Labor progression and pain management remain critical challenges in obstetric care, and pharmacologic interventions may optimize labor dynamics. Recent evidence has identified dexamethasone as a promising candidate. A systematic review demonstrated that parenteral dexamethasone significantly reduced the interval from induction to active labor by a mean difference of 70 minutes and shortened the first stage of labor by 88 minutes [1].

However, as a systemic corticosteroid, dexamethasone raises clinical concerns regarding hyperglycemia, immunosuppression, and potential teratogenic effects, thereby limiting its use in patients with diabetes or those at risk of infection [2-4]. Concurrently, a limited number of recent studies (n=7) have suggested that intravaginal magnesium sulfate (MgSO₄) may be an effective and safe intervention for labor acceleration [5-12]. A recent randomized controlled trial (RCT) by Rouhzendeh et al. [9] indicated that its topical application reduced labor pain severity and shortened both the first and second stages of labor by enhancing cervical effacement through osmotic mechanisms. Furthermore, a systematic review and meta-analysis by Makvandi et al. [12] consolidated evidence from seven RCTs, demonstrating that vaginal MgSO₄ significantly increased cervical dilatation and effacement and shortened the active phase of labor. However, no studies have directly compared intravaginal MgSO₄ with systemic dexamethasone to determine their relative efficacy, safety, or suitability for high-risk populations [5-11].

To our knowledge, no previous study has employed an adaptive platform design for labor acceleration interventions or conducted a three-arm comparison of these approaches. As the first study to implement this methodology in obstetric research, we designed a Bayesian adaptive platform trial with an initial pragmatic sample size of 50 participants per arm for interim analysis, given the absence of prior data to inform a formal power calculation.

Our study is the first to directly compare intravenous (IV) dexamethasone (8 mg), intravaginal MgSO₄ (50%; 10 mL), and routine care using an adaptive design. This approach prioritizes patient safety by allowing early termination of the IV dexamethasone arm if intravaginal MgSO₄ demonstrates noninferiority or superiority, thereby minimizing maternal and fetal exposure to systemic corticosteroids. The platform architecture enables ethical resource allocation through dynamic adjustment of enrollment based on emerging efficacy and safety data.

As the first application of an adaptive trial design in labor acceleration research, this study will determine whether topical MgSO₄ can match or surpass the labor-accelerating effects of IV dexamethasone. The findings may establish a safer alternative for high-risk populations while demonstrating the value of responsive methodologies in obstetric clinical trials.

This Bayesian adaptive, three-arm, parallel-group RCT was conducted to compare the effectiveness of interventions for accelerating labor among primiparous women. Participants received intravaginal MgSO₄ (50%; 10 mL), IV dexamethasone (8 mg), or routine care (control). Employing an adaptive platform design, the trial incorporated predefined interim analyses to allow potential modifications, including early termination of the IV dexamethasone arm if intravaginal MgSO₄ demonstrated noninferiority or superiority, thereby prioritizing participant safety. Due to the absence of previous direct comparative studies to inform a formal sample size calculation for a Bayesian adaptive design, we initiated the trial with a pragmatic cohort of 150 women (50 per arm) for the first planned interim analysis. This sample size was considered sufficient for the adaptive algorithm to generate meaningful posterior probabilities for decision-making. Participants were randomly assigned to the study arms using block randomization with varying block sizes (3, 6, and 12) to enhance allocation balance and concealment within the adaptive framework. Sealed envelopes were used to ensure allocation concealment. The results presented here are based on this interim analysis cohort.

This was an open-label trial; therefore, blinding of participants and health care providers was not feasible due to the nature of the interventions. However, outcome assessors (third-party clinicians) and data analysts remained blinded to group assignments throughout the trial and until after the final analysis to minimize bias. The primary outcomes (labor duration and Bishop score) were objectively measured, thereby reducing the risk of assessment bias.

Eligible participants were primiparous women aged 18 years to 35 years at 38 weeks’ to 42 weeks’ gestation with a singleton cephalic presentation, a Bishop score <6, no high-risk conditions (e.g., preeclampsia, gestational diabetes, fetal anomalies), and no contraindications to intravaginal MgSO₄ or IV dexamethasone (e.g., myasthenia gravis, uncontrolled diabetes). Women who declined to participate were excluded. The primary efficacy analysis was conducted on a per-protocol basis and was prespecified to exclude participants who required cesarean delivery for arrest of labor. This approach was chosen to directly evaluate the effect of the intervention on accelerating labor progression, as cesarean delivery at this stage constitutes definitive treatment failure for the outcome of labor duration. It is important to note that no participants met this exclusion criterion, as all women in the study achieved vaginal delivery; therefore, the per-protocol population was identical to the intention-to-treat population for this interim analysis. Baseline characteristics were documented before the intervention.

