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Efficacy and safety of misoprostol versus oxytocin for labor induction in women with prelabor rupture of membranes: a meta-analysis

BMC Pregnancy and Childbirth volume 25, Article number: 461 (2025) Cite this article

Abstract

Background

Prelabor rupture of membranes (PROM) complicates 8% of pregnancies, often necessitating labor induction to prevent maternal and neonatal complications. Misoprostol, a cost-effective prostaglandin, has been proposed as an alternative to oxytocin for labor induction in PROM cases, but its efficacy and safety remain debated.

Methods

The PubMed, Web of science, Embase, Google scholar, ClinicalTrials.gov, and Cochrane Library databases were searched on January 25, 2025. Randomized controlled trials (RCTs) comparing misoprostol and oxytocin for labor induction in term PROM were eligible. The primary outcomes were vaginal birth within 24 h and the induction to delivery interval. Secondary outcomes included the duration of second stage of labor, the induction to active labor, cesarean section, postpartum hemorrhage (PPH), and other maternal/neonatal complications.

Results

Data from 20 RCTs involving 2,980 participants were analyzed. Misoprostol significantly reduced the induction-to-delivery interval and the duration of the second stage of labor compared to oxytocin (WMD = -62.82, 95% CI (-110.56, -15.08); WMD = -4.29, 95% CI (-8.05, -0.52), respectively). It also lowered the risk of PPH (OR = 0.63, 95% CI (0.41, 0.98)). However, no significant differences were found in other outcomes between misoprostol and oxytocin.

Conclusions

Misoprostol is a viable alternative to oxytocin for labor induction in PROM, offering shorter labor durations and reduced PPH risk without compromising maternal and neonatal outcomes. Further researches are needed to optimize dosing, administration routes, and assess maternal satisfaction.

Peer Review reports

Introduction

Prelabor rupture of membranes (PROM), defined as amniotic membrane rupture preceding labor initiation, represents a significant obstetric complication affecting approximately 8% of gestations [1]. Epidemiologic data indicate that term PROM accounts for over 60% of all cases [2]. Chorioamnionitis is a major complication of PROM, with an incidence ranging from 6 to 10% in general PROM populations, escalating to 40% in cases exceeding 24 h duration [3]. Prolonged membrane rupture (> 24 h) is associated with increased maternal risks, demonstrating a 14% elevation in composite morbidity outcomes including septic complications, hemorrhagic events requiring transfusion, puerperal infections, acute renal impairment, and hospital readmission [4]. PROM can also lead to adverse neonatal outcomes such as respiratory distress, neonatal sepsis, intraventricular hemorrhage, and birth asphyxia [5, 6]. Immediate induction is considered the optimal management strategy for term PROM to ensure the safety of both the mother and the neonate, which is supported by the American College of Obstetricians and Gynecologists [1].

Induction of labor (IOL) has been managed using a variety of techniques, including medicinal and mechanical methods. Cervical ripening is crucial for successful induction of labor, especially in cases of PROM. This physiological preparation requires cervical softening, thinning, and dilation to facilitate successful labor initiation. Clinical evidence demonstrates that oxytocin-induced labor in women with unripe cervical conditions carries a significant risk profile, with induction failure rates increasing and subsequent 30–40% cesarean section, compounded by extended labor duration that predisposes to maternal-neonatal infectious complications [7]. In women with low Bishop scores, prostaglandin use has been shown to be more effective for cervical ripening [8]. Prostaglandins, such as dinoprostone (PGE2), are effective in cervical ripening and labor induction [9]. These preparations, however, are costly, unstable at room temperature [10].

An interesting alternative to these agents is misoprostol. Misoprostol is a synthetic prostaglandin E1, has been widely studied and shown to be effective in achieving cervical ripening and inducing labor. Studies indicate that it can significantly reduce the time from induction to delivery [11, 12]. Because misoprostol is afordable, heat stable, and simple to use, making it a cost-effective option for labor induction, especially in resource-limited settings [13]. Misoprostol exerts its cervical ripening effects primarily through dual mechanisms: facilitating collagen degradation while simultaneously suppressing collagen production within cervical tissue [14]. In contrast, oxytocin stimulates uterine contraction only [15].

