The DINE study will test the hypothesis that potentially avoidable NICU-based exposures contribute to the neuro-cognitive and somatic impairments prevalent among NICU graduates. This hypothesis is drawn from the documented impact of phthalate exposure on early development in term-born children, and the acknowledged presence of these toxic chemicals in the NICU. Third trimester in utero exposure to phthalates have been linked to poorer childhood performance in cognition, motor function, attention, hyperactivity and social behavior. Phthalate exposure is also associated with altered onset of puberty and asthma. The multi-site cohort and approach will clarify the role of NICU-based phthalate exposure on high-prevalence clinical outcomes.

Background: Each year in the United States, over 300,000 preterm infants are admitted to neonatal intensive care units (NICUs) where they are exposed to a chemical-intensive hospital environment during a developmentally vulnerable period. Many life-saving and supportive respiratory, nutritional, hematologic and pharmaceutical therapies in the NICU expose preterm infants to potentially harmful chemicals during a life stage analogous to the third trimester of gestation. The NIH-funded DINE study capitalizes on the infrastructure, biorepositories, and extensive clinical databases of four existing preterm cohorts to explore the hypothesis that early life exposure to phthalates adversely impacts neurodevelopment, lung function, growth, adiposity, and pubertal development in childhood.

The scientific premise of the DINE study is that early life exposure to phthalates, a class of chemical plasticizers ubiquitous in the NICU, has long-lasting harmful effects on child health and development, and that these harmful effects are magnified in children born preterm. This premise is based on strong evidence of multisystem adverse health effects in term-born children who are exposed to phthalates in utero during the third trimester of pregnancy or in early infancy. In preterm infants, however, rigorously obtained data on the health effects of phthalates are scant. Dermal, inhalational and intravenous exposures to phthalates are widespread in some NICUs, where preterm infants are cared for during the sensitive "third trimester" developmental window. Moreover, premature infants experience a high prevalence of the adverse health effects that are associated with early life exposures to phthalates in term-born children, including altered neurodevelopment, poor pulmonary function, and maladapted growth. A rigorous, well-designed, sufficiently powered study of NICU-based phthalate exposures and long-term health outcomes of preterm infants has the potential to change care practices, promote regulatory policy changes and lead to mitigation of phthalate exposures in the NICU.

Significance: The proposed research is expected to identify modifiable sources of developmental risk for NICU patients that can inform and improve hospital care and long-term outcome. Moreover, our findings could lead to relatively inexpensive NICU interventions, such as use of non-phthalate containing medical materials, dosing guidelines for elemental metals and guidance for parents and staff on infant stress-reduction, and policy changes (e.g. regulation of the phthalates used in medical devices or changes to the trace metal content of parenteral nutrition) with significant positive potential impacts on life-long morbidities common among NICU graduates. Information gleaned from studying our highly-exposed, highly-vulnerable population may elucidate health impacts of early life exposures that translate to risk reduction in the general population.

Inclusion Criteria:

• Children who were study participants in one of the four extant preterm cohorts (PROP, TOLSURF, NICU-HEALTH, and PENUT) that comprise the combined DINE cohort and who were followed to study endpoint at one of the clinical sites in DINE.
• Newly recruited preterm infants admitted to the NICU at the Icahn School of Medicine at Mount Sinai
• Newly recruited preterm and term infants who participated in the PRISM study at University of Rochester
• Parents agreed to be re-contacted or local Institutional Review Board (IRB) grants permission to recontact families to obtain consent to participate in DINE.

Exclusion Criteria:

• Family requested that they not be contacted after their child completed the parent study
• Family is unlikely to be available for long-term follow-up

Former preterm infants who were participants hospitalized in the NICU of one of the 8 clinical sites participating in the UH3 phase of the ECHO and DINE studies and whose parents had consented to participate in one of the 4 extent cohorts of the following NIH-supported studies: Prematurity and Respiratory Outcomes Program (PROP), the Trial of Late Surfactant (TOLSURF), the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) study and the Preterm Erythropoietin Neuroprotection Trial (PENUT) study and agreed to longitudinal follow up of infants as part of DINE

All efforts, within reason, are made to keep protected health information (PHI) private, including data gathered for research studies. Using or sharing ("disclosure") such data must follow federal privacy rules. All PHI about children in the study will be entered into REDCap, a secure, web-based data collection platform. Study patients will be identified only by a study identification (ID) number. Access to the REDCap study database is restricted to study personnel, password protected and behind a Medical Center firewall. The study child's name and medical record number will appear only on the Screening Log which contains no other PHI. Only the study team will have access to the Screening Log.