Effect of Epidural Dexmedetomidine as an Adjuvant to Local Anesthetics for Labor Analgesia: A Meta-Analysis of Randomized Controlled Trials

Background This study aims to determine the analgesic effect and safety of dexmedetomidine as an adjuvant to epidural local anesthetics during labor. Methods Randomized controlled trials comparing epidural blocks with or without dexmedetomidine for labor analgesia were comprehensively searched. Review manager 5.4 was used to analyze the extracted data. Results Compared with placebo and opioids, dexmedetomidine relieved labor pain of 15 min (P=0.002), 30 min (P=0.01), and 120 min (P=0.02) after block and at the moment of fetal disengagement (P=0.0002), decreased mean arterial pressure of 120 min (P=0.01), heart rate of 30 min (P=0.003), 60 min (P < 0.00001), and 120 min (P < 0.00001) after block, blood loss (P=0.02), and the incidence of nausea/vomiting (P=0.006), and increased the incidence of maternal bradycardia (P=0.04). However, sensitivity analysis only found that the incidence of nausea/vomiting was significantly different. Compared with placebo, dexmedetomidine relieved labor pain of 30 min after block (P < 0.00001) and did not increase the incidences of side effects, but only two studies were enrolled. Compared with opioids, dexmedetomidine decreased the incidence of nausea/vomiting (P=0.002), increased the incidence of maternal bradycardia (P=0.04), and had a similar effect on labor pain relief; however, sensitivity analysis found that significant difference existed only at the incidence of nausea/vomiting. Other outcomes from meta-analysis or subgroup analysis were not different. Conclusions Epidural dexmedetomidine has the potential to offer a better analgesic effect than placebo, similar labor pain control to opioids, and has no definite adverse effects on the parturient or fetus, but more high-quality studies are needed to confirm these conclusions.


Introduction
Labor pain causes significant suffering to parturients, both physically and mentally. Additionally, it increases the risk of childbirth [1,2] and, to some extent, increases the rate of cesarean section [3]. Labor analgesia refers to the use of various methods to reduce or eliminate maternal labor pain and is increasingly applied in obstetrics [3]. e features of ideal labor analgesia include maternal and fetal safety, rapid onset, good analgesic effect, and few adverse reactions [3].
Currently, epidural analgesia with local anesthetics has been the most effective and preferred choice for labor and delivery [4,5]. However, it also has some disadvantages during labor, including motor blockade, maternal hypotension, longer second stage of labor, and urinary retention [6].
us, a major challenge for anesthesiologists is the correct balance of local anesthetics and the management of complications. Local anesthetics combined with opioids were used to address these challenges. However, it has been shown that epidural opioids are often accompanied by adverse effects, such as respiratory depression, lethargy, pruritus, nausea, and vomiting [7].
Dexmedetomidine, a highly selective α2-adrenoceptor agonist, possesses anxiolytic, sedative, and analgesic properties without causing respiratory depression [8,9]. Moreover, dexmedetomidine combined with local anesthetics has been successfully used for epidural labor analgesia with few side effects [10,11]; however, no published meta-analysis has evaluated the effect of epidural dexmedetomidine on labor analgesia. To provide a high evidence level for clinical application, we conducted a meta-analysis comparing dexmedetomidine with placebo or opioids as an adjuvant to local anesthetics for labor analgesia with respect to analgesic effect and safety.

Methods
is meta-analysis was conducted by following recommendations of the Cochrane Handbook for Systematic Reviews of Interventions [12] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13].
e study was registered with PROSPERO (CRD42020167287).

Search Strategy. Two authors comprehensively searched
Embase (1980-2020.08), PubMed (1966-2020.08), Medline (1966-2020.08), and the Cochrane Library using keywords ("labor OR labour OR vaginal delivery OR vaginal," "analgesia OR pain," and "dexmedetomidine") without language restriction. e databases of https://clinicaltrials.gov/ and Chinese Clinical Trial Registry were also searched by using the following keywords: "labor OR labour OR vaginal delivery OR vaginal" and "dexmedetomidine." e search strategy can be found in Appendix A. e references of the identified trials and systematic reviews were also manually searched to identify any potentially relevant trials.

Inclusion
Criteria. Trials were included in our metaanalysis to determine whether they met the PICOS (patients, intervention, comparator, outcome, and study design) criteria. (1) Patients: nulliparous women undergoing epidural anesthesia during labor. (2) Intervention: epidural block with epidural dexmedetomidine for labor analgesia without dosage restriction. (3) Comparator: epidural block with or without epidural opioids (morphine, fentanyl, sufentanil, and remifentanil) for labor analgesia. (4) Outcomes: visual analog scale (VAS) for pain, mode of delivery, duration of labor, blood pressure, heart rate (HR), blood loss, onset of analgesia, motor block, level of sedation, complications, fetal 1-min and 5-min Apgar scores, and umbilical artery pH and partial pressure of oxygen (PaO 2 ). (5) Study design: randomized controlled trials (RCTs). Trials with insufficient outcome data were excluded. Two authors independently assessed the eligibility of studies. In cases of disagreement, a consensus was reached through discussion with a third author where necessary.

