Effect of anesthesia on the success rate of external cephalic version: GRADE- assessed systematic review and meta-analysis of randomized controlled trials

Background External cephalic version (ECV) is a medical procedure in which an extracorporeal manipulation is performed to render the breech presentation (BP) fetus in the cephalic position. The use of anesthesia to facilitate repositioning has been evaluated in various randomized clinical trials (RCTs), but its potential effectiveness remains controversial. Methods A systematic literature search was carried out in 8 electronic databases. In the meta-analysis, a random effects model was used to calculate the pooled relative risk (RR) and its 95% confidence interval (CI), and the pooled standardized mean difference (SMD) and its 95% CI, in order to systematically assess the effect of anesthesia on the success rates of ECV, vaginal delivery, cesarean delivery as well as other outcomes. Relevant subgroup analyses, publication bias test and sensitivity analyses were also conducted. Results This review included 17 RCTs. Women who received anesthesia had a significantly higher incidence of successful ECV (RR: 1.37, 95% CIs: 1.19-1.58) and vaginal delivery (RR: 1.23, 95% CIs: 1.03-1.47), and a significantly lower incidence of cesarean delivery (RR: 0.69, 95% CIs: 0.53-0.91), compared with those who did not. Conclusion The administration of anesthesia not only significantly reduces maternal pain but also significantly increases the success rate of ECV in women with malpresentation at term, leading to a significant rise in the incidence of vaginal delivery. However, it may increase the incidence of maternal hypotension. Systematic review registration The protocol was prospectively registered with PROSPERO, registration CRD42022381552. Supplementary Information The online version contains supplementary material available at 10.1186/s13643-024-02616-y.


Introduction
The breech position (BP) is a prevalent anomalous fetal position encountered in clinical settings.It is noteworthy that roughly 96% of BP fetuses spontaneously reorient themselves to the cephalic position by 32 weeks of gestation.However, the remaining 4% of fetuses keep in the BP until full-term delivery [1].The breech vaginal delivery poses a significant risk of cord prolapse, trauma, asphyxia, and even death of the newborn.As a result, many medical institutions have made cesarean delivery the standard approach for BP [2].However, cesarean delivery has a number of possible adverse effects on the mother and newborn, including abnormal uterine bleeding, maternal urinary difficulties, neonatal asthma, and childhood overweight and obesity, which are gradually gaining public attention [3,4].Fortunately, the external cephalic version (ECV) provides a potential alternative to cesarean delivery, and its success rate is high in reducing the cesarean rate and overall cost of care without increasing the risk of perinatal complications [2,5].Moreover, ECV has been recommended by the Obstetrics and Gynecology societies of the United Kingdom, the United States, and other countries [6,7].
ECV is a medical procedure in which the BP fetus is externally manipulated to present in the cephalic position.Its success rate ranges from 35% to 86%, with an average success rate of 58% [8].Gestational age, number of deliveries, placental position, expertise of the obstetrician, etc. may affect the success rate of ECV [9].And the reaction of pregnant women to the pain produced by the ECV procedure largely influenced the procedure.In the early stages, many pregnant women ask to stop the procedure midway because of the unbearable pain [9].With the development of medical technology, various anesthetic interventions have been used to assist in the implementation of ECV, such as epidural anesthesia [8], spinal anesthesia [10], inhaled anesthesia [11], intravenous anesthesia [12] and so on.
However, the use of anesthesia in ECV is controversial.While some studies confirmed that anesthetic analgesia significantly enhances the success rate of ECV [13,14], others demonstrated no difference in the success rate of ECV with or without anesthesia [11,15].In addition, the toxic effects of anesthetics and excessive external force may cause adverse events [16,17].Assessing the possible risks and benefits of using anesthesia during ECV can help physicians and the public make benefit-maximizing decisions, which has important practical implications.A systematic review and meta-analysis by Goetzinger et al. retrieved randomized controlled trials (RCTs) published from 1966 to April 2011 and found that regional anesthesia was associated with higher ECV success rates and did not increase the incidence of adverse events [18].Magro-Malosso et al. performed a pooled analysis of RCTs through January 2016 and evaluated the effect of neuraxial analgesia on ECV compared to intravenous anesthesia or no anesthesia.And this meta-analysis concluded that neuraxial analgesia improves the success rate of ECV [19].In recent years, there has been an increasing number of RCTs on the effects of anesthesia on ECV.The aim of our study was to pool relevant published RCTs to systematically assess the effect of anesthesia (general and regional anesthesia) on the success rate of ECV and possible side effects.

