Inducing labor after fetal demise: a systematic review and meta-analysis of the efficacy and safety of mifepristone and misoprostol combination versus misoprostol alone

Abstract

Introduction

Intrauterine fetal demise (IUFD), one of the most tragic outcomes of pregnancy, affects approximately 1% of pregnancies. This systematic review aims to assess the efficacy and safety of mifepristone combined with misoprostol versus misoprostol alone in inducing labor in women with IUFD.

Methods

We conducted a comprehensive literature search of scientific databases from their inception up to July 29, 2024. Randomized controlled trials (RCTs) comparing the Efficacy and Safety of mifepristone and misoprostol with misoprostol alone in women with IUFD were included. The quality of the included RCTs was assessed using the Cochrane risk of bias tool (RoB). All analyses were performed using RevMan version 5.4. To determine the quality of evidence, we used the GRADE tool.

Results

Ten RCTs were included in the qualitative and quantitative synthesis. The analysis revealed a significant reduction in the induction delivery interval with the combination treatment, with a total mean difference of - 7.86 h (MD = - 7.86, 95% CI: - 9.98 to - 5.73, p < 0.00001), favoring mifepristone plus misoprostol. There was a significant reduction in the number of misoprostol doses needed (MD = - 1.38, 95% CI: - 1.82 to - 0.94, p < 0.00001) and in the total misoprostol dose (MD = - 60.51, 95% CI: - 106.98 to - 14.04, p = 0.01), favoring the use of mifepristone plus misoprostol. The quality of evidence ranged from low to moderate.

Conclusion

Our study provides compelling evidence that the combination therapy of mifepristone and misoprostol results in a significant reduction in the induction delivery interval and total dosage of misoprostol required for successful labor induction compared to misoprostol administered alone. Further high-quality research is essential to confirm these results.

Introduction

Intrauterine fetal demise (IUFD), one of the most tragic outcomes of pregnancy, affects approximately 1% of pregnancies. The World Health Organization (WHO) defines IUFD as the death of a fetus at 28 weeks of gestation or later, with a fetal weight of at least 1000 g [1]. Several factors can contribute to IUFD, including maternal systemic diseases like diabetes mellitus and hypertension, as well as fetal factors such as infections, immune hemolytic disorders, umbilical cord accidents, metabolic abnormalities, congenital anomalies, and placental insufficiency [2].

Over 90% of women experiencing intrauterine fetal demise (IUFD) go into spontaneous labor within three weeks following the fetus's death. Nonetheless, earlier medical intervention is frequently vital to address potential risks to the mother, such as emotional distress, psychological trauma, and physical complications. This intervention might begin at the mother’s request or be advised by healthcare practitioners to avert negative outcomes. Postponing evacuation raises the risk of coagulation disorders and intrauterine infections by approximately 10%, which can detrimentally impact the woman’s physical, psychological, and social health [3]. In light of these possible complications after IUFD, timely labor induction is essential [4]. Inducing labor in cases of IUFD can often be more complex than in live births, likely because fetal demise usually occurs during the second or early third trimester, a period when the cervix remains immature and the uterus is less responsive to oxytocin [5].

The ideal medication for pregnancy termination should not only be effective and safe but also cost-effective to reduce the financial burden on patients [6]. Prostaglandins are commonly used to induce labor in cases of IUFD, particularly when the cervix is immature, as has been studied extensively [7]. Among these, misoprostol, a prostaglandin E1 analog, is widely used due to its low cost, stability at room temperature, and ease of use. Misoprostol functions by attaching to prostaglandin receptors in the myometrium, which triggers uterine contractions and aids in cervical ripening. This twofold effect enhances cervical softening, dilation, and uterine contractions required for inducing labor. Its adaptability across different administration methods—oral, vaginal, sublingual, or buccal—makes it suitable for diverse clinical situations scenarios. However, while effective, misoprostol is not without side effects. Common adverse effects include fever, nausea, vomiting, dizziness, diarrhea, and headache. The most serious potential complications are abnormal uterine activity, such as tachysystole or uterine rupture, particularly in cases of high or repeated dosages [8].

