OBJECTIVE:To examine whether hydrocortisone (HC) modified the relationship of patent ductus arteriosus (PDA) to outcomes among infants born extremely preterm and enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NRN) HC trial. STUDY DESIGN:This was a posthoc secondary analysis of infants born <30 weeks' gestation and enrolled in the NRN HC Trial. The primary outcome was moderate to severe bronchopulmonary dysplasia (BPD) or death. Secondary outcomes included moderate to severe BPD, death, necrotizing enterocolitis, late-onset sepsis, days of mechanical ventilation, oxygen supplementation, Z-scores for growth, home oxygen, BPD severity, neurodevelopmental impairment, and moderate to severe cerebral palsy. Analyses for interaction between PDA (defined as treatment to achieve PDA closure) and HC were performed for the primary and secondary outcomes. RESULTS:Of 800 infants enrolled in the NRN HC trial, PDA was treated in 198 HC treated and 197 placebo-treated infants. HC did not modify the relationship of PDA with BPD or death (P = .93). Regardless of HC treatment, PDA was associated with a significant increase in duration of ventilatory support, oxygen supplementation at 36 weeks postmenstrual age (PMA), BPD severity, decreased weight-for-age Z-score at 36 weeks PMA, moderate to severe BPD, or death at 36 weeks PMA and home oxygen support. CONCLUSIONS:HC after the second postnatal week did not alter the relationship between PDA and BPD or death among infants born extremely preterm. PDA was associated with several adverse outcomes regardless of HC treatment.

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.

The Kaiser Permanente Perinatal Research Unit developed an online risk prediction web-based tool that has led to drastic reductions in empiric antibiotic administration: the neonatal early-onset sepsis calculator.1 Use of the tool has been adopted quickly by many neonatal clinics worldwide, both in clinical and research contexts. However, the current international reliance on the Kaiser Permanente web tool might impede accessibility (eg, if the tool became temporarily unavailable) and adherence to local regulations for external users.

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.

In a recent issue of the Archives, Batra et al presented a systematic review and metaanalysis comparing two strategies for weaning neonates from positive pressure mechanical ventilation: synchronised intermittent mandatory ventilation (SIMV) and pressure support ventilation (PSV). With the former, some breaths are assisted and others are not, but with the latter, all breaths are synchronised with some positive pressure assistance. Analyses like this are valuable, as choices of ventilation strategies in our nurseries are typically based on personal preferences rather than carefully developed evidence. The small sizes of the trials identified for this metaanalysis demonstrate the difficulty of enrolling sufficient numbers of subjects to produce useful information. When such evidence is available, it must be assessed with careful attention to detail, particularly when it suggests that one approach or another may lead to superior outcomes. The analysis by Batra et al exemplifies some of the pitfalls in grappling with these challenges. We are indebted to them for taking on this important task. The only identified significant difference between effects of the two weaning strategies was shorter duration of weaning from assisted ventilation in the PSV arms of these trials. Because some may rely on it to guide practice, this conclusion requires close scrutiny. There are several reasons to view it with scepticism. First, the patient populations from which subjects were drawn and eligibility criteria for trial enrolment were quite diverse (table 1). The study of term infants with meconium aspiration syndrome reported by Wu et al is almost certainly an outlier (with different babies, a different disease and different lung mechanics), so it should not be analysed along with the others. Even the others may be too heterogeneous for pooling in a metaanalysis. Inconsistency among the definitions of ‘duration of weaning’ is of even greater concern, as it indicates that the different studies may not be measuring the same (or perhaps even similar) things. Concerns about heterogeneity of the trials are borne out by the statistical tests for heterogeneity presented in the paper (I=90%). Identifying trials suitable for pooling in metaanalysis is often challenging. Closer inspection of figure 4A in Batra et al reveals other reasons for concern about this conclusion. The values for the SIMV group from the Nayeri study should be 45±46.482, not 46.482±0.737 (the difference in means thereby becomes insignificant). The SDs estimated from nonparametric measures for two of the studies do not match those obtained using the spreadsheet provided as a supplement to the cited methodology paper. For the Dimitriou paper, these should be 243.01, 107.32, 113.74 and 130.60, not 261.01, 115.27, 122.17 and 140.28. The SD for time for weaning with SIMV in the Unal trial should be 145.5, not 45.5. The Reyes data are in days (as in the original paper) and should have been converted to hours for this analysis. These errors are highly consequential, as erroneous estimates of the SEM translate directly into incorrect weightings in the metaanalysis (in addition to just being wrong). Accurate data extraction is difficult, especially from publications in unfamiliar languages. To compound these concerns, it is not clear that it is appropriate to use the method of Wan et al for conversion of nonparametric statistics into estimates of the mean±SD as applied in this context. With the exception of the Wu trial, the data distributions for these data sets appear to be markedly skewed, with SD approaching or exceeding the corresponding means. As the method for metaanalyses of continuous data assumes some semblance to normality in the data, it seems dubious to force this highly skewed data into the standard metaanalysis tool. At a minimum, these data should be normalised by a log transformation before inference of mean and SD values according to Wan et al’s method. After log transformation, the data from Dimitriou et al appear to be approximately normally distributed, however, as shown in the figure in that paper (where the data are plotted on a log scale). Because log transformation converts the analysis from differences (with units) to ratios (unitless) of the means, this also obviates issues related to use of different units for outcome measures across trials. Accurate conversion of summary statistics into consistent, analysable formats is often far from straightforward. Reanalysis of the data from the studies assembled by Batra et al with these caveats in mind (and making some necessary—but potentially perilous—assumptions about the SEs in the data) yields findings of interest, however (figure 1). These calculations indicate that the mean natural logarithm of the duration of weaning is reduced by 0.54 (95% CI –0.80 to –0.28). In other words, the duration of weaning with PSV is reduced by 54% from that required with SIMV. This leaves open the possibility that PSV may be superior to SIMV in management of preterm infants who require ventilation. This is a hypothesis to be tested, not an actionable fact, however. The concerns about small sample size, comparability of the patient populations and inconsistent outcome definitions remain. Along with evidence of heterogeneity in the data even after transformation (I=63.7%; figure 1), that should engender wariness in interpreting and applying these results. This metaanalysis does support the conclusion that larger studies are needed to compare these ventilation modes, as one of them may be preferable, and evidence to guide these practices is sorely lacking. In addition to explicit ventilation and weaning protocols, precise and reproducible measures for duration of ventilator weaning will be required. It is premature to conclude that PSV shortens the time for which ventilation is required, though. Authors do not bear sole responsibility. The issues outlined above could have been recognised and remediated in the manuscript review and revision process. Demonstrably, readers cannot rely on that happening consistently, even in highly reputable journals. The remedy for this is not obvious, but provision of sufficient data (in online appendices, if necessary) to allow validation of findings of metaanalyses, regression models and the like should be mandatory. Fortunately, these authors have done so. Users of these works should trust, but be able to verify. Metaanalysis is a very useful tool for gleaning information from the often sparse data available to inform our practices. This methodology underlies the numerous analyses provided in the Cochrane Database of Systematic Reviews, for which detailed guidelines and specific analytical tools have been provided. These analyses are neither simple nor easy to perform, and findings Pediatrics, Stanford University School of Medicine, Stanford, California, USA

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.

