Table 4.

Safety Considerations, Evidence Gaps, and Research Priorities for Peripartum Esketamine

Safety Issue or Population	Current Evidence	Evidence Source	Principal Uncertainty	Clinical Implication	Research Priority	Reference
Transient neuropsychiatric effects	Dizziness, perceptual changes, dissociation, hallucinations, or dream-like experiences have been reported more frequently after esketamine; most reported events were brief and self-limited.	Obstetric RCTs and evidence syntheses	Definitions and ascertainment varied; patient acceptability and functional impact were inconsistently assessed.	Short-term neuropsychiatric effects require observation during and immediately after administration and should be incorporated into benefit–risk assessment.	Standardized adverse-event assessment and direct comparison of bolus, infusion, and PCIA regimens.	[7–9,63,64,75–78]
Maternal hemodynamics and hypertensive disorders	Transient increases in blood pressure or heart rate may occur, although major instability was uncommon in selected trial populations.	RCTs and evidence syntheses	Women with severe pre-eclampsia, uncontrolled hypertension, or major cardiovascular disease were commonly excluded or underrepresented.	Short-term tolerability findings in selected populations cannot be generalized to severe hypertensive disorders of pregnancy.	Dedicated prospective studies or registries in hypertensive and other high-risk obstetric populations.	[7–9,63,64,75,76]
Placental transfer and fetal exposure	Ketamine crosses the placenta rapidly after intravenous administration; animal data suggest that clinically relevant S-ketamine doses may not substantially reduce uterine blood flow.	Human placental-transfer study and animal experiment	Esketamine-specific maternal–fetal pharmacokinetic data are sparse, and animal uterine-perfusion findings may not translate directly to human pregnancy.	Maternal recovery should not be used as a surrogate for negligible fetal exposure; animal findings provide mechanistic context rather than proof of fetal safety.	Paired maternal, cord-blood, and neonatal pharmacokinetic studies.	[28,30]
Short-term neonatal outcomes	Studied regimens have not consistently worsened Apgar scores, neonatal neurobehavioral measures, or NICU admission.	Obstetric RCTs and cohorts	Most studies were not powered for uncommon neonatal events and assessed only early outcomes.	Findings are reassuring for short-term tolerability but should not be interpreted as established developmental safety.	Standardized neonatal endpoints and larger multicenter safety cohorts.	[29,39,40]
Lactation exposure	Ketamine and its metabolites were detected at low and rapidly declining concentrations in breast milk; estimated relative infant doses were below 1%.	Small human pharmacokinetic studies	Few participants; limited infant plasma and clinical outcome data; findings may not apply to all esketamine regimens.	Current evidence is insufficient to define a universal fixed breastfeeding-interruption interval.	Larger lactation pharmacokinetic studies incorporating infant exposure and clinical outcomes.	[31,32]
Developmental and early-pregnancy safety	Human early-pregnancy evidence is limited to case-level observation, while animal and broader preclinical studies raise potential neurobehavioral and developmental-neurotoxicity concerns.	Case report and preclinical studies	Species, dose, exposure duration, and developmental stage differ substantially from typical low-dose peripartum regimens; long-term human offspring data are lacking.	Preclinical findings should be regarded as signals for surveillance rather than estimates of human risk; neither safety nor harm can be inferred from isolated human cases.	Pregnancy exposure registries and long-term offspring neurodevelopmental follow-up.	[88–91]
Special obstetric populations	Exploratory studies have included women with gestational diabetes, preoperative anxiety, and category-1 cesarean delivery.	Small RCTs, cohorts, or case series	Limited sample size, selection bias, and lack of replication.	Findings should not be generalized to all high-risk pregnancies.	Prespecified studies in clinically defined high-risk subgroups.	[83,92,93]
Combination regimens	Esketamine has frequently been combined with opioids, dexmedetomidine, or other analgesic agents.	RCTs	Independent efficacy and adverse effects attributable to esketamine are difficult to isolate.	Outcomes from combination regimens should not be attributed exclusively to esketamine.	Factorial or head-to-head comparative-effectiveness trials.	[33,41–43,94]

Abbreviations: NICU, neonatal intensive care unit; PCIA, patient-controlled intravenous analgesia; RCT, randomized controlled trial.