Mifepristone is a 19-nor steroid, a competitive antagonist to progesterone and glucocorticoid receptors, priming the myometrium and cervix for prostaglandin activity. Evidence suggests that pretreatment with mifepristone enhances the stimulatory effect of misoprostol on uterine muscles, increasing both the amplitude and frequency of uterine contractions [9]. It is recommended to administer mifepristone 1 to 2 days before induction. However, other studies indicate that a shorter interval between mifepristone and misoprostol may also be effective [10]. This could lead to the use of lower doses of misoprostol for labor induction [11].

Although numerous studies have explored various combination regimens for managing IUFD, an optimal method with consistently good outcomes has yet to be established. In the absence of a standardized approach for labor induction in IUFD cases, this systematic review aims to assess the efficacy and safety of mifepristone combined with misoprostol versus misoprostol alone in inducing labor in women with IUFD, focusing on studies involving women with a mean gestational age in the third trimester.

Methods

The meta-analysis was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [12]. PROSPERO records this study protocol under the reference number 2024 CRD42024579676 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024579676).

Search for relevant research

Two different authors (MA, MS) searched databases such as MEDLINE/PUBMED, Scopus, Science Direct, Google Scholar, the Cochrane library, and the trial and systematic review reference lists until July 29, 2024. We imposed no time or language restrictions on article retrieval. Conflicts were resolved by consensus after being discussed with another author (SM). We used both keywords and Medical Subject Headings terms (MeSH-terms) in the search method. (Table 1). By adapting the Boolean operators to the syntax of every database record, we were able to increase sensitivity (“OR”) and precision (“AND”).

Table 1 Search strategy

Study selection

We adhered to the framework of the participants, interventions, comparators, and outcomes (PICO). Pre-specified inclusion criteria were: (1) Population: women undergoing labor induction after fetal demise, with a mean gestational age in the third trimester.. (2) The intervention involved women receiving a combination of misoprostol and mifepristone; (3) The comparison involved women receiving only misoprostol, regardless of the dosage or delivery method. (4) The study reported at least one of the following outcomes: the induction delivery interval, the number of misoprostol doses, and the total dose of misoprostol in micrograms. Secondary outcomes were maternal side effects. The exclusion criteria encompassed the following: (1) observational studies, reviews, meta-analyses, case reports, conferences, guidelines, and animal studies; (2) studies that lacked clear inclusion or exclusion criteria for participants; (3) duplicate publications from the same researcher or institution; (4) studies that failed to report endpoints or had inadequate data.

Data extraction

Potential studies were identified from literature databases and uploaded to EndNote 21 to remove duplication. After that, two researchers independently removed studies that did not meet the inclusion and exclusion criteria by reviewing the titles and abstracts. To decide which research should be included, the full texts of the other articles were read. A third researcher was consulted to resolve any disagreements. Key data, including characteristics of the included studies (first author, year of publication, country, sample size), intervention measures, control measures, and findings reported (primary and secondary outcomes), were independently extracted by two researchers and input into Excel.

Risk of bias assessment and evidence certainty

The assessment of potential bias in randomized trials was conducted utilizing the Cochrane risk-of-bias instrument for randomized trials (RoB), which adheres to the standards specified in the Cochrane Handbook for systematic reviews of interventions [13]. The RoB tool evaluates randomization, blinding of the study participants, personnel, and outcome assessor, incomplete outcome data, selective reporting, and other potential sources of bias. The total RoB is graded as low, unclear, and high. All authors examined any disagreements before reaching a consensus. To determine the quality of evidence for primary outcomes, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. This tool categorizes systematic reviews or meta-analyses into four groups: ‘high,’ ‘moderate,’ ‘low,’ and ‘very low’ [14]. Two researchers independently performed the GRADE assessment and resolved any discrepancies through discussion.

