Neonatal Follow-Up Program: Valued Partner In Research Endeavors

By Hallam Hurt, MD, Education Director and Attending Neonatologist, Neonatal Follow-Up Program

In the midst of a busy day providing hands-on clinical care and developmental evaluations to vulnerable babies and children in our Neonatal Follow-up Program (NFP), there is another less visible but vital activity: research. Some research endeavors include real-time, specific, hands-on assessments by medical providers and developmental psychologists. Other endeavors rely remotely on data generated during NFP visits. Yet others capitalize on the steady stream of patients coming through our doors to recruit families into studies that are conducted elsewhere. While the NFP often is the silent partner in these endeavors, NFP involvement is crucial to provision of meaningful data. Here, to highlight the broad portfolio of research to which the NFP is integral, we describe several ongoing or recently completed investigations.

Neonatal research network

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) is a consortium of 15 academic centers conducting research to improve the outcomes of high-risk newborns and their families. For many NRN trials, neurodevelopmental outcome at 2 to 2.5 years is utilized to determine the effect or lack of effect of certain practices. The following examples further illustrate some of the ongoing NRN research activities:

Generic Follow-up Study: This repository does not require randomization of infants to one intervention or another. Rather, it provides a unique opportunity to gather valuable data about outcomes of infants born at fewer than 27 weeks. Infants of this gestational age are followed in the NFP, with the so-called “key” visit occurring at 22 to 26.5 months corrected age. At this visit, families are consented for their child’s data to be placed in a database and no actual research is conducted. Existence of this database then enables investigators to pose questions and interrogate the database for answers.

You may wonder, if no research per se is conducted at this visit, what does happen? Meticulous, structured neurodevelopmental evaluations are carried out by certified medical and developmental examiners. Further, careful histories are documented including hospitalizations and operations post-discharge, vision and hearing outcomes, medication use, subspecialty care involvement, equipment needs, and sociodemographic data.

All the resultant data are entered into the NRN database that investigators may utilize. For example, CHOP Neonatologist Erik Jensen, MD, and his colleagues constructed a new definition of bronchopulmonary dysplasia (BPD) through evaluation of data for 2,677 infants. The definition that best predicted early childhood morbidity was mode of respiratory support at 36 weeks’ postmenstrual age regardless of supplemental oxygen use. This definition is increasingly used by clinicians and researchers around the world; for example, the Vermont Oxford Network now uses this definition. (Jensen et al; AJRCCM 2019)

• Darbepoetin Trial to Improve Red Cell Mass and Neuroprotection of Preterm Infants (DARBE): In this trial, infants born before 29 weeks were randomized to receive darbepoetin or placebo. Neurodevelopmental follow-up was recently completed, and final analyses are underway.
• Patent Ductus Arteriosus (PDA) Trial: Infants are enrolled at 2 to 21 days to receive treatment or expectant management of symptomatic PDA. Enrollment is ongoing. Follow-up evaluations are conducted at 22 to 26.5 months corrected age.
• Budesonide in Babies (BiB): This is a randomized clinical trial of the use of budesonide in surfactant as compared to surfactant alone, for which follow-up again will be conducted at 22 to 26.5 months corrected age.
• Hydrocortisone for BPD Respiratory and Developmental Outcomes (HYBRID): This trial differs from the BiB trial in that it involves assessments at ages 5 to 7 years corrected age. The children being assessed were originally enrolled in the Hydrocortisone for BPD Trial described above and evaluated at 22 to 26.5 months. Evaluations at older ages are felt to confer a more accurate assessment of a child’s capabilities and provide the opportunity to evaluate functional outcomes and domains that cannot be measured at earlier ages, such as executive function and motor coordination. In addition, CHOP is one of only five centers at which the children also undergo pulmonary function testing with impulse oscillometry, a novel approach to understanding the childhood effects of both prematurity and BPD on longer-term respiratory outcomes.
• Transfusion Of Prematures at 5 Years (TOP 5): Similar to HYBRID, TOP 5 is evaluating children at 5 to 7 years corrected age. The children being assessed are those infants originally enrolled in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored TOP trial, also previously evaluated at 22 to 26.5 months corrected age. As with HYBRID, investigations conducted at later ages are felt to provide more nuanced assessment than those assessments conducted at earlier ages, along with more accurate information about whether additional supports may be necessary to help the children thrive in school.
• Eat, Sleep, Console (ESC): This study was a step-wedge study of the ESC approach to management of newborns who were exposed to opioids while in utero. In-hospital outcomes of this study were recently presented and demonstrated decreased length of stay and less pharmacologic treatment of exposed infants when the ESC management approach was used. Two-year outcome is essential for demonstrating longer-term safety of this approach.
• Outcomes of Babies with Opioid Exposure (OBOE): This is a four-center longitudinal study that enrolls infants who were exposed to opioids while in utero and control infants who were not exposed. Infants undergo serial MRIs and neurodevelopmental assessments during the first two years of life in order to examine the early childhood neuroanatomic, neurodevelopmental and behavioral impacts of opioid exposure.

Additional nfp research endeavors include:

• Pulmonary Hypoplasia Program: In this CHOP program, subjects are evaluated for medical and neurodevelopmental outcome as well as by surgical specialists who are involved. A registry accrued through these visits allows conclusions to be drawn from a large database.
• Validation of SNAKE Sleep Questionnaire for Children with Severe Psychomotor Impairment: This observational study funded by the Cerebral Palsy Foundation involves children 3 to 24 months of age either with cerebral palsy (CP) or at high risk for CP. Comparison will be made to the Brief Infant Sleep Questionnaire.
• A Positive Parent-focused Training for Upper Limb Exposure with Sensorimotor Feedback (APPLES): Infants 4 to 13 months who either have CP or are at high risk for CP and demonstrate an asymmetry of tone and function are recruited. After enrollment, subjects are randomized to either a telehealth therapy program or a parent support program with in-person evaluations at weeks 1, 6 and 12. This study is funded by the Cerebral Palsy Foundation.
• REDCap Database: At all NFP visits, data are collected, regardless of subject gestational age or whether the subject is enrolled in any investigation. These data, ranging from first visit birth history and perinatal data, to data from all subsequent visits (conducted at semi-annual or annual ages through pre-K), are transferred to CHOP’s Research Electronic Data Capture (REDCap) database. To date, there are about 30,000 such encounters. As with the NRN generic database, these data also may be interrogated to assess various outcomes or morbidities at gestational ages specific to our NFP population. Such data can be particularly helpful to the clinicians in the CHOP Newborn Care Network NICUs — which combine CHOP’s extensive resources with the experience and facilities of local hospitals — because they represent our local outcomes.
• Parent Perspectives on BPD: Sometimes parents, rather than the children themselves, are the focus of research studies conducted in the NFP. CHOP Neonatology Fellow, K.P. Callahan, MD, has recently completed recruitment into one such study. Using a discrete choice experiment, Dr. Callahan directly asked 100 parents of infants previously diagnosed with BPD what outcomes are important to them. Knowing which outcomes are most important to parents will allow researchers to prioritize these outcomes in parent counseling and in future studies.

Last word …

None of these projects could be carried out without the tremendous energy and hard work of myriad individuals (too many to name!) ranging from concept inception to the last data point entered. Further, it should be noted that these studies are not exclusively conducted at the NFP site at CHOP’s Buerger Center for Advanced Pediatric Care in Philadelphia. Other valued partners in many of these endeavors include NFP sites at Pennsylvania Hospital and Virtua. Together, we provide the essential outcomes data that will shape the future of neonatal care.