Pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants.

BACKGROUND: New drugs to target different pathways in pulmonary hypertension has resulted in increased combination therapy, but details of this use in infants are not well described. In this large multicenter database study, we describe the pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants. METHODS: We identified inborn infants discharged home from a Pediatrix neonatal ICU from 1997 to 2020 exposed to inhaled nitric oxide, sildenafil, epoprostenol, or bosentan for greater than two consecutive days. We compared clinical variables and drug utilisation between infants receiving simultaneous combination and monotherapy. We reported each combination's frequency, timing, and duration and graphically represented drug use over time. RESULTS: Of the 7681 infants that met inclusion criteria, 664 (9%) received combination therapy. These infants had a lower median gestational age and birth weight, were more likely to have cardiac and pulmonary anomalies, receive cardiorespiratory support, and had higher in-hospital mortality than those receiving monotherapy. Inhaled nitric oxide and sildenafil were most frequently used, and utilisation of combination and monotherapy for all drugs increased over time. Inhaled nitric oxide and epoprostenol were used in infants with a higher gestational age, earlier postnatal age, and shorter duration than sildenafil and bosentan. Dual therapy with inhaled nitric oxide and sildenafil was the most common combination therapy. CONCLUSION: Our study revealed an increased use of combination pulmonary vasodilator therapy, favouring inhaled nitric oxide and sildenafil, yet with considerable practice variation. Further research is needed to determine the optimal combination, sequence, dosing, and disease-specific indications for combination therapy.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Mortality Risk Factors among Infants Receiving Dialysis in the Neonatal Intensive Care Unit.

OBJECTIVES: To identify risk factors associated with mortality for infants receiving dialysis in the neonatal intensive care unit (NICU). STUDY DESIGN: In this retrospective cohort study, we extracted data from the Pediatrix Clinical Data Warehouse on all infants who received dialysis in the NICU from 1999 to 2018. Using a Cox proportional hazards model with robust SEs we estimated the mortality hazard ratios associated with demographics, birth details, medical complications, and treatment exposures. RESULTS: We identified 273 infants who received dialysis. Median gestational age at birth was 35 weeks (interquartile values 33-37), median birth weight was 2570 g (2000-3084), 8% were small for gestational age, 41% white, and 72% male. Over one-half of the infants (59%) had a kidney anomaly; 71 (26%) infants died before NICU hospital discharge. Factors associated with increased risk of dying after dialysis initiation included lack of kidney anomalies, Black race, gestational age of <32 weeks, necrotizing enterocolitis, dialysis within 7 days of life, and receipt of paralytics or vasopressors (all P < .05). CONCLUSION: In this cohort of infants who received dialysis in the NICU over 2 decades, more than 70% of infants survived. The probability of death was greater among infants without a history of a kidney anomaly and those with risk factors consistent with greater severity of illness at dialysis initiation.

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018.

OBJECTIVE: To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. STUDY DESIGN: We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. RESULTS: The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin. CONCLUSION: Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

Developing lay summaries and thank you notes in paediatric pragmatic clinical trials.

INTRODUCTION: Better transparency of research results and participant engagement may help address poor participant accrual in paediatric clinical research. We conducted formative research to assess the acceptability of lay summaries and thank you notes, as well as to refine and expand guidance on participant and family engagement in Pediatric Trials Network's (PTN) pragmatic paediatric clinical research. METHODS: Informed by draft PTN guidance, we conducted in-depth qualitative interviews with adolescent clinical trial participants and caregivers of paediatric participants in four trials conducted by PTN across eight sites. Participants were shown multiple versions of mock lay summaries and thank you notes and asked questions on their preferences for content and layout, and on trial communications. We used applied thematic analysis to analyse the data. RESULTS: We interviewed 27 individuals engaged in PTN research: 24 caregivers and 3 adolescents. During a trial, participants want regular updates on study progress, reminders of the study purpose and reassurances of data confidentiality. After the trial, participants want to learn the aggregated results, particularly medication effectiveness. Participants reported that lay summaries should include a review of the study's purpose, methods and length, and that they expect to learn individual-level results. Participants stated that thank you notes must be of sufficient length to be meaningful. CONCLUSIONS: This is the first study to describe stakeholder preferences for thank you note content and layout. Using these findings, we finalized PTN's trial communication guidance for use in future PTN trials. Research is needed to determine the effect of lay summaries and thank you notes on improving public transparency regarding clinical trials and paediatric trial recruitment and completion. PATIENT OR PUBLIC CONTRIBUTION: By design, stakeholders (adolescent trial participants and caregivers of pediatric trial participants) contributed to PTN's guidance on the content and layout of lay summaries and thank you notes through their participation in the in-depth interviews.

Association between Nephrotoxic Drug Combinations and Acute Kidney Injury in the Neonatal Intensive Care Unit.

