004DOI Listing
March 2018

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

Am J Perinatol 2018 06 30;35(7):616-623. Epub 2017 Nov 30.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.

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.
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http://dx.doi.org/10.1055/s-0037-1608928DOI Listing
June 2018

The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants.

Semin Fetal Neonatal Med 2017 10 17;22(5):302-307. Epub 2017 Jul 17.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.

Over the last four decades, non-steroidal anti-inflammatory drugs have been widely used to induce closure of the patent ductus arteriosus (PDA) in preterm infants. Evidence to support this practice is lacking, despite performance of >50 randomized trials. The credibility of those trials may have been compromised by high rates of open treatment in controls, era of study prior to advent of modern practices, or inclusion of insufficient numbers of very immature infants. Meta-analyses show little impact of those factors on main conclusions. Essentially all trials reporting important long-term outcomes (other than mortality) initiated treatment within five days after birth, so no evidence regarding later treatment is available. Accruing clinical experience suggests that long-term outcomes are not compromised, and may be improved, with non-interventional management strategies. Future studies to identify preterm infants at greatest risk of potential harm from a persistent PDA, particularly after the second postnatal week, are urgently needed.
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http://dx.doi.org/10.1016/j.siny.2017.07.004DOI Listing
October 2017

Hey, Doctor, Leave the PDA Alone.

Authors:
William E Benitz

Pediatrics 2017 08 12;140(2). Epub 2017 Jul 12.

Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California

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http://dx.doi.org/10.1542/peds.2017-0566DOI Listing
August 2017

Prophylactic Indomethacin-Is It Time to Reconsider?

J Pediatr 2017 08 25;187:8-10. Epub 2017 May 25.

Division of Neonatal and Developmental Medicine Stanford University School of Medicine Palo Alto, California. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2017.04.066DOI Listing
August 2017

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

Am J Perinatol 2017 08 4;34(10):990-995. Epub 2017 Apr 4.

Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California.

 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.  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.  More infants in era 2 (35/89, 39%) compared with era 1 (22/120, 18%) had conservative PDA management ( < 0.01). Despite no difference in surgical ligation rate, infants in era 2 had ligation later (median 24 vs. 8 days,  < 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,  = 0.003).  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.
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http://dx.doi.org/10.1055/s-0037-1601442DOI Listing
August 2017

Umbilical Cord Care in the Newborn Infant.

Pediatrics 2016 09;138(3)

Postpartum infections remain a leading cause of neonatal morbidity and mortality worldwide. A high percentage of these infections may stem from bacterial colonization of the umbilicus, because cord care practices vary in reflection of cultural traditions within communities and disparities in health care practices globally. After birth, the devitalized umbilical cord often proves to be an ideal substrate for bacterial growth and also provides direct access to the bloodstream of the neonate. Bacterial colonization of the cord not infrequently leads to omphalitis and associated thrombophlebitis, cellulitis, or necrotizing fasciitis. Various topical substances continue to be used for cord care around the world to mitigate the risk of serious infection. More recently, particularly in high-resource countries, the treatment paradigm has shifted toward dry umbilical cord care. This clinical report reviews the evidence underlying recommendations for care of the umbilical cord in different clinical settings.
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http://dx.doi.org/10.1542/peds.2016-2149DOI Listing
September 2016

An Electronic Health Record Investigation of Lenticulostriate Vasculopathy Features.

Am J Perinatol 2017 Feb 29;34(3):253-258. Epub 2016 Jul 29.

Department of Pediatrics-Neonatology, Stanford University, Stanford, California.

 Lenticulostriate vasculopathy (LSV) is characterized by linear hyperechogenicities in the basal ganglia found on the head ultrasounds of infants. We reviewed electronic health records of infants with and without LSV to investigate whether physician dictations indicated symptoms which could reflect subtle basal ganglia injury.  In a case-control study, we analyzed data from 46 infants with LSV and 127 controls. Infants were stratified between term and preterm birth. Odds ratios (ORs) and 95% confidence intervals were calculated for tone abnormalities, apnea, feeding difficulties, seizures, and movement abnormalities in the presence of LSV.  Both term and preterm infants with LSV showed elevated risks for tone abnormalities (OR: 3.6 and 2.9, respectively). Term infants with LSV showed elevated risks for hypotonia (OR: 4.3), apnea (OR: 2.9), and feeding difficulties (OR: 4.1). Preterm infants with LSV showed elevated risks for truncal hypotonia (OR: 3.9) and hyperreflexia (OR: 3.9).  Our findings provide some evidence that LSV is associated with an increased risk of early signs of abnormal development, possibly relating to signs of subtle basal ganglia injury. Historically LSV has been considered incidental. The associations identified here suggest that LSV findings are worthy of further study.
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http://dx.doi.org/10.1055/s-0036-1585417DOI Listing
February 2017

Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections.

Pediatrics 2016 Jan 30;137(1). Epub 2015 Dec 30.

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Children's Healthcare of Atlanta, Atlanta, Georgia;

Background: Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth.

Methods: Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected ≤ 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset.

Results: Early-onset infections were diagnosed in 389 of 396,586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence.

Conclusions: Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.
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http://dx.doi.org/10.1542/peds.2015-2323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702021PMC
January 2016

Patent Ductus Arteriosus in Preterm Infants.

Pediatrics 2016 Jan 15;137(1). Epub 2015 Dec 15.

Despite a large body of basic science and clinical research and clinical experience with thousands of infants over nearly 6 decades,(1) there is still uncertainty and controversy about the significance, evaluation, and management of patent ductus arteriosus in preterm infants, resulting in substantial heterogeneity in clinical practice. The purpose of this clinical report is to summarize the evidence available to guide evaluation and treatment of preterm infants with prolonged ductal patency in the first few weeks after birth.
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http://dx.doi.org/10.1542/peds.2015-3730DOI Listing
January 2016