Data Extraction.
Two reviewers independently retrieved the relevant data from the articles using a standard data extraction form. e primary outcome was the VAS score on a 0-10 scale during labor. If the pain scale was assessed by a 0-100 scale, then, it was converted to a 0-10 scale by dividing by 10. e secondary outcomes were the mode of delivery, duration of labor, onset of analgesia, blood pressure, HR, blood loss, motor block, level of sedation, complications, 1min and 5-min Apgar scores, and umbilical artery pH and PaO 2 . Missing data were requested from study authors.

Assessment of Methodological Quality.
Two authors assessed the quality of the included studies independently based on the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions and a modified Jadad 7point scale. A study with a modified Jadad score <4 points is regarded as low-quality [14]. If the number of included RCTs was ≥10, publication bias was assessed by a funnel plot [15].

Statistical
Analysis. Review Manager software 5.4 was used for meta-analysis. Mean differences (MDs) with 95% confidence intervals (CIs) were used to assess continuous outcomes. Odds ratios (ORs) with 95% CIs were used to assess dichotomous outcomes. Statistical heterogeneity among the included studies was assessed by P and I 2 . e control group included placebo and opioids, so all metaanalyses were conducted by using a random-effect model. e inverse variance and Mantel-Haenszel methods were used to combine separate statistics. Sensitivity analysis was conducted by omitting one study in turn to examine the reliability and conclusiveness of the available evidence. Subgroup analysis was conducted in accordance with different controls (placebo or opioids). A P value less than 0.05 was considered significant.
Additionally, trial sequential analysis (TSA) software 0.9.5.10 Beta was used to examine the reliability and conclusiveness of the available evidence according to a previous meta-analysis [16,17]. To calculate the required information size (RIS), all outcomes used two-sided tests with a type I error of 5% and a power of 80%, continuous outcomes used an empirical mean difference, and dichotomous outcomes used a low bias-based relative risk reduction and a literaturebased incidence in controls (5% for nausea/vomiting [18]).

Secondary
Outcomes. Statistical differences ( Table 2, Supplementary Figures 2-5) between the dexmedetomidine group and control group were detected with the measurement of mean arterial pressure (MAP) of 120 min (P � 0.01) after block, HR of 30 min (P � 0.003), 60 min (P < 0.00001), and 120 min (P < 0.00001) after block, blood loss (P � 0.02), and incidences of maternal bradycardia (P � 0.04) and nausea/vomiting (P � 0.006). Other outcomes, including the duration of first and second stages, mode of delivery, onset of analgesia, MAP of 15 min, 30 min, and 60 min after block and at the moment of fetal disengagement, HR of 15 min after block and the moment of fetal disengagement, level of motor block assessed by a modified Bromage scale, 1-min and 5-min Apgar scores, umbilical artery pH and PaO 2 , and incidences of hypotension, itching, shivering, urinary retention, and fetal HR abnormality, were not significantly different ( Table 2, Supplementary Figures 2-11). Heterogeneities among studies were detected at the time of the first (I 2 � 92%) and second (I 2 � 97%) stages, onset of analgesia (I 2 � 93%), MAP of 15 min (I 2 � 91%) and 30 min (I 2 � 52%) after block, and at the moment of fetal disengagement (I 2 � 92%), HR of 15-min after block (I 2 � 93%) and at the moment of fetal disengagement (I 2 � 96%), level of motor block (I 2 � 95%), and umbilical artery PaO 2 (I 2 � 96%). Evidence-Based Complementary and Alternative Medicine

Sensitivity Analysis and Subgroup Analysis and TSA.
To examine the reliability and conclusiveness of the positive results mentioned above, sensitivity analysis was conducted and we found that the incidence of nausea/vomiting was significantly different regardless of which study was omitted, and no heterogeneities were detected (data not shown). To further confirm the conclusiveness of the incidence of nausea/vomiting, TSA was performed, and the Z curve crossed the conventional boundary, TSA boundary, and RIS (Supplementary Figure 12).
Subgroup analysis of all outcomes was conducted through different controls (placebo or opioids). Compared with placebo (Table 3), a significant difference was detected at a VAS score of 30 min after block (P < 0.00001), but sensitivity analysis could not be conducted because only two studies of 158 participants were enrolled. Compared with opioids (Table 3), significant differences were detected regarding the incidences of maternal bradycardia (P � 0.04, I 2 � 0%) and nausea/vomiting (P � 0.002, I 2 � 0%) with no heterogeneities. To confirm the reliability and conclusiveness of the results of the subgroup analysis, sensitivity analysis was further carried out, and it was only found that the incidence of nausea/ vomiting always had significant differences regardless of which study was omitted (data not shown).