Statistical analyses

We performed a meta-analysis based on aggregate data from eligible studies that reported comparisons of misoprostol combined with mifepristone versus only misoprostol. Risk ratio (RR) with a 95% confidence interval (CI) was used as a measure of the effect size for the categorical data. The mean difference (MD) with the 95% CI was calculated as the effect size for the endpoint with continuous data. The I² index was used to quantify the heterogeneity of each study. We considered heterogeneity to be significant when the I² statistic was ≥ 50%. A random‐effects model was adopted if there was evidence of heterogeneity. Otherwise, a fixed‐effects model was used. We conducted sensitivity analyses by omitting each study and evaluating the effect on RR, MD, and heterogeneity. Subgroup analyses for the primary and secondary outcomes were performed based on the time interval between the administration of mifepristone and misoprostol. The results were displayed as a forest plot. Funnel plots were utilized for ten or more included trials to assess publication bias and the potential asymmetry in the results. This visual representation helped to evaluate the robustness of our findings and the likelihood of any biases affecting the overall outcomes. A p-value < 0.05 was considered statistically significant. All data analyses were performed by the Review Manager (RevMan) (Version 5.4).

Ethical considerations

The study protocol was approved by the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Ref. No: IR.AJUMS.REC.1403.172).

Results

Search results

In Fig. 1, the PRISMA 2020 flow diagram illustrates the systematic review process. During the identification phase, 346 records were identified through database searching. Additionally, 7 records were found via other sources, resulting in a combined total of 353 records. After removing duplicates, 248 records underwent screening. Among these, 209 records were excluded based on title and abstract review. The full texts of the remaining articles were then assessed for eligibility. Ultimately, 27 articles were excluded for specific reasons such as differences in study design, population, or methodology, leaving 10 RCTs included in the qualitative and quantitative synthesis. as detailed in the PRISMA 2020 flow diagram (Fig. 1).

Fig. 1

PRISMA 2020 flow diagram for systematic reviews

Included RCTs

Table 2 presents the characteristics of RCTs included in this review. All identified studies utilized a parallel design and two-armed trials. Sample sizes across the studies varied from 40 [15] to 120 [16] participants. The trials were published between 2011[15] and 2024 [17]. Geographically, 7 studies were conducted in India [8, 15, 16, 18,19,20,21] and one trial each took place in Nepal [22], Nigeria [17], and Bangladesh [11]. Across all the studies, the Mifepristone dosage remained consistent at 200 mg. In seven studies, the interval between administering Mifepristone and Misoprostol ranged from 24 h [8, 11, 16, 17, 20,21,22], and in three studies, it extended to 38 to 48 h [15, 18, 19]. Additionally, the control group in three of these studies received a Mifepristone placebo [8, 17, 19].

Table 2 Characteristics of the included RCTs

Description of risk of bias

The risk of bias assessment for the included studies is illustrated in Figs. 2 and 3. Overall, the analysis reveals a mixed risk profile across various domains. For random sequence generation, a majority of studies demonstrated a low risk of bias, while allocation concealment showed a more concerning trend, with several studies classified as having an unclear risk of bias. Performance bias, indicated by the blinding of participants and personnel, also raised significant concerns, as many studies did not adequately address this aspect. This is particularly challenging in studies involving intrauterine fetal death, where conducting a double-blind RCT is inherently difficult due to ethical and practical considerations. Similarly, the risk of detection bias was classified as unclear in many studies, often due to insufficient information about whether outcome assessors were blinded to group assignments. Most studies demonstrated a low risk concerning incomplete outcome data and selective reporting, effectively addressing issues related to missing data and providing comprehensive reporting of outcomes. The low risk in these areas enhances the credibility of the findings, suggesting that the results are more likely to reflect the true effects of the interventions studied. However, while some domains exhibited low risk, the presence of high and unclear risks in key areas emphasizes the need for caution when interpreting the results of these trials.

