Methylxanthine use in infants with hypoxic-ischemic encephalopathy: a retrospective cohort study.

Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration.

Epidemiology and outcomes of bacterial meningitis in the neonatal intensive care unit.

OBJECTIVE: Examine pathogen distribution, antibiotic resistance patterns, and hospital outcomes of infants with bacterial meningitis in neonatal intensive care units (NICUs) in the US from 2013-2018. STUDY DESIGN: Infants were divided into 2 groups based on age at the time of meningitis: early-onset (0-3 days) and late-onset (>3 days). We compared demographics, clinical characteristics, epidemiology, hospital outcomes, distribution of organisms and resistance, and blood culture timing relative to cerebrospinal fluid culture. RESULTS: From 345 NICUs, 659 infants were diagnosed with bacterial meningitis. The cumulative incidence was 1.1-1.3 cases/1000 NICU discharges. Median gestational age was 33 weeks, median birth weight was 1910 grams, 12% failed hearing screening, and 9% died prior to discharge. Of 141 cases of E. coli meningitis, 53% were resistant to ampicillin. CONCLUSIONS: Significant morbidities occur in infants with culture-proven meningitis in NICUs. Culture and subsequent discernment of sensitivity are crucial to guide definitive therapy.

Hospital-Onset Bacteremia Among Neonatal Intensive Care Unit Patients.

Importance: The Centers for Disease Control and Prevention plans to introduce hospital-onset bacteremia (HOB) as a health care-associated infection measure. The epidemiology and clinical characteristics of HOB among infants admitted to the neonatal intensive care unit (NICU) are unknown. Objective: To estimate the rate of HOB among infants admitted to the NICU, measure the association of HOB risk with birth weight group and postnatal age, and estimate HOB-attributable mortality. Design, Setting, and Participants: This retrospective multicenter cohort study and emulated trial from 2016 to 2021 included a convenience sample of 322 NICUs in the United States. Participants were infants admitted to participating NICUs for 4 or more days. Exposures: The primary exposures were birth weight and postnatal age. Additional exposures included small for gestational age and central line presence. Main Outcomes and Measures: The primary study outcomes were HOB and HOB-attributable mortality. Results: Of 451 443 included infants, 250 763 (55.6%) were male, 200 680 (44.4%) were female, and 62 091 (13.8%) were born 1500 g or less. Of 9015 HOB events that occurred among 8356 infants (2%) during 8 163 432 days at risk (unadjusted incidence rate, 1.1 per 1000 patient-days; 95% CI, 1.0-1.2), 4888 HOB events (54.2%) occurred in the absence of a central line. Within the first 2 weeks after birth, the HOB rate was 14.2 per 1000 patient-days (95% CI, 12.6-16.1) among infants born 750 g or less, to 0.4 events per 1000 patient-days among infants born more than 2500 g (95% CI, 0.4-0.5). Among infants born 750 g or less, the relative HOB risk decreased by 90% after day 42 compared with days 4 to 14 (incidence rate ratio [IRR], 0.10; 95% CI, 0.1-0.1). Conversely, among infants born more than 2500 g, the relative HOB risk increased by 50% after day 42 compared with days 4 to 14 (IRR, 1.5, 95% CI, 1.2-1.9). Compared with otherwise similar infants without HOB, infants with HOB had an absolute difference in attributable mortality of 5.5% (95% CI, 4.7-6.3). Conclusions and Relevance: This study found that HOB events in the NICU are associated with increased mortality. Birth weight is an important risk factor for HOB; however, the relative rate of HOB decreases over postnatal age among low-birth-weight infants and increases among infants born more than 2500 g. Identifying strategies to prevent HOB and programs to decrease HOB risk are urgently needed to reduce infant mortality.

Acyclovir Dosing Practices Across a Multicenter Cohort of Neonatal Intensive Care Units.

BACKGROUND: Acyclovir is the first-line therapy for neonatal herpes simplex virus infections. Therapy can mitigate morbidity and mortality but carries a risk for toxicity. We aimed to compare acyclovir dosing in neonatal intensive care units to published recommendations based on population pharmacokinetic (PopPK) analysis. METHODS: We performed a multicenter cohort study of infants in neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2020. We included all infants who received acyclovir with complete dosing information. Our primary outcome was the proportion of courses with dosing within 80%-120% of the PopPK recommended daily dose and at the recommended dosing frequency. We compared dosing before and after the publication of the 2014 PopPK recommendations using linear probability modeling. RESULTS: We identified 6862 infants with complete dosing information across 308 centers. Dosing met PopPK recommendations for 41% of treatment courses for infants <30 weeks postmenstrual age (PMA), 71% for infants 30 to <36 weeks PMA and <1% for infants ≥ 36 weeks PMA. Comparison of dosing from 1997 to 2013 with that from 2015 to 2020 showed a significant increase in dosing meeting PopPK recommendations for infants <30 weeks PMA (P = 0.008) and infants 30 to <36 weeks PMA (P = 0.02) but not infants ≥ 36 weeks PMA (P = 0.29). No significant increase in dosing meeting PopPK recommendations was seen for any PMA group when comparison was limited to more recent years (2008-2013 vs. 2015-2020). CONCLUSIONS: Dosing meeting PopPK recommendations increased over time for some PMA groups, but dosing different than PopPK recommendations remains common. More research is needed to clarify optimal dosing strategies in these infants.

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit.

BACKGROUND: In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. METHODS: This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. RESULTS: Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. CONCLUSIONS: Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

Mortality Risk in US Neonatal Intensive Care Unit Infants by Birth Size Classifications Comparing Three Growth Curves.

INTRODUCTION: Three widely referenced growth curves classify infant birth anthropometric measurements as small (SGA), appropriate (AGA), or large (LGA) for gestational age (GA) differently. We assessed how these differences in assignment affect the identification and prediction of neonatal intensive care unit (NICU) mortality risk in US preterm infants. METHODS: Birth data of infants admitted to NICUs from the Pediatrix Clinical Data Warehouse (2013-2018) were analyzed. Birth weight, length, and head circumference of 46,724 singleton infants (24-32 weeks GA) were classified as SGA, AGA, or LGA using the Olsen, Fenton, and INTERGROWTH-21st curves. NICU mortality risk based on birth size classification was analyzed using unadjusted and adjusted logistic regression stratified by GA. RESULTS: Odds of mortality were increased with SGA classification at all GAs, size measurements, and curve sets, compared with AGA infants. LGA classification for weight was associated with lower mortality risk at 24 weeks GA and higher risk at 30 weeks GA. Odds of mortality did not differ significantly across curve sets. Classification of size at birth alone had relatively low predictive ability to identify mortality risk, with unadjusted AUCs near 0.5 for all analyses. CONCLUSION: There were no significant differences across curve sets in predicting mortality. Classification of size at birth is a relatively imprecise method to identify infants at risk for NICU mortality.

Direct-to-participant recruitment of mothers and infants: A strategic approach during challenging pandemic times.

Under traditional circumstances, most clinical trials rely on in-person operations to identify, recruit, and enroll study participants and to complete study-related visits. During unusual circumstances, such as the COVID-19 pandemic, the typical clinical trial model is challenged and forced to explore alternative approaches to implementing study recruitment, participant enrollment, and data collection strategies. One such alternative is a direct-to-participant approach which leverages electronic resources and relevant technological devices (e.g., smart phones) available to researchers and patients. This approach functions under the assumption that a participant has access to a device that connects to the internet such as a smart phone, tablet, or computer. Researchers are then able to transition a typical paper-based, in-person model to an electronic-based, siteless, remote study. This article describes the challenges clinicians and researchers faced when implementing a direct-to-participant study approach during the COVID-19 pandemic. The lessons learned during this study of infant populations could help increase efficiency of future trials, specifically, by lessening the burden on participants and clinicians as well as streamlining the process for enrollment and data collection. While direct-to-adult participant recruitment is not a novel approach, our findings suggest that studies attempting to recruit the infant population may benefit from such a direct-to-participant approach.

Neonatal Intensive Care Unit Resource Use for Infants at 22 Weeks' Gestation in the US, 2008-2021.

