Search

Objective: To describe parents' motivations for and against participation in neonatal research, including the views of those who declined participation., Study Design: We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation., Results: Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a "guinea pig" were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations., Conclusions: Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes., Competing Interests: Declaration of Competing Interest Conflicts of interest: The authors have no conflicts of interest relevant to this article to disclose. Funding/Support: This study was supported by National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K23HD103872, supporting Elliott Weiss). Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1 TR00231, supporting Benjamin Wilfond and Kathryn Porter). Role of Funder/Sponsor: The NIH had no role in the design and conduct of this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Despite strong evidence for its utility in clinical management and diagnosis of intracranial hemorrhage (ICH), the use of neonatal cranial point-of-care ultrasound (POCUS) has not been standardized in neonatal intensive care units (NICUs) in the United States. The primary aim of this study was to evaluate the feasibility of training NICU providers to perform cranial POCUS by tracking the quality of image acquisition following training., Methods: Observational single-center cohort study of cranial POCUS images obtained by trained neonatal practitioners (attendings, fellows, and advanced practice providers) using a protocol developed by a radiologist and neonatologist. Exams were performed on infants born ≤1250 g and/or ≤30 weeks gestation within the first 3 days after birth. A survey to assess attitudes regarding cranial POCUS was given before each of three training sessions. Demographic and clinical data collection were portrayed with descriptive statistics. Metrics of image quality were assessed by a radiologist and sonographer independently. Analysis of trends in quality of POCUS images over time was performed using a multinomial Cochran-Armitage test., Results: Eighty-two cranial POCUS scans were performed over a 2-year period. Infant median age at exam was 14 hours (IQR 7-22 hours). Metrics of image quality depicted quarterly demonstrated a significant improvement in depth (P = .01), gain (P = .048), and quality of anatomy images captured (P < .001) over time. Providers perceived increased utility and safety of cranial POCUS over time., Conclusion: Cranial POCUS image acquisition improved significantly following care team training, which may enable providers to diagnose ICH at the bedside., (© 2024 American Institute of Ultrasound in Medicine.)

Objective: This study aimed to examine fetal and neonatal inflammatory and neurologic complications associated with maternal coronavirus disease 2019 (COVID-19) infection., Study Design: Case-series using a convenience sample of neonates cared for in a large referral-based children's hospital neonatal intensive care unit between September 2021 and May 2022., Results: We identified seven neonates with exposure to maternal severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) and a presentation consistent with inflammatory complications. All had some degree of neurologic injury with neuroimaging findings including restricted diffusion indicating injury in the white matter, cortex, deep gray structures, and splenium of the corpus callosum as well as intracranial hemorrhage. In addition, many infants had cytopenia and abnormal coagulation studies. Placental pathology, when available, revealed inflammation, clot with calcifications, and hematomas with associated infarcts., Conclusion: Neonates born to mothers with SARS-CoV-2, even when negative for the virus themselves, may have complications consistent with a systemic inflammatory syndrome. Placental pathology as well as neurologic imaging in infants with neurologic findings may help to support this diagnosis., Key Points: · A systemic inflammatory response may cause illness in babies born to mothers with a history of COVID-19.. · Inflammatory markers and placental pathology are helpful in supporting this diagnosis.. · Consider neuroimaging in infants of mothers with a history of COVID-19 with neurologic findings.., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Parents struggle with being asked to participate in neonatal research. Past work has largely failed to include views of minoritized parents, low-socioeconomic status parents, and those who declined research. We aimed to describe parents' preferences related to learning about eligibility for neonatal research., Methods: Qualitative interviews of parents who were asked to enroll their infant in neonatal research. Themes related to parental experiences and preferences for learning about neonatal research were identified using content analysis., Results: Many parents desired greater involvement of their clinical team. Emotions at the time of recruitment were critically important to parents' experience, where were deeply impacted by interpersonal relationships with research staff., Discussion: Increased involvement of the clinical team and greater sensitivity to the stressors around parent and infant conditions at the time of recruitment for neonatal research should be considered by those attempting to improve recruitment for neonatal research., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To describe in-hospital morbidities and mortality among twins and triplets delivered at ≥26 to ≤34 weeks gestational age (GA) while controlling for prematurity and growth restriction., Study Design: Retrospective analysis of inborn infants discharged from a neonatal intensive care unit (NICU) managed by the Pediatrix Medical Group between 2010 and 2018., Result: Among 247 437 infants included, 27.4% were multiples. Adjusted for GA and other factors typically known prior to delivery, in-hospital morbidities varied by plurality and generally were more common in singletons. The odds of death prior to discharge were less for twins at 0.74 (95% CI: 0.67-0.83) and triplets at 0.69 (95% CI: 0.51-0.92) compared to singletons., Conclusion: Singletons experience greater morbidity and mortality compared to twins and triplets born ≥26 weeks to ≤34 weeks GA, except PDA requiring procedural intervention, ROP requiring treatment, and longer length of stay., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Rapid genetic testing in the critical care setting may guide diagnostic evaluation, direct therapies, and help families and care providers make informed decisions about goals of care. We tested whether a simplified DNA extraction and library preparation process would enable us to perform ultra-rapid assessment of genetic risk for a Mendelian condition, based on information from an affected sibling, using long-read genome sequencing and targeted analysis., Methods: Following extraction of DNA from cord blood and rapid library preparation, genome sequencing was performed on an Oxford Nanopore PromethION. FASTQ files were generated from original sequencing data in near real-time and aligned to a reference genome. Variant calling and analysis were performed at timed intervals., Results: We optimized the DNA extraction and library preparation methods to create sufficient library for sequencing from 500 μL of blood. Real-time, targeted analysis was performed to determine that the newborn was neither affected nor a heterozygote for variants underlying a Mendelian condition. Phasing of the target region and prior knowledge of the affected haplotypes supported our interpretation despite a low level of coverage at 3 hours of life., Conclusion: This proof-of-concept experiment demonstrates how prior knowledge of haplotype structure or familial variants can be used to rapidly evaluate an individual at risk for a genetic disease. While ultra-rapid sequencing remains both complex and cost prohibitive, our method is more easily automated than prior approaches and uses smaller volumes of blood, thus may be more easily adopted for future studies of ultra-rapid genome sequencing in the clinical setting., Competing Interests: Joseph Guillory, Androo J. Markham, and Daniel R. Garalde are employees of Oxford Nanopore Technologies (ONT). Miranda P.G. Zalusky, Jonas A. Gustafson, and Cate R. Paschal have received travel support from ONT. Danny E. Miller is on a scientific advisory board at ONT and has received travel support from ONT to speak on their behalf. Danny E. Miller and Evan E. Eichler are engaged in a research agreement with ONT. Evan E. Eichler is a scientific advisory board (SAB) member of Variant Bio, Inc. Danny E. Miller holds stock options in MyOme.