Fig. 2

Risk of bias summary: review authors’ judgments about each risk of bias item for each included study

Fig. 3

Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies

Meta-analysis findings

Induction delivery interval

The forest plot of Fig. 4 illustrates the pooled MD in the induction delivery interval (hours) between mifepristone plus misoprostol and misoprostol alone. The analysis reveals a significant reduction in the induction delivery interval with the combination treatment, with a total mean difference of − 7.86 h (MD = − 7.86, 95% CI: − 9.98 to − 5.73, p < 0.00001), favoring mifepristone plus misoprostol. We used a random effect model because of the significant heterogeneity (Chi² = 8.07, I² = 81%, p < 0.00001).

Fig. 4

Forest plot of the pooled mean differences (MD) of the effect of mifepristone plus misoprostol compared to misoprostol on the induction delivery interval (hours)

The subgroup analysis indicates that in the 24-h interval, the mean difference was − 8.59 h (95% CI: − 11.37 to − 5.81, p < 0.00001), with substantial heterogeneity (I² = 85%). The mean difference in the 36–48 h interval was − 6.19 h (95% CI: − 7.84 to − 4.53, p < 0.00001), showing no heterogeneity (I² = 0%). Sensitivity analysis confirmed the robustness of these findings, as the overall effect remained significant across various scenarios, reinforcing the efficacy of mifepristone in reducing the induction delivery interval compared to misoprostol alone.

The funnel plot in Fig. 5 depicts the effect of mifepristone plus misoprostol compared to misoprostol alone on the induction delivery interval. The plot reveals asymmetry, with a noticeable clustering of studies on the right side of the MD line, suggesting a trend toward positive MD values. This clustering may indicate an underlying effect, such as a treatment benefit, contributing to the observed positive results. The predominance of studies on the right side raises concerns about potential publication bias, implying that studies with non-significant or negative outcomes are less likely to be published, while those showing favorable treatment effects are more prominently featured. This phenomenon can distort the overall perception of the treatment’s efficacy.

Fig. 5

Funnel plot of the effect of mifepristone plus misoprostol compared to misoprostol

Number of misoprostol doses

The forest plot in Fig. 6 illustrates the pooled MD in the number of misoprostol doses required when comparing mifepristone plus misoprostol to misoprostol alone. The overall analysis reveals a significant reduction in the doses needed with the combination treatment, showing a mean difference of − 1.38 (95% CI: − 1.82 to − 0.94, p < 0.00001), favoring mifepristone plus misoprostol. Subgroup analysis indicates that within the 24-h interval, the mean difference was − 1.37 (95% CI: − 1.90 to − 0.83, p < 0.00001), accompanied by substantial heterogeneity (I² = 88%). In contrast, the 36–48-h interval showed a mean difference of − 1.41 (95% CI: − 1.90 to − 0.91, p < 0.00001) with low heterogeneity (I² = 0%). Sensitivity analysis further validated these findings, demonstrating that the overall effect remained significant across various scenarios, thus reinforcing the conclusion that mifepristone plus misoprostol significantly reduces the number of misoprostol doses needed compared to misoprostol alone. Publication bias was not evaluated because of the limited number of RCTs.

Fig. 6

Forest plot of the pooled mean differences (MD) of the effect of mifepristone plus misoprostol compared to misoprostol on the number of misoprostol doses

Total dose of misoprostol

The forest plot in Fig. 7 displays the pooled MD regarding the total dose of misoprostol (in micrograms) required when comparing mifepristone plus misoprostol to misoprostol alone. The overall analysis indicates a significant reduction in the total dose required with the combination treatment, showing a MD of − 60.51 (95% CI: − 106.98 to − 14.04, p = 0.01), favoring the combination of mifepristone and misoprostol. In this forest plot, we employed a random-effects model due to the observed heterogeneity among the studies (Chi² = 101.17, I² = 97%, p < 0.00001).