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/ .

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 310 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, 10134 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. (J Pediatr 2023;256:98-104).

In the article "Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis" by Achten et al (J Pediatr 2021;234:77-84.e8), errors occurred in Table III of this article. The online version of the article has since been updated.Table IIITable of all EOS casesOrganismGA (wk)Highest maternal temp (°C)Maternal GBS statusROM (h)Maternal antibiotics & timingClinical status at initial assessmentClinical status in 1st 12 hAge at onset of clinical signs (h)Calculator risk at initial assessment (cases/1000)Calculator risk at 12 h (cases/1000)Management recommended at birthManagement recommended at 12 hOther40 3/736.3Unknown0None or <2 hWellWellNR0.010.01RoutineRoutineE. coli41 2/736.4Negative0None or <2 hWellIll30.010.50RoutineStronglyGBS38 5/735.7Unknown10None or <2 hWellIll30.020.80RoutineStronglyGBS39 4/736.7Unknown0None or <2 hWellIll110.010.63RoutineStronglyCoNS39 1/736.7Unknown7GBS abx >2 hWellWellNR0.010.01RoutineRoutineBacillus spp, CoNS38 6/736.5Negative1.43None or <2 hWellWell500.020.02RoutineRoutineE. coli37 5/737.1Unknown1GBS abx >2 hWellWellNR0.020.02RoutineRoutineL. monocytogenes3937.0Unknown0None or <2 hWellWell160.020.02RoutineRoutineGBS4136.2Negative7None or <2 hWellWell10.020.02RoutineRoutineEnterococcus spp4036.2Negative12.2None or <2 hWellWell480.020.02RoutineRoutineGBS41 6/736.1Unknown6None or <2 hWellIll90.021.18RoutineStronglyGBS40 2/736.8Unknown1.6None or <2 hWellIll60.031.53RoutineStronglyGBS39 3/736.6Negative6None or <2 hWellIll50.031.53RoutineStronglyL. monocytogenes3636.6Unknown0None or <2 hWellWell150.030.03RoutineRoutineGBS40 3/736.7Unknown4None or <2 hWellIll70.031.75RoutineStronglyGBS3937.0Positive0None or <2 hWellWell14.50.030.03RoutineRoutineGBS3936.6Unknown8None or <2 hWellIll70.041.81RoutineStronglyGBS40 5/736.9Unknown1.8None or <2 hWellIll100.041.98RoutineStronglyGBS39 5/736.8Unknown5None or <2 hWellIll70.042.06RoutineStronglyVGS38 5/736.7Unknown8.0None or <2 hWellWell140.040.04RoutineRoutineCoNS39 2/737.0Negative3None or <2 hWellWellNR0.040.04RoutineRoutineGBS3936.9Negative5None or <2 hWellIll120.052.35RoutineStronglyGBS38 1/736.0Unknown79None or <2 hWellIll70.052.41RoutineStronglyGBS38 4/736.8Unknown7None or <2 hWellWell220.050.05RoutineRoutineOther36 4/736.8Negative1None or <2 hWellWellNR0.050.05RoutineRoutineGBS37 3/737.0Unknown1None or <2 hWellWell—0.050.05RoutineRoutineGBS41 3/736.7Negative8.3None or <2 hWellIll90.052.76RoutineStronglyE. coli40 6/736.7Unknown12None or <2 hWellIll10.052.83RoutineStronglyGBS37 4/736.8Unknown5None or <2 hWellIll10.062.86RoutineStronglyGBS39 4/737.0Unknown5.5None or <2 hWellWell360.060.06RoutineRoutineEnterococcus spp39 5/737.0Unknown6None or <2 hWellWell370.060.06RoutineRoutineGBS40 4/736.7Negative19None or <2 hWellWell—0.060.06RoutineRoutineGBS3837.0Unknown4None or <2 hWellWell520.060.06RoutineRoutineGBS3937.2Negative3None or <2 hWellIll50.063.19RoutineTreatOther3937.3Negative2None or <2 hWellWellNR0.063.31RoutineRoutineGBS39 1/737.2Negative3.5None or <2 hWellIll60.060.06RoutineTreatMoraxella38 2/736.6Positive8None or <2 hWellIll120.073.45RoutineTreatGBS3836.9Unknown9None or <2 hWellIll120.073.62RoutineTreatGBS41 5/736.9Unknown5None or <2 hWellWell240.070.07RoutineRoutineE. coli39 3/736.8Negative28None or <2 hWellWellNR0.083.80RoutineRoutineS. aureus40 6/736.6Negative36None or <2 hWellIll60.073.85RoutineTreatGBS36 6/736.7Unknown8None or <2 hWellIll60.073.87RoutineTreatGBS38 6/736.9Unknown16None or <2 hWellIll80.080.08RoutineTreatGBS40 2/736.8Unknown23None or <2 hWellIll60.080.08RoutineTreatGBS4236.8Unknown7None or <2 hWellIll110.083.93RoutineTreatOther39 2/737.2Negative6None or <2 hWellWellNR0.083.94RoutineRoutineGBS38 6/736.7Unknown36None or <2 hWellIll50.084.11RoutineTreatGBS36 1/737.3Unknown0None or <2 hWellWell440.090.09RoutineRoutineGBS36 4/736.8Unknown5None or <2 hWellWell360.090.09RoutineRoutineGBS38 6/737.0Unknown16None or <2 hWellWell360.090.09RoutineRoutineGBS4137.1Positive27Broad abx 2-4 hWellWell—0.090.09RoutineRoutineE. coli41 2/738.0Unknown3.1GBS abx >2 hWellIll100.105.27RoutineTreatGBS3837.2Unknown8None or <2 hWellWell160.110.11RoutineRoutineCoNS38 4/737.2Negative13None or <2 hWellWellNR0.110.11RoutineRoutineS. aureus35 6/737.1Unknown17GBS abx >2 hWellWellNR0.120.12RoutineRoutineCoNS39 2/737.5Negative6None or <2 hWellWellNR0.120.12RoutineRoutineGBS4037.4Unknown8.8None or <2 hWellWell—0.130.13RoutineRoutineGBS37 2/737.1Unknown12None or <2 hWellIll120.146.97RoutineTreatGBS4037.4Positive50Broad abx ≥4 hWellWell—0.140.14RoutineRoutineE. coli38 6/737.8Positive9.5GBS