Several randomized controlled trials (RCTs) have conducted comparative analyses of misoprostol versus oxytocin administration in term PROM, evaluating their respective impacts on labor processes and perinatal outcomes [16,17,18,19,20,21]. Though Lin et al. demonstrated the effectiveness and safety of misoprostol for induction of labor in term PROM when compared oxytocin in their meta-analysis [22], it has been two decades since then and several new RCTs have been published and the results are conflicting [23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Some studies report that misoprostol is more effective in reducing the induction-to-delivery interval compared to oxytocin [16, 19, 23, 26, 27, 29, 34], while others find no significant difference [17, 24]. Therefore, there is a need evaluate this issue. The aim of this study was to conduct a meta-analysis of RCTs investigating the efficiency and safety of misoprostol, compared with oxytocin on delivery and neonatal outcomes among women with term PROM. This analysis can aggregate data from multiple studies to provide a more robust and comprehensive assessment. By standardizing outcome measures, it can also offer clearer insights into the comparative effectiveness of misoprostol and oxytocin. The findings from this meta-analysis could inform clinical guidelines and decision-making, providing evidence-based recommendations for the use of misoprostol or oxytocin in labor induction for women with PROM.

Methods

Registration

This meta-analysis was pre-registered (PROSPERO Registered ID: CRD42025649820), and reported according to the PRISMA 2020 statement [37].

Search strategy

Two investigators (A.C. and S.S.) designed the search strategy. The search strategy was applied in the PubMed, Web of science, Embase, Google scholar, ClinicalTrials.gov, and Cochrane Library databases on Jan 25, 2025. Keywords included: “Prelabor rupture of membranes”; “Misoprostol”; and “Oxytocin”. In addition, article references were manually searched to further identify literature that met the criteria.

Study selection

Study selection was conducted using Endnote (version 20; Clarivate Analytics, Philadelphia, Pennsylvania, USA). Two investigators (G.Z. and G.S.) performed the selection process. Individual studies from our retrieval were first screened based on titles and abstracts. If a judgment could not be made based on titles and abstracts, we proceeded to read the full text. Any discrepancies between the two reviewers were resolved through discussion or consultation with the senior reviewers (J.L.).

Eligibility criteria

Original studies were eligible if they met the following criteria: (1) Population: pregnant women at or greater than 36 weeks of gestation with PROM. (2) Intervention: misoprostol for labor induction. (3) Comparison: oxytocin for labor induction. (4) Outcome: vaginal birth within 24 h; the induction to delivery interval; the duration of second stage of labor; the induction to active labor; the rate of cesarean section; other maternal and neonatal complications. (5) Study design: RCTs with full text in English.

Original studies were ineligible for the following reasons: (I) evidence of prior uterine surgery; (II) nonvertex presentation; (III) maternal contraindication to prostaglandin use or chorioamnionitis; (IV) spontaneous labor onset or fetal distress.

Outcomes

The primary outcomes were vaginal birth within 24 h and the induction to delivery interval. Secondary outcomes included the duration of second stage of labor, the induction to active labor, the rate of cesarean section, hyperstimulation, tachysystole, postpartum hemorrhage (PPH), chorioamnionitis, neonatal intensive care unit (NICU) admission, Apgar score at 1 min, Apgar score at 5 min, cord pH, and meconium-stained liquor.

Data extraction

Two researchers (A.C. and S.S.) performed the data extraction independently. In case of disagreement, they discussed and reached a consensus with the help of a third reviewer (J.L.). Data included first author, year of publication, country, interventions and controls, sample size in each group, age (years), gestational weeks, intervention details, and outcomes.

