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British Journal of Anaesthesia
BJA

Epidural analgesia, intrapartum hyperthermia, and neonatal brain injury: a systematic review and meta-analysis

Published:November 17, 2020DOI:https://doi.org/10.1016/j.bja.2020.09.046

      Abstract

      Background

      Epidural analgesia is associated with intrapartum hyperthermia, and chorioamnionitis is associated with neonatal brain injury. However, it is not known if epidural hyperthermia is associated with neonatal brain injury. This systematic review and meta-analysis investigated three questions: (1) does epidural analgesia cause intrapartum hyperthermia, (2) is intrapartum hyperthermia associated with neonatal brain injury, and (3) is epidural-induced hyperthermia associated with neonatal brain injury?

      Methods

      PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched from inception to January 2020 using Medical Subject Headings (MeSH) terms relating to epidural analgesia, hyperthermia, labour, and neonatal brain injury. Studies were reviewed independently for inclusion and quality by two authors (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach). Two meta-analyses were performed using the Mantel–Haenszel fixed effect method to generate odds ratios (ORs) and 95% confidence intervals (CIs).

      Results

      Forty-one studies were included for Question 1 (646 296 participants), 36 for Question 2 (11 866 021 participants), and two studies for Question 3 (297 113 participants). When the mode of analgesia was randomised, epidural analgesia was associated with intrapartum hyperthermia (OR: 4.21; 95% CI: 3.48–5.09). There was an association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54–2.3.06). It was not possible to quantify the association between epidural-induced hyperthermia and neonatal brain injury.

      Conclusions

      Epidural analgesia is a cause of intrapartum hyperthermia, and intrapartum hyperthermia of any cause is associated with neonatal brain injury. Further work is required to establish if epidural-induced hyperthermia is a cause of neonatal brain injury.

