By Sara B. DeMauro, MD, MSCE, Program Director, Neonatal Follow-Up Program

Sara B. DeMauro, MD, MSCE Sara B. DeMauro, MD, MSCE, Program Director, Neonatal Follow-Up Program Investigators in CHOP’s Division of Neonatology have a robust portfolio of active clinical research in diverse patient populations, including preterm infants, infants exposed to opioids in utero, infants with chronic lung disease, and children who are considered high risk for longer-term disabilities because of prematurity or neonatal illness. We are well-funded by both the National Institutes of Health (NIH) and private foundations. We take extreme pride in being able to offer our patients and their families the opportunity to participate in this exciting research, and we are hopeful that this work will continue to yield important insights into the optimal care of infants and young children.

Chronic Lung Disease

Inhaled Tobramycin • PI: Erik Jensen, MD, MSCE

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity, is a leading pediatric cause of lifelong disability and early death among very preterm infants. Strikingly, there are no drug therapies shown to improve outcomes for infants with BPD. Our research seeks to resolve this care gap.

An abundance of data support a causal link between pathologic microbial invasion of the lower respiratory tract (LRT) and worsening of respiratory health in chronic lung illness. Our work, and others’, has shown that the presence of pathogenic Gram-negative rod (GNR) bacteria in the lungs of ventilator dependent very preterm infants with BPD is an independent risk factor for significant and enduring respiratory morbidity. Systemically administered antibiotics do not adequately penetrate the lung epithelial lining fluid to eradicate these bacteria. In contrast, inhaled antibiotics deliver drug directly to the site of infection, offering a safer and more effective alternative. Inhaled tobramycin is an antibiotic with proven efficacy in other chronic respiratory illnesses complicated by GNR infection of the LRT. However, inhaled tobramycin is only FDA approved for use in patients 6 years and older.

The purpose of this phase 1 trial of inhaled tobramycin is to establish the preliminary dose tolerability, efficacy, and pharmacokinetic data required to design and conduct the first randomized, placebo-controlled trial of this promising drug therapy in infants with BPD. This study is poised to identify the first drug therapy that improves long-term outcomes in this under-studied disease.

Opioid Exposed Infants

Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) 

Newborns exposed to opioids in the womb are at risk for neonatal opioid withdrawal syndrome (NOWS) or neonatal abstinence syndrome. NOWS symptoms can include tremors; excessive crying and irritability; and problems with sleeping, feeding, and breathing. The incidence of NOWS in the United States has increased more than five-fold since 2004 to almost 7 per 1,000 hospital births. Little is known about the long-term effects of this condition, and there are few standard, evidence-based treatments for NOWS.

The Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Longitudinal Study — also known as the Outcomes of Babies with Opioid Exposure Study (OBOE) — is a longitudinal cohort study that aims to quantify the effects of antenatal opioid exposure and NOWS on the trajectory of brain development over the first two years of life, examine associations with developmental and neurobehavioral outcomes, and explore how specific factors (differing antenatal and postnatal exposures, severity of neonatal opioid withdrawal, maternal stress/depression/parenting) modify these effects. The study will also identify risk factors for adverse sequelae to optimize neurodevelopmental, behavioral, and family outcomes.


Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants • PI: Eric C. Eichenwald, MD

The goal of this dose-finding randomized clinical trial was to determine if cycled phototherapy can control total serum bilirubin levels while reducing phototherapy exposure to potentially avoid increased mortality with continuous phototherapy among extremely low-birth-weight newborns. The study — which was published in April 2020 — found that cycled phototherapy (≥15 min/h titrated to total serum bilirubin level) substantially decreased mean phototherapy hours (34 vs. 72) with a minimally higher mean peak total serum bilirubin level (7.1 vs 6.4 mg/dL), similar mean brainstem auditory-evoked response, mean wave V latency (7.42 vs 7.32 milliseconds), and fewer deaths (10.2% vs 13.4%). A large, randomized trial is now needed to assess whether cycled phototherapy would increase survival and survival without impairment in small, preterm infants.

