ABSTRACT Neonatal Opioid Withdrawal Syndrome (NOWS) is a major public health problem in the USA. Since 2000- 2012, the incidence of NOWS has increased five-fold to almost 6 per 1,000 hospital births and the associated health care expenditures have increased from $200 million to $1.5 billion. Limited data are available on the effects of antenatal opioid exposure on the brain and neurodevelopment because of small sample sizes and difficulty controlling for important environmental variables. The OBOE (Outcomes of Babies with Opioid Exposure) study, an ongoing NICHD-funded longitudinal study enrolling infants with and without antenatal opioid exposure at birth and following them to two years of age, attempts to address these limitations by collecting comprehensive exposure data from parental report and from infant umbilical cord analysis; advanced neuroimaging data to evaluate brain development; standardized information on the home environment, maternal mental health, and parenting; and neuro- developmental outcomes to 2 years of age. The OBOE consortium, comprised of 4 highly performing clinical centers, a data coordinating center, and a neuroimaging core, has completed our goal enrollment of 200 opioid-exposed infants and 100 unexposed infants. In response to RFA-HD-24-014, we now propose to complete follow-up to age two years in our OBOE cohort to fulfill our main study objectives. The CHOP/PENN site has enrolled 46 infants (34 exposed and 12 controls), completing 53 MRIs across 2 timepoints thus far, contributing to the publication of multiple abstracts and three manuscripts using OBOE data, and developing the CONSENTER intervention to improve recruitment of exposed and control patients. For this renewal grant, we will continue progress toward our aims to: 1) determine the impact of antenatal opioid exposure on brain structure and connectivity over the first two years of life; 2) define medical, developmental, and behavioral trajectories over the first two years of life in exposed infants; and 3) determine how the home environment, maternal mental health, and parenting modify trajectories of brain connectivity and neurodevelopment over the first two years of life. Our progress so far, with enrollment completed and success in following this difficult population, shows that we can successfully complete the objectives of the OBOE study.

PROJECT NARRATIVE Children exposed to opioids antenatally can have behavioral problems, lower school achievement, and changes seen on brain MRI scans compared to unexposed children. The CHOP/PENN site is one of 4 sites to enroll 200 exposed infants and 100 unexposed controls as part of the OBOE (Outcomes of Babies with Opioid Exposure) study. As part of this RFA, we will follow this cohort to age 2 to evaluate brain structure and function, examine development and behavior, and determine the relative effects of opioid exposure versus other environmental factors on outcomes.