Methods
Our study has been registered (registration number: CRD42022381552) with the PROSPERO database before December 16, 2022 (https:// www.crd.york.ac.uk/ prosp ero/ displ ay_ record.php?ID= CRD42 02238 1552).We did not use individual data but published data.These data have been widely utilized in research and are generally available.Therefore, we confirm that any aspect of the work covered in this manuscript has been conducted with ethical approval.We used the Cochrane Handbook for Systematic Reviews of Interventions for the preparation and conduct of this meta-analysis.We reported this meta-analysis with reference to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [20].

Search strategies
The literature searching was completed on January 2, 2024 for relevant available articles (no restrictions on language or date of publication) from the following databases: (1) s1.Relevant Chinese technical terms for the Chinese databases were used to search for published articles.Furthermore, references of all relevant articles and reviews were retrieved to search for additional eligible studies.The primary outcome was successful ECV, incidence of vaginal delivery, and cesarean delivery.Secondary outcomes were incidence of vaginal breech delivery, emergency cesarean delivery, transient bradycardia, nonreassuring fetal testing (excluding transient bradycardia) after ECV, maternal discomfort, maternal pain score, abruption placentae, vaginal bleeding or postpartum hemorrhage, satisfaction scores, and hypotension.More information on the time points and scales specifics of the different studies outcomes was shown in Table s2.

Inclusion and exclusion criteria Inclusion criteria
Studies were included in this meta-analysis if they met the following criteria: (1) research must be the RCT study; (2) The study population was only women ≥36 weeks of gestation; (3) The exposure factors were general or regional anesthesia, including epidural anesthesia, spinal anesthesia, inhalation anesthesia and intravenous anesthesia; (4) The control groups were all blank controls without anesthesia (placebo); (5) The data of the experimental and control groups were complete, including the number of occurrences in the experimental group and the total number of occurrences in the control group and the total number of occurrences in the control group; (6) If the same population had multiple publications, the study with the larger sample size or more information available was selected.

Exclusion criteria
The exclusion criteria were as follows: (1) non-RCTs studies; (2) studies in women <36 weeks' gestation; (3) unrelated, repeatedly published literature with no relevant data; (4) comments or letters to the editor, case reports, and abstracts only; and (5) preprint servers, such as medRxiv/bioRxiv, etc.

Data extraction
After removing duplicates, all abstracts and titles were independently screened by two evaluators (LL and ZF) to remove irrelevant articles.We downloaded and read the full text of potential studies and included those that met the selection criteria for this systematic review.Data extraction of the included literature was performed by 2 investigators (LL and ZF).Data extraction included: name of first author, year of study, study region, number of study subjects, type of anesthesia, primary outcome and secondary outcomes.Corresponding authors were contacted twice (reminder emails were sent after the first email) if the data required for the meta-analysis were not available in the published article.

Quality assessment
Two reviewers independently assessed the risk of bias within each study by using a Cochrane risk of bias instrument [21,22].We evaluated random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other sources of bias.The assessors resolve the differences through discussion, and two arbitrators decide on any unresolved differences.When risk of bias varied across included studies, we stratified studies according to risk of bias and produced two estimates of the intervention effect: from trials at low risk of bias and from all studies.The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to determine the certainty of the evidence [23].

Statistical analysis
Statistical analyses of all data were performed with Stata (version 15.0; Stata Corp, College Station, TX) and Rev-Man (version 5.3; Cochrane library) software.Relative risk (RR) is the frequency of the outcome in the exposed group divided by the frequency of the outcome in the control group.RR and 95% confidence intervals (95% CIs) were estimated for binary outcomes.Standardized mean difference (SMD) was obtained by dividing the difference between the estimated means of the two groups by the mean standard deviation [24].The SMD express the size of the treatment effect in each study relative to the variability observed in that study [25] .SMD and 95% CIs were calculated for continuous outcomes, which eliminates the effect of dimension when combining statistics [26].The pooled RR is considered statistically significant if 95% CI did not contain 1, and the pooled SMD is considered statistically significant if 95% CI did not contain 0. To generalize our findings beyond the included studies, the random-effects model is the most appropriate model for meta-analysis [27].Individual and pooled estimates were illustrated using forest plots.Subgroup analyses were also performed to examine the impact of anesthesia on the success rate of ECV according to study region and type of anesthesia.Sensitivity analyses were performed to explore whether a study had a substantial effect on the outcome.Publication bias was assessed qualitatively by funnel plots and quantitatively by Begg test and Egger's test.In all analyses, P values less than 0.05 were considered statistically significant.