Importance: Dexmedetomidine, an α2-adrenergic agonist, is not approved by the Food and Drug Administration for use in premature infants. However, the off-label use of dexmedetomidine in premature infants has increased 50-fold in the past decade. Currently, there are no large studies characterizing dexmedetomidine use in US neonatal intensive care units (NICUs) or comparing the use of dexmedetomidine vs opioids in infants., Objectives: To describe dexmedetomidine use patterns in the NICU and examine the association between dexmedetomidine and opioid use in premature infants., Design, Setting, and Participants: A multicenter, observational cohort study was conducted from November 11, 2022, to April 4, 2023. Participants were inborn infants born between 22 weeks, 0 days, and 36 weeks, 6 days, of gestation at 1 of 383 Pediatrix Medical Group NICUs across the US between calendar years 2010 and 2020., Main Outcome and Measure: Exposure to medications of interest defined as total days of exposure, timing of use, and changes over time., Results: A total of 395 122 infants were included in the analysis. Median gestational age was 34 (IQR, 32-35) weeks, and median birth weight was 2040 (IQR, 1606-2440) g. There were 384 infants (0.1% of total; 58.9% male) who received dexmedetomidine. Infants who received dexmedetomidine were born more immature, had lower birth weight, longer length of hospitalization, more opioid exposure, and more days of mechanical ventilation. Dexmedetomidine use increased from 0.003% in 2010 to 0.185% in 2020 (P < .001 for trend), while overall opioid exposure decreased from 8.5% in 2010 to 7.2% in 2020 (P < .001 for trend). The median postmenstrual age at first dexmedetomidine exposure was 31 (IQR, 27-36) weeks, and the median postnatal age at first dexmedetomidine exposure was 3 (IQR, 1-35) days. The median duration of dexmedetomidine receipt was 6 (IQR, 2-14) days., Conclusion and Relevance: The findings of this multicenter cohort study of premature infants suggest that dexmedetomidine use increased significantly between 2010 and 2020, while overall opioid exposure decreased. Future studies are required to further examine the short- and long-term effects of dexmedetomidine in premature and critically ill infants.