Participants in the intravaginal MgSO₄ group received 10 mL of 50% MgSO₄ administered intravaginally into the posterior fornix at the onset of the active phase of labor. Participants in the IV dexamethasone group received 8 mg (2 mL) of IV dexamethasone diluted in 10 mL of distilled water and administered as a slow bolus over 2 minutes. The control group received standard obstetric care without additional pharmacologic intervention. Labor progression was monitored through serial vaginal examinations and the Bishop score was recorded at baseline and 2 hours. The primary outcomes were the duration of the latent phase (from the onset of labor to 4 cm cervical dilation) and the duration of the active phase (from 4 cm to full cervical dilation). Secondary outcomes included the 5-minute Apgar score, neonatal blood glucose levels (measured using a glucometer within the first 2 hours after delivery), and maternal adverse effects (i.e., nausea, hypertension, and perineal irritation).

The study was approved by the Institutional Review Board (IR.ABZUMS.REC.1403.076) and was prospectively registered with the Iranian Registry of Clinical Trials (IRCT ID: IRCT20230823059227N2). Written informed consent was obtained from all participants.

Statistical analyses were conducted using both frequentist and Bayesian approaches. For frequentist analyses, continuous variables were compared using analysis of variance when normally distributed or the Kruskal-Wallis test when non-normally distributed, and categorical variables were analyzed using the chi-square test or Fisher’s exact test, as appropriate. Post hoc analyses employed Bonferroni adjustment to control for multiple comparisons. Longitudinal analysis of Bishop scores was performed using a mixed-effects model with the aligned rank transform (ART) to account for non-normality and repeated measures, with post hoc tests adjusted for multiplicity.

Bayesian analyses utilized hierarchical models with the following specifications. 1) Longitudinal bishop scores: a linear mixed-effects model with random participant intercepts, using a Gaussian likelihood and noninformative priors (fixed effects: normal [0, 2]; random effects: cauchy [0, 1]). 2) Labor phase durations: lognormal regression models adjusted for baseline imbalances in age and weight gain, with normal (0, 5) priors specified for fixed effects. And 3) treatment contrasts: posterior probabilities of superiority were calculated using estimated marginal means (emmeans) and median differences with 95% credible intervals (CrI) were reported.

Causal inference was performed using inverse probability weighting (IPW), with propensity scores derived from logistic regression (covariates: age and weight gain). These weights were applied in survey-weighted generalized linear models to estimate average treatment effects.

An interim analysis was prespecified after enrollment of 50 participants per group. Stopping rules for the IV dexamethasone arm were triggered if the posterior probability of intravaginal MgSO₄ superiority (Bishop score difference >0) or equivalence (|Δ| <0.5) reached ≥85% during the 4- to 8-hour critical window. Sensitivity analyses were conducted using alternative prior distributions (e.g., weakly informative priors) in the Bayesian models, confirming the robustness of the primary findings.

The pilot study enrolled 150 pregnant women in the latent phase of labor who were randomized to one of three groups: control (n=50), intravaginal MgSO₄ (n=50), and IV dexamethasone (n=50). The baseline characteristics of the study participants are presented in Table 1.

This study provides robust evidence that intravaginal MgSO₄ demonstrates superior clinical efficacy to IV dexamethasone for labor acceleration, with a favorable safety profile. The findings indicate that intravaginal MgSO₄ reduced both latent and active phase durations to a greater extent than IV dexamethasone, shortening the latent phase by 3.0 hours compared with 1.8 hours for IV dexamethasone and the active phase by 1.99 hours compared with 1.09 hours for IV dexamethasone. These results are particularly noteworthy because they represent the first direct comparison of these two pharmacologic approaches and address a fundamental gap in the obstetric literature. Both interventions demonstrated comparable peak effects on cervical effacement and dilation within the critical 4- to 8-hour window, as reflected by similar improvements in Bishop score at 6 hours (3.06 points for intravaginal MgSO₄ and 3.05 points for IV dexamethasone). However, the more consistent acceleration of labor observed with intravaginal MgSO₄ suggests potential differences in underlying mechanisms of action with important clinical implications.

The higher efficacy of intravaginal MgSO₄ may result from its combined osmotic and calcium channel-blocking effects at the local tissue level. In contrast to the systemic effects of dexamethasone mediated through the hypothalamic-pituitary-adrenal axis and prostaglandin production, MgSO₄ exerts its effects via aquaporin-3-mediated cervical hydration and modulation of myometrial contractility [5,13]. Recent evidence supports this dual mechanism. Mappa et al. [14] described magnesium’s role in downregulating inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) and reducing nuclear factor kappa B activation, thereby contributing to cervical remodeling and decreased contractility, whereas Zafari Zangeneh and Hantoushzadeh provided updated insights into magnesium’s inhibition of L-type calcium channels, which directly reduces myometrial excitability [15]. This local mechanism not only maximizes efficacy but also circumvents the systemic risks associated with corticosteroid therapy, which is particularly relevant for vulnerable populations. The safety advantages are substantial, as intravaginal MgSO₄ avoids the well-documented risks of dexamethasone, including hyperglycemia, immunosuppression, and fluid retention. This distinction renders MgSO₄ particularly suitable for labor management in patients with diabetes, in whom dexamethasone’s metabolic effects may complicate glycemic control, and in immunocompromised patients, in whom infection risk must be minimized [4,16,17].