Study selection and characteristics
An electronic search finalized 419 publications, and 32 potentially relevant studies were finally screened after eliminating duplicates and screening titles and abstracts.Of the 32 potentially relevant studies, a total of 16 publications met the inclusion criteria [8-12, 14, 15, 28-36].The detailed process of literature screening is shown in Fig. 1.Therefore, 16 publications with a total of 17 RCTs were finally included in this meta-analysis, of which the study by Khaw et al. [10] included two RCTs .The characteristics of the included studies are shown in Table 1.
The inclusion and exclusion criteria were presented in Table 2.
Subgroup analysis of different anesthesia types (Table 4) showed that regional anesthesia significantly increased the success rate of ECV.The ECV success rate with regional anesthesia was 1.65 times higher than that without anesthesia (RR: 1.65, 95% CIs: 1.38-1.98,P<0.001,I 2 =37.8%), whereas the use of general anesthesia did not have a significant effect on ECV success (RR: 1.16, 95% CIs: 1.00-1.34,P=0.052,I 2 = 19.9%).Comparison of the different types of regional anesthesia revealed that both spinal anesthesia (RR: 1.48, 95% CIs: 1.17-1.89,P=0.003,I 2 =71.0%) and epidural anesthesia (RR: 1.91, 95% CIs: 1.36-2.68,P=0.005,I 2 =0%) significantly increased the success rate of ECVs, with the use of epidural anesthesia had a greater likelihood of ECV success.For the different types of general anesthesia, inhalation anesthesia (RR: 1.00, 95% CIs: 0.84-1.19,P=0.244,I 2 =0%) did not have a significant effect on ECV success, whereas intravenous anesthesia (RR: 1.27, 95% CIs: 1.05-1.54,P=0.005,I 2 =17.6%) significantly improved ECV success.Moreover, we found that regional anesthesia significantly reduced the incidence of cesarean delivery (RR: 0.65, 95% CIs: 0.43-0.97,P=0.005,I 2 =76.8%), while there was no statistically significant correlation between general anesthesia (RR: 0.92, CI: 0.77-1.11,P=0.227,I 2 =25.9%) and the incidence of cesarean delivery.In terms of vaginal delivery rate, we found that although regional anesthesia (RR: 1.32, CI: 0.98-1.80,P=0.062,I 2 =81.0%) had no significant effect on vaginal delivery rate, one type of regional anesthesia, epidural anesthesia (RR: 2.20, CIs: 1.20-4.03,P<0.001,I 2 =53.0%), significantly increased the vaginal delivery rate.Neither general anesthesia nor the specific type (inhalation anesthesia, intravenous anesthesia) was significantly associated with vaginal delivery rates.The above results showed that there are differences in the effects of different types of anesthesia on the success rate of ECV, the incidence of vaginal delivery, and the incidence of cesarean delivery; however, there is a large overlap in the 95% CIs of the effect values for the different subgroups, and therefore the differences between the subgroups cannot yet be considered statistically significant.
For the different regions (Table 5), we extracted raw data from 17 studies (Khaw et al., 2015 [10] included two RCTs).The results showed that anesthesia significantly increased the success rate of the ECV in Asia (RR: 1.41, 95% CIs: 1.12-1.68,P=0.005,I 2 =72.1%) and North America (RR: 1.46, 95% CIs: 1.03-2.07,P<0.001,I 2 =45.4%).In Europe, anesthesia improved the success rate of the ECV, but the difference was not statistically significant (RR: 1.04, 95% CIs: 0.88-1.23,P = 0.323, I 2 = 0%).The above results showed that there are differences in the effects of different regions on the success rate of ECV; however, there is a large overlap in the 95% CIs of the effect values for the different subgroups, and therefore the differences between the subgroups cannot yet be considered statistically significant.

