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Background: Among opioid-exposed infants, psychiatric medication co-exposure is common. Our objective was to compare Neonatal Abstinence Syndrome (NAS) outcomes based on individual psychiatric medication co-exposures.Methods: A retrospective study of 744 opioid-exposed mother-infant dyads from a single institution was performed. Mothers on pharmacotherapy with methadone or buprenorphine at delivery were included. Data were collected on maternal demographics, psychiatric medication use, and NAS outcomes, including any medication treatment, adjunctive medication treatment, length of hospital stay (LOS), and opioid treatment days. The extent to which individual psychiatric medication and polypharmacy exposure were associated with NAS outcomes was assessed using multivariable regression.Results: Fifty-four percent of the mothers were on ≥1 psychiatric medication, with 32% on ≥2 or psychiatric medications (polypharmacy group). In adjusted models, polypharmacy exposure was associated with longer LOS (β = 4.31 days, 95% CI 2.55-6.06) and opioid treatment days (β = 3.98 days, 95% CI 2.24-5.72) and more treatment with adjunctive medication for NAS (aOR = 2.49, 95% CI 1.57-3.95). Benzodiazepines were associated with longer LOS (β = 4.94, 95% CI 2.86-7.03) and opioid treatment days (β = 4.86, 95% CI 2.61-6.75), and more adjunctive medication treatment (aOR = 2.57, 95% CI 1.49-4.42). Gabapentin was associated with longer LOS (β = 2.79, 95% CI 0.54-5.03), more NAS medication treatment (aOR = 2.96, 95% CI 1.18-7.42) including more adjunctive medications (aOR = 1.92, 95% CI 1.05-3.53).Conclusion: For infants of mothers with OUD who are also on concurrent psychiatric medications, polypharmacy was associated with worse NAS severity. When medically indicated, limiting use of multiple psychiatric medications, particularly benzodiazepines and gabapentin, during pregnancy should be considered to improve NAS outcomes. [ABSTRACT FROM AUTHOR]