Importance: During the past decade, clinical guidance about the provision of intensive care for infants born at 22 weeks' gestation has changed. The impact of these changes on neonatal intensive care unit (NICU) resource utilization is unknown. Objective: To characterize recent trends in NICU resource utilization for infants born at 22 weeks' gestation compared with other extremely preterm infants (≤28 weeks' gestation) and other NICU-admitted infants. Design, Setting, and Participants: This is a serial cross-sectional study of 137 continuously participating NICUs in 29 US states from January 1, 2008, through December 31, 2021. Participants included infants admitted to the NICU. Data analysis was performed from October 2022 to August 2023. Exposures: Year and gestational age at birth. Main Outcomes and Measures: Measures of resource utilization included NICU admissions, NICU bed-days, and ventilator-days. Results: Of 825 112 infants admitted from 2008 to 2021, 60 944 were extremely preterm and 872 (466 [53.4%] male; 18 [2.1%] Asian; 318 [36.5%] Black non-Hispanic; 218 [25.0%] Hispanic; 232 [26.6%] White non-Hispanic; 86 [9.8%] other or unknown) were born at 22 weeks' gestation. NICU admissions at 22 weeks' gestation increased by 388%, from 5.7 per 1000 extremely preterm admissions in 2008 to 2009 to 27.8 per 1000 extremely preterm admissions in 2020 to 2021. The number of NICU admissions remained stable before the publication of updated clinical guidance in 2014 to 2016 and substantially increased thereafter. During the study period, bed-days for infants born at 22 weeks increased by 732%, from 2.5 per 1000 to 20.8 per 1000 extremely preterm NICU bed-days; ventilator-days increased by 946%, from 5.0 per 1000 to 52.3 per 1000 extremely preterm ventilator-days. The proportion of NICUs admitting infants born at 22 weeks increased from 22.6% to 45.3%. Increases in NICU resource utilization during the period were also observed for infants born at less than 22 and at 23 weeks but not for other gestational ages. In 2020 to 2021, infants born at less than or equal to 23 weeks' gestation comprised 1 in 117 NICU admissions, 1 in 34 of all NICU bed-days, and 1 in 6 of all ventilator-days. Conclusions and Relevance: In this serial cross-sectional study of 137 US NICUs from 2008 to 2021, an increasing share of resources in US NICUs was allocated to infants born at 22 weeks' gestation, corresponding with changes in national clinical guidance.

Prescribing practices of inhaled corticosteroids for premature infants in the neonatal intensive care unit.

OBJECTIVE: Despite limited safety and efficacy data, inhaled corticosteroids (ICS) are prescribed to premature infants in the neonatal intensive care unit (NICU). We examined contemporary use and risk factors for ICS use in the NICU. STUDY DESIGN: Infants <33 weeks gestational age and <1500 gm birth weight discharged from Pediatrix Medical Group NICUs between 2010 and 2020 were included. We evaluated the association between ICS prescription and clinical characteristics using univariable and multivariable logistic regression. RESULTS: Of 74,123 infants from 308 NICUs, 9253 (12.5%) were prescribed ICS: budesonide, fluticasone, or beclomethasone. Diagnosis of bronchopulmonary dysplasia (BPD), earlier gestational age, male sex, longer mechanical ventilation, oxygen support, and systemic steroids were independent risk factors for ICS prescription. CONCLUSIONS: Use of ICS is common in many NICUs and is associated with a diagnosis of BPD and healthcare utilization. Prospective trials are needed to establish the safety, efficacy, and optimal indication in this vulnerable population.

The association between antenatal corticosteroids exposure and postnatal growth in infants born between 23 and 29 weeks of gestation.

OBJECTIVE: To assess the association between antenatal corticosteroids exposure and postnatal growth in infants born at 23-29 weeks' gestation. STUDY DESIGN: This retrospective study used data from the Pediatrix Clinical Data Warehouse. Maternal-infant dyads from 2018 to 2020 were included. Inverse propensity weighting (IPW) was applied to balance pre-treatment confounders. Primary outcomes included postnatal weight, length, and head circumference growth trajectory percentiles. RESULT: The unadjusted cohort consisted of 11,912 dyads. After IPW adjustment, there were 23,231 dyads. Exposed infants showed higher postnatal trajectory percentiles for weight (by 3.4%), length (by 1.8%), and head circumference (by 2.5%) when compared to non-exposed infants. The positive association between antenatal corticosteroids and postnatal growth was only observed in infants not exposed to preeclampsia/eclampsia/HELLP syndrome or without fetal growth restriction. CONCLUSION: Antenatal corticosteroids exposure is associated with better postnatal growth. The study is limited by its retrospective nature.