Quality assessment

The Cochrane Collaboration’s tool was used to evaluate each trial before data statistics, which had seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases [38, 39]. The quality evaluation charts were generated using the “robvis” package of the R software (version 3.6.3; R Foundation, Vienna, Austria) [40].

Statistical analysis

The pooled effects are presented as the odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CIs). Heterogeneity was assessed using the I2 statistic. If there was no heterogeneity (P > 0.1 or I2 < 50%), a fixed-effects model was used to estimate the pooled effect; otherwise, a random-effects model was utilized. When heterogeneity existed, we conducted subgroup analyses based on the route of misoprostol administration and study published year. Sensitivity analyses were directed to assess the influence of the individual study on the overall estimate. We analyzed the symmetry of a funnel plot to evaluate possible small sample effects, and used Begg’s and Egger’s tests to evaluate publication bias in the included studies. A p-value < 0.05 was considered statistically significant for asymmetry. Trim-and-fill analysis was performed to ‘normalize’ the asymmetric funnel plot [41]. An overall grading of the quality of evidence was conducted using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Statistical analyses were performed using Stata (version 17.0; StataCorp, College Station, TX, USA).

Results

Literature selection

Figure 1 shows the flow diagram for study selection. We identified 604 studies from six databases. After considering the inclusion and exclusion criteria, 20 studies were selected for analysis [16,17,18,19,20,21, 23,24,25,26,27,28,29,30,31,32,33,34,35,36].

Fig. 1
figure 1

Flow-chart of study selection

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Study characteristics

All studies were conducted from 1997 to 2024 (Table 1). There were 2,980 patients involved, including 1,502 patients in the misoprostol group, and 1,478 patients in the oxytocin groups. Patient were from Africa (Egypt and Kenya), Asia (China, India, Iran, Nepal, Turkey, and Thailand), and North America (Canada and USA). Details of misoprostol and oxytocin interventions are shown in Table 1. The inclusion and exclusion criteria of the involved studies are summarized.

Table 1 Characteristics of included studies
Full size table

Risk of bias of included studies

The assessment of the risk of bias is presented in Figs. 2 and 3. According to the Cochrane risk-of-bias tool for RCTs, all trials had high risk of bias (performance bias) because it was not possible to blind the physician and the patient to which individuals.

Fig. 2
figure 2

Risk of bias summary

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Fig. 3
figure 3

Risk of bias graph

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Meta-analysis of primary outcomes

There was no difference between misoprostol and oxytocin in terms of vaginal birth within 24 h (OR = 0.87, 95% CI (0.57, 1.32), p = 0.502, I2 = 0%). Misoprostol was superior compared to oxytocin in reducing the induction to delivery interval according to a random effect model (WMD = -62.82, 95% CI (-110.56, -15.08), p = 0.010, I2 = 86%, Fig. 4).

Fig. 4
figure 4

Forest plots (random effect model) of meta-analysis of the difference between misoprostol and oxytocin in the induction to delivery interval. WMD, weighted mean difference

Full size image

Meta-analysis of secondary outcomes

Misoprostol was superior compared to oxytocin in reducing the duration of second stage of labor (WMD = -4.29, 95% CI (-8.05, -0.52), Table 2). The risk of PPH was lower in the misoprostol group than the oxytocin group (OR = 0.63, 95% CI (0.41, 0.98), Table 2). There was no difference between misoprostol and oxytocin in other secondary outcomes (Table 2).

Table 2 Meta-analysis of the effects of misoprostol administration on delivery and neonatal outcomes compared with Oxytocin
Full size table

Subgroup analysis

The results of four outcomes, including the induction to delivery interval, the duration of second stage of labor, the induction to active labor (min), and Apgar score at 5 min, had high heterogeneity (I2 = 86.0; I2 = 67.2; I2 = 89.5; I2 = 83.1, respectively). Subgroup analysis was performed based on the route of misoprostol administration to explore the source of heterogeneity.