NICU Antibiotics and Outcomes Trial • Site PI: Karen M. Puopolo, MD, PhD

The Division of Neonatology will soon be recruiting for the NICU Antibiotics and Outcomes (NANO) Trial, the first randomized, multi-center study to address the practice of universal empiric administration of intravenous antibiotics to extremely low gestation infants. Because intra-amniotic infection is believed to prompt as many as two-thirds of preterm births, such infants commonly receive antibiotics immediately after birth and often for prolonged periods thereafter, even in the absence of microbiologically-confirmed infection. Early antibiotic exposures are increasingly linked to poor long-term outcomes among preterm infants.

The NANO Trial is funded by the National Institutes of Health (NIH) and seeks to enroll 800 infants born ≤28 weeks gestation in a blinded, placebo-controlled multicenter randomized clinical trial of empiric antibiotics. The aims of the study are to determine if the composite incidence of late-onset infection, necrotizing enterocolitis or death in infants that receive empiric antibiotics is significantly different than the incidence among infants that receive placebo, as well as to determine if the content of the intestinal microbiome differs among these infants. The results from this study may validate current clinical practice patterns regarding antibiotic administration, or they may provide a critical rationale for further reducing antibiotic usage in the NICU.

Early School-age Outcomes

Hydrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study • PI: Sara B. DeMauro, MD, MSCE

Bronchopulmonary dysplasia (BPD) affects up to half of extremely preterm infants, and is associated with significant adverse respiratory, developmental, educational, and health economic outcomes. The Hydrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study builds on the NICHD Neonatal Research Network (NRN) Hydrocortisone for BPD Trial to characterize the functional respiratory and developmental outcomes of this established trial population at 5 years corrected age, or early school age. Functional assessments, which cannot be performed before early school age, provide parents and schools with a realistic picture of a child’s strengths and challenges in everyday scenarios, so that appropriate services can be provided to prevent school failure.

This study addresses several critical knowledge gaps about the early school-age outcomes of children with neonatal respiratory failure, based on both the severity of BPD and exposure to HC, as well as the relationships between respiratory and developmental outcomes. These results will have immediate impact on counseling of parents in the neonatal intensive care unit and management of neonates in the unit and after discharge. In addition, these data will be essential for the development of future intervention studies aimed to improve the long-term outcomes of preterm infants with respiratory failure.

Transfusion of Prematures (TOP) Trial • PI: Sara B. DeMauro, MD, MSCE

Up to 95% of premature infants undergo red blood cell (RBC) transfusion while in the intensive care unit, yet it is unknown whether more restrictive or more liberal transfusions will lead to optimal brain development. The Transfusion of Prematures (TOP) Trial is a multi-center study funded by the NHLBI and supported by the NICHD Neonatal Research Network (NRN). The primary objective of the TOP Trial is to assess survival and rates of neurodevelopmental impairment at 22-26 months corrected age in extremely low birth weight (ELBW) infants that are randomized to either liberal or restrictive RBC transfusion thresholds. The trial began enrollment in December 2012, reached the target sample size of 1,824 infants on time in April 2017, and completed two-year follow-up of >93% of participants in February 2020.

Although major deficits in motor and cognitive function may be detected at 22-26 months of age, these infants are too young to assess cognitive, behavioral, and coordination skills that, if impaired, can lead to problems with academic skills, motor performance or adaptive functioning in home or school environments, conditions that are far more prevalent in this population and create substantial morbidity for the children and their families. The TOP 5 Study will assess functional neurodevelopmental outcomes of infants randomized to two different transfusion thresholds in the TOP Trial at 5 years corrected age and provide evidence about which approach to neonatal transfusion (liberal or restrictive) minimizes damage to vulnerable neuronal circuits and, in turn, which transfusion strategy will improve both short and long-term outcomes for these vulnerable premature infants.