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Background: Despite advances in medicine, pregnancy complications including gestational diabetes mellitus (GDM), pre-eclampsia, and sepsis are prevalent. The current ACOG guidelines recommend multiple drug-related interventions to improve outcomes. However, there is hesitancy by patients and providers about pharmaceutical use during pregnancy. Objective: To compare pharmacologic interventions of aspirin, azithromycin, and metformin to current guidelines and determine their efficacy in decreasing maternal and neonatal morbidity and mortality. Methods: A systemic review (SR) of peer-reviewed randomized controlled trials (RCTs) evaluated advantages in pharmaceutical treatment and prophylaxis in reduction of pregnancy-related disorders. A total of 43478 participants were in the five articles with different demographics across twelve countries for a more diverse population. Results: Aspirin was found to be beneficial in the treatment plan for pre-eclampsia. However, the addition of enoxaparin did not show benefit in lowering incidence of the condition. Metformin showed a decrease in adverse events related to pre-gestational type 2 diabetes mellitus without improving neonatal outcomes. Addition of azithromycin as prophylaxis in cesarean sections and vaginal deliveries reduced incidence of postpartum infections and sepsis. Conclusion: This research reviews the pharmacologic use of aspirin, azithromycin, and metformin during the perinatal period. Each of these pharmacologic interventions may aid in prevention and treatment of pre-eclampsia and sequelae, postpartum infections and sepsis, and diabetes mellitus to reduce maternal and neonatal morbidity and mortality. There is a need for ongoing research to study long term effects, improve strategies of treatment, and enhance maternal and neonatal health worldwide.