OBJECTIVE: To determine the incidence of acute kidney injury (AKI) in infants exposed to nephrotoxic drug combinations admitted to 268 neonatal intensive care units managed by the Pediatrix Medical Group. STUDY DESIGN: We included infants born at 22-36 weeks gestational age, ≤120 days postnatal age, exposed to nephrotoxic drug combinations, with serum creatinine measurements available, and discharged between 2007 and 2016. To identify risk factors associated with a serum creatinine definition of AKI based on the Kidney Disease: Improving Global Outcomes criteria, we performed multivariable logistic and Cox regression adjusting for gestational age, sex, birth weight, postnatal age, race/ethnicity, sepsis, respiratory distress syndrome, baseline serum creatinine, and duration of combination drug exposure. The adjusted odds of AKI were determined relative to gentamicin + indomethacin for the following nephrotoxic drug combinations: chlorothiazide + ibuprofen; chlorothiazide + indomethacin; furosemide + gentamicin; furosemide + ibuprofen; furosemide + tobramycin; ibuprofen + spironolactone; and vancomycin + piperacillin-tazobactam. RESULTS: Among 8286 included infants, 1384 (17%) experienced AKI. On multivariable analysis, sepsis, lower baseline creatinine, and duration of combination therapy were associated with increased odds of AKI. Furosemide + tobramycin and vancomycin + piperacillin-tazobactam were associated with a decreased risk of AKI relative to gentamicin + indomethacin in both the multivariable and Cox regression models. CONCLUSIONS: In this cohort, infants receiving longer durations of nephrotoxic combination therapy had an increased odds of developing AKI.

Impact of COVID-19-related School Closures on the Drivers of Child Health.

The COVID-19 pandemic resulted in large-scale school closures in an effort to reduce the spread of disease. This article reviews the potential impact of COVID-19-related school closures on the health of children in North Carolina, with particular attention to the impact of school closures on drivers of child health.

Probiotic Use and Safety in the Neonatal Intensive Care Unit: A Matched Cohort Study.

OBJECTIVE: To determine the prevalence of probiotic administration in infants born preterm over time, as well as the association between probiotic administration and select adverse outcomes. STUDY DESIGN: We performed a multicenter cohort study of infants 23-29 weeks of gestational age admitted to 289 neonatal intensive care units from 1997 to 2016. We evaluated the type of probiotics given and prevalence of exposure to probiotics over time and by site. We matched infants exposed to probiotics by several factors to unexposed infants receiving enteral feeds on the same postnatal day. We performed conditional logistic regression to evaluate the association between probiotics exposure and adverse outcomes, including necrotizing enterocolitis (NEC), bloodstream infections, meningitis, and death. RESULTS: Of 78 076 infants, 3626 (4.6%) received probiotics. Probiotic use increased over the study period and varied among neonatal intensive care units. We matched 2178 infants exposed to probiotics to 33 807 without exposure. Probiotic administration was associated with a decrease in NEC (OR 0.62, 95% CI 0.48-0.80) and death (OR 0.52, 95% CI 0.39-0.70), an increase in Candida infection (OR 2.23, 95% CI 1.29-3.85), but no increase in bloodstream infection (OR 0.86, 95% CI 0.70-1.05) or meningitis (OR 1.18, 95% CI 0.40-3.46). CONCLUSIONS: Probiotic use increased over time and was associated with decreased odds of NEC and death. Prospective, randomized-controlled studies of specific probiotic products are needed to further investigate the safety and efficacy of probiotics in preterm infants.

Development of a Prospective Real-World Data Clinical Registry of Children and Adolescents With Migraine.

OBJECTIVE: To develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real-world data of sufficient quality to support regulatory submissions and provide site-based infrastructure support for future clinical trials. BACKGROUND: As new migraine treatments come to market, pediatric efficacy and safety trials of these agents are needed. A clinical registry is an ideal regulatory strategy to provide both real-world data and site infrastructure to execute these trials. DESIGN: Multicenter, multistakeholder, prospective real-world data clinical registry of children and adolescents, 4-17 years of age, diagnosed with migraine with or without aura. Participants will be followed for up to 12 months at 3-month intervals, with interval recording of clinical data at study sites and self-reported data via mobile health application, as well as biobanking. We developed electronic case report forms that incorporated routinely collected clinical data with National Institute of Neurological Disorders and Stroke Headache Common Data Elements (Version 2.0). All data are captured in a 21 CFR Part 11 - compliant electronic data capture system - augmented by a real-time, web-based, and customizable data visualization platform. We engaged vendors to provide ancillary biobanking, patient data entry, and data visualization services. RESULTS: We used an iterative and highly collaborative multistakeholder approach to design and implement a streamlined registry protocol with input from all participating US sites. At each design and implementation step, we received input from therapeutic area experts, the US Food and Drug Administration (FDA), the National Institutes of Health, patient and parent advocates, health technology partners, drug developers, and site-based clinical investigators. The registry is governed by a multistakeholder steering committee with representation from sites, industry partners, patient advocates, and a member from the FDA (non-voting with respect to steering committee matters). The multistakeholder and site-driven approach to registry design and execution was highly efficient and resulted in the first patient enrolled within 6 months of concept development. CONCLUSIONS: By ensuring regulatory compliant implementation of the registry, we created both a source of real-world data and a multisite platform for the conduct of future clinical trials that can be submitted to regulatory authorities to support inclusion of pediatric data in approved drug labeling. A highly collaborative approach with broad stakeholder engagement at all stages of the registry development was a key to our operational success.