Study quality assessment and risk of bias
Using the Cochrane risk of bias assessment tool, all RCTs included in the meta-analysis had low risks of bias in most criteria.The risk of bias graph and summary are illustrated in Fig. 3.The five domains where most assessments were 'low' risk were "random sequence generation" (n=13), "allocation concealment" (n=13), "incomplete outcome data" (n=16), "selective reporting" (n=15) and "other bias" (n=10).'Unclear' risk assessments were most common in "blinding of participants and personnel" (n=8).Only one domain with the most 'high' risk assessments were "blinding of participants and personnel" (n=9).The study with the least risk of bias assessments was Wang et al. [31] with seven low risk assessments.Four studies (two are included in Khaw et al, 2015) had six 'low' risk assessments across domains [10,14,35].Two studies with the most (n=3) uncertainty in risk of bias across domains was Yang et al. [32] and Dugoff et al. [9].The studies with the highest risk of bias across domains (n=3) were Han et al. [34], Dochez et al. [15] and Burgos et al. [11].Most of the included studies showed an overall low risk of bias.However, for domains 4 and 5: Blinding of participants and personnel and Blinding of outcome assessment, the overall risk of bias was  high.The fact that most studies did not blind medical personnel and that anesthetic injections and surgical procedures were performed by them contributed to the high risk of this bias.Because the behavioral intervention process cannot be fully blinded, this bias is present in all studies and ultimately leads to an overestimation of effects.There was a low risk of bias in the Cochrane risk of bias assessment, and the GRADE assessment showed a moderate to high certainty of anesthesia's effect on the primary outcomes (Fig. 4).In addition, the funnel plot, constructed from the studies corresponding to successful ECV, vaginal delivery and cesarean delivery, did not suggest the presence of potential publication bias (Fig. 5).The Begg's test and Egger's test did not reveal publication bias.In this study, for successful ECV, the P-value for Begg's test was 0.149 and for Egger's test was 0.005.For vaginal delivery, the P-value for Begg's test was 0.115 and for Egger's test was 0.013.For cesarean delivery, the P-value for Begg's test was 0.322 and for Egger's test was 0.502.

Sensitivity analysis
For successful ECV, vaginal delivery, and cesarean delivery, the conclusions were not altered after excluding each article to calculate the heterogeneity and effect size.Sensitivity analysis results are shown in Fig. 6.

Discussion
It is a widely recognized fact that the primary objective of ECV is to reposition the fetus in order to increase the likelihood of vaginal delivery.Our meta-analysis indicates that the success rate of ECV among pregnant women who were anesthetized was 1.37 times higher than those who were not anesthetized.Moreover, the rate of vaginal delivery was 1.23 times higher in the anesthetized group, and the risk of cesarean delivery was significantly lower.However, it should be noted that not all types of anesthesia were equally effective.Inhalation anesthesia did not have a statistically significant effect on the success rate of ECV compared to the control group without anesthesia.
Our meta-analysis included three studies that employed nitrous oxide (N 2 O) as an analgesic gas for inhalation anesthesia, but none of them showed a significant effect on the success rate of ECV [11,15,35].N 2 O is an easy-to-use and safe analgesic, but its analgesic power is only one-third to one-half that of clinical doses of intravenous fentanyl [37], which may not be sufficient to affect the performance of ECV procedures.Intravenous, spinal, and epidural anesthesia have all been found to contribute to successful ECV.However, it was observed that only the administration of epidural anesthesia led to a significant increase in the rate of vaginal delivery and a decrease in the rate of cesarean delivery.The role of epidural anesthesia was also supported by Mancuso et al., who reported a 1.8-fold increase in ECV success and a 2.2-fold increase in vaginal delivery of cephalic infants under epidural anesthesia [8].Conversely, spinal anesthesia, which is another form of regional anesthesia, did not have a significant effect on the rate of cesarean delivery or vaginal delivery.This may be due to the differences in characteristics of the anesthesia and the mechanism of action.In conclusion, our findings suggest that epidural anesthesia may be more suitable for ECV, and that further research should explore the specific types and doses of anesthetics required for optimal epidural anesthesia.
Although the utilization of intravenous and spinal anesthesia increased the success rate of ECV, its effectiveness on vaginal delivery or cesarean delivery did not been significantly demonstrated.The use of anesthesia during ECV may have implications for cesarean and vaginal delivery.Specifically, the expected discomfort and pain during ECV might prompt some pregnant women to decline the procedure, choosing instead to have a cesarean section during childbirth.And the use of anesthesia may increase their willingness to undergo ECV and improve the success of the procedure while increasing the likelihood of vaginal delivery [36,38].However, there are many other factors that affect cesarean and vaginal delivery.One study conducted on pregnant women in Thailand discovered that a history of vaginal delivery, maternal body mass index (BMI), estimated fetal weight and gestational age were all significant factors affecting the probability of a successful vaginal delivery [39].In many cases, the decision to perform a cesarean section is often highly dependent on the obstetrician-gynecologist. Consequently, for fetuses in BP, the healthcare providers should make an evaluation based on multiple factors, taking into account not only the appropriate type of anesthesia for ECV, but also the necessity of performing ECV.Furthermore, we observed a minimal occurrence of adverse events in all studies; however, the use of anesthesia may heighten the possibility of maternal hypotension.Despite the wide CIs in the meta-analysis regarding hypertension, possibly influenced by heterogeneity, our results indicate that the potential harm caused by anesthesia warrants significant attention in clinical practice.We speculated that the heterogeneity might stem from variations in inclusion and exclusion criteria across the studies or differences in the methods used to measure blood pressure.Only the study by Mancuso et al. [8] provided details on the measurement of maternal blood pressure, while no such information was reported in the other studies.Maternal hypotension is a common complication of spinal anesthesia and has a strong correlation with perinatal outcomes [40].This is primarily because sympathetic relaxation produced by spinal blockade leads to vasodilation, which can result in maternal hypotension.Maternal hypotension may impact uterine blood flow and fetal circulation, leading to fetal hypoxia, bradycardia, and acidosis [41].In the event that anesthesia is employed during ECV surgery, it is crucial to monitor any changes in maternal blood pressure and implement preventive and corrective measures promptly.
Our study discovered distinct impacts of anesthesia use on the effectiveness of ECV in various regions, which may be attributed to the primary type of anesthesia employed, the ECV surgical technique, and cultural disparities in pain management.Regrettably, the limited quantity of relevant studies prevented us from conducting a more detailed analysis by further categorizing the type of anesthesia.Such categorization can be conducted in subsequent studies to refine the findings.
The strengths of our study are the inclusion of relevant RCTs published to date, the low bias of included studies, and the moderate quality.At the same time, there are some limitations of this study.First, although our meta-analysis performed subgroup analyses of different types of anesthesia, the anesthetic drugs used in different studies and the doses of the drugs were different, which may have an impact on the results.Currently, there is a lack of uniform standards internationally regarding anesthesia care for ECV, and the further studies of anesthetic drugs could be conducted to try to explore the types of anesthetic drugs and doses used that are most appropriate for ECV.Second, there was large overlap in the 95% CIs of effects between groups in the subgroup analysis results of this study.Although one subgroup analysis was statistically significant while another was not, the latter may simply reflect a lack of information rather than a smaller (or no) effect [42].Thus, our study was only able to explore possible sources of heterogeneity through subgroup analyses and could not clarify differences between subgroups.Third, maternal age, parity, and estimated fetal weight may be confounding factors in different studies [43], and the heterogeneity caused by these factors is difficult to control.Finally, most of the RCTs we included were designed to study successful ECV as a primary outcome and were not sufficiently competent to detect differences in the incidence of cesarean delivery and other perinatal outcomes, resulting in our meta-analysis of other outcomes being less comprehensive.