abx >2 hWellIll120.157.61RoutineTreatGBS37 3/737.2Negative14.8None or <2 hWellWell360.160.15RoutineRoutineOther3836.6Negative0None or <2 hEquivocalEquivocalNR0.150.16RoutineRoutineVGS41 1/737.7Negative2.4None or <2 hWellWell400.160.16RoutineRoutineGBS37 5/737.2Unknown17None or <2 hWellWell640.160.16RoutineRoutineE. coli37 5/737.4Unknown8None or <2 hWellIll120.168.20RoutineTreatCoNS41 1/738.0Negative14Broad abx 2-4 hWellWellNR0.160.16RoutineRoutineGBS38 4/737.4Unknown16None or <2 hWellWell250.170.17RoutineRoutineGBS38 4/737.8Unknown3None or <2 hWellEquivocal50.172.12RoutineBlood cultureGBS37 4/737.1Negative33None or <2 hWellWell240.180.18RoutineRoutineCoNS40 1/736.5Negative1None or <2 hEquivocalEquivocal210.190.19RoutineRoutineGBS40 2/737.4Unknown22None or <2 hWellWell140.190.19RoutineRoutineGBS3636.6Unknown36None or <2 hWellWell—0.200.20RoutineRoutineGBS4137.3Negative27.6None or <2 hWellIll30.2010.23RoutineTreatE. coli35 5/736.8Unknown14None or <2 hWellWell260.210.21RoutineRoutineGBS41 3/737.5Unknown10None or <2 hWellWell—0.210.21RoutineRoutineOther38 4/736.9Unknown0None or <2 hEquivocalEquivocalNR0.2211.13RoutineRoutineGBS37 5/737.2Unknown34None or <2 hWellIll60.220.22RoutineTreatVGS4138.3Negative11.5Broad abx 2-4 hWellWell—0.230.22RoutineRoutineOther37 3/737.2Unknown29None or <2 hWellWellNR0.220.23RoutineRoutineOther40 5/739.3Negative0GBS abx >2 hWellWellNR0.270.27RoutineRoutineVGS41 3/737.4Negative29.1None or <2 hWellWell—0.270.27RoutineRoutineGBS40 5/737.3Negative59None or <2 hWellWell—0.280.28RoutineRoutineGBS40 2/736.7Unknown2None or <2 hEquivocalIll30.331.40RoutineStronglyE. coli4138.3Unknown25Broad abx 2-4 hWellWell—0.330.33RoutineRoutineGBS3938.3Positive0.2None or <2 hWellWell—0.340.34RoutineRoutineE. coli41 4/738.2Negative1.4None or <2 hWellWell—0.340.34RoutineRoutineE. coli4036.3Unknown0None or <2 hIllIll00.350.35StronglyStronglyGBS39 2/737.9Positive49GBS abx >2 hWellWell—0.350.35RoutineRoutineGBS38 3/737.9Negative14.7None or <2 hWellIll4.50.3517.96RoutineTreatOther37 6/736.5Unknown4None or <2 hEquivocalEquivocalNR0.360.36RoutineRoutineCoNS39 5/737.9Unknown20None or <2 hWellWellNR0.380.38RoutineRoutineGBS4038.3Positive0.4None or <2 hWellWell240.380.38RoutineRoutineE. coli37 6/738.1Positive22GBS abx >2 hWellWellNR0.410.41Frequent VSFrequent VSGBS40 1/738.3Positive1None or <2 hWellWell150.460.46Frequent VSFrequent VSE. coli40 3/738.1Negative16None or <2 hWellWellNR0.480.48Frequent VSFrequent VSGBS38 1/736.5Negative14None or <2 hEquivocalIll9.00.502.14RoutineStronglyVGS4138.8Unknown15Broad abx ≥4 hWellWell—0.510.51Frequent VSFrequent VSE. faecalis41 6/737.9Negative16None or <2 hWellWellNR0.530.53Frequent VSFrequent VSGBS38 5/737.9Unknown38None or <2 hWellWell—0.550.55Frequent VSFrequent VSS. aureus40 5/738.4Negative7None or <2 hWellWellNR0.592.49Frequent VSFrequent VSGBS38 6/736.9Unknown5None or <2 hEquivocalIll20.590.59RoutineStronglyVGS38 2/736.8Negative7.1None or <2 hEquivocalEquivocal24.50.600.59RoutineRoutineOther34 4/737.1Unknown65GBS abx >2 hWellWellNR0.590.60Frequent VSFrequent VSE. faecalis38 5/736.5Unknown25None or <2 hEquivocalEquivocalNR0.610.61RoutineRoutineGBS38 3/736.8Negative8.9None or <2 hEquivocalEquivocal33.90.630.63RoutineRoutineOther37 4/736.8Negative6None or <2 hEquivocalEquivocalNR0.690.69RoutineRoutineEnterococcus spp3736.6Negative8.1None or <2 hEquivocalEquivocal—0.700.70RoutineRoutineGBS37 3/736.5Negative19None or <2 hEquivocalIll30.713.02RoutineTreatGBS38 2/738.2Unknown22None or <2 hWellWell—0.720.72Frequent VSFrequent VSGBS3837.1Negative3.1None or <2 hEquivocalEquivocal27.60.780.78RoutineRoutineE. coli36 5/737.2Unknown14Broad abx ≥4 hEquivocalEquivocalNR0.810.81RoutineRoutineOther38 5/737.1Negative6None or <2 hEquivocalEquivocalNR0.840.84RoutineRoutineS. aureus42 3/738.3Unknown59Broad abx 2-4 hWellWell—0.890.89Frequent VSFrequent VSGBS37 3/736.7Negative17.1None or <2 hEquivocalIll6.90.933.94RoutineTreatS. aureus40 5/737.0Negative13None or <2 hEquivocalEquivocalNR1.021.02Blood cultureBlood cultureOther37 2/737.0Negative6None or <2 hEquivocalEquivocalNR1.051.05Blood cultureBlood cultureGBS35 6/737.0Positive83None or <2 hWellWell331.071.07Blood cultureBlood cultureGBS39 1/737.2Unknown8None or <2 hEquivocalIll31.084.57Blood cultureTreatGBS40 4/737.0Unknown15None or <2 hEquivocalIll11.104.65Blood cultureTreatGBS42 2/738.5Unknown63GBS abx >2 hWellWell—1.181.18Blood cultureBlood cultureGBS39 3/737.1Negative17.68None or <2 hEquivocalIll41.205.08Blood cultureTreatE. coli39 5/738.9Negative9None or <2 hWellWellNR1.255.20Blood cultureBlood cultureGBS38 4/737.1Unknown14None or <2 hEquivocalIll101.231.25Blood cultureTreatOther3736.8Unknown0None or <2 hIllIllNR1.291.29StronglyStronglyCoNS34 4/736.9Unknown2GBS abx >2 hEquivocalEquivocalNR1.291.29Blood cultureBlood cultureVGS36 