Fig. 7

Forest plot of the pooled mean differences (MD) of the effect of mifepristone plus misoprostol compared to misoprostol on the total dose of misoprostol in micrograms

Subgroup analysis reveals that in the 24-h interval, the mean difference was − 51.70 (95% CI: − 104.09 to 0.70, p = 0.05), with substantial heterogeneity (I² = 97%). In the 36–48-h interval, the MD was − 87.70 (95% CI: − 112.86 to − 62.54, p < 0.00001), indicating a significant effect.

Maternal side effects

The forest plot Fig. 8 visually represents the pooled RR comparing the combined regimen of mifepristone plus misoprostol to misoprostol alone on the some maternal side effects. Across all reported maternal side effects, the combined regimen (mifepristone plus misoprostol) appears to be advantageous. Notably, the combined regimen shows statistical significance only concerning fever (RR = 0.36, 95% CI: 0.16 to 0.80, p = 0.01) and shivering (RR = 0.38, 95% CI: 0.15 to 0.94, p = 0.04). In other words, when compared to misoprostol alone, the mifepristone plus misoprostol combination significantly reduces the risk of fever and shivering. These findings suggest that the combined regimen may be more favorable for managing maternal side effects during the specified treatment. The low heterogeneity suggests that the studies included in the meta-analysis were relatively consistent in their findings regarding the maternal side effects of the two treatment regimens and therefore a fixed effect model was used.

Fig. 8

Forest plot of the pooled risk ratio (RR) of the effect of mifepristone plus misoprostol compared to misoprostol on the maternal side effects

Maternal side effects and comparison of regimens

The forest plot in Fig. 8 visually represents the pooled RR comparing the combined regimen of mifepristone plus misoprostol to misoprostol alone regarding specific maternal side effects, including fever, shivering, nausea, and vomiting. These outcomes were suitable for meta-analysis, and the results were quantified. Maternal complications were generally minimal across all studies, with no reports of severe adverse events such as uterine hyperstimulation, tachysystole, postpartum hemorrhage, uterine rupture, or coagulopathy. Although these complications were mentioned in the studies, they were not included in the meta-analysis due to limited data and the inability to perform quantitative analysis. Mild gastrointestinal side effects, including nausea, vomiting, and diarrhea, were observed in both groups, with slightly higher frequencies in the misoprostol-alone group. However, the combined regimen of mifepristone plus misoprostol demonstrated a statistically significant reduction in the risk of fever and shivering compared to misoprostol alone (RR = 0.36, 95% CI: 0.16 to 0.80, p = 0.01 for fever; RR = 0.38, 95% CI: 0.15 to 0.94, p = 0.04 for shivering). These findings suggest that the combined regimen may be more favorable in managing certain maternal side effects, with low heterogeneity supporting the consistency of results across the included studies. Retained placenta occurred in a small number of cases in both groups but did not lead to major complications or require extensive interventions. Overall, no cases of severe complications, such as hemorrhage or sepsis, were recorded, and both regimens were well-tolerated.

Certainty of the evidence

Table 3 presents the GRADE evidence profiles for primary outcomes across the trials included in the systematic review. The quality of evidence concerning the induction-to-delivery interval was rated as low due to both publication bias and a serious risk of bias. The grading for the number of misoprostol dosages was moderate, with a decrease in ranking associated with bias risk. Additionally, the grading for the total misoprostol dosage was low, primarily due to bias risk and imprecision. These findings underscore the necessity for further research.

Table 3 GRADE evidence profiles for primary outcomes among the trials included in the systematic review

Discussion

Inducing labor in cases of IUFD presents significant challenges due to the cervix’s immaturity and reduced uterine responsiveness, particularly in the second and third trimesters [5]. While numerous studies have investigated various drug combinations for managing IUFD, no universally optimal method with consistently positive outcomes has been identified. This systematic review and meta-analysis aimed to compare the combined use of Mifepristone and Misoprostol versus Misoprostol alone in terms of clinical outcomes primary (induction to delivery interval, number of misoprostol doses, total dose of misoprostol) and secondary (maternal complications) in women with IUFD between 20 and 42 weeks of gestation. We reviewed 10 RCTs in this analysis.