The sublingual route was statistically significant with minimal heterogeneity for “induction to delivery interval” and “duration of the second stage of labor”. All p values for between-subgroup heterogeneity were greater than 0.05 (p = 0.832; p = 0.676; p = 0.069; p = 0.266, respectively), indicated that different routes of misoprostol administration were not the main source of heterogeneity. All p values for between-subgroup heterogeneity were greater than 0.05 (p = 0.356; p = 0.676; p = 0.101; p = 0.576, respectively), indicated that different published years of involved studies were not the main source of heterogeneity.

Sensitivity analysis and publication bias

To assess the sensitivity of between-study heterogeneity, sensitivity analyses were performed by sequentially removing each study. No apparent change occurred for most outcomes when an individual study was omitted (Table 2). However, for the duration of second stage of labor, the seven study-specific WMDs ranged from a low of -7.33 (95% CI: -16.36, 1.70) after omitting the study by Unthanan et al. [33] to a high of -2.56 (95% CI: -3.57, -1.55) after omitting the study by Ngai et al. [19] in the sensitivity analyses. For the risk of PPH, the eleven study-specific ORs ranged from a low of 0.59 (95% CI: 0.37, 0.92) after omitting the study by Ahmed et al. [34] to a high of 0.73 (95% CI: 0.43, 1.26) after omitting the study by Pouralil et al. [28] in the sensitivity analyses. These two outcomes of the sensitivity analyses showed instability.

No publication bias was detected by funnel plots, Begg’s test, and Egger’s tests for most outcomes (Table 2). However, an obvious publication bias was revealed in our evaluation of the funnel plots for NICU admission, confirmed by Begg’s tests (P = 0.024). Trim-and-fill analysis by imputation of six studies resulted in OR of 1.32 (95% CI: 0.95, 1.83).

Discussion

Research gap

PROM is a unique indication for IOL, and a timely and appropriate intervention is need to manage PROM effectively, thereby reducing the risk of complications for both the mother and the fetus. Oxytocin is a widely used and effective agent for labor induction in PROM cases. However, the oxytocin route of administration was mainly intravenous, which restricts the mother’s mobility. Therefore, to avoid the risk of uncontrolled oxytocin infusion and hyperstimulation, oxytocin administration required special medical monitoring [42]. Misoprostol has gained attention due to its cost-effectiveness, ease of administration, and potential efficacy. However, existing studies comparing misoprostol and oxytocin for labor induction in PROM present conflicting results regarding efficacy and safety [23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Furthermore, methodologies, dosages, and outcome measures involved in these studies vary significantly. Our study attempts to synthesize existing evidence, standardize outcome measures, guide clinical practice, and identify research gaps. This comprehensive approach can lead to more informed and effective clinical decisions, ultimately improving maternal and neonatal health outcomes.

Summary of main results

As the results shown in the present study, misoprostol can be considered a viable alternative to oxytocin for labor induction in patients with PROM. The findings of our meta-analysis suggested that misoprostol was associated with significantly shorter induction to delivery interval and duration of second stage of labor, and lower risk of PPH. There were no differences in vaginal birth within 24 h, the rate of cesarean section, other maternal and neonatal outcomes between misoprostol and oxytocin.

Efficacy of misoprostol versus oxytocin on the duration of labor

The duration of labor is the most important factor and prolonged labor is indeed a significant cause contributing to maternal and neonatal morbidity. The finding of misoprostol on reducing induction to delivery interval is supported by pharmacokinetic studies [14, 43]. Misoprostol exerts its pharmacological actions at both the cervical and uterine levels while the effect of oxytocin predominantly targets the uterus. When attempting to induce labor using oxytocin in the situation where the cervix is unfavorable, it is analogous to attempting to drive a vehicle against a firmly shut gate. On the other hand, misoprostol has the ability to first prepare the cervix, metaphorically “opening the gate” before the subsequent stimulation of uterine contractions.