Background: Cerebral near-infrared spectroscopy is a non-invasive tool used to measure regional cerebral tissue oxygenation (rScO 2 ) initially validated in adult and pediatric populations. Preterm neonates, vulnerable to neurologic injury, are attractive candidates for NIRS monitoring; however, normative data and the brain regions measured by the current technology have not yet been established for this population., Methods: This study's aim was to analyze continuous rScO 2 readings within the first 6-72 h after birth in 60 neonates without intracerebral hemorrhage born at ≤1250 g and/or ≤30 weeks' gestational age (GA) to better understand the role of head circumference (HC) and brain regions measured., Results: Using a standardized brain MRI atlas, we determined that rScO2 in infants with smaller HCs likely measures the ventricular spaces. GA is linearly correlated, and HC is non-linearly correlated, with rScO 2 readings. For HC, we infer that rScO 2 is lower in infants with smaller HCs due to measuring the ventricular spaces, with values increasing in the smallest HCs as the deep cerebral structures are reached., Conclusion: Clinicians should be aware that in preterm infants with small HCs, rScO 2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue., Impact: Clinicians should be aware that in preterm infants with small head circumferences, cerebral near-infrared spectroscopy readings of rScO 2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. This highlights the importance of rigorously re-validating technologies before extrapolating them to different populations. Standard rScO 2 trajectories should only be established after determining whether the mathematical models used in NIRS equipment are appropriate in premature infants and the brain region(s) NIRS sensors captures in this population, including the influence of both gestational age and head circumference., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified., Study Design: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test., Result: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified., Conclusions: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care., Competing Interests: Declaration of Competing Interest DEM holds stock options in MyOme and is engaged in a research agreement with Oxford Nanopore Technologies. No other author declares a competing financial interest. REDCap grant support from NCATS/NIGH: UL1 TR002319, KL2 TR002317, and TL1 TR002318. DEM is supported by NIH grant DP5OD033357., (Published by Elsevier Inc.)

Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18-22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0-6 h, 6-24 h, 24-48 h, and 48-72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5-3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0-6 h (aOR 17.0, 95%CI 4.3-67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.

Infections remain a leading cause of neonatal death, especially among the extremely preterm infants. To evaluate the incidence, pathogenesis, and in-hospital outcomes associated with sepsis among hospitalized extremely preterm infants born at 24-0/7 to 27-6/7 weeks of gestation, we designed a post hoc analysis of data collected prospectively during the Preterm Epo Neuroprotection (PENUT) Trial, NCT #01378273. We analyzed culture positive infection data, as well as type and duration of antibiotic course and described their association with in-hospital morbidities and mortality. Of 936 included infants, 229 (24%) had at least one positive blood culture during their hospitalization. Early onset sepsis (EOS, ≤3 days after birth) occurred in 6% of the infants, with Coagulase negative Staphylococci (CoNS) and Escherichia Coli the most frequent pathogens. Late onset sepsis (LOS, >day 3) occurred in 20% of the infants. Nearly all infants were treated with antibiotics for presumed sepsis at least once during their hospitalization. The risk of confirmed or presumed EOS was lower with increasing birthweight. Confirmed EOS had no significant association with in-hospital outcomes or death while LOS was associated with increased risk of necrotizing enterocolitis and death. Extremely premature infants with presumed sepsis as compared to culture positive sepsis had lower rates of morbidities. In conclusion, the use of antibiotics for presumed sepsis remains much higher than confirmed infection rates. Ongoing work exploring antibiotic stewardship and presumed, culture-negative sepsis in extremely preterm infants is needed.

Background: Pleuropulmonary blastoma (PPB) is a rare mesenchymal malignancy of the lung and is the most common pulmonary malignancy in infants and children. Cystic PPB, the earliest form of PPB occurring from birth to approximately two years of age, is often mistaken for a congenital pulmonary airway malformation, as the two entities can be difficult to distinguish on imaging and pathology. Diagnosis of PPB should prompt workup for DICER1 syndrome, an autosomal dominant tumor predisposition syndrome. We report a newborn with a congenital PPB presenting with tachypnea and hypoxia, who was found to have variant of uncertain clinical significance (VUS) in DICER1., Case Presentation: A term female infant developed respiratory distress shortly after birth. Initial imaging was concerning for a congenital pulmonary airway malformation versus congenital diaphragmatic hernia, and she was transferred to a quaternary neonatal intensive care unit for management and workup. Chest CT angiography demonstrated a macrocytic multicystic lesion within the right lower lobe without systemic arterial supply. The pediatric surgery team was consulted, and the neonate underwent right lower lobectomy. Pathology revealed a type I PPB. Oncology and genetics consultants recommended observation without chemotherapy and single gene sequencing of DICER1, which identified a germline VUS in DICER1 predicted to alter splicing. RNA-sequencing from blood demonstrated that the variant resulted in an in-frame deletion of 29 amino acids in a majority of transcripts from the affected allele. Due to the patient's young age at presentation and high clinical suspicion for DICER1 syndrome, tumor surveillance was initiated. Renal and pelvic ultrasonography were unremarkable., Conclusion: We present the case of a term neonate with respiratory distress and cystic lung mass, found to have a type I PPB with a germline VUS in DICER1 that likely increased her risk of DICER1-related tumors. Nearly 70% of patients with PPB demonstrate germline mutations in DICER1. Review of RNA sequencing data demonstrates the difficulty in classifying splice variants such as this. Penetrance is low, and many patients with pathogenic DICER1 variants do not develop a malignancy. Best practice surgical and oncologic recommendations include an individualized approach and tumor board discussion. This case highlights the importance of a multidisciplinary team approach and the utility of international registries for patients with rare diagnoses., (© 2023. The Author(s).)