      Keywords

      • The authors performed a systematic review and meta-analysis of the evidence linking epidural analgesia, intrapartum hyperthermia, and neonatal brain injury.
      • The evidence suggests that epidural analgesia is a cause of intrapartum hyperthermia. Although intrapartum hyperthermia is associated with an increase in the risk of neonatal brain injury, the association with epidural-induced hyperthermia is not clear.
      • Further evidence is needed to allow us to determine whether epidural-induced hyperthermia is an independent risk factor for neonatal brain injury.
      Neonatal brain injury is a devastating condition with lifelong consequences for the individual, their families, and healthcare organisations. Its prevalence in England is approximately 5 per 1000 live births.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      It is difficult to estimate the total financial burden, but an indication may be derived from the amounts awarded as a result of medical litigation. In 2012, an analysis of maternity claims by the National Health Service Litigation Authority reported that the value of claims for the period 2000–10 was £1.26 billion.
      NHS Litigation Authority
      Ten years of maternity claims: an analysis of NHS Litigation Authority data.
      The term ‘neonatal brain injury’ refers to a spectrum of disease that includes neonatal encephalopathy and cerebral palsy.
      • Granild-Jensen J.B.
      • Rackauskaite G.
      • Flachs E.M.
      • Uldall P.
      Predictors for early diagnosis of cerebral palsy from national registry data.
      The aetiology of neonatal brain injury is multifactorial.
      • Rees S.
      • Inder T.
      Fetal and neonatal origins of altered brain development.
      Although the terms ‘neonatal brain injury’ and ‘birth asphyxia’ are sometimes used synonymously, overt evidence of intrapartum hypoxia is present in less than 20% of cases of cerebral palsy.
      • Speer M.
      • Perlman J.M.
      Modest hypothermia as a neuroprotective strategy in high-risk term infants.
      In contrast, chorioamnionitis is present in up to 31% of cases and is associated with a 2.1-fold increased risk of cerebral palsy.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      ,
      • Wilson-Costello D.
      • Borawski E.
      • Friedman H.
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      • Fanaroff A.A.
      • Hack M.
      Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.
      However, in many studies, the diagnosis of chorioamnionitis is made clinically: elevated maternal temperature (hyperthermia) with or without other features of infection, such as tachycardia (maternal or fetal), leucocytosis, or foul-smelling vaginal discharge.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      During the intrapartum period, clinical parameters have poor sensitivity for the prediction of microbiologically proven infection, and so it is not clear if the increased risk of brain injury is confined to parturients with infection or if intrapartum hyperthermia of any cause is detrimental to the neonatal brain.
      • Curtin W.M.
      • Katzman P.J.
      • Florescue H.
      • Metlay L.A.
      Accuracy of signs of clinical chorioamnionitis in the term parturient.
      Intrapartum hyperthermia may be secondary to intrapartum infection or epidural analgesia (epidural hyperthermia). The most common form of intrapartum infection is bacterial genito-urinary tract infection, which has an incidence of 4%.
      • Woodd S.L.
      • Montoya A.
      • Barreix M.
      • et al.
      Incidence of maternal peripartum infection: a systematic review and meta-analysis.
      Epidural hyperthermia, also known as epidural-related fever, refers to the situation in which a parturient who has an epidural for labour analgesia develops an elevated body temperature.
      • Fusi L.
      • Maresh M.J.A.
      • Steer P.J.
      • Beard R.W.
      Maternal pyrexia associated with the use of epidural analgesia in labor.
      It was first reported in 1989 that epidural analgesia increases the risk of intrapartum hyperthermia, and over the ensuing 30 yr, this association has been extensively studied.
      • Jansen S.
      • Lopriore E.
      • Naaktgeboren C.
      • et al.
      Epidural-related fever and maternal and neonatal morbidity: a systematic review and meta-analysis.
      ,
      • Anim-Somuah M.
      • Smyth R.M.
      • Cyna A.M.
      • Cuthbert A.
      Epidural versus non-epidural or no analgesia for pain management in labour.
      However, it remains a somewhat enigmatic condition, and the underlying mechanism remains unclear. Previous systematic reviews have demonstrated that epidural analgesia does not increase the risk of intrapartum infection and that it is not selected by parturients with a greater risk of intrapartum infection (selection bias).
      • Jansen S.
      • Lopriore E.
      • Naaktgeboren C.
      • et al.
      Epidural-related fever and maternal and neonatal morbidity: a systematic review and meta-analysis.
      ,
      • Anim-Somuah M.
      • Smyth R.M.
      • Cyna A.M.
      • Cuthbert A.
      Epidural versus non-epidural or no analgesia for pain management in labour.
      Consequently, the most likely explanation is that epidural hyperthermia is a distinct condition secondary to either cholinergic sympathetic blockade, immunomodulation, or both.
      • Mullington C.J.
      • Low D.A.
      • Strutton P.H.
      • Malhotra S.
      Body temperature, cutaneous heat loss and skin blood flow during epidural anaesthesia for emergency caesarean section.
      • del Arroyo A.G.
      • Sanchez J.
      • Patel S.
      • et al.
      Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.
      • Wohlrab P.
      • Boehme S.
      • Kaun C.
      • et al.
      Ropivacaine activates multiple proapoptotic and inflammatory signaling pathways that might subsume to trigger epidural-related maternal fever.
      The increasing evidence linking intrapartum hyperthermia and neonatal brain injury, and the recognition of epidural hyperthermia as a distinct condition have raised the question of whether epidural-induced hyperthermia is an independent risk factor for neonatal brain injury, distinct from the established risk factor of intrapartum infection.
      • Greenwell E.A.
      • Wyshak G.
      • Ringer S.A.
      • Johnson L.C.
      • Rivkin M.J.
      • Lieberman E.
      Intrapartum temperature elevation, epidural use, and adverse outcome in term infants.
      ,
      • Lieberman E.
      • Eichenwald E.
      • Mathur G.
      • Richardson D.
      • Heffner L.
      • Cohen A.
      Intrapartum fever and unexplained seizures in term infants.
      Currently, no systematic reviews have sought to investigate this question. The aims of this systematic review and meta-analysis were to investigate if there is (1) a causal link between epidural analgesia and intrapartum hyperthermia, (2) an association between intrapartum hyperthermia (of any cause, rather than chorioamnionitis) and neonatal brain injury, and (3) an association between epidural-induced hyperthermia and neonatal brain injury. Meta-analyses were performed to assess the strength of these links and to provide estimates of the effect sizes.

      Methods

      This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was prospectively registered on the PROSPERO register (CRD42020164144).
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting Items for systematic reviews and meta-analyses: the PRISMA statement.
      ,

      National Institute for Health Research. PROSPERO: international prospective register of systematic review. Available from: https://www.crd.york.ac.uk/prospero/(accessed 3 June 2020).

