Split-dosing of Methadone During Pregnancy and Postpartum Period: A Systematic Review of Outcomes

The primary objective of this study is to conduct a systematic review of the scientific literature on the practice of methadone split-dosing, where the total daily dose is divided into 2 or more doses taken 10-12 hours apart rather than administered as a single daily dose. The review aims to evaluate the perinatal effects of this dosing regimen on maternal, fetal, and neonatal outcomes.

A systematic review was conducted by searching 6 databases, including APA PsycInfo, the Cochrane Library, CINAHL, Embase, PubMed, and Scopus, through the last search date of June 13, 2023. We included studies that reported maternal, fetal, or neonatal outcomes. Multiple researchers screened references. Data were extracted using a standardized spreadsheet, including study details and outcomes, and included studies were assessed for bias independently by 2 researchers using JBI Critical Appraisal Tools.

The systematic search yielded 612 unique references, of which 8 studies met the criteria. These studies focused on investigating the pharmacokinetics of methadone during pregnancy, fetal responses to maternal methadone administration, variables related to maternal substance use disorder treatment, and outcomes related to birth or neonatal health. The findings demonstrated significant alterations in methadone metabolism during pregnancy due to increased methadone metabolism as a result of enhanced hepatic enzyme activity (CYP3A4 and CYP2B6), resulting in lower plasma methadone levels and requiring dose adjustments. Neonatal outcomes were favorable, including higher birth weights, reduced preterm birth risk, improved intrauterine growth, and reduced neonatal abstinence syndrome (NAS).

The evidence suggests that pregnancy significantly alters methadone metabolism, subsequently impacting both maternal and neonatal outcomes. These findings demonstrate that split-dosing of methadone is associated with more favorable outcomes compared with once-daily dosing.