Association of Low-Dose Ketamine and Ketamine–Midazolam Administration with Postpartum Depressive Symptoms, Postoperative Pain, and Adverse Events in Cesarean Deliveries Under Spinal Anesthesia

Background and Objectives: To evaluate the associations of low-dose ketamine administered alone or with midazolam after umbilical cord clamping with postpartum depressive symptoms, postoperative pain, and intraoperative adverse events in patients undergoing cesarean delivery under spinal anesthesia. Materials and Methods: In this prospective, nonrandomized, controlled observational cohort study, 300 patients were classified into three groups according to the treatment received during routine clinical care, which was determined by their pain and anxiety status after umbilical cord clamping. Patients with pain but no anxiety received intravenous ketamine (0.5 mg/kg); those with both pain and anxiety received ketamine (0.5 mg/kg) plus midazolam (0.01 mg/kg); and those with neither received no additional medication. Each group included 100 patients. Edinburgh Postnatal Depression Scale (EPDS) scores were assessed preoperatively and at postpartum weeks 1, 2, and 4. Postoperative pain was assessed using visual analog scale (VAS) scores at 2, 4, 12, and 24 h. Time to first rescue analgesic requirement and intraoperative adverse events were recorded. Results: At postpartum week 4, EPDS scores (primary outcome) differed between groups, with lower median scores in both treatment groups than in the control group (overall comparison, p = 0.032); in models adjusted for preoperative EPDS score, both treatment groups had lower EPDS scores than the control group. Positive EPDS screening (score ≥ 11) occurred in 15% of the ketamine group, 17% of the ketamine–midazolam group, and 30% of the control group (p = 0.017). The group × time interaction for repeated EPDS scores was significant (p = 0.0055). Compared with controls, both treatment groups had lower VAS scores at 2 and 4 h and a longer time to first rescue analgesic requirement (all overall comparisons, p < 0.001); these associations persisted after adjustment for procedure duration. At 12 and 24 h, a significant pairwise difference from the control group was observed only for ketamine alone. Hallucinations occurred in 32%, 18%, and 2% of patients in the ketamine, ketamine–midazolam, and control groups, respectively (p < 0.001). Other adverse events were numerically less frequent with ketamine–midazolam than with ketamine alone, but the pairwise differences were not statistically significant. Conclusions: Low-dose ketamine administered after umbilical cord clamping, either alone or with midazolam, was associated with lower postpartum depressive symptom scores and a lower rate of positive EPDS screening in adjusted analyses, as well as lower early postoperative pain scores and a longer time to first rescue analgesic requirement. Although adverse events were numerically less frequent with ketamine–midazolam than with ketamine alone, this study did not establish a statistically significant tolerability advantage. Given the nonrandomized, symptom-based treatment selection and potential confounding by indication, these findings should be interpreted as preliminary associations that require confirmation in randomized controlled trials of efficacy and safety before clinical recommendations can be made.