Trends in COVID-19 diagnoses and outcomes in infants hospitalized in the neonatal intensive care unit.

OBJECTIVE: Characterize the prevalence of coronavirus disease 2019 (COVID-19) diagnosis among mothers with infants hospitalized in 294 neonatal intensive care units (NICUs), and demographics and outcomes of infants with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure in utero. STUDY DESIGN: Cohort study of infants discharged from NICUs 01/2020-09/2021. We defined groups based on infant diagnosis, infant testing, and maternal SARS-CoV-2 infection status. We compared demographics, clinical characteristics, and outcomes. RESULTS: Of 150,924 infants, 94% had no COVID-related diagnosis or test; 247 (0.2%) infants tested positive for COVID-19 and were more likely to require mechanical ventilation. Infants with unknown maternal status and negative testing were more commonly premature, outborn, and had longer hospitalizations. CONCLUSION: In this large cohort of hospitalized infants, most had no known exposure to COVID-19. Adverse outcomes and mortality were rare. Further studies are needed to evaluate the long-term effects of COVID-19 in this population.

Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22-24 weeks' gestational age.

OBJECTIVE: To describe the epidemiology, risk factors, and timing of spontaneous intestinal perforation (SIP) among infants born at 22-24 weeks' gestational age (GA). STUDY DESIGN: Observational cohort study among infants born at 22-24 weeks' GA in 446 neonatal intensive care units. RESULTS: We identified 9712 infants, of whom 379 (3.9%) developed SIP. SIP incidence increased with decreasing GA (P < 0.001). Antenatal magnesium (odds ratio (OR) 1.42; 95% confidence interval (CI), 1.09-1.85), antenatal indomethacin (OR 1.40; 95% CI, 1.06-1.85), postnatal indomethacin (OR 1.61; 95% CI, 1.23-2.11), and postnatal hydrocortisone exposure (OR 2.02; 95% CI 1.50-2.73) were associated with SIP. Infants who lost 15-20% (OR 1.77; 95% CI, 1.28-2.44) or >20% (OR 2.04; 95% CI, 1.46-2.85) of birth weight had higher odds of SIP than infants with weight loss <10%. CONCLUSIONS: Antenatal magnesium exposure, antenatal indomethacin exposure, postnatal hydrocortisone exposure, postnatal indomethacin exposure, and weight loss ≥15% were associated with SIP.

Morbidity and mortality of twins and triplets compared to singleton infants delivered between 26-34 weeks gestation in the United States.

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.

Underimmunization of very low birth weight infants at discharge from the neonatal intensive care unit.

OBJECTIVE: To quantify immunization status among premature infants discharged from neonatal intensive care units (NICUs), and identify risk factors for underimmunization. STUDY DESIGN: We performed a cohort study of infants <33 weeks gestation discharged home between 2011 and 2020 from 241 NICUs. Using multivariable logistic regression, we examined the association between risk factors and underimmunization at discharge, defined as <1 dose of 5 vaccine types when discharged at 60-119 days of age and <2 doses when discharged at 120-179 days of age. RESULTS: Of 30,766 infants discharged at 60-119 days of age, 14% were underimmunized. Among 4358 infants discharged at 120-179 days of age, 53% were underimmunized. For infants discharged at 60-119 days of age, ventilator support within 30 days of discharge was associated with underimmunization. Having a surgical procedure was associated with underimmunization in both groups. CONCLUSION: A large proportion of premature infants discharged from the NICU are underimmunized.

Diagnostic Utility of Cerebrospinal Fluid White Blood Cell Components for the Identification of Bacterial Meningitis in Infants.