6/736.8Negative0None or <2 hIllIll01.321.32StronglyStronglyE. coli3939.5Unknown14.0GBS abx >2 hWellIll121.4268.62Blood cultureTreatGBS39 6/739.0Positive27Broad abx 2-4 hWellWell—1.461.46Blood cultureBlood cultureGBS4137.3Negative9None or <2 hEquivocalIll31.516.38Blood cultureTreatGBS39 5/737.5Negative7.37None or <2 hEquivocalIll81.596.71Blood cultureTreatE. coli4039.0Negative12.3None or <2 hWellWell—1.681.68Blood cultureBlood cultureGBS40 1/737.4Negative6Broad abx ≥4 hIllIll01.691.69StronglyStronglyOther3936.7Negative5None or <2 hIllIllNR1.721.72StronglyStronglyCoNS40 1/736.8Positive13.78GBS abx >2 hIllIll01.851.85StronglyStronglyL. monocytogenes35 3/739.2Unknown1.7GBS abx >2 hWellWell—1.861.86Blood cultureBlood cultureOther3736.6Negative2None or <2 hIllIllNR1.901.90StronglyStronglyGBS4237.0Unknown20None or <2 hEquivocalIll11.948.17Blood cultureTreatVGS40 1/737.4Unknown0None or <2 hIllIll01.951.95StronglyStronglyGBS34 2/737.0Unknown72None or <2 hWellWell—1.971.97Blood cultureBlood cultureGBS36 3/737.2Negative5.3None or <2 hEquivocalIll7.32.048.61Blood cultureTreatE. coli36 4/737.2Negative10None or <2 hEquivocalEquivocalNR2.399.75Blood cultureBlood cultureGBS3637.0Unknown8None or <2 hEquivocalIll32.322.33Blood cultureTreatGBS39 5/737.0Negative3.18None or <2 hIllIll02.332.37StronglyStronglyGBS40 3/736.9Negative4.4None or <2 hIllIll02.372.39StronglyStronglyGBS40 2/737.0Unknown84None or <2 hEquivocalIll12.5010.51Blood cultureTreatOther3739.1Negative7None or <2 hWellWellNR2.712.71Blood cultureBlood cultureOther36 5/737.6Negative3None or <2 hEquivocalEquivocalNR2.752.75Blood cultureBlood cultureVGS40 1/737.8Negative9.5None or <2 hEquivocalEquivocalNR2.872.87Blood cultureBlood cultureE. coli36 1/737.3Unknown58.08GBS abx >2 hEquivocalEquivocal52.942.94Blood cultureBlood cultureGBS39 5/736.9Negative10None or <2 hIllIllNR2.962.96StronglyStronglyGBS42 2/737.3Unknown14None or <2 hEquivocalEquivocal—3.033.03TreatTreatGBS39 4/737.8Negative13None or <2 hEquivocalIll63.1513.21TreatTreatE. coli4039.4Negative14None or <2 hWellWell103.313.31TreatTreatGBS38 6/736.8Unknown16None or <2 hIllIll03.313.31TreatTreatGBS40 2/737.6Unknown26None or <2 hEquivocalIll33.4314.37TreatTreatBacillus spp37 1/737.0Unknown2None or <2 hIllIll03.483.48TreatTreatE. coli39 2/737.5Unknown18.8GBS abx >2 hIllIll03.593.59TreatTreatGBS41 4/736.7Negative15.2None or <2 hIllIll03.683.68TreatTreatGBS36 3/737.2Negative24.2None or <2 hEquivocalEquivocal—3.743.74TreatTreatGBS38 4/737.1Unknown6None or <2 hIllIll03.773.77TreatTreatGBS4137.4Unknown1None or <2 hIllIll04.014.01TreatTreatGBS40 2/737.1Negative9None or <2 hIllIllNR4.074.07TreatTreatOral flora39 3/737.0Negative15.75None or <2 hIllIll04.144.14TreatTreatGBS3839.3Negative25.5None or <2 hWellIll64.424.31TreatTreatVGS38 5/739.5Negative16.6None or <2 hWellWell124.314.35TreatTreatGBS40 4/737.0Unknown12.75None or <2 hIllIll04.35186.69TreatTreatGBS40 5/737.3Unknown3.5None or <2 hIllIll04.504.50TreatTreatGBS41 3/736.9Unknown12None or <2 hIllIll04.544.51TreatTreatVGS38 2/737.0Negative14.25None or <2 hIllIll04.534.51TreatTreatL. monocytogenes39 6/737.1Negative13None or <2 hIllIllNR4.514.53TreatTreatL. monocytogenes39 6/737.1Negative13None or <2 hIllIllNR4.514.54TreatTreatGBS3737.7Unknown11None or <2 hEquivocalIll54.5919.16TreatTreatGBS4137.1Unknown10None or <2 hIllIll05.085.08TreatTreatE. coli36 1/737.0Negative1.83None or <2 hIllIll05.395.38TreatTreatGroup G Strept.39 6/736.9Negative40.98None or <2 hIllIll05.585.39TreatTreatE. coli40 1/739.3Negative53None or <2 hWellWell—5.385.58TreatTreatNot specified37 6/737.0Negative21None or <2 hIllIll05.975.97TreatTreatGBS38 1/737.1Unknown16None or <2 hIllIllNR6.005.98TreatTreatGBS40 2/737.2Negative16None or <2 hIllIll05.986.00TreatTreatGBS3737.0Negative12None or <2 hIllIllNR6.456.45TreatTreatVGS41 4/737.1Unknown12None or <2 hIllIll06.506.50TreatTreatE. coli41 4/739.7Negative10.5None or <2 hWellWell—6.636.63TreatTreatGBS42 1/739.4Unknown17None or <2 hWellWell—6.676.67TreatTreatGBS38 3/736.8Unknown63None or <2 hIllIll06.906.78TreatTreatE. coli4137.2Unknown14None or <2 hIllIllNR6.786.90TreatTreatGBS37 2/737.2Unknown9None or <2 hIllIll07.287.28TreatTreatOther39 5/737.3Negative22None or <2 hIllIllNR7.657.53TreatTreatE. coli41 4/737.2Negative13.1None or <2 hIllIll07.537.59TreatTreatVGS40 3/737.0Unknown45None or <2 hIllIll07.597.64TreatTreatGBS + E. coli40 6/737.3Negative15.45None or <2 hIllIll07.647.65TreatTreatOther4137.4Unknown9None or <2 hIllIllNR7.777.71TreatTreatE. coli39 5/738.2Negative9.52GBS abx >2 hIllIll07.717.77TreatTreatCoNS38 2/737.4Negative13None or <2 hIllIllNR8.128.12TreatTreatGBS3836.9Unknown60None or <2 hIllIll08.658.65TreatTreatVGS36 4/737.2Negative6.8None or <2 hIllIll08.728.72TreatTreatGBS37 3/737.1Unknown23None or <2 hIllIllNR8.728.72TreatTreatVGS35 