Target Trial Emulation for Pharmacologic Treatment of Neonatal Opioid Withdrawal Syndrome

Neonatal Opioid Withdrawal Syndrome (NOWS) occurs in infants who were exposed to opioids during pregnancy and may lead to symptoms such as irritability, feeding difficulties, and trouble sleeping. Many hospitals treat these symptoms with either morphine or buprenorphine, but it is not yet known whether one medication helps infants recover more quickly. This study aims to answer that question by reviewing information already documented in medical records from hospitals that routinely use one of these treatments.

The study will include approximately 796 infants, all born at 36 weeks' of gestation or later and treated for NOWS with either buprenorphine or morphine as part of usual clinical care. Data will be collected from about 22 hospitals across the United States. Researchers will review existing medical record information such as the infant's birth characteristics, withdrawal symptoms, details of treatment (including medication choice and dosing approach), feeding practices, non-pharmacologic care, and clinical outcomes-including the key measure of how long it took for the infant to become medically ready for discharge.

Because treatment decisions are made by the clinical team and not assigned by the study, researchers will use advanced statistical methods to compare outcomes between infants who received buprenorphine and those who received morphine. These methods allow the team to adjust for differences between infants and hospitals, helping ensure that comparisons are as fair and accurate as possible. The goal is to estimate how outcomes would differ if all infants received one medication versus the other in real-world practice.

No infants or parents will be contacted for this study, and no additional treatments, tests, or procedures will be performed. All data come from routine clinical care. The regulatory review for this project determined that informed consent from families is not required because the study uses only existing medical information and does not involve any interaction with participants or changes to medical care. All collected data will be handled securely and in compliance with federal privacy requirements.

The information learned from this research may help improve care for future infants with NOWS by providing clearer evidence on how commonly used treatments compare in supporting recovery.

• Length of hospital stay (count) [Time frame: From date of birth until date of hospital discharge (estimated to be < 90 days).]
• Length of primary opioid treatment (count) [Time frame: From date of birth until date of last primary opioid dose administration (estimated to be < 90 days).]
• Number of primary opioid doses administered (count) [Time frame: From date of birth until date of last primary opioid dose administration (estimated to be < 90 days).]
• Receipt of secondary medication (binary) [Time frame: From date of birth until date of first non-opioid secondary medication administration or until date of hospital discharge, whichever comes first (estimated to be < 90 days).]
• Inpatient composite safety outcome (binary) [Time frame: From date of birth until date of first occurrence of seizure or excessive weight loss more than 15% from birthweight or until date of last primary opioid dose administration, whichever comes first (estimated to be < 90 days).]
• Inpatient composite critical safety outcome (binary) [Time frame: From date of birth until date of first occurrence of non-accidental trauma or death or until date of last primary opioid dose administration, whichever comes first (estimated to be < 90 days).]
• Inpatient composite safety outcome after receipt of pharmacologic treatment (binary) [Time frame: From date of first primary opioid dose administration until date of first occurrence of seizure or excessive weight loss more than 15% from birthweight or until date of hospital discharge, whichever comes first (estimated to be < 90 days).]
• Inpatient composite critical safety outcome after receipt of pharmacologic treatment (binary) [Time frame: From date of first primary opioid dose administration until date of first occurrence of non-accidental trauma or death or until date of hospital discharge, whichever comes first (estimated to be < 90 days).]