BACKGROUND: To evaluate the diagnostic and predictive utility of cerebrospinal fluid (CSF) white blood cell (WBC) components in the diagnosis of bacterial meningitis in infants discharged from the neonatal intensive care unit (NICU). METHODS: We identified a cohort of infants discharged from a Pediatrix NICU between 1997 and 2020 who did not have an immunodeficiency, had at least 1 CSF culture collected within the first 120 days of life, and at least 1 CSF laboratory specimen obtained on the day of culture collection. We only included an infant's first CSF culture and excluded cultures from CSF reservoirs and those growing contaminants or nonbacterial organisms. We examined the utility of CSF WBC components to diagnose or predict bacterial meningitis by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios, and area under the receiver operating curve (AUC) at different cutoff values for each parameter. We performed subgroup analysis excluding infants treated with antibiotics the day before CSF culture collection. RESULTS: Of the 20 756 infants that met the study inclusion criteria, 320 (2%) were diagnosed with bacterial meningitis. We found (AUC [95% CI]) CSF WBC count (0.76 [0.73-0.79]), CSF neutrophil count (0.74 [0.70-0.78]), and CSF neutrophil percent (0.71 [0.67-0.75]) had the highest predictive values for bacterial meningitis, even when excluding infants with early antibiotic administration. CONCLUSIONS: No single clinical prediction rule had the optimal discriminatory power for predicting culture-proven bacterial meningitis, and clinicians should be cautious when interpreting CSF WBC parameters in infants with suspected meningitis.

Late-Onset Sepsis Evaluation and Empiric Therapy in Extremely Low Gestational Age Newborns.

BACKGROUND: Little is known about late-onset sepsis (LOS) evaluations in extremely low gestational age newborns (ELGANs). We describe frequencies of LOS evaluation in ELGANs, infant characteristics, and empiric therapy choices during evaluations. METHODS: Cohort study of infants 22-28 weeks gestational age (GA) discharged from 243 centers from 2009 to 2018, excluding infants with congenital anomalies, discharged or deceased prior to postnatal day (PND) 2, or admitted after PND 2. A new LOS evaluation was defined as the first blood culture obtained between PND 3 and 90, or one obtained ≥1 day following a negative culture and ≥10 days from prior positive cultures. We determined numbers of evaluations and percentage positive by GA, center, and over time. We described characteristics associated with positive evaluations, infants with LOS, and empiric antimicrobials. We calculated descriptive and comparative statistics using Wilcoxon rank sum, Fisher's exact, or Pearson chi-square tests, as appropriate. RESULTS: Of 47,187 included infants, 67% had ≥1 LOS evaluation and 21% of evaluated infants had ≥1 LOS (culture positive) episode; 1.6 evaluations occurred per infant and 10% were positive. The percentage of infants evaluated and positive for LOS was higher at earlier GA. LOS was associated with inotrope support (15% vs. 9%; p < .001) and invasive mechanical ventilation (66% vs. 51%; p < .001). Infants with positive cultures were more likely than infants with negative cultures to receive empiric antimicrobials during the LOS evaluation (95% vs. 73%; p < .001). CONCLUSIONS: Among ELGANs, earlier GA and postnatal age were associated with LOS evaluation and positive cultures. Most infants undergoing evaluation were started on empiric antimicrobials.

Association Between Hypoglycemia and the Occurrence of Early Onset Sepsis in Premature Infants.

BACKGROUND: We examined the association between hypoglycemia and the occurrence of early onset sepsis (EOS) in premature infants admitted to the neonatal intensive care unit (NICU). METHODS: We included infants discharged from 358 NICUs between 1997 and 2020 with gestational age <34 weeks, ≥1 culture collected in the first 3 days of life, and ≥1 serum glucose value recorded on the day of or day prior to culture collection. We used multivariable logistic regression and inverse probability weighting (IPW) and constructed models for three definitions of hypoglycemia: American Academy of Pediatrics (AAP), Pediatric Endocrine Society, and a definition based on neurodevelopmental studies. We performed subgroup analysis in EOS episodes caused by Gram-negative and Gram-positive organisms. RESULTS: Of the 62,178 infants and 64,559 cultures that met study inclusion criteria, 739 (1%) cultures were positive. The median (25th, 75th percentile) glucose value was 75 mg/dL (50, 106) on the day of or day prior to a positive culture versus 70 mg/dL (50, 95) on the day of or day prior to a negative culture. We found that hypoglycemia was not associated with the occurrence of EOS for all organisms and Gram-positive organisms, whereas there was a small but significant association between the lower AAP glucose cutoff value and EOS due to Gram-negative organisms (logistic regression: risk difference [RD] 0.24% [95% CI, 0.01-0.47]; IPW: RD 0.22% [95% CI, 0.00-0.43]). CONCLUSIONS: Hypoglycemia may be an early marker of EOS, particularly in episodes caused by Gram-negative organisms and when using a stricter definition of hypoglycemia.