3/737.5Unknown0None or <2 hIllIll09.529.52TreatTreatGBS35 1/736.8Unknown45GBS abx >2 hIllIll09.759.75TreatTreatGBS42 1/737.2Unknown13None or <2 hIllIll09.879.87TreatTreatGBS37 6/737.5Unknown10None or <2 hIllIllNR9.949.94TreatTreatE. coli36 1/737.1Negative8.6None or <2 hIllIll010.3110.31TreatTreatCoNS34 1/737.0Negative0None or <2 hIllIllNR12.1712.17TreatTreatVGS3537.0Unknown2None or <2 hIllIll012.6212.62TreatTreatVGS38 5/737.6Negative22.6None or <2 hIllIll013.0113.01TreatTreatE. coli38 6/737.6Negative25None or <2 hIllIll013.3613.36TreatTreatEnterococcus spp4137.8Unknown8None or <2 hIllIll013.8113.81TreatTreatE. coli38 1/738.1Negative2.5None or <2 hIllIll014.1014.10TreatTreatGBS36 2/737.3Unknown12None or <2 hIllIll015.2615.26TreatTreatE. coli41 6/737.5Negative18.2None or <2 hIllIll015.3415.34TreatTreatNot specified3938.0Negative12None or <2 hIllIll017.8217.82TreatTreatGBS37 5/737.2Unknown89None or <2 hIllIll018.7018.70TreatTreatGBS4038.3Unknown50GBS abx >2 hIllIll020.1020.10TreatTreatGBS35 4/737.0Negative27None or <2 hIllIll020.4120.41TreatTreatE. coli41 1/739.1Positive17.1GBS abx >2 hEquivocalEquivocal—20.7420.74TreatTreatEnterococcus spp39 1/738.7Negative25.5Broad abx ≥4 hIllIll022.1822.18TreatTreatGBS37 1/738.9Negative8None or <2 hEquivocalEquivocalNR23.4423.36TreatTreatGBS41 6/737.8Unknown15None or <2 hIllIll023.3623.44TreatTreatH. influenzae40 2/738.5Unknown62Broad abx 2-4 hIllIll031.5331.53TreatTreatCoNS39 4/739.4Negative11None or <2 hEquivocalEquivocalNR34.7234.72TreatTreatH. influenzae38 3/739.4Negative9None or <2 hEquivocalEquivocal—35.6435.64TreatTreatNot specified41 4/738.2Unknown16None or <2 hIllIll039.4637.15TreatTreatE. coli40 4/738.8Negative39.1Broad abx 2-4 hIllIll039.1439.14TreatTreatEnterococcus spp40 3/738.3Negative21None or <2 hIllIll037.1539.46TreatTreatGBS4039.0Unknown24Broad abx 2-4 hIllIll040.7640.76TreatTreatE. coli37 3/739.0Negative18Broad abx ≥4 hIllIll042.9842.98TreatTreatGBS39 1/739.3Negative16GBS abx >2 hIllIll051.2151.21TreatTreatGBS3939.5Positive2.78GBS abx >2 hIllIll066.3166.31TreatTreatPneumococcus38 4/738.9Negative15.8None or <2 hIllIll080.6280.62TreatTreatNot specified39 2/739.3Negative14None or <2 hIllIll0126.23126.23TreatTreatE. coli4039.3Negative16.6None or <2 hIllIll0136.13136.13TreatTreatOther40 3/739.4Negative17None or <2 hIllIllNR163.94163.94TreatTreatE. coli40 3/739.3Negative162.7Broad abx 2-4 hIllIll0167.71167.71TreatTreatNot specified34 1/737.2Negative197None or <2 hIllIll0225.89225.89TreatTreatNot specified34 1/737.3Positive322None or <2 hIllIll0411.84411.84TreatTreatBlood culture, blood culture and frequent vital signs; CoNS, coagulase-negative staphylococcus; E. coli, Escherichia coli; H. influenzae, Haemophilus influenzae; GA, gestational age; GBS, Group B Streptococcus; Group G Strept., Group G Streptococcus; NR, not reported for any subjects in source report; ROM, duration of ruptured membranes at birth; Strongly, strongly consider starting empiric antibiotics; S. aureus., Staphylococcus aureus; Strep., Streptococcus; VGS, viridans group streptococci; VS, vital signs; —, data not available for this subject. Temperatures reported in Fahrenheit were converted to Celsius and rounded to the first decimal place for use in risk calculations. Open table in a new tab In the article "Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis" by Achten et al (J Pediatr 2021;234:77-84.e8), errors occurred in Table III of this article. The online version of the article has since been updated. Blood culture, blood culture and frequent vital signs; CoNS, coagulase-negative staphylococcus; E. coli, Escherichia coli; H. influenzae, Haemophilus influenzae; GA, gestational age; GBS, Group B Streptococcus; Group G Strept., Group G Streptococcus; NR, not reported for any subjects in source report; ROM, duration of ruptured membranes at birth; Strongly, strongly consider starting empiric antibiotics; S. aureus., Staphylococcus aureus; Strep., Streptococcus; VGS, viridans group streptococci; VS, vital signs; —, data not available for this subject. Temperatures reported in Fahrenheit were converted to Celsius and rounded to the first decimal place for use in risk calculations. Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-AnalysisThe Journal of PediatricsVol. 234PreviewTo provide a comprehensive assessment of case stratification by the Neonatal Early-Onset Sepsis (EOS) Calculator, a novel tool for reducing unnecessary antibiotic treatment. Full-Text PDF Open Access

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.

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.