In this meta-analysis, we observed a significant difference in the induction-to-delivery interval when comparing the combination of mifepristone and misoprostol to misoprostol alone. The results indicated that the majority of studies reported successful labor induction occurring within the first 24 h of initiating the combined treatment regimen [8, 11, 16, 17, 20,21,22]. However, it is noteworthy that certain studies [18, 19, 23] highlighted instances where labor induction was postponed by 36 to 48 h. This variability in induction time was systematically assessed across all included studies; nonetheless, the evidence remains insufficient to draw definitive conclusions. The delay in labor induction following IUFD may not only intensify the emotional distress experienced by the mother, but also heightens the risk of serious complications such as coagulopathies and infections. These complications can adversely affect the woman’s overall health and well-being [24, 25]. Given the implications of prolonged delivery in IUFD cases, the results of this meta-analysis suggest that combination therapy could potentially mitigate these adverse outcomes. The expedited induction associated with the mifepristone and misoprostol regimen may provide a more compassionate approach to management, reducing both the psychological burden on the mother and the associated health risks. Therefore, considering the promising findings of this analysis, further research must be conducted to solidify the understanding of these therapeutic interventions and their long-term effects on both maternal and neonatal outcomes.

The induction-to-delivery interval is a critical outcome in evaluating labor induction methods; however, the presence of publication bias poses a significant concern in interpreting this metric. Additionally, the assessment of bias in such trials is inherently challenging, as most studies in this area are limited by their design. These design limitations make it difficult to eliminate performance and detection bias entirely. This underscores the need for further investigations that prioritize transparency, comprehensiveness, and innovative approaches to minimize bias while maintaining ethical standards. Addressing these challenges is crucial to ensuring a more accurate understanding of the potential benefits and limitations of different induction strategies, ultimately informing better clinical decision-making and optimizing patient outcomes in labor induction practices.

The comparison of the number of misoprostol dosing was meticulously analyzed across various studies [8, 11, 16, 17, 20,21,22], primarily over a 24-h timeframe. However, the implications of dosing were also examined in studies [18, 23] that evaluated induction over an extended period of 36 to 48 h. These findings indicate that the pharmacokinetics of misoprostol and the timing of administration can play critical roles in determining the induction-to-delivery interval. In our study, we found that the total amount of misoprostol administered in the combination therapy with mifepristone was significantly lower than that used when misoprostol was given as a standalone treatment. This observation is noteworthy, as it suggests that the addition of mifepristone may enhance the efficacy of misoprostol, allowing for a reduction in dosage without compromising the effectiveness of labor induction. This reduction not only highlights the potential cost-effectiveness of the combination approach but also presents an opportunity to reduce the risk of side effects commonly associated with higher doses of misoprostol. Upon examining the methodologies and dosages of misoprostol employed in these studies, it becomes evident that the administration strategy must be tailored according to gestational age. Variations in gestational age may influence uterine responsiveness to misoprostol, thus impacting the overall induction outcomes. Lower doses may be particularly advantageous in certain populations, potentially facilitating a smoother labor induction process while minimizing the likelihood of adverse events such as hyperstimulation or gastrointestinal side effects [26]. Future studies should aim to delineate the optimal dosing strategies tailored to specific clinical scenarios to maximize both maternal safety and therapeutic efficacy.