Background: Infants born extremely preterm (<28 weeks' gestation) are at high risk of neurodevelopmental impairment (NDI) with 50% of survivors showing moderate or severe NDI when at 2 years of age. We sought to develop novel models by which to predict neurodevelopmental outcomes, hypothesizing that combining baseline characteristics at birth with medical care and environmental exposures would produce the most accurate model., Methods: Using a prospective database of 692 infants from the Preterm Epo Neuroprotection (PENUT) Trial, which was carried out between December 2013 and September 2016, we developed three predictive algorithms of increasing complexity using a Bayesian Additive Regression Trees (BART) machine learning approach to predict both NDI and continuous Bayley Scales of Infant and Toddler Development 3rd ed subscales at 2 year follow-up using: 1) the 5 variables used in the National Institute of Child Health and Human Development (NICHD) Extremely Preterm Birth Outcomes Tool, 2) 21 variables associated with outcomes in extremely preterm (EP) infants, and 3) a hypothesis-free approach using 133 potential variables available for infants in the PENUT database., Findings: The NICHD 5-variable model predicted 3-4% of the variance in the Bayley subscale scores, and predicted NDI with an area under the receiver operator curve (AUROC, 95% CI) of 0.62 (0.56-0.69). Accuracy increased to 12-20% of variance explained and an AUROC of 0.77 (0.72-0.83) when using the 21 pre-selected clinical variables. Hypothesis-free variable selection using BART resulted in models that explained 20-31% of Bayley subscale scores and AUROC of 0.87 (0.83-0.91) for severe NDI, with good calibration across the range of outcome predictions. However, even with the most accurate models, the average prediction error for the Bayley subscale predictions was around 14-15 points, leading to wide prediction intervals. Higher total transfusion volume was the most important predictor of severe NDI and lower Bayley scores across all subscales., Interpretation: While the machine learning BART approach meaningfully improved predictive accuracy above a widely used prediction tool (NICHD) as well as a model utilizing NDI-associated clinical characteristics, the average error remained approximately 1 standard deviation on either side of the true value. Although dichotomous NDI prediction using BART was more accurate than has been previously reported, and certain clinical variables such as transfusion exposure were meaningfully predictive of outcomes, our results emphasize the fact that the field is still not able to accurately predict the results of complex long-term assessments such as Bayley subscales in infants born EP even when using rich datasets and advanced analytic methods. This highlights the ongoing need for long-term follow-up of all EP infants., Funding: Supported by the National Institute of Neurological Disorders and StrokeU01NS077953 and U01NS077955., Competing Interests: S.E.J. declares receiving royalties from editing Avery's Diseases of the Newborn. S.E.J., B.A.C., D.E.M., and P.J.H. received salary support as part of funding for the PENUT trial. All other authors declare that they have no relevant conflicts of interest., (© 2022 The Author(s).)

Background: Methemoglobinemia can be an acquired or congenital condition. The acquired form occurs from exposure to oxidative agents. Congenital methemoglobinemia is a rare and potentially life-threatening cause of cyanosis in newborns that can be caused by either cytochrome B 5 reductase or hemoglobin variants known as Hemoglobin M., Case Presentation: A term male infant developed cyanosis and hypoxia shortly after birth after an uncomplicated pregnancy, with oxygen saturations persistently 70-80% despite 1.0 FiO2 and respiratory support of CPAP+ 6 cm H2O. Pre- and post-ductal saturations were equal and remained below 85%. Initial radiographic and echography imaging was normal. Capillary blood gas values were reassuring with normal pH and an elevated pO2. Investigations to rule out hemolysis and end-organ dysfunction were within acceptable range. Given the absence of clear cardiac or pulmonary etiology of persistent cyanosis, hematologic causes such as methemoglobinemia were explored. No family history was available at the time of transfer to our institution. Unconjugated hyperbilirubinemia > 5 mg/dL (442 μmol/L) interfered with laboratory equipment measurement, making accurate methemoglobin levels unattainable despite multiple attempts. Initial treatment with methylene blue or ascorbic acid was considered. However, upon arrival of the presumed biological father, a thorough history revealed an extensive paternal family history of neonatal cyanosis due to a rare mutation resulting in a hemoglobin M variant. Given this new information, hematology recommended supportive care as well as further testing to confirm the diagnosis of congenital methemoglobinopathy. Whole genome sequencing revealed a likely pathogenic variation in hemoglobin. The neonate was discharged home at 2 weeks of age on full oral feeds with 0.25 L/min nasal cannula as respiratory support, with close outpatient follow-up. By 5 weeks of age, he was weaned off respiratory support., Conclusion: Congenital methemoglobinemia should be considered in the differential diagnosis for newborns with persistent hypoxemia despite normal imaging and laboratory values. Accurate quantification of methemoglobin concentrations is challenging in neonates due to the presence of other substances that absorb light at similar wavelengths, including HbF, bilirubin, and lipids., (© 2022. The Author(s).)