See related article, p 283In this volume of The Journal, Clyman et al present analysis of data collected in the Patent Ductus Arteriosus: TO LEave it alone or Respond And Treat Early (PDA-TOLERATE) trial, examining the hypothesis that the risk of bronchopulmonary dysplasia (BPD) in infants born before 28 weeks of gestation is linked to interaction between prolonged positive-pressure ventilation and prolonged exposure to a moderate-to-large patent ductus arteriosus (PDA).1Clyman R.I. Kaempf J. Liebowitz M. Erdeve O. Bulbul A. Hakansson S. et al.Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial.J Pediatr. 2021; 229: 283-288.e2Abstract Full Text Full Text PDF Scopus (12) Google Scholar This study represents the capstone of a triad of recent inquiries into these relationships by Clyman et al.1Clyman R.I. Kaempf J. Liebowitz M. Erdeve O. Bulbul A. Hakansson S. et al.Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial.J Pediatr. 2021; 229: 283-288.e2Abstract Full Text Full Text PDF Scopus (12) Google Scholar, 2Clyman R.I. Hills N.K. Liebowitz M. Johng S. Relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus shunt and the risk of developing bronchopulmonary dysplasia or death before 36 weeks.Am J Perinatol. 2020; 37: 216-223Crossref PubMed Scopus (20) Google Scholar, 3Clyman R.I. Hills N.K. The effect of prolonged tracheal intubation on the association between patent ductus arteriosus and bronchopulmonary dysplasia (grades 2 and 3).J Perinatol. 2020; 40: 1358-1365Crossref PubMed Scopus (10) Google Scholar Such post hoc analyses are fraught with potential for false discoveries, but these reports are notable not for what they find but for what they do not and, therefore, deserve close attention. See related article, p 283 The prior 2 reports draw upon data collected prospectively for over 15 years at a single center (University of California San Francisco). The first shows that the risk of death or BPD was greater among infants in whom a moderate-to-large PDA was present for 7 days or more (OR 2.57 vs infants exposed for <7 days; 95% CI 1.71-3.87, P < .0001).2Clyman R.I. Hills N.K. Liebowitz M. Johng S. Relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus shunt and the risk of developing bronchopulmonary dysplasia or death before 36 weeks.Am J Perinatol. 2020; 37: 216-223Crossref PubMed Scopus (20) Google Scholar The rates of the combined outcome (or, conversely, survival without BPD) did not differ among groups with durations of PDA exposure ≥7 days (P = .66; Figure; available at www.jpeds.com). In the second report, grade 2-3 BPD (defined as requiring nasal cannula flow rates >2 L/minute, noninvasive positive airway pressure, or invasive mechanical ventilation at a postmenstrual age of 36-0/7- 36-6/7 weeks4Jensen E.A. Dysart K. Gantz M.G. McDonald S. Bamat N.A. Keszler M. et al.The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach.Am J Respir Crit Care Med. 2019; 200: 751-759Crossref PubMed Scopus (169) Google Scholar) was also more likely in infants exposed to moderate-to-large PDA for ≥7 days (OR 5.10; 95% CI 2.58-10.1, P < .0001); again, longer exposures (beyond 7 days) were not associated with incremental risk (P = .67 by 2-by-3 χ2).3Clyman R.I. Hills N.K. The effect of prolonged tracheal intubation on the association between patent ductus arteriosus and bronchopulmonary dysplasia (grades 2 and 3).J Perinatol. 2020; 40: 1358-1365Crossref PubMed Scopus (10) Google Scholar This relationship held only for infants who required invasive ventilation for ≥10 days; among those intubated for <10 days, the risk of grade 2-3 BPD was low and did not significantly increase whether exposed to PDA for <1 week (2%) or for several weeks (6%; P = .13).3Clyman R.I. Hills N.K. The effect of prolonged tracheal intubation on the association between patent ductus arteriosus and bronchopulmonary dysplasia (grades 2 and 3).J Perinatol. 2020; 40: 1358-1365Crossref PubMed Scopus (10) Google Scholar Examination of these relationships in the PDA-TOLERATE cohort confirmed that prolonged exposure to PDA (≥10 days) was associated with increased risk of either any BPD or grade 2-3 BPD only in infants who were intubated for ≥10 days (OR 5.81; 95% CI 1.55-21.6, and 7.23; 1.12-46.4, respectively), but not among those who were intubated for <10 days (OR 0.86; 95% CI 0.22-3.33 and 1.17; 0.17-7.80, respectively). Among infants intubated for ≥10 days, neither the rates of any BPD nor of grade 2-3 BPD differed among groups exposed to PDA for 11-14, 15-20, or ≥20 days (P = .16 and .64 by 2-by-3 χ2, respectively). Few prior studies have similarly evaluated the relationship between the duration of PDA exposure and BPD. Mirza et al also found that longer exposure to a “significant” PDA is associated with an increased rate of death or BPD (aOR 1.37; 95% CI 1.03-1.82), but did not indicate whether PDA was treated as a bivariate or continuous variable. However, there was no difference in unadjusted risk between infants with PDA for 1-2 weeks (51%) compared with those exposed for >2 weeks (59%; P = .97).5Mirza H. Garcia J. McKinley G. Hubbard L. Sensing W. Schneider J. et al.Duration of significant patent ductus arteriosus and bronchopulmonary dysplasia in extremely preterm infants.J Perinatol. 