These findings corroborate previous research while advancing the field in several important ways. The results for IV dexamethasone confirm the findings of Mohaghegh et al. [1] meta-analysis regarding its labor-accelerating effect and are further supported by a recent RCT by Ranjbar et al. [18], which demonstrated that dexamethasone administration during the active phase significantly shortened labor duration and enhanced cervical dilation. Notably, our head-to-head trial demonstrated the superiority of MgSO₄ over IV dexamethasone [1]. Earlier studies on MgSO₄, such as those by Fakour et al. [5] and Rouhzendeh et al. [9], demonstrated its superiority over placebo but did not include an active comparator. The present study addresses this evidence gap by showing the superiority of MgSO₄ not only over usual care but also over an established pharmacologic intervention. The mechanistic evidence helps explain why MgSO₄ achieved more sustained acceleration of labor despite similar peak Bishop scores: its osmotic effects may promote continued cervical remodeling over time, whereas dexamethasone’s systemic effects may produce more transient improvements [13].

These findings have several clinical implications. Intravaginal MgSO₄ may be considered a promising first-line pharmacologic therapy for labor acceleration in various obstetric settings, pending further validation. Its greater effectiveness and favorable safety profile represent a meaningful advancement in obstetric practice. IV dexamethasone may remain useful when local (e.g., vaginal) therapies are contraindicated, such as in cases of preterm premature rupture of membranes or active genital infection [19]. The differential effects of intravaginal MgSO₄ on labor phases-reducing the latent phase by 3.0 hours and the active phase by 1.99 hours-highlight its potential role in managing labor disorders. The shortened latent phase may be beneficial in cases of arrested early labor, whereas the accelerated active phase may reduce the need for additional interventions in prolonged labor.

A pertinent consideration is how intravaginal MgSO₄ integrates into the existing pharmacologic armamentarium for labor management, particularly in comparison with cornerstone agents such as prostaglandins and oxytocin [20,21]. Although highly effective, these standard therapies have well-documented limitations: prostaglandins are associated with uterine tachysystole and maternal gastrointestinal adverse effects, and oxytocin requires controlled infusion and carries risks of uterine hyperstimulation and water intoxication. In this context, intravaginal MgSO₄ represents a mechanistically distinct approach. Its proposed dual mechanism-osmotic hydration and calcium channel modulation-facilitates cervical effacement and dilation through local physiologic processes with minimal systemic absorption [5,13,22-24]. Future studies should incorporate advanced monitoring techniques, such as electrohysterography, as reviewed by Rosen and Yogev [25], to objectively assess uterine contractility patterns and evaluate the hypothesis that MgSO₄ improves uterine discoordination by selectively relaxing the lower uterine segment. Importantly, in our trial, the MgSO₄ group demonstrated a favorable safety profile, with no observed cases of uterine tachysystole or fetal distress. These findings, demonstrating efficacy comparable to that of a potent systemic corticosteroid, position intravaginal MgSO₄ not as a replacement but as a potential alternative in selected clinical scenarios. Such scenarios may include early labor augmentation before the initiation of oxytocin or in patients for whom prostaglandin-associated adverse effects are particularly undesirable. Future direct comparative trials against these standard agents are warranted to more definitively establish its role in clinical practice.

Several limitations of this study should be acknowledged. Baseline differences in participant characteristics, particularly gestational weight gain, were statistically adjusted for; however, residual confounding cannot be excluded. The single-site design may limit generalizability, although the rigorous methodology and use of Bayesian analytical approaches strengthen internal validity. Furthermore, while this study focused on clinical outcomes, quantitative hysterographic monitoring of uterine contractions was not performed. Such objective data-now attainable through advanced electrohysterography techniques [25]-would have provided additional insight into the precise effects of intravaginal MgSO₄ on uterine contractility patterns and uterine discoordination. Long-term neonatal outcomes beyond immediate Apgar scores were not assessed, which is an important consideration given the accelerated labor observed. Although neonatal glucose levels were measured after delivery and no hyperglycemia was detected, the absence of serial glucose measurements limits the ability to fully exclude transient metabolic disturbances. Future studies should incorporate serial neonatal glucose monitoring to more comprehensively evaluate metabolic safety. In addition, cost-effectiveness analyses of intravaginal MgSO₄ are warranted, as the observed reduction in labor duration may translate into meaningful health care cost savings.

In conclusion, the present study supports intravaginal MgSO₄ as a promising agent for labor acceleration, demonstrating substantial efficacy with a favorable safety profile. These findings question the conventional preference for systemic therapies over localized treatments in obstetric management [1]. By showing that local osmotic therapy may achieve greater efficacy than systemic corticosteroid therapy, the results open new avenues for investigating localized mechanisms in labor management. These advances have the potential to improve outcomes for laboring patients while reducing systemic risk, particularly among high-risk populations. Overall, this study contributes to the advancement of evidence-based obstetric practice, with direct implications for clinical decision-making and important directions for future research.