It is critical that researchers gather evidence of factors that identify infants at risk of out-of-home placement based on types of substance exposures and demographic characteristics. This study applied a validated medical record data extraction tool on data derived from a multi-site ( N = 30) pediatric clinical trials network (ISPCTN) study of Neonatal Opioid Withdrawal (ACT NOW study). Participants included 1808 birthing parent-infant dyads with documented NOWS scoring or prenatal opioid exposure. Non-Hispanic White pregnant persons comprised the largest proportion of the sample (69.8%), followed by Non-Hispanic Black (11.6%), Non-Hispanic Multiracial and Other race (8.5%), and Hispanic (6.2%). Most notably, infant prenatal substance exposure across alcohol, cocaine, meth/amphetamine, and opioids, had the lowest possibility of discharging to parent(s). Additionally, latent class analysis identified distinct classes of substance use during pregnancy that were associated with different probabilities of discharging to parent(s). Specifically, less than half of infants (47%–49%) in the Poly-use and Meth/amphetamine classes were discharged to their parent(s). Severity of infant withdrawal symptoms influenced placement decisions within the Poly-use and Prescription Opioid classes. Findings can inform standard practices for increasing support for pregnant persons and substance-exposed infants including identification, subsequent referrals, communication with Child Protective Services, and plans of safe care.