Conclusion
The administration of anesthesia not only significantly reduces maternal pain, but also significantly increases the success rate of ECV among women with malpresentation at term, which then increases the incidence of vaginal delivery and reduces the incidence of cesarean delivery.However, it may increase the incidence of maternal hypotension.Possible confounders such as maternal age, parity, estimated fetal weight, etc. need to be controlled for to further refine the meta-analysis.

Fig. 1
Fig. 1 Flow diagram of the study search and selection process

Fig. 2
Fig. 2 Results of meta-analysis of anesthesia on the risk of successful ECV, vaginal delivery (B) and cesarean delivery (C)

Fig. 3
Fig. 3 Risk of bias graph (A) and summary (B)

Table 1
Characteristics of the included trials

Table 2
[10]usion and exclusion criteria of the included trialsFetal abnormalities, intrauterine fetal death, suspicion of fetal growth restriction, fetal weight above 3800 g, maternal cardiovascular disease, American Society of Anesthesiologists class >2, severe hypertension, allergy to any trial medications, amniotic fluid index<4 cm, Doppler cerebroplacental ratio >5th percentile, abnormal cardiotocographic recordings, contraindications to vaginal delivery, uterine abnormalities, coagulation disorders, Rhesus incompatibility, multiple gestation, rupture of membranes and/or placental abruption Khaw et al, 2015[10]American Society of Anesthetists status I-II, term parturients, breech-presenting fetus Contraindications to ECV including patients with known uterine scar or anomaly,

Table 2
(continued) GAGestational age, wks weeks, NST Nonstress test, EFW Estimated fetal weight, IUGR Intrauterine growth restriction, FHR Fetal heart rate, AFI Amniotic fluid index, ASA American Society of Anesthetists, BMI Body mass index, ECV External cephalic version, N 2 O Nitrous oxide, BP Breech presentation, HIV Human immunodeficiency virus

Table 3
Primary and secondary outcomes

Table 3
(continued)Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported

Table 3
(continued) ECV External cephalic version, RR Relative risk, SMD Standardized mean difference, VAS Visual analog scale, NRPS Numerical Rating Pain Scale

Table 4
Subgroup analysis of successful ECV, vaginal delivery and cesarean delivery among different types of anesthesia ECV External cephalic version, RR Relative risk, CIs Confidence intervals

Table 5
Subgroup analysis of successful ECV in different regionsECV External cephalic version, RR Relative risk, CIs Confidence intervals