       Literature search

      PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched electronically in January 2020 by two independent reviewers (SM and JK) using separate Medical Subject Headings (MeSH) terms (Table 1). To investigate a causal link between epidural analgesia and intrapartum hyperthermia (study Question 1), the MeSH terms for epidural analgesia, hyperthermia, labour, and types of study were combined with the Boolean operator ‘AND’. To investigate the association between intrapartum hyperthermia (of any cause) and neonatal brain injury (study Question 2), the MeSH terms for hyperthermia, labour, neonatal brain injury, and types of study were combined. To investigate the association between epidural hyperthermia and neonatal brain injury (study Question 3), all MeSH terms were combined with the Boolean operator ‘AND’. All databases were searched from inception until the search date (January 13, 2020). Included study designs were peer-reviewed RCTs and prospective and retrospective cohort and case–control studies. Participant inclusion criteria were human females who were pregnant and underwent labour for delivery of a neonate. Included exposures and outcomes were epidural analgesia, intrapartum hyperthermia (temperature ≥37.5°C), and neonatal brain injury. Non-English language papers were excluded. A full description of the inclusion and exclusion criteria is found in Supplementary Table 1.
      Table 1Medical Subject Headings (MeSH) terms for electronic database search.
      Hyperthermia
       fever∗ OR hyperthermia∗ OR chorioamnionitis OR temperature OR sepsis OR infection OR septicaemia
      Terms for epidural analgesia
       epidural OR combined spinal epidural OR CSE OR neuraxial block OR neuraxial blockade
      Labour
       labour∗ OR labor OR intrapartum
      Adverse neurological neonatal outcomes
       neonatal brain injury OR neonatal neurological outcome OR cerebral palsy OR neonatal encephalopathy OR neonatal seizures OR therapeutic hypothermia
      Types of study
       retrospective OR prospective OR randomised OR randomised controlled OR observational OR cohort studies OR RCT OR randomised∗ OR cohort OR case-control
      Titles were uploaded to a reference manager software (EndNote X7; Clarivate Analytics, Boston, MA, USA) and duplicates were removed. All titles were searched and reviewed by two independent authors (SM and JK). Full-text articles were obtained for those titles that fulfilled the inclusion and exclusion criteria. Reference lists of included studies were also screened for any additional studies. After review of abstracts, full-text articles were reviewed to ensure they met the inclusion criteria. If any clarification was required about a study, authors were contacted via e-mail; if no response was obtained from the author(s) within 1 month, their study was excluded from the analysis. Any disagreements regarding inclusion were reviewed by a third independent author (CJM), who made the final decision.

       Data extraction and analysis

      Data were extracted independently by two authors (SM and JK). Extracted parameters included study design, number of participants, gestation at the time of delivery, neonate birth weight, study exposures, and study outcomes. All data extraction was reviewed by a third author (CJM).
      Two meta-analyses were performed using Review Manager 5.3 (The Cochrane Collaboration, London, UK). Data were extracted for study Questions 1 and 2; it was not possible to perform a meta-analysis for study Question 3, as only two studies were included. Studies were excluded from the meta-analysis if there was no comparison group, the outcome data were already included in another study (to prevent double counting of data), or no event data were available. For the meta-analysis, only adverse neurological neonatal outcomes that had a long-term effect on the child were included (early-onset seizures; neonatal encephalopathy; Bayley Scales of Infant Development, 2nd Edn. (BSID-II) score; and radiological and clinical diagnoses of cerebral palsy).
      • Bayley N.
      Bayley Scales of infant development.
      A hierarchy of outcome significance was used to determine which outcome to extract in the case of a study including two or more outcomes (early-onset seizures < neonatal encephalopathy < BSID-II score < radiological cerebral palsy < clinical cerebral palsy); the outcome with the most significant long-term significance was included.
      Forest plots were generated and overall odds or risk ratios with 95% confidence intervals (CIs) were calculated using the Mantel–Haenszel fixed effect method. Statistical significance was defined as a P-value <0.05. An I2 statistic was calculated as a measure of statistical heterogeneity and classified as per the Cochrane Handbook: 0–40% non-significant, 30–60% moderate heterogeneity, 50–90% substantial heterogeneity, and 75–100% considerable heterogeneity.