Efficacy of misoprostol versus oxytocin on PPH

The current analysis showed misoprostol significantly reduced the risk of PPH compared to oxytocin. However, the effect of misoprostol on PPH is conflicting. Li et al. found no significant difference in postpartum blood loss between misoprostol and oxytocin groups [44], but Wuntakal et al. indicated that misoprostol induction was associated with increased blood loss compared to oxytocin [45]. Further studies are recommended to clarify these findings and optimize misoprostol use for labor induction and PPH prevention.

Safety of misoprostol versus oxytocin on mothers

The frequent uterine hyperstimulation event is a major concern when misoprostol is used in IOL. In the present study, such significant effect was not seen for hyperstimulation, which is consistent with previous studies [22, 46]. However, several studies indicate that misoprostol is associated with a higher incidence of uterine hyperstimulation compared to oxytocin. Mozurkewich et al. reported that vaginal misoprostol was associated with more uterine hyperstimulation than oxytocin [47]. Wing et al. found no significant differences in neonatal outcomes between the two drugs, although misoprostol had a higher likelihood of uterine hyperstimulation [48]. The route and dose of administration may also impact the risk of hyperstimulation. Kerr et al. showed that vaginal misoprostol has been associated with more uterine hyperstimulation with fetal heart rate changes compared to oral misoprostol [49]. Patte et al. suggested that higher doses of misoprostol, such as the 200 µg vaginal insert, have been shown to significantly increase the risk of uterine hyperstimulation compared to lower doses like the 100 µg insert [50]. In the present meta-analysis, none of the studies included used a dose greater than 100 µg of misoprostol, which may explain why misoprostol showed no increased risk of hyperstimulation compared to oxytocin in our study.

Chorioamnionitis is another issue that needs to be paid attention in IOL of PROM. In the current analysis, we did not find significant difference in chorioamnionitis between misoprostol and oxytocin. For the risk of infection, both methods seem to be similar though shorter time of induction has potential effect in reducing intraamniotic infection in theory. This result may be due to the limited sample size and the preventive antibiotics is widely used when PROM occurs.

Safety of misoprostol versus oxytocin on fetuses

Our study found that there were no significant differences in Apgar scores, meconium-stained liquor, cord pH, and NICU admissions between misoprostol and oxytocin groups. These findings are in consistent with several previous studies [46, 51, 52]. But Li et al. reported a higher incidence of meconium-stained liquor with misoprostol use, which can be a marker of fetal distress [44]. Overall, the use of misoprostol for labor induction appears to be safe for neonatal outcomes, with no significant differences in key metrics such as Apgar scores and NICU admissions when compared to oxytocin. However, careful monitoring is necessary to ensure the safety for neonatal outcome.

Strengths and limitations

This meta-analysis exhibits several significant strengths. It stands as the only comprehensive review of RCTs conducted over the past two decades that directly evaluates the efficacy and safety of misoprostol versus oxytocin for labor induction in cases of PROM. The study encompasses a robust sample size of 2,980 participants, which is likely to provide ample statistical power to identify potential associations. Moreover, despite the observation of considerable heterogeneity in some of the summarized outcomes, we performed subgroup analyses to investigate and elucidate the underlying causes of this variability. These methodological strategies contribute to the study’s credibility and depth of analysis.

This study has several limitations that should be acknowledged. First, we are unable to evaluate maternal satisfaction, which is an important issue to consider when identifying the ideal labor induction method due to lack information on women’s views in the original studies. Crane’s study assessed the satisfaction of women with oral misoprostol compared to oxytocin and indicated that maternal satisfaction was increased in those who received oral misoprostol [20]. Conversely, Bender et al. determined that maternal satisfaction was enhanced in patients receiving oxytocin [36]. As of now, no other investigations have contrasted the satisfaction of patients administered misoprostol with that of those given intravenous oxytocin. The experience and satisfaction of mothers during childbirth are vital for their emotional and psychological well-being, influencing their future health choices and overall quality of care. Therefore, future RCTs should consider the maternal satisfaction when assessing the effects of misoprostol and oxytocin on labor induction.