Discussion
is meta-analysis was performed to investigate the effectiveness and safety of epidural dexmedetomidine during labor analgesia. In total, five RCTs comparing dexmedetomidine with placebo and four RCTs comparing dexmedetomidine with opioids were enrolled for metaanalysis. Pooled data from our meta-analysis found that compared with placebo and opioids, epidural dexmedetomidine decreased the VAS score, MAP, HR, blood loss, and the incidence of nausea/vomiting, and increased the incidence of maternal bradycardia. However, sensitivity analysis only found that the incidence of nausea/vomiting always had significant differences. Moreover, when compared with placebo, subgroup analysis found that dexmedetomidine relieved labor pain and did not increase the incidences of side effects; however, sensitivity analysis of labor pain could not be conducted for only two studies enrolled. When compared with opioids, subgroup analysis found that dexmedetomidine decreased the incidence of nausea/vomiting, increased the incidence of maternal bradycardia, and had similar effect on labor pain. However, sensitivity analysis only found that the incidence of nausea/vomiting always had significant differences. In addition, both meta-analysis and subgroup analysis found no significant differences in other outcomes. Taken together, this meta-analysis found that epidural dexmedetomidine had the potential to alleviate labor pain and did not increase the incidences of adverse effects compared with placebo, provided similar analgesic effects and decreased the incidence of nausea/vomiting compared with opioids, indicating that dexmedetomidine can replace opioids and be safely used in epidural block during labor analgesia.
Although many meta-analyses have demonstrated that single-shot injection of subarachnoid or epidural dexmedetomidine prolongs the duration of analgesia and decreases Li et al. [25] Li et al. [26] Liu et al. [27] Selim et al. [21] Jun et al. [3] Zhang and Li [22] Zhang et al. [24] Zhao et al.  Evidence-Based Complementary and Alternative Medicine better pain control during labor than placebo, but more high-quality studies are needed to strengthen this conclusion. e greatest concern of epidural dexmedetomidine administration is safety. According to these meta-analyses [28,31], although epidural dexmedetomidine significantly reduced the incidence of bradycardia compared with placebo, the incidence of hypotension was not different, and the overall risk of hypotension and bradycardia was statistically insignificant. Similarly, no definite conclusions were reached for epidural dexmedetomidine to increase the incidences of hypotension and bradycardia when compared with placebo and/or opioids in this study. Nausea and vomiting are the most common side effects of epidural anesthesia [28]. ree prior meta-analyses [28,31,32] found that the incidence of nausea/vomiting was not different between epidural dexmedetomidine and placebo. A recent meta-analysis [35] has found that epidural dexmedetomidine significantly reduced the incidence of nausea/vomiting compared with epidural opioids, which is completely consistent with our results.
Taken together, epidural dexmedetomidine has no definite adverse effects on the parturient.
Different from other surgeries, the safety of the fetus should be considered in the cesarean section and labor analgesia. Compared with placebo, spinal anesthesia with intrathecal dexmedetomidine had no significant differences in the 1-min or 5-min Apgar scores or umbilical arterial pH and PaO 2 [29]. In this study, epidural dexmedetomidine had no differences in the duration of stages, mode of delivery, 1min or 5-min Apgar scores, umbilical artery pH and PaO 2 , and fetal HR with placebo and/or opioids, indicating that epidural labor analgesia with dexmedetomidine is safe for fetuses.
Some limitations are present in our meta-analysis. Except for the incidence of nausea/vomiting, due to the small sample size and heterogeneity among the included studies, other outcomes were unable to draw firm conclusions; additional high-quality RCTs are required to fully evaluate these outcomes. e actual dose of dexmedetomidine was not mentioned in all enrolled RCTs; thus, this study did not

Conclusion
Dexmedetomidine as an adjuvant to epidural local anesthetics has the potential to offer a better analgesic effect than placebo, similar labor pain control to opioids, and has no definite adverse effects on the parturient or fetus. Still, more high-quality RCTs are needed to confirm these conclusions.

Data Availability
e data used to support the findings of this study are included within the article.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
Nijuan Li conceptualized the study, curated the data, and wrote the original draft. Li Hu curated the data and wrote the original draft. Chunping Li was responsible for software and did formal analysis. Xuelin Pan supervised the study and reviewed and edited the manuscript. Yong Tang conceptualized and supervised the study and reviewed and edited the manuscript.