Rifampin Pharmacokinetics and Safety in Preterm and Term Infants.

Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach. Rifampin PK was best characterized by a one-compartment model; drug clearance increased with increasing size (body weight) and maturation (PNA). There were no adverse events related to rifampin. Simulated weight and PNA-based intravenous dosing regimens administered once daily (<14 days PNA, 8 mg/kg; ≥14 days PNA, 15 mg/kg) in infants resulted in comparable exposures to adults receiving therapeutic doses of rifampin against staphylococcal infections and TB. (This study has been registered at ClinicalTrials.gov under identifier NCT01728363.).

Amphotericin B Penetrates into the Central Nervous System Through Focal Disruption of the Blood Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis.

Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 µg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.

Furosemide Exposure and Prevention of Bronchopulmonary Dysplasia in Premature Infants.

OBJECTIVE: To evaluate the association between furosemide exposure and risk of bronchopulmonary dysplasia (BPD). STUDY DESIGN: This retrospective cohort study included infants (2004-2015) born at 23-29 weeks gestational age and 501-1249 g birth weight. We compared the demographic and clinical characteristics of infants exposed and not exposed to furosemide between postnatal day 7 and 36 weeks postmenstrual age. We examined the association between furosemide exposure and 2 outcomes: BPD and BPD or death. We performed multivariable probit regression models that included demographic and clinical variables in addition to 2 instrumental variables: furosemide exposure by discharge year, and furosemide exposure by site. RESULTS: Of 37 693 included infants, 19 235 (51%) were exposed to furosemide; these infants were more premature and had higher respiratory support. Of 33 760 infants who survived to BPD evaluation, 15 954 (47%) had BPD. An increase in the proportion of furosemide exposure days by 10 percentage points was associated with a decrease in both the incidence of BPD (4.6 percentage points; P = .001), and BPD or death (3.7 percentage points; P = .01). CONCLUSIONS: More days of furosemide exposure between postnatal day 7 and 36 weeks was associated with decreased risk of BPD and a combined outcome of BPD or death.

Pharmacokinetics of ticarcillin-clavulanate in premature infants.

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6-44 days) and gestational age of 25 weeks (23-28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043-0.075]) compared with a PNA ≥14-45 days (0.078 L/kg/h [0.047-0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14-45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 µ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 µg/mL), increased dosing frequency or extended infusion are necessary.

Neonatal Therapeutics: Considerations for Dosing.

Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures to drugs that lack adequate data on safety, efficacy, and appropriate dosing in this population. Key physiologic differences between neonates and older children and adults affect drug absorption, distribution, metabolism, and elimination. Adequate understanding and consideration of these differences is essential to ensure optimal dosing of therapeutic agents in this vulnerable population. Moreover, direct study of neonates through appropriately designed pharmacokinetic and pharmacodynamic studies can ensure the development of safe and effective therapeutics in our youngest populations of patients.

Population Pharmacokinetics and Safety of Solithromycin following Intravenous and Oral Administration in Infants, Children, and Adolescents.

Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n = 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.).

Effect of fluconazole prophylaxis on Candida fluconazole susceptibility in premature infants.

Objectives: Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole-resistant Candida species. Methods: We evaluated the susceptibility to fluconazole of Candida isolates from premature infants (<750 g birth weight) enrolled in a multicentre, randomized, placebo-controlled trial of fluconazole prophylaxis. Candida species were isolated through surveillance cultures at baseline (study day 0-7), period 1 (study day 8-28) and period 2 (study day 29-49). Fluconazole MICs were determined for all Candida isolates. Results: Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P < 0.001) and 2 (3% versus 27%; P < 0.001). After the baseline period, two infants (1%) were colonized with at least one fluconazole-resistant Candida in each group. Median fluconazole MIC was similar in both treatment groups at baseline and period 1. However, in period 2, median MIC was higher in the fluconazole group compared with placebo (1.00 versus 0.50 mg/L, P = 0.01). There was no emergence of resistance observed and no patients developed invasive candidiasis with a resistant Candida isolate. Conclusions: Fluconazole prophylaxis decreased Candida albicans and 'non-albicans' Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.