Second, the high heterogeneity among the studies may be due to different doses of misoprostol. This highlights the need for further studies with standardized dosing and administration protocols to reduce heterogeneity and provide more consistent evidence, thereby improving the reliability of findings in this area.

Additionally, it was not possible to blind the physician and the patient to which individuals were enrolled in each group because of the different shape and administration. Though objective outcomes are not affected by bias, the clinical decisions made by physicians may be potentially influenced.

Forth, the included RCTs span a wide period of time, with the earliest study dating back to 1997. Therefore, the evolving clinical practices and protocols during these three decades may increase heterogeneity.

Future direction

First, future network meta-analysis need involved more RCTs, and explore the optimal dose and route of misoprostol for labor induction in women with PROM. Second, future RCTs should consider the maternal satisfaction when assessing effectiveness and safety of different methods of labor induction. Results on patient-reported outcomes will help clinicians make better clinical decisions. Third, there is limited direct evidence on the combined use of misoprostol and oxytocin for labor induction in patients with PROM [53]. Future researches can aim to evaluate combined applications. Several studies have evaluated the effectiveness and safety of using Foley catheter versus misoprostol to induce labor in women with PROM [54, 55]. Previous studies also compared Foley catheter and oxytocin for labor induction in women with PROM [56, 57]. Network meta-analysis could be conducted to compare different methods including combination regimens to refine clinical protocols. Forth, in future studies, the Medical Foundation 36-week PE risk model can be applied to identify high-risk groups to avoid fetal distress related to placental dysfunction after induction of labor [58]. In clinical practice, the timing and mode of labor induction could be optimized based on this model in combination with the indication for labor induction, gestational age, and parity, in order to optimize the induction strategy and reduce the risk of adverse outcomes.

Conclusion

The findings of this meta-analysis revealed that the use of misoprostol for IOL of PROM reduced the induction to delivery interval and duration of second stage of labor compared with oxytocin, without compromising maternal and neonatal outcomes. Furthermore, misoprostol led to a significant reduction in the rate of PPH compared with oxytocin. Considering the ease with which misoprostol can be administered by different routes, its cost-effectiveness and accessibility, as well as the current and previous studies, misoprostol is a suitable method of inducing labor in cases of PROM and may have potential as an oxytocin alternative. However, the optimal dose, preferred route of administration and maternal satisfaction need to be further studied.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CI:

Confidence interval

IOL:

Induction of labor

NICU:

Neonatal intensive care unit

OR:

Odds ratio

PPH:

Postpartum hemorrhage

PROM:

Prelabor rupture of membranes

RCT:

Randomized controlled trial

WMD:

Weighted mean difference

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Acknowledgements

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Funding

This project was supported by the Liaoning Provincial Natural Science Foundation of China (2022-MS-202).

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Authors and Affiliations

  1. Department of Obstetrics, Shunyi Women’s and Children’s Hospital of Beijing Children’s Hospital, Beijing, China

    Anluzi Che

  2. Department of Obstetrics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China

    Si Si & Jing Liu

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  1. Anluzi Che
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  2. Si Si
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Contributions

Anluzi Che contributed to the literature collection and manuscript writing; Si Si contributed to the literature collection, data analysis, and manuscript writing; Jing Liu contributed to project development and manuscript writing. All authors contributed intellectually to the work. All authors read and approved the final manuscript.

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Correspondence to Jing Liu.

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The study was approved by the Institutional Review Board (IRB) of the First Hospital of China Medical University (NO. 2025034 on Jan 27, 2025). The study followed the principles of the Declaration of Helsinki. The IRB of the First Hospital of China Medical University waived the need for informed consent because this was a meta-analysis study based on published data.

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Che, A., Si, S. & Liu, J. Efficacy and safety of misoprostol versus oxytocin for labor induction in women with prelabor rupture of membranes: a meta-analysis. BMC Pregnancy Childbirth 25, 461 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12884-025-07592-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12884-025-07592-2

Keywords

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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