Objective: We hypothesized that videolaryngoscope use for tracheal intubations would differ across NICUs, be associated with higher first attempt success and lower adverse events., Study Design: Data from the National Emergency Airway Registry for Neonates (01/2015 to 12/2017) included intubation with direct laryngoscope or videolaryngoscope. Primary outcome was first attempt success. Secondary outcomes were adverse tracheal intubation associated events and severe desaturation., Results: Of 2730 encounters (13 NICUs), 626 (23%) utilized a videolaryngoscope (3% to 64% per site). Videolaryngoscope use was associated with higher first attempt success (p < 0.001), lower adverse tracheal intubation associated events (p < 0.001), but no difference in severe desaturation. After adjustment, videolaryngoscope use was not associated with higher first attempt success (OR:1.18, p = 0.136), but was associated with lower tracheal intubation associated events (OR:0.45, p < 0.001)., Conclusion: Videolaryngoscope use is variable, not independently associated with higher first attempt success but associated with fewer tracheal intubation associated events., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Hypoxic-ischemic encephalopathy (HIE) occurs in 1-4:1000 live births. Although neonates with moderate-severe HIE have been studied over several decades, newborns with mild HIE remain understudied, including seizure occurrence, electroencephalography (EEG) characteristics, and outcome., Methods: We conducted a retrospective cohort study of neonates ≥35 weeks of gestation with mild HIE who underwent therapeutic hypothermia to correlate the early EEG background pattern with clinical course and outcomes., Results: Of the included 29 neonates, 10 infants had a moderately to severely abnormal EEG background and 19 had either a normal or a mildly abnormal background. Those with moderately to severely abnormal background also had more multiorgan dysfunction (90% vs 42%, P = 0.02) and a higher incidence of subdural and intraventricular hemorrhages (80% vs 26%, P = 0.02). The overall seizure incidence was 20.7% and was significantly higher in newborns with more severely abnormal background compared to neonates with less abnormal background (50% vs 5%; P = 0.01; relative risk, 9.5; 95% confidence interval, 1.28-70.6). Seizure onset was between 11 and 63 hours of life. Regardless of the EEG background pattern, seizures were brief with an overall low seizure burden. None of the newborns with normal or mildly abnormal background had a new onset of seizures after 24 hours of recording or developed epilepsy during infancy., Conclusions: In neonates with mild HIE, early moderately to severely abnormal EEG background is common and strongly associated with an increased risk for seizures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Evaluate maximal weight loss (MWL) and total fluid administration (TFA) association in first week after birth with outcomes among extremely preterm (EP) newborns., Study Design: We performed a retrospective analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating first-week MWL, TFA, and association with in-hospital outcomes., Results: Among n = 883 included EP neonates, n = 842 survived ≥ 7 days and were included in outcome analyses. MWL between 5% to 15% was associated with decreased odds of necrotizing enterocolitis compared to MWL > 15% (OR 0.49, 95% CI 0.25-0.98). Average TFA > 150 mL/kg birthweight/day was associated with increased odds of necrotizing enterocolitis (OR 3.22, 95% CI 1.40-7.42) and patent ductus arteriosus requiring surgery (OR 2.14, 95% CI 1.10-4.15)., Conclusion: MWL between 5% to 15% is a potentially optimal window of MWL. Increasing average TFA in the first week is associated with adverse neonatal outcomes. Prospective studies evaluating MWL and TFA and relationship to outcomes in EP neonates are needed., Clinical Trial Registration: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273, https://clinicaltrials.gov/ct2/show/NCT01378273 ., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Importance: Practice variability exists in the use of corticosteroids to treat or prevent bronchopulmonary dysplasia in extremely preterm infants, but there is limited information on longer-term impacts., Objective: To describe the use of corticosteroids in extremely preterm infants and evaluate the association with neurodevelopmental outcomes., Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) randomized clinical trial, conducted at 19 participating sites and 30 neonatal intensive care units (NICUs) in the US. Inborn infants born between 24 0/7 and 27 6/7 weeks gestational age between December 2013 and September 2016 were included in analysis. Data analysis was conducted between February 2021 and January 2022., Exposures: Cumulative dose of dexamethasone and duration of therapy for dexamethasone and prednisolone or methyl prednisolone were evaluated., Main Outcomes and Measures: Demographic and clinical characteristics were described in infants who did or did not receive corticosteroids of interest and survived to discharge. Neurodevelopmental outcomes at 2 years of age were evaluated using the Bayley Scales of Infant Development-Third Edition (BSID-III) at corrected age 2 years., Results: A total of 828 extremely preterm infants (403 [49%] girls; median [IQR] gestational age, 26 [25-27] weeks) born at 19 sites who survived to discharge were included in this analysis, and 312 infants (38%) were exposed to at least 1 corticosteroid of interest during their NICU stay, including 279 exposed to dexamethasone, 137 exposed to prednisolone or methylprednisolone, and 79 exposed to both. Exposed infants, compared with nonexposed infants, had a lower birth weight (mean [SD], 718 [168] g vs 868 [180] g) and were born earlier (mean [SD] gestational age, 25 [1] weeks vs 26 [1] weeks). The median (IQR) start day was 29 (20-44) days for dexamethasone and 53 (30-90) days for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. The median (IQR) cumulative dose of dexamethasone was 1.3 (0.9-2.8) mg/kg. After adjusting for potential confounders, treatment with dexamethasone for longer than 14 days was associated with worse neurodevelopmental outcomes, with mean scores in BSID-III 7.4 (95% CI, -12.3 to -2.5) points lower in the motor domain (P = .003) and 5.8 (95% CI, -10.9 to -0.6) points lower in the language domain (P = .03), compared with unexposed infants., Conclusions and Relevance: These findings suggest that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at corrected age 2 years. Potential unmeasured differences in the clinical conditions of exposed vs unexposed infants may contribute to these findings. Improved standardization of treatment and documentation of indications would facilitate replication studies.

Importance: Understanding why and how extremely preterm infants die is important for practitioners caring for these infants., Objective: To examine risk factors, causes, timing, and circumstances of death in a modern cohort of extremely preterm infants., Design, Setting, and Participants: A retrospective cohort review of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial between December 13, 2013, and September 26, 2016, was conducted. A total of 941 infants born between 24 0/7 and 27 6/7 weeks of gestation enrolled at 19 US sites comprising 30 neonatal intensive care units were included. Data analysis was performed from October 16, 2020, to December 1, 2021., Main Outcomes and Measures: Risk factors, proximal causes, timing, and circumstances of in-hospital death., Results: Of the 941 enrolled infants, 108 died (11%) before hospital discharge: 38% (n = 41) at 24 weeks' gestation, 30% (n = 32) at 25 weeks' gestation, 19% (n = 20) at 26 weeks' gestation, and 14% (n = 15) at 27 weeks' gestation. An additional 9 infants (1%) died following hospital discharge. In descending order, the primary causes of death included respiratory distress or failure, pulmonary hemorrhage, necrotizing enterocolitis, catastrophic intracranial hemorrhage, sepsis, and sudden unexplained death. Fifty percent of deaths occurred within the first 10 days after birth. The risk of death decreased with day of life and postmenstrual age such that an infant born at 24 weeks' gestation who survived 14 days had the same risk of death as an infant born at 27 weeks' gestation: conditional proportional risk of death, 0.08 (95% CI, 0.03-0.13) vs 0.06 (95% CI, 0.01-0.11). Preterm labor was associated with a decreased hazard of death (hazard ratio [HR], 0.45; 95% CI, 0.31-0.66). Infant clinical factors associated with death included birth weight below the tenth percentile for gestational age (HR, 2.11; 95% CI, 1.38-3.22), Apgar score less than 5 at 5 minutes (HR, 2.19; 95% CI, 1.48-3.24), sick appearance at birth (HR, 2.49; 95% CI, 1.69-3.67), grade 2b-3 necrotizing enterocolitis (HR, 7.41; 95% CI, 5.14-10.7), pulmonary hemorrhage (HR, 10.0; 95% CI, 6.76-18.8), severe intracranial hemorrhage (HR, 4.60; 95% CI, 3.24-5.63), and severe sepsis (HR, 4.93; 95% CI, 3.67-7.21). Fifty-one percent of the infants received comfort care before death., Conclusions and Relevance: In this cohort study, an association between mortality and gestational age at birth was noted; however, for each week that an infant survived, their risk of subsequent death approximated the risk observed in infants born 1 to 2 weeks later, suggesting the importance of an infant's postmenstrual age. This information may be useful to include in counseling of families regarding prognosis of survival.