2019; 39: 1648-1655Crossref PubMed Scopus (17) Google Scholar Schena et al described increased rates of death or BPD with exposures to hemodynamically significant PDA (≥E2, ≥E3, or E4 by McNamara classification6McNamara P.J. Sehgal A. Towards rational management of the patent ductus arteriosus: the need for disease staging.Arch Dis Child Fetal Neonatal Ed. 2007; 92: F424-F427Crossref PubMed Scopus (245) Google Scholar) for more than 7 days (unadjusted OR 3.85, 2.18-6.78; 3.45, 1.83-6.50; and 15.1, 1.43-156, respectively). In multivariate analysis, exposure to E2 PDA had no significant impact, but E3-E4 PDA was associated with increased risk (aOR 1.70 per week of exposure, 95% CI 1.09-2.66). Durations of E3-E4 exposures were relatively short and a minority of subjects were exposed to E3-E4 PDA for >7 days (4.8 ± 6.2 days and 38%, respectively, among infants who died or developed BPD); the gradient of risk within subjects with exposures >7 days was not assessed.7Schena F. Francescato G. Cappelleri A. Picciolli I. Mayer A. Mosca F. et al.Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia.J Pediatr. 2015; 166: 1488-1492Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The results reported in these recent reports are, therefore, both novel and highly informative. These results have important implications. First, as suggested by Clyman et al, infants who are intubated for <10 days do not need treatment to close a persistently patent ductus, even if it is moderate-to-large.1Clyman R.I. Kaempf J. Liebowitz M. Erdeve O. Bulbul A. Hakansson S. et al.Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial.J Pediatr. 2021; 229: 283-288.e2Abstract Full Text Full Text PDF Scopus (12) Google Scholar Second, because infants intubated for ≥10 days do not accrue incremental risk of death or BPD with further exposure to a moderate-to-large PDA, there appears to be little, if anything, to be gained from treatment to close the ductus after 10 days of age. Numerous randomized trials and several meta-analyses of early PDA treatment have failed to demonstrate reduction in mortality or BPD10Benitz W.E. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?.J Perinatol. 2010; 30: 241-252Crossref PubMed Scopus (241) Google Scholar, 11Fowlie P.W. Davis P.G. McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.Cochrane Database Syst Rev. 2010; 7: CD000174PubMed Google Scholar, 12Slaughter J.L. Reagan P.B. Newman T.B. Klebanoff M.A. Comparative effectiveness of nonsteroidal anti-inflammatory drug treatment vs no treatment for patent ductus arteriosus in preterm infants.JAMA Pediatr. 2017; 171: e164354Crossref PubMed Scopus (34) Google Scholar, 13Ohlsson A. Shah P.S. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants.Cochrane Database Syst Rev. 2020; 1: CD010061PubMed Google Scholar, 14Ohlsson A. Shah S.S. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.Cochrane Database Syst Rev. 2020; 1: CD004213PubMed Google Scholar, 15Ohlsson A. Walia R. Shah S.S. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.Cochrane Database Syst Rev. 2020; 2: CD003481PubMed Google Scholar, 16Sankar M.N. Benitz W.E. Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?.J Perinatol. 2020; 40: 1863-1870Crossref PubMed Scopus (2) Google Scholar, 8Cooke L. Steer P. Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants.Cochrane Database Syst Rev. 2003; 2: CD003745PubMed Google Scholar, 9Mosalli R. Alfaleh K. Prophylactic surgical ligation of patent ductus arteriosus for prevention of mortality and morbidity in extremely low birth weight infants.Cochrane Database Syst Rev. 2008; 1: CD006181Google Scholar; early treatment to close the PDA is ineffective, with the exceptions of increased ductal closure (and a resultant decrease in “rescue” treatment or ligation) and possibly reduced severe intraventricular hemorrhage. Although a few individual trials have reported effects on other secondary or post hoc outcomes,1Clyman R.I. Kaempf J. Liebowitz M. Erdeve O. Bulbul A. Hakansson S. et al.Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial.J Pediatr. 2021; 229: 283-288.e2Abstract Full Text Full Text PDF Scopus (12) Google Scholar only reduction in intraventricular hemorrhage appears to be reproducible (but does not appear to be mediated by PDA closure17Ment L.R. Duncan C.C. Ehrenkranz R.A. Kleinman C.S. Pitt B.R. Taylor K.J. et al.Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants.J Pediatr. 