In the analysis of maternal outcomes, the findings showed that the two methods have significant differences in terms of maternal complications, especially fever and shivering. This result was highlighted in most studies. Other side effects such as vomiting, and nausea were also less common in the combined treatment than in the misoprostol-only group. Similarly, in a meta-analysis comparing the side effects of the combination regimen with misoprostol alone, researchers found that fever was less common in the intervention group. However, no statistically significant difference was observed between the two groups in terms of nausea, vomiting, diarrhea, pain, and headache [27], which is consistent with the results of our meta-analysis. In our study, although the secondary outcomes regarding nausea and shivering were reported in only two studies, we included them in our analysis to ensure transparency and to provide a comprehensive overview of the available evidence. While the limited number of studies diminishes the statistical power and generalizability of these findings, reporting these outcomes highlights important gaps in the literature. These outcomes may have clinical significance and warrant further investigation in future research. We acknowledge this limitation and caution against overinterpreting the results related to these outcomes.

In the present study, the quality of evidence regarding the induction-to-delivery interval was rated as low, largely attributable to concerns about publication bias and a serious risk of bias inherent in many of the included studies. This assessment raises critical questions about the generalizability of the results, as publication bias can skew the understanding of treatment efficacy when negative or inconclusive findings remain unpublished. Conversely, the grading for the number of misoprostol dosages was rated as moderate; however, this ranking was diminished due to recognized risks of bias, suggesting that while there is some consistency across studies, caution is warranted in interpreting these results. Furthermore, the evaluation of the total misoprostol dosage received a low grade, reflective of both bias risk and imprecision in data reporting. Such imprecision signifies that although trends may indicate benefits associated with the combination therapy, the variability in dosing strategies and outcomes necessitates more rigorous, well-designed studies to better elucidate these relationships. Collectively, these findings point to the crucial need for future research aimed at addressing these biases and providing clearer, more precise evidence to better inform clinical practice in labor induction protocols.

Strengths and limitations

This study stands out due to its thorough and systematic methodology, employing an extensive literature search strategy that placed no time limits, thus capturing a diverse range of relevant RCTs. Focusing solely on RCTs enhances the reliability of our findings, as these types of studies are specifically designed to reduce bias and deliver strong evidence. Recently, a meta-analysis reviewed the application of mifepristone and misoprostol for labor induction after fetal demise, analyzing seven studies [28]. However, a subsequent critical letter published about this meta-analysis pointed out significant methodological flaws, particularly the omission of relevant studies because the search strategy did not encompass Google Scholar or other potentially significant databases [29]. Consequently, their analysis may have overlooked studies that could affect the overall results. In contrast, our systematic review and meta-analysis feature a more thorough search strategy that includes studies from various databases, resulting in the incorporation of ten RCTs. This more inclusive approach facilitates a more thorough assessment of the efficacy and safety of mifepristone combined with misoprostol compared to misoprostol alone, filling gaps in the earlier meta-analysis and providing a more comprehensive view of this essential subject. This larger sample size enhances the power of our analysis and provides a more reliable estimate of treatment effects. However, the high heterogeneity among the included studies poses a significant limitation. Variability in study designs, participant characteristics, treatment protocols, and outcome measures can obscure the true effects of the interventions under investigation. To address this challenge, we employed sensitivity analyses, subgroup analyses, and appropriate statistical methods to adjust for heterogeneity. However, it remains imperative to acknowledge that despite these efforts, residual heterogeneity may still affect the robustness of our conclusions. Furthermore, while our grading process adhered to the GRADE criteria, it revealed that the quality of the evidence varied considerably, particularly concerning the induction-to-delivery interval, where low quality was primarily influenced by publication and bias risks. This variability highlights the necessity for caution when interpreting the results and underlines the need for additional high-quality RCTs to further elucidate the efficacy and safety of the combined treatment approach.

Conclusion

In conclusion, our study provides compelling evidence that the combination therapy of mifepristone and misoprostol results in a significant reduction in the total misoprostol required for successful labor induction compared to misoprostol administered alone. Nonetheless, further high-quality research is essential to confirm these results, resolve existing uncertainties, and refine treatment protocols to improve maternal and neonatal health outcomes.