Invasive fungal infections remain the leading causes of morbidity and mortality in neonates, especially preterm and very low birth weight infants. Most invasive fungal infections are due to Candida or Aspergillus species, and other fungi are increasingly reported and described. Appropriate identification and treatment are required to augment activity and reduce the toxicity of antifungal drugs. Successful use of antifungals in the vulnerable neonatal population is important for both prevention and treatment of infection. Strategies for prevention, including prophylactic antifungal therapy as well as reducing exposure to modifiable risk factors, like limiting antibiotic exposure, discontinuation of central catheters, and hand hygiene are key techniques to prevent and decrease rates of invasive fungal infections. In conclusion, this is a review of the most common causes, prevention strategies, prophylaxis, and treatment of invasive fungal infections in neonates., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 24 0/7 -27 6/7  weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age., Study Design: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models., Results: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age., Conclusions: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patent ductus arteriosus (PDA) may be found in 0.1-0.2% of term infants, but the average incidence is at least five-fold higher in premature infants, correlating inversely with birth weight and gestational age. While not all patients with a PDA require treatment, the deleterious effects of persistent left-to-right shunting across the ductus can have important short- and long-term consequences. Medical and interventional approaches to PDA closure have evolved greatly in the past decade and add to the decision-making pathways. This article summarizes the pathophysiology of PDA and characterizes the medical, surgical and endovascular treatment approaches., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 24 0/7 to 27 6/7  weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age., Study Design: Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age., Results: ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores., Conclusions: Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Prematurity and low birth weight (LBW) are risk factors for increased morbidity and mortality in infants with congenital heart defects (CHDs). We sought to describe survival, inhospital morbidities, and 2-year neurodevelopmental follow-up in LBW infants with CHD., Study Design: We included infants with birth weight (BW) <2,500 g diagnosed with CHD (except isolated patent ductus arteriosus) admitted January 2013 to March 2016 to a single level-IV academic neonatal intensive care unit. We reported CHD prevalence by BW and gestational age; selected in-hospital morbidities and mortality by infant BW, CHD type, and surgical intervention; and developmental outcomes by Bayley's scales of infant and toddler development, third edition (BSID-III) scores at age 2 years., Results: Among 420 infants with CHD, 28 (7%) underwent cardiac surgery. Median (25th and 75th percentiles) gestational age was 30 (range: 27-33) weeks and BW was 1,258 (range: 870-1,853) g. There were 134 of 420 (32%) extremely LBW (<1,000 g) infants, 82 of 420 (20%) were small for gestational age, and 51 of 420 (12%) multiples. Most common diagnosis: atrial septal defect (260/420, 62%), followed by congenital anomaly of the pulmonary valve (75/420, 18%). Most common surgical procedure: pulmonary artery banding (5/28, 18%), followed by the tetralogy of Fallot corrective repair (4/28, 14%). Survival to discharge was 88% overall and lower among extremely LBW (<1,000 g, 81%) infants and infants undergoing surgery (79%). Comorbidities were common (35%); retinopathy of prematurity and bronchopulmonary dysplasia were most prevalent. BSID-III scores were available on 148 of 176 (84%); any scores <85 were noted in 73 of 148 (49%), with language being most commonly affected., Conclusion: Among LBW infants with congenital heart disease, hospital mortality varied by BW and cardiac diagnosis., Key Points: · In low birth weight infants with congenital heart disease, survival varied by birth weight and cardiac diagnosis.. · Overall survival was higher than previously reported.. · There were fewer morbidities than previously reported.. · Bayley's scale-III scores at 2 years of age were <85 for nearly half.., Competing Interests: None declared., (Thieme. All rights reserved.)

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood., Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age., Design, Setting, and Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020., Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay., Main Outcomes and Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III)., Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure., Conclusions and Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.

Objective: To evaluate the most commonly used medications and in-hospital morbidities and mortality in infants born 22-24 weeks of gestation., Study Design: Multicenter retrospective cohort study of infants born 22-24 weeks of gestation (2006-2016), without major congenital anomalies and with available medication data obtained from neonatal intensive care units managed by the Pediatrix Medical Group., Results: This study included 7578 infants from 195 sites. Median (25th, 75th percentile): birthweight was 610 g (540, 680); the number of distinct medications used was 13 (8, 18); and different antimicrobial exposure was 4 (2, 5). The most common morbidities were BPD (41%) and grade III or IV IVH (20%), and overall survival varied from 46% (2006) to 57% (2016)., Conclusions: A large number of medications were used in periviable infants. There was a high prevalence of in-hospital morbidities, and survival of this population increased over the study period.

Objective: To evaluate antenatal corticosteroids (ANS) use in pregnant women with hypertension., Study Design: Retrospective analysis of ANS use in the Perinatal Quality Collaborative of North Carolina between 2015 and 2017., Results: Twenty-five centers participated, with 9% (1580/17,692) of mothers delivering at <34 weeks; of these, 81% (1286/1580) received a full course of ANS, which was not different between phases (p = 0.32), or between Level III/IV neonatal intensive care units (NICUs; 82%), and I/II NICUs (76%) (p = 0.05). In Level III/IV NICUs, White mothers were more likely to receive ANS (87%) than African Americans (77%) or other race/ethnicity (80%) (including Hispanics) (p = 0.001). ANS use did not differ among mothers with different payers (p = 0.94)., Conclusion: The rates of full ANS courses did not significantly increase from 2015-2017 and disparities persisted. Targeted efforts to improve ANS exposures among hypertensive African American and Hispanic mothers, as well as in community hospital settings are needed.

