Background <p>Neuraxial analgesia is the gold standard for labor pain relief, yet procedure-related neurological symptoms may occur. Guided by the theory of neuraxial homeostasis, this study compared a sequential spinal-epidural analgesia (SSEA) technique with conventional combined spinal-epidural analgesia (CSEA) to determine whether preserving neuraxial stability was associated with a reduction in neurological symptoms and enhanced maternal satisfaction.</p> Methods <p>In this randomized trial, 740 parturients requesting labor analgesia were assigned to receive either SSEA (subarachnoid injection followed by epidural catheterization, <i>n</i> = 368) or conventional CSEA (needle-through-needle technique, <i>n</i> = 372). The primary outcome was analyzed in the intention-to-treat (ITT) population of all 740 randomized participants. For secondary outcomes assessed after delivery, 116 women who underwent cesarean section were not applicable for analyses requiring vaginal delivery, leaving 624 parturients who completed vaginal delivery (312 per group) for those specific analyses. The primary outcome was the incidence of intraprocedural neurological symptoms (radiating pain or involuntary muscle twitching during puncture). Secondary outcomes included post-procedural neurological symptoms, adverse effects, analgesic efficacy (Visual Analogue Scale [VAS] scores), analgesic quality, maternal/fetal outcomes, and maternal satisfaction (5-point Likert scale). An exploratory structural equation model (SEM) examined factors influencing satisfaction.</p> Results <p>Baseline characteristics were balanced. In the ITT analysis (<i>n</i> = 740), SSEA was associated with a significantly lower incidence of intraprocedural neurological symptoms (1.36% vs. 23.12%; risk difference [RD] − 0.218, 95% CI − 0.267 to − 0.169; <i>P</i> &lt; 0.001). Among the 624 vaginal deliveries, SSEA also showed lower rates of neurological symptoms at 48&#xa0;h (0.32% vs. 2.56%; RD − 0.022, − 0.041 to − 0.004; <i>P</i> = 0.019), lower back pain (1.28% vs. 6.41%; RD − 0.051, − 0.081 to − 0.021; <i>P</i> = 0.001), and persistent paresthesia at 1 week (0% vs. 5.13%; RD − 0.051, − 0.076 to − 0.026; <i>P</i> &lt; 0.001). Overall maternal satisfaction was higher with SSEA (12.81 ± 1.46 vs. 11.26 ± 1.23; Cohen’s <i>d</i> = 1.15; <i>P</i> &lt; 0.001), driven by greater satisfaction with the overall experience (<i>d</i> = 2.08) and willingness to recommend (<i>d</i> = 0.98), whereas satisfaction with pain relief did not differ (<i>P</i> = 0.139). VAS scores, adverse effects, and maternal/fetal outcomes were comparable between groups. In an exploratory SEM, intraprocedural neurological symptoms showed the strongest negative association with satisfaction (standardized <i>β</i>=–0.140, <i>P</i> &lt; 0.001), followed by poor analgesic quality (<i>β</i>=–0.101, <i>P</i> = 0.011) and higher mean VAS (<i>β</i>=–0.092, <i>P</i> = 0.023).</p> Conclusion <p>In this study, preserving neuraxial homeostasis by performing spinal puncture before epidural catheterization was associated with a lower incidence of observed neurological symptoms and higher maternal satisfaction scores compared with conventional CSEA, without compromising analgesic efficacy. While these findings suggest potential benefits of the SSEA technique, confirmation in blinded, multi-center trials is needed, and the assessment of satisfaction was limited by the use of a non-validated instrument.</p> Trial registration <p>ChiCTR, ChiCTR2500111828. Registered 30 November 2023 (prospectively registered); first participant enrolled 10 February 2024.</p>