Bupivacaine for Epidural Labour Analgesia and the Influence of Local Anaesthetic Choice (Bupivacaine vs Ropivacaine) on the Development of Epidural-Related Maternal Fever: Systematic Review and Meta-Analysis

Abstract

Background: Epidural-related maternal fever (ERMF) is a side effect of epidural analgesia (EA) during labour that has been linked to perinatal and neonatal morbidity. It has been proposed that local anaesthetics used for EA lead to maternal fever through a sterile inflammation mechanism. Bupivacaine and ropivacaine are the most widely used local anaesthetics. Bupivacaine, however, is associated with higher toxic effects than other local anaesthetic drugs. Nevertheless, existing evidence concerning the aetiology of ERMF remains scarce. Objectives: This study aims to assess the relationship between bupivacaine EA and maternal fever and investigate the influence of local anaesthetic choice on the development of ERMF during labour. Furthermore, this study will comprehensively examine the literature discussing the mechanisms of sterile inflammation and the possible role of local anaesthetics. Methods: A systematic review and metal-analysis was conducted. The PubMed database and the reference list of randomised control trials (RCTs) that compared bupivacaine EA with nonepidural alternative analgesic medication and studies that compared bupivacaine and ropivacaine EA for the incidence of maternal fever (Temperature ≥ 37.5°C) published from inception to June 2021 were searched; the last search was conducted on 27 June 2021. Studies were included based on eligibility criteria and outcomes and assessed using the risk-of-bias tool (RoB 2.0) for RCTs. Data were extracted by one person via a designed form for relevant characteristics. Main results: Reports detailing 44 out of 368 RCTs were assessed for full-text eligibility. A total of six studies involving 2,729 women in labour were included to evaluate the first outcome (incidence of maternal fever after administration of bupivacaine EA versus non-epidural analgesic medication). In addition, one study involving 565 women was used to examine the other outcome (influence of local anaesthetic choice on ERMF by comparing bupivacaine with ropivacaine). The overall RoB was ‘unclear’ for one study, while the others were considered ‘high risk’. Meta-analysis results of studies regarding the first outcome suggested that the incidence of maternal fever is significantly higher when administering bupivacaine EA compared to intravenous opioids analgesia (risk ratio 3.93; 95% confidence interval 3.03, 5.09; P < 0.00001; 𝐼 2 = 14%; low heterogeneity). Only a qualitative analysis of the second outcome was conducted due to a lack of studies; however, the study reported no significant difference between the bupivacaine and ropivacaine groups on the incidence of fever (17% and 14%, respectively). Conclusion: Bupivacaine EA is significantly associated with maternal fever. However, due to the lack of data, the influence of local anaesthetic choice on ERMF could not be determined. Furthermore, the existing evidence is insufficient to determine whether the aetiology of maternal fever is solely due to sterile inflammation and whether bupivacaine or other local anaesthetics are the sources of this inflammation. Nonetheless, local anaesthetic sterile inflammation and inflammasome activation via immunomodulation and cell injury mechanisms are likely to play a role. Further studies investigating the role of local anaesthetics are needed.