Background: Gastrostomy tube (G-tube) placement is a long-term alternative to oral or nasogastric feeding for premature infants who cannot safely feed orally or need supplemental nutrition for adequate growth., Methods: We compared daily weight changes for G-tube infants 14 and 30 days preplacement and postplacement, excluding the first 7 days post-G-tube insertion. Infants <37 weeks of gestation without major congenital anomalies and discharged from 327 United States neonatal intensive care units (2004-2013) were included. Incidence of in-hospital outcomes including hypoxic ischemic encephalopathy, intraventricular hemorrhage grade 3 or 4, necrotizing enterocolitis, and patent ductus arteriosus ligation was examined. Additionally, we estimated a treatment effect model in which infants with a G-tube were matched 1:1 to untreated controls based on propensity scores; main outcome was the average treatment effect (weight gain) for treated infants during the 7, 14, or 30 days immediately prior to discharge., Results: Of 329,254 infants, 1393 (0.4%) received a G-tube, increasing from 0.2% in 2004 to 0.6% in 2013. Daily weight gain was significantly less during days 8-14 postplacement compared with 14 days preplacement but was similar between 30 days preplacement and 8-30 days postplacement. After matching, G-tube infant weight gain during the 7 days predischarge was less than among controls, but there was no difference in weight gain between treated and control patients for 14 days and 30 days predischarge., Conclusions: The prevalence of G-tube placement has increased. G-tube use in infants was not associated with improved short-term daily weight gain., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Objective: Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life., Study Design: We included infants with a birth weight <1000 g born 23 0/7-29 6/7 weeks gestational age (GA) and with a length of stay ≥10 weeks, admitted between 2014 and 2016 to a single neonatal intensive care unit., Results: Of 54 infants, median (25th, 75th percentile) GA and birth weight were 25 weeks (24, 26) and 665 g (587, 822), respectively. Median number of blood draws per infant decreased from 57 (49, 65) in week 1 to 12 (8, 22) in week 10. Median volume of blood extracted was 83 mL (70, 97), and median number of blood transfusions was 8 (5, 10)., Conclusions: This cohort experienced a high number and volume of blood draws. Draw frequency and transfusions decreased over the first 10 weeks of life.

Objective: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants., Study Design: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events., Results: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis., Conclusions: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To characterize the association between gentamicin dosing, duration of treatment, and ototoxicity in hospitalized infants., Study Design: This retrospective cohort study conducted at 330 neonatal intensive care units (2002-2014) included inborn infants exposed to gentamicin with available hearing screen results, and excluded infants with incomplete dosing data and major congenital anomalies. Our primary outcome was the final hearing screen result performed during hospitalization: abnormal (failed or referred for further testing in one or both ears) or normal (bilateral passed). The 4 measures of gentamicin exposure were highest daily dose, average daily dose, cumulative dose, and cumulative duration of exposure. We fitted separate multivariable logistic regression models adjusted for demographics, comorbidities, and other clinical events., Results: A total of 84 808 infants met inclusion/exclusion criteria; median (25th, 75th percentile) gestational age and birth weight were 35 weeks (33, 38) and 2480 g (1890, 3184), respectively. Failed hearing screens occurred in 3238 (3.8%) infants; failed screens were more likely in infants of lower gestational age and birth weight, who had longer hospital lengths of stay, higher rates of morbidities, and were small for gestational age. Median highest daily dose, average daily dose, and cumulative dose were 4.0 mg/kg/day (3.0, 4.0), 3.8 mg/kg/day (3.0, 4.0), and 12.1 mg/kg (9.1, 20.5), respectively. Median cumulative duration of exposure was 3 days (3, 6). In adjusted analysis, gentamicin dose and duration of therapy were not associated with hearing screen failure., Conclusions: Gentamicin dosing and duration of treatment were not associated with increased odds of failed hearing screen at the time of discharge from initial neonatal intensive care unit stay., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Diazoxide is used to treat infants with persistent hypoglycemia, but the prevalence of its use and adverse effects are not well described. We report demographic and clinical characteristics of infants treated with diazoxide in neonatal intensive care units (NICUs)., Study Design: Retrospective cohort study of infants 24-41 weeks' gestation admitted to 392 NICUs from 1997-2016, comparing characteristics between hypoglycemic infants exposed/not exposed to diazoxide. For diazoxide courses > 1 day, we report percentages of infants starting diuretics and/or developing new ventilator/oxygen requirement during therapy., Results: Among 1,249,466 infants, 185,832 had hypoglycemia; 1066/185,832 (0.57%) received diazoxide. Diazoxide use increased over time (P = 0.001). Infants receiving diazoxide varied from 0-14.9% among centers. New diuretic courses were associated with 91/664 (14%), and new oxygen or ventilator requirement during therapy was associated with 64/556 (12%) and 34/647 (5%), respectively., Conclusions: Diazoxide use in NICU settings has increased over time. Infants receiving diazoxide commonly received diuretics.

Invasive fungal infections are a significant cause of morbidity and mortality in infants and children. Early diagnosis is critical, and treatment with the appropriate drug and dose should be initiated promptly. Although an increasing number of studies have examined dosing of antifungals in this population, pediatric safety and efficacy data are lacking., (Copyright © 2017 Elsevier Inc. All rights reserved.)