Morphine vs Methadone Treatment for Infants with Neonatal Abstinence Syndrome.

OBJECTIVE: To estimate the relationship of initial pharmacotherapy with methadone or morphine and length of stay (LOS) in infants with neonatal abstinence syndrome (NAS) admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: From the Pediatrix Clinical Data Warehouse database, we identified all infants born at ≥36 weeks of gestation between 2011 and 2015 who were diagnosed with NAS (International Classification of Diseases, Ninth Revision code 779.5) and treated with methadone or morphine in the first 7 days of life. We used multivariable Cox proportional hazards regression analysis to quantify the association between initial treatment and LOS after adjusting for maternal age, maternal race/ethnicity, maternal drug use, maternal smoking, gestational age, small for gestational age status, inborn status, and discharge year. RESULTS: We identified a total of 7667 eligible infants, including 1187 treated with methadone (15%) and 6480 treated with morphine (85%). Birth weight, gestational age, and sex were similar in the 2 groups. Methadone treatment was associated with a 22% shorter median LOS (18 days [IQR, 11-30 days] vs 23 days [IQR, 16-33]; P < .001) and a 19% shorter median NICU stay (17 days [IQR, 10-29 days] vs 21 days [IQR, 14-36 days]; P < .001). After adjustment, methadone was associated with a shorter LOS (hazard ratio for discharge, 1.24; 95% CI, 1.11-1.37; P < .001) CONCLUSION: Among infants born at ≥36 weeks of gestation with NAS, initial methadone treatment was associated with a shorter LOS compared with morphine treatment. Future prospective comparative effectiveness trials to treat infants with NAS are needed to verify this observation.

Predictors of Prolonged Breast Milk Provision to Very Low Birth Weight Infants.

OBJECTIVE: To identify factors associated with prolonged maternal breast milk (BM) provision in very low birth weight (VLBW) infants. STUDY DESIGN: This was a cohort study of VLBW infants who initially received maternal BM and were born at one of 197 neonatal intensive care units managed by the Pediatrix Medical Group from 2010 to 2012. We used multivariable logistic regression to identify demographic, clinical, and maternal factors associated with provision of maternal BM on day of life (DOL) 30 and at discharge. RESULTS: Median gestational age for all infants was 28 weeks (25th, 75th percentiles: 26, 30), and median maternal age was 28 years (23, 33). Of 8806 infants, 6261 (71%) received maternal BM on DOL 30, and 4003 of 8097 (49%) received maternal BM at discharge to home. Predictors of maternal BM provision at DOL 30 included increased maternal age, white maternal race, absence of history of necrotizing enterocolitis or late-onset sepsis, higher household income, lower education level, lack of donor BM exposure, and lower gestational age. CONCLUSIONS: Our results suggest that maternal-infant demographic and clinical factors and household neighborhood socioeconomic characteristics were associated with provision of maternal BM at 30 postnatal days to VLBW infants. Identification of these factors allows providers to anticipate mothers' needs and develop tailored interventions designed to improve rates of prolonged maternal BM provision and infant outcomes.

Association of Atrial Septal Defects and Bronchopulmonary Dysplasia in Premature Infants.

OBJECTIVE: To evaluate the association between the presence of an atrial septal defect (ASD) and the odds of developing bronchopulmonary dysplasia (BPD) in premature infants. STUDY DESIGN: We identified a cohort of infants that underwent at least one echocardiogram assessment, birth weight 501-1249 g, and gestational age 23-30 weeks discharged from the neonatal intensive care unit from 2004 to 2016. We used a BPD risk estimator to calculate the predicted risk of developing BPD at 6 postnatal ages within the first 28 days of life. We examined the association between the presence of an ASD and the development of BPD using 2 multivariable logistic regression models for each BPD risk severity on each postnatal day. The first model adjusted for predicted BPD risk and the second added therapeutic interventions for BPD. RESULTS: Of 20 496 infants from 228 NICUs who met inclusion criteria, 8892 (43%) were diagnosed with BPD and 1314 (6%) had an ASD. BPD was present in 48% of infants with an ASD and 43% of infants without an ASD. In infants with an ASD, the OR of developing BPD was higher after adjusting for predicted risk of BPD plus therapeutic interventions, regardless of postnatal age or predicted BPD risk severity. CONCLUSIONS: The presence of an ASD was associated with an increased odds of BPD in this cohort. Future trials should consider ASD as a potentially modifiable risk factor in this vulnerable population.

Evaluation of Gentamicin Exposure in the Neonatal Intensive Care Unit and Hearing Function at Discharge.

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.