1985; 107: 937-943Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 18Ment L.R. Duncan C.C. Ehrenkranz R.A. Kleinman C.S. Taylor K.J. Scott D.T. et al.Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates.J Pediatr. 1988; 112: 948-955Abstract Full Text PDF PubMed Scopus (77) Google Scholar, 19Ment L.R. Oh W. Ehrenkranz R.A. Phillip A.G. Vohr B. Allan W. et al.Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial.J Pediatr. 1994; 124: 951-955Abstract Full Text PDF PubMed Scopus (84) Google Scholar). Because most subjects in these trials were enrolled and randomized in the first 7 days after birth,16Sankar M.N. Benitz W.E. Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?.J Perinatol. 2020; 40: 1863-1870Crossref PubMed Scopus (2) Google Scholar the potential utility of later treatment has remained largely unexplored. The present data help close that gap. The PDA-TOLERATE data, along with the 2 antecedent papers, indicate that we should not expect benefit from later treatment, as later PDA closure—even among infants receiving prolonged ventilation in the presence of a moderate-to-large PDA—is not associated with incremental risks for BPD, grade 2-3 BPD, or the combined outcome of death or BPD. Neither early nor late treatment obviates these risks. Another important implication should not be overlooked. The step increases in BPD risk with exposures exceeding 7-10 days indicate that persistence of the PDA is a biomarker for an increased risk of BPD.1Clyman R.I. Kaempf J. Liebowitz M. Erdeve O. Bulbul A. Hakansson S. et al.Prolonged tracheal intubation and the association between patent ductus arteriosus and bronchopulmonary dysplasia: a secondary analysis of the PDA-TOLERATE trial.J Pediatr. 2021; 229: 283-288.e2Abstract Full Text Full Text PDF Scopus (12) Google Scholar Absence of a dose-response relationship between duration of ductal patency and risk of BPD beyond that threshold, however, casts doubt on the underlying hypothesis that prolonged exposure to excessive pulmonary blood flow has a causal role in development or progression of BPD. A recent update to the classic Bradford Hill criteria for causality cautioned “While the presence of a dose-response relationship does not always support causality, its absence when expected would lead us to doubt causality.”20Howick J. Glasziou P. Aronson J.K. The evolution of evidence hierarchies: what can Bradford Hill's 'guidelines for causation' contribute?.J R Soc Med. 2009; 102: 186-194Crossref PubMed Scopus (135) Google Scholar As Altman and Bland have stated, “it is usually reasonable not to accept a new treatment unless there is positive evidence in its favour.”21Altman D.G. Bland J.M. Absence of evidence is not evidence of absence.BMJ. 1995; 311: 485Crossref PubMed Scopus (1108) Google Scholar Curiously, endorsement of therapies to close the PDA in preterm infants seems to have evolved into the argument that “we don't know that it is not effective, and it makes sense that it might be, so let's just do it.” That argument is flawed for several reasons: First, evidence of efficacy (ie, that the patient actually benefits from the treatment) is lacking in this instance. Second, we do know that treatment to close the ductus is ineffective (for achievement of outcomes other than ductal closure itself) in all circumstances for which there are reliable data. Although the available data do not definitively preclude the possibility that treatment to close the PDA may be beneficial in special circumstances, uncertainty around the nature of those specific situations should lead to design and execution of randomized trials to assess the potential for benefit in those situations. Mitra and McNamara have recently provided a thoughtful and comprehensive framework for design of informative trials.22Mitra S. McNamara P.J. Patent ductus arteriosus—time for a definitive trial.Clin Perinatol. 2020; 47: 617-639Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Only after such trials demonstrate true utility—defining which outcomes are prevented in which infants by which intervention—should treatment be adopted into clinical practice. Until such evidence is available, we have an obligation to our patients to stop exposing them to therapies that are, at best, unproven, and in most instances, apparently ineffective. Those who wish to continue to do so must shoulder the obligation to provide evidence that supports the efficacy of those practices. Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trialThe Journal of PediatricsVol. 229PreviewIn the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD. Full-Text PDF

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.

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.

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.