Despite growing knowledge of pregnancy‐induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence‐based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user‐driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best‐evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end‐users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose‐related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit–risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses.