Labor analgesia has been widely accepted in clinical practice, and an epidural block remains the most effective method of providing pain relief during labor.1–3 Previous meta-analyses, however, have indicated that epidural analgesia may slightly prolong the second stage of labor and increase the instrumental birth rate compared with nonepidural analgesia.4,5 Effects on the second stage of labor may be mediated by the concentration of local anesthetics. Compared with low concentrations of local anesthetics (LCLAs), defined as bupivacaine ≤0.1%, the use of high concentrations (HCs) of local anesthetics for labor epidural analgesia increases the instrumental birth rate.6 HCs of local anesthetics may impede motor function during the second stage of labor or cause pelvic floor muscle and abdominal muscle relaxation that interferes with fetal rotation during descent.7 Because of these concerns, LCLAs have become increasingly popular for epidural labor analgesia. Individual randomized controlled trials, however, have yielded inconsistent or conflicting findings8–19 on the obstetric outcomes of epidural analgesia with LCLAs compared with nonepidural analgesia.
One previous meta-analysis compared epidural analgesia with LCLA with nonepidural analgesia20; epidural analgesia was associated with a longer second stage of labor and an increased rate of instrumental birth. The meta-analysis, however, only included studies published before 2002, did not attempt to examine the quality of evidence, and defined LCLA as bupivacaine ≤0.125%. Given the changing definition of LCLA to bupivacaine ≤0.1%,6,21 and the additional trials published since 2002, we performed this systematic review and meta-analysis to compare the effects of epidural analgesia with LCLAs with that of nonepidural analgesia on obstetric outcomes.
This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The protocol was registered with PROSPERO under number CRD42015025971 on September 7, 2015.
We searched electronic databases for related reviews and references of meta-analyses on April 18, 2016. The searches were performed in PubMed, Embase, and the Cochrane controlled trials register (CENTRAL). We applied the highly sensitive search strategy of the Cochrane Collaboration to identify trials.22 The search strategy combined free text words and controlled vocabulary Medical Subject Heading terms. The full details of the search strategy are provided in the Appendix. The search equation for PubMed was adapted for each database. There were no limitations of language, time of publication, and article types. To reduce publication bias, the ongoing trials at ClinicalTrials.gov and the proceedings from the American Society of Anesthesiologists annual meetings over the last 5 years (from July 2010 to August 2015) also were retrieved.
Inclusion and Exclusion Criteria
Trials meeting the following criteria were included: (1) they were randomized controlled trials (RCTs), (2) they compared LCLAs of epidural analgesia with nonepidural analgesia, and (3) the full-text article was available. LCLAs were defined as ≤0.1% bupivacaine or an equipotent concentration of ropivacaine (≤0.17%) or levobupivacaine (≤0.1%).23–25 Epidural analgesia included epidural or combined-spinal-epidural analgesia. Nonepidural analgesia included systemic opioids, nitrous oxide, or nonpharmacologic analgesia.
Studies were excluded if epinephrine was given by epidural injection (because it may enhance the efficacy and prolong the duration of analgesia26) or if the obstetric outcomes were not evaluated. Studies that used HCs of local anesthetics for the initial loading dose were not excluded.
Primary and Secondary Outcomes
The primary outcomes were the duration of the second stage of labor and the instrumental birth rate. The second stage was defined as the time from full cervical dilation to delivery. The secondary outcomes were the duration of the first stage of labor, the cesarean delivery rate, and the spontaneous vaginal delivery (SVD) rate. The first stage was defined as the time from regular uterine contractions to full cervical dilation.
Data were retrieved independently by 2 researchers (T.W. and S.S.); disagreements were considered by a third researcher (S.H.) and discussed until a consensus was reached. One researcher (T.W.) designed a standard data extraction form in Excel, and the other researchers (S.S. and S.H.) amended and validated the design of this form before it was used for data extraction. The authors of the studies were contacted (by S.H.) and asked to provide missing data when possible. Information regarding the general characteristics of the study (first author and country), participants (characteristics of the population and parity), experimental interventions (timing and methods of analgesia, technique of administration, and doses), and outcomes were extracted. Dichotomous outcomes were extracted as the presence or absence of an effect. For continuous data, the means and SDs were obtained. If only the mean was provided, then the SD was obtained from the authors.
The quality of each study included in the meta-analysis was reviewed with the Cochrane Collaboration’s tool for assessing the risk of bias.27 The quality assessment methodology included the evaluation of random sequence generation, allocation concealment, the blinding of participants and personnel, the blinding of the outcome assessment, incomplete outcome data, selective reporting, and other bias. The overall quality was graded as a low risk of bias, a high risk of bias, or an unclear risk of bias for each domain via the use of a standardized tool.27 The quality of the enrolled trials were evaluated independently by 2 researchers (T.W. and S.S.), and differences in opinion were resolved by discussion with another researcher (S.H.).
The quality of each result was assessed by the GRADE system (version 3.6, the GRADE Working Group)28 and was graded with 1 of 4 levels: high quality, moderate quality, low quality, and very low quality. High-quality evidence was a RCT with no serious defects. The evidence level was downgraded according to 5 factors: risk of bias, inconsistency, indirectness, imprecision, and publication bias; it was upgraded according to 3 factors: large effect, plausible confounding, and dose response.
Review Manager (RevMan version 5.2.5; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for the data analysis. For dichotomous variables, the risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. For continuous variables that were evaluated with different methods among the included studies, the standardized mean difference (SMD) and 95% CI were calculated, whereas the mean difference (MD) and 95% CI were calculated for those that were evaluated with the same method. The I2 statistic was used for heterogeneity assessment, and I2 > 50% was considered as substantial heterogeneity. A random effects model was adopted for the data analysis in the case of heterogeneity, and a fixed effect model was used when heterogeneity was not found. The sources of heterogeneity were investigated by an analysis of prespecified subgroups that were defined according to the administration technique (ie, either continuous epidural infusion [CEI] or both CEI and a patient-controlled epidural analgesia [CEI + PCEA]) and whether rescue analgesia was used. P values for the interaction between subgroup and treatment effect were used to compare the treatment effects across subgroups29 (the criterion for significance was .15). To control the Type I error rate for multiple hypothesis testing, we used the Bonferroni correction as follows:30
The significance criterion for each test ,
where α is our priori significance level of 0.05 for the family of comparisons, and c is the number of comparisons. We calculated the power for each primary outcome with the post hoc power analysis using the G*Power 3.1 software.31,32 Sensitivity analyses were conducted to check the robustness of the data by removing each study one by one, excluding studies with a high risk of bias, those that administered nonpharmacologic analgesia to the control group, those that administered bupivacaine, or those that involved multiparous parturients. Potential publication bias was assessed with a funnel plot. In the absence of bias, these plots resemble a symmetrical inverted funnel.
A total of 4170 related studies were obtained from the database search, and 5 citations were retrieved from the manual reference-list search of the eligible studies. There were 2143 studies that were removed because they were duplicates. Then, we excluded 1755 studies after the initial review of the title and 196 after the abstract was reviewed. There were 81 studies that were considered relevant and were read in full. Of the 81 articles, 29,17 were written by the same authors and had the same data; thus, only one of them9 was ultimately included. After reviewing the full texts, 10 RCTs (published between 2002 and 2014) were selected for inclusion (Figure 1). No unpublished study in clinicaltrial.gov met the inclusion criteria.
A total of 1809 subjects were included in this meta-analysis, 904 were assigned to the epidural analgesia group, and 905 were assigned to the nonepidural analgesia group. Of the included trials, combined-spinal-epidural analgesia was used in 1 trial,8 and epidural analgesia was used in the other 9 trials.9–11,14–16,18,19,33 Ropivacaine was used in 5 trials,8,10,11,14,33 bupivacaine in 3 trials,9,15,16 and levobupivacaine in 2 trials.18,19 PCEA was used in 1 trial,16 CEI in 4 trials,8,10,11,18 CEI + PCEA in 3 trials,9,15,33 and manual administration in 2 trials.14,19 For the control group in the included trials, nonpharmacologic analgesia was used in 4 trials,8,14,18,33 remifentanil in 4 trials,9–11,19 pethidine in 1 trial,15 and fentanyl in 1 trial.16 Six trials included nulliparous parturients only,8,14–16,18,33 and 4 recruited both nulliparous and multiparous parturients.9–11,19 Characteristics of the included studies are listed in Table 1.
Assessment of the Risk of Bias Among the Included Studies
Eight trials were classified as having an unclear risk of bias and 2 as high risk of bias. The bias risk assessment is illustrated in Figure 2. The quality assessment of each result is illustrated in the Supplemental Digital Content 1 (https://links.lww.com/AA/B562). Two results were of moderate quality, 2 were low, and 1 was high. The reduction in the result quality was caused by inconsistency, indirectness, or imprecision of the results.
Effect on the Duration of the Second Stage of Labor
Eight studies with a total of 1445 women were included in the analysis of the duration of the second stage of labor. There was no significant difference between groups in the duration of the second stage of labor (MD = 5.71 minutes, 95% CI, −6.14 to 17.83, P = .36; I2 = 94%, Power = 0.99) (Table 2). The CIs were quite wide, and the heterogeneity was high. P values for the interaction between subgroup and treatment effect were both >0.15 (Table 3). The duration of the second stage of labor was not sensitive to a single study, and the pooled MD remained statistically insignificant after exclusion of individual studies. Likewise, there were no significant differences in the estimates after we excluded studies that administered nonpharmacologic analgesia to the control group, 2 studies with a high risk of bias, studies that administered bupivacaine, or those involving multiparous parturients. No evidence of publication bias was evident by visual inspection of the funnel plot (Figure 3).
Effect on the Instrumental Birth Rate
Eight trials with a total of 1442 women were included in this analysis. There was no significant difference between groups in the instrumental birth rate (RR = 1.52, 95% CI, 0.97–2.4; P = .07; I2 = 38%; Power = 0.86) (Table 2). P values for the interaction between subgroup and treatment effect were both >.15 (Table 3). The subgroup analysis showed a trend that parturients who received LCLAs through a CEI had a higher instrumental birth rate than those who received nonepidural analgesia (RR = 1.71, 95% CI, 1.07–2.74; P = .02; I2 = 0%). No difference in the instrumental birth rate was found whether or not rescue analgesia was used (Table 3). We sequentially removed each study, nonpharmacologic analgesia studies, high risk bias studies, administered bupivacaine studies, multiparous parturient studies, and then reanalyzed the remaining dataset; there were no major changes in the direction or magnitude of the statistical findings. No obvious asymmetry was detected in the funnel plots (Figure 4).
Effect on the Cesarean Delivery Rate
Nine trials involving 1681 women were analyzed. There was no significant difference between groups in the cesarean delivery rate (RR = 0.8, 95% CI, 0.6–1.05; P = .11; I2 = 0%) (Table 2).
Effect on the SVD Rate
Six trials with a total of 1456 women were included in this analysis. There was no significant difference between groups in the SVD rate (RR = 0.98, 95% CI, 0.91–1.06; P = .62; I2 = 25%) (Table 2). After removal of studies concerning with pharmacologic analgesia, we compared SVD rates between women undergoing epidural analgesia with LCLA and those receiving nonpharmacologic analgesia, and no major changes in the direction or magnitude of the statistical findings were observed.
Effect on the Duration of the First Stage of Labor
Four trials, which involved 438 women, were analyzed. There was no significant difference between groups in the duration of the first stage of labor (MD = 17.34 minutes, 95% CI, −5.89 to 40.56; P = .14; I2 = 0%) (Table 2).
To our knowledge, this is the first meta-analysis of RCTs that focused on comparing the obstetric outcomes of epidural with LCLAs and nonepidural analgesia in recent decades. It revealed that, compared with nonepidural analgesia, LCLAs for epidural analgesia is not associated with a prolonged duration of labor or any differences in the mode of delivery. Caution is advised in interpreting this result, given weakness in quality of the included studies.
For the duration of the second stage of labor, statistical power of the included studies was sufficient (power = 0.99), but the trial quality was “low” according to the GRADE profiler (Supplementary Digital Content 1), with substantial heterogeneity (Table 2, I2 = 94%). Secondary analyses to determine the causes of heterogeneity among the studies failed to identify significant interactions between any subgroup and treatment effect. Specifically, interactions grouped according to the administration technique (CEI or CEI + PCEA) and whether rescue analgesia was used for the duration of the second stage of labor were not significant (P > .15). We speculate that unmeasured confounders (eg, different timings of labor analgesia administration, doses of rescue analgesia, or indications for cesarean delivery and instrumental birth) may have contributed to the overall variation.
For the mode of delivery, we identified no differences in the rates of instrumental birth, cesarean delivery, or SVD. Our primary analysis focusing on the instrumental birth rate was based on moderate quality of evidence with limited statistical heterogeneity (Table 2, I2 = 38%). The statistical power of 0.86 and the lower limit of the 95% CI approach 1 suggest that a clinically meaningful difference cannot be excluded with confidence. It is notable that the point estimates for instrumental vaginal delivery (RR = 1.52) and cesarean delivery (RR = 0.8) trend in opposite directions; against the composite of these 2 outcomes, the point estimate for SVD approaches 1.0, with a 95% CI that excludes any clinically meaningful difference (RR = 0.98, 95% CI, 0.91–1.06). Future analyses should explore the hypothesis that epidural analgesia facilitates instrumental vaginal delivery for cases that would otherwise require cesarean birth.
Our findings contradict the 2002 meta-analysis of Liu and Sia,20 which found that epidural analgesia with LCLAs, compared with IV opioids, increase the risk of an instrumental vaginal delivery (odds ratio = 2.11, 95% CI, 0.95–4.65) and prolong the second stage of labor (weighted MD = 15.2 minutes, 2.1–28.2 minutes). Liu and Sia’s study included 7 studies published between 1971 and 2002; our meta-analysis included studies published between 2002 and 2014. In addition, Liu and Sia used ≤0.125% bupivacaine as the cutoff value for a low concentration dose, whereas we used ≤0.1% bupivacaine/levobupivacaine or ≤0.17% ropivacaine. Thus, our results more accurately reflect the effects of contemporary epidural analgesia with LCLAs on obstetric outcomes.
CEI is the traditional administration technique for labor analgesia but has been associated with high rates of breakthrough pain and an increase in the anesthesiologist’s workload.34–36 PCEA allows the patient to self-manage her labor pain, with the advantage of limiting the problems of overdosing and underdosing. CEI + PCEA, another administration technique, has been proven to increase maternal satisfaction, reduce the consumption of local anesthetic, and decrease motor block compared with CEI.37,38 A few trials revealed that there was no difference in the obstetric outcomes when analgesia was administered through these 3 manners.34,39–42 An exploratory analysis indicates that parturients who received LCLAs through CEI without PCEA had a greater instrumental birth rate than those who received nonepidural analgesia, a finding that was not confirmed for the other modes of administration. Further research is needed to confirm or refute this result.
There are some limitations of this meta-analysis. First, the number of included trials in this meta-analysis was small because of a fairly restrictive definition of LCLA. As concentrations of local anesthetics have declined progressively over time, only 10 trials published in 2002 or later met inclusion criteria. Second, methodologic limitations with studies and statistical heterogeneities among studies were significant. Some biases are unavoidable. For example, it is not possible to blind either anesthesiologists or patients to the presence or absence of epidural analgesia. Other biases could be corrected in future high quality randomized trials. For example, the indications of cesarean delivery and instrumental birth were not specified in some of the included articles, which allowed for the subjective intervention by doctors.
In conclusion, compared with nonepidural analgesia, epidural analgesia with LCLAs is not associated with a prolonged duration of the second stage of labor or an increased instrumental birth rate. Moreover, secondary analyses revealed no difference in the spontaneous delivery rate, suggesting that a women’s decision to accept or forego neuraxial analgesia does not impact mode of delivery when contemporary analgesic strategies are used. These findings are limited by significant heterogeneity among studies and low quality shown by the GRADE profiler. In the future, large-sample, high-quality RCTs should be performed to verify our conclusions.
PUBMED Search Equation
The following search strategy was developed for PubMed and was adapted for the other databases to be searched.
Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision); PubMed format
- (1) Randomized controlled trial [Publication Type]
- (2) Controlled clinical trial [Publication Type].
- (3) Randomized [Title/Abstract]
- (4) Randomly [Title/Abstract]
- (5) 1 OR 2 OR 3 OR 4
- (6) Humans [mesh terms]
- (7) 5 AND 6
- (8) Ropivacaine [Supplementary Concept]
- (9) Bupivacaine [Mesh]
- (10) Bupivacaine [tiab]
- (11) Ropivacaine [tiab]
- (12) Levobupivacaine [tiab]
- (13) 8 OR 9 OR 10 OR 11 OR 12
- (14) Labour [Title/Abstract]
- (15) Labor [Title/Abstract]
- (16) 14 OR 15
- (17) Analgesia [mesh terms]
- (18) 7 AND 13 AND 16 AND 17
Name: Ting-Ting Wang, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Name: Shen Sun, MD.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Name: Shao-Qiang Huang, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
This manuscript was handled by: Jill M. Mhyre, MD.
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