Intranasal Dexmedetomidine for Postpartum Depression Prevention

1. Background Postpartum depression (PPD) is a common and serious mental health disorder affecting approximately 10% to 20% of women globally, with reported rates as high as 25% in China and up to 40% to 48% in socioeconomically disadvantaged regions. PPD typically occurs within the first few weeks to months after childbirth, with symptoms including persistent low mood, feelings of worthlessness, and suicidal ideation. PPD not only affects maternal mental health but is also a major contributor to pregnancy-related deaths, accounting for up to 68% of such cases. Furthermore, PPD negatively impacts infant emotional, cognitive, and social development, disrupts maternal-infant bonding, and increases family economic burden.

Dexmedetomidine (Dex) is a highly selective α2-adrenergic receptor agonist with sedative, anxiolytic, analgesic, and sympatholytic properties. Studies have shown that Dex can inhibit excessive norepinephrine release, reduce pro-inflammatory cytokines, increase anti-inflammatory cytokines, and upregulate brain-derived neurotrophic factor (BDNF), thereby alleviating stress and inflammatory responses and improving depressive symptoms. Numerous clinical studies have demonstrated that Dex administered during cesarean section significantly reduces the incidence of PPD. However, no studies have investigated the effect of Dex on PPD prevention in women undergoing vaginal delivery.

Intranasal administration offers advantages including rapid absorption, high bioavailability (82%), non-invasiveness, patient acceptability, and avoidance of first-pass hepatic metabolism. A previous study found that intranasal Dex (0.5 μg/kg) before labor analgesia improved epidural analgesic effects and reduced procedural pain during epidural puncture. Therefore, intranasal Dex may have potential for reducing PPD in women undergoing vaginal delivery, but high-quality clinical evidence is currently lacking. 2. Objectives Primary Objective: To evaluate the effect of intranasal dexmedetomidine administered before combined spinal-epidural labor analgesia on the incidence of PPD at 42 days postpartum in women undergoing vaginal delivery.

Secondary Objectives: To evaluate the effect of intranasal Dex on the incidence of PPD at 7 days postpartum, postpartum sleep quality, labor analgesic efficacy, safety (adverse event rates), labor characteristics, mode of delivery, and neonatal outcomes. 3. Study Design This is a prospective, randomized, double-blind, placebo-controlled, single-center superiority trial with a 1:1 allocation ratio, conducted at Chengdu Jinjiang Maternal and Child Health Hospital. 4. Intervention Participants in the experimental arm receive a single dose of intranasal dexmedetomidine 50 μg (25 μg per nostril) immediately before initiation of combined spinal-epidural labor analgesia. Participants in the comparator arm receive an equal volume of intranasal normal saline (one spray per nostril), identical in appearance, color, odor, and packaging to the active intervention. 5. Labor Analgesia Protocol After cervical dilation ≥ 1 cm, combined spinal-epidural analgesia is performed at the L3-4 interspace. Following epidural puncture, 2 mL of 0.1% ropivacaine with 0.5 μg/mL sufentanil is administered intrathecally, and an epidural catheter is advanced 3-5 cm. A test dose of 3 mL 1.5% lidocaine is injected. After 30 minutes of observation, a patient-controlled epidural analgesia pump is connected. The pump is programmed for programmed intermittent epidural bolus mode with a solution of 0.1% ropivacaine + 0.5 μg/mL sufentanil. Pump settings: pulse dose 8 mL/h, background infusion 2 mL/h, patient-controlled bolus 5 mL, lockout interval 20 minutes, maximum hourly limit 25 mL. 6. Randomization and Blinding Participants are randomized in a 1:1 ratio using a computer-generated random sequence with a block size of 4. Allocation is concealed in sequentially numbered, opaque, sealed envelopes. The attending anesthesiologist who prepares and administers the study drug is aware of group allocation (unblinded) but is not involved in any postoperative follow-up or outcome assessment. Participants, outcome assessors, data managers, and statisticians are blinded to group assignment. 7. Sample Size Calculation Based on preliminary clinical observations at the study center, the incidence of PPD at 42 days postpartum among women receiving labor analgesia for vaginal delivery is approximately 30%. The investigators hypothesize that intranasal Dex will reduce the PPD incidence by 50% relative (from 30% to 15%, an absolute reduction of 15%). Assuming a two-sided α of 0.05, power (1-β) of 0.80, and a 10% dropout rate, a sample size of 135 participants per group (270 total) is required, calculated using PASS 2023 software. 8. Statistical Analysis Statistical analysis will be performed using R software (version 4.3.1). The primary analysis will be based on the modified intention-to-treat (mITT) principle, with the mITT population defined as randomized participants who received the intranasal intervention and completed at least one postpartum follow-up. Participants who undergo intrapartum cesarean section will remain in their original groups for analysis. No imputation will be performed for missing data due to loss to follow-up; complete case analysis will be used instead.

Normality of continuous variables will be assessed using the Kolmogorov-Smirnov test. Normally distributed variables will be presented as mean ± standard deviation and analyzed using independent sample t-tests. Non-normally distributed variables will be presented as median with interquartile range and analyzed using rank-sum tests. Categorical variables will be presented as percentages and analyzed using chi-square tests or Fisher's exact tests. A P-value \< 0.05 will be considered statistically significant. 9. Ethical Consideration The study has been reviewed and approved by the Ethics Committee of Chengdu Jinjiang Maternal and Child Health Hospital (Approval Number: 202510). Written informed consent will be obtained from all participants prior to enrollment. All study procedures will strictly adhere to relevant ethical standards and regulations to safeguard participant safety and privacy. 10. Expected Outcomes The investigators anticipate that intranasal Dex administered before labor analgesia will significantly reduce the incidence of PPD in women undergoing vaginal delivery and improve maternal mental health and quality of life. Specifically, the Dex group is expected to have a significantly lower incidence of PPD compared to the control group, with superior EPDS scores at 7 and 42 days postpartum and better sleep quality. Additionally, the Dex group is expected to demonstrate better pain management during labor without significantly increased adverse events, and neonatal outcomes are expected to be comparable between groups.

• Incidence of Postpartum Depression at 7 Days Postpartum [Срок оценки: At 7 days postpartum]
• Postpartum Sleep Quality [Срок оценки: 7 days and 42 days postpartum]
• Pain Scores During Labor [Срок оценки: Before analgesia, 30 minutes, 1 hour, and 3 hours after analgesia]
• Sedation Scores During Labor [Срок оценки: Before analgesia, 30 minutes, 1 hour, and 3 hours after analgesia]
• Labor Characteristics [Срок оценки: During labor and delivery, assessed up to 24 hours]
• Duration of Labor Analgesia [Срок оценки: From initiation of analgesia to delivery or discontinuation, assessed up to 24 hours]
• Mode of Delivery [Срок оценки: At delivery, assessed on the day of delivery]
• Incidence of Bradycardia [Срок оценки: During labor and delivery, assessed up to 24 hours]
• Incidence of Hypotension [Срок оценки: During labor and delivery, assessed up to 24 hours]
• Incidence of Nausea and Vomiting [Срок оценки: During labor and delivery, assessed up to 24 hours]
• Incidence of Respiratory Depression [Срок оценки: During labor and delivery, assessed up to 24 hours]
• Incidence of Oversedation [Срок оценки: During labor and delivery, assessed up to 24 hours]