Editor, We read with great interest the recent article by Chu et al.1 on the use of prophylactic esketamine to reduce postpartum depression (PPD) in primiparae undergoing elective caesarean section. The multicentre, double-blind, randomised controlled trial addresses a critical area of maternal health, and we commend the authors for their rigorous methodology. However, we wish to highlight several important considerations regarding the clinical applicability of this intervention, particularly concerning breastfeeding, postpartum recovery, and the modest nature of the observed benefit. First, while the study provides reassuring data on neonatal Apgar scores and the absence of observed short-term feeding difficulties, the potential risks associated with breastfeeding warrant further discussion. Given that the terminal half-life of esketamine is approximately 7 to 12 h in humans,2 and that the intervention included both an intravenous bolus and a 24-h patient-controlled intravenous analgesia (PCIA) infusion, the question of neonatal drug exposure through breast milk is clinically significant. Although the authors monitored infants for 72 h postdelivery for overt adverse events, the absence of formal pharmacokinetic data on esketamine concentrations in breast milk represents a substantial gap in our understanding of neonatal safety. Without such data, clinicians cannot provide evidence-based guidance on whether to temporarily withhold breastfeeding, ‘pump and dump’, or proceed with caution. We recommend that future studies prioritise breast milk sampling to quantify infant exposure and establish clear, evidence-based recommendations for breastfeeding women, thereby enabling truly informed shared decision-making. Second, the central nervous system adverse effects observed present dual challenges for both postpartum and postoperative recovery.3–4 In the current trial, nearly one-third (31.7%) of patients in the esketamine group experienced such effects, with dizziness (10.98% intra-operatively, 12.80% at 24 h), hallucinations (10.37%) and dissociation (5.49%) all significantly more common than in the control group. While the authors correctly note that these symptoms were predominantly mild and self-limiting, their impact on a new mother's ability to ambulate safely and care for her newborn infant in the immediate postpartum period should not be underestimated. Early mobilisation is a cornerstone of enhanced recovery, and symptoms such as dizziness may increase the risk of falls or impair a mother's confidence in handling her baby.5 Notably, these findings are consistent with another recent study,6 which reported an even higher overall incidence of neuropsychiatric adverse events (45.1%) in parturients receiving esketamine, suggesting that the true burden of these symptoms may be underappreciated. We believe a more detailed discussion of how these side effects affected early postpartum functioning, mobility and maternal-infant bonding would add valuable context for clinicians weighing the risks and benefits. These concerns are amplified by the findings of the IMPAKT ERAS trial,7 which evaluated ketamine in 1522 patients undergoing major abdominal surgery within an established ERAS protocol. That study found that patients receiving ketamine experienced significantly higher odds of ICU transfer [odds ratio (OR) 2.03; 95% confidence interval (CI) 1.14 to 3.63) and lower odds of meeting early discharge milestones (OR 0.68; 95% CI 0.50 to 0.93). Furthermore, ketamine was associated with significantly higher rates of debilitating dizziness (OR 6.05; 95% CI 3.02 to 12.11), debilitating hallucinations (OR 2.69; 95% CI 1.09 to 6.65), and other severe side-effects (OR 1.94; 95% CI 1.27 to 2.96). Although the IMPAKT trial studied ketamine rather than esketamine, and in a different surgical population, the consistency of the signal – particularly the high rates of central nervous system adverse effects and their impact on recovery – suggests that the risks observed in the current trial may be more consequential than the authors suggest. If even a fraction of the 31.7% of patients experiencing central nervous system effects in this study had outcomes comparable to those in the IMPAKT trial (such as delayed discharge or higher levels of care), the net benefit of esketamine prophylaxis could be substantially diminished. Third, we wish to explore the clinical meaningfulness of the primary outcome more deeply. While the reduction in PPD incidence at 7 days (4.89% vs. 15.19%) is statistically significant and suggests a tangible group-level benefit, this must be balanced against the intervention's impact on recovery. The authors acknowledge that the use of PCIA conflicts with Enhanced Recovery After Caesarean (ERAC) principles, potentially delaying ambulation and return to normal function. When a modest symptomatic benefit is coupled with a deviation from evidence-based recovery pathways and a measurable increase in central nervous system adverse events, the overall risk-benefit calculus for routine prophylaxis in low-risk women becomes complex. Finally, we strongly support the authors’ call for future research to optimise the route, dosage, and duration of esketamine administration. Given that the current PCIA regimen deviates from evidence-based analgesic standards, we agree that future studies should investigate the use of esketamine combined with neuraxial opioids. Such a design would align with ERAC principles while potentially preserving the prophylactic benefit against PPD. These studies should also incorporate formal assessments of postpartum function, maternal–infant interaction, and breast milk pharmacokinetics to provide a more complete picture of the intervention's risk–benefit profile.
Du et al. (Wed,) studied this question.