      Ryan R. Heterogeneity and subgroup analyses in Cochrane Consumers and Communication Group reviews: planning the analysis at protocol stage. Available from: http://cccrg.cochrane.org/sites/cccrg.cochrane.org/files/public/uploads/heterogeneity_subgroup_analyses_revising_december_1st_2016.pdf (accessed 3 June 2020).

      Funnel plots were generated to assess publication bias for any analysis including 10 or more studies. Egger's regression test was performed to quantitatively assess the presence of funnel plot asymmetry. Two pre-specified subgroup analyses were performed. For study Question 1, only RCTs were included. For study Question 2, only studies where the exposure was intrapartum hyperthermia alone were included, rather than hyperthermia as a factor in a clinical diagnosis of chorioamnionitis. Additionally, as preterm birth and low birth weight are major factors in the development of neonatal brain injury, for Question 2, a second subgroup analysis divided studies into term/normal-birth-weight neonates vs preterm/low-birth-weight neonates.

       Quality assessment

      Two authors (SM and JK) independently assessed the methodological quality of each selected article using Cochrane's risk-of-bias tool.
      For RCTs, the risk-of-bias tool evaluates the risk of selection bias, performance bias, detection bias, attrition, and reporting bias, and for observational studies, it evaluates the risk of confounding, selection bias, performance bias, detection bias, attrition, and reporting bias. Each study was rated as having either a ‘low’, ‘unclear’, or ‘high’ risk of bias. A third author (CJM) was the final independent assessor for any disagreements.
      Two authors (SM and JK) independently assessed the quality of evidence for each study question (including subgroup analyses) using Cochrane's Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

      Schunemann H BJ, Guyatt G, Oxman A. GRADE Handbook. Available from: https://gdt.gradepro.org/app/handbook/handbook.html (accessed 3 June 2020).

      According to GRADE methodology, the baseline quality rating for RCTs is ‘high’ and for observational studies is ‘low’. Six quality assessment criteria (risk of bias, inconsistency, indirectness, imprecision, publication bias, and others) were used to judge evidence quality, after which the ratings were either downgraded or upgraded. Evidence was downgraded one or two levels in the presence of a serious or very serious concern, respectively.

      Results

      The literature search and study selection procedure are summarised in Figure 1. After removing duplicates, 739 records were screened for study Question 1 (epidural analgesia and intrapartum hyperthermia), 786 for Question 2 (intrapartum hyperthermia and neonatal brain injury), and 54 for Question 3 (epidural hyperthermia and adverse neonatal neurological outcome). After reviewing full texts, a total of 41 studies were included for Question 1 (39 for meta-analysis), 36 for Question 2 (31 for meta-analysis), and 2 for Question 3. The study characteristics are summarised in Table 2. Full descriptions of study characteristics and risk of bias are presented in Supplementary Tables 2 and 3 and Supplementary Figure 1.
      Fig 1
      Fig 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for each study question.
      Fig 1
      Fig 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for each study question.
      Table 2Summary of study characteristics. BSID-II, Bayley Scales of Infant Development, 2nd Edn.; BW, birth weight; CSE, combined spinal–epidural; HIE, hypoxic–ischaemic encephalopathy; IVH, intraventricular haemorrhage; PCA, patient-controlled analgesia; PVL, periventricular leucomalacia. ∗Retrospective and prospective design. Included in ‘epidural analgesia and intrapartum hyperthermia’ meta-analysis. Stratified into term and preterm deliveries. Included in ‘epidural analgesia and intrapartum hyperthermia’ and ‘intrapartum hyperthermia and neonatal brain injury’ meta-analyses.
      Reference (publication year)SampleStudy designExposureOutcomeGestation/BW
      Epidural analgesia and intrapartum hyperthermia
      Abramovici and colleagues
      • Abramovici A.
      • Szychowski J.M.
      • Biggio J.R.
      • Sakawi Y.
      • Andrews W.W.
      • Tita A.
      Epidural use and clinical chorioamnionitis among women who delivered vaginally.
      (2014)
      1785Cohort (RCT: 2° analysis)Epidural vs no epiduralClinical chorioamnionitisAll deliveries
      Agakidis and colleagues
      • Agakidis C.
      • Agakidou E.
      • Thomas S.P.
      • Murthy P.
      • Lloyd D.J.
      Labor epidural analgesia is independent risk factor for neonatal pyrexia.
      (2011)
      960Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)Full term
      Baheri and colleagues
      • Baheri B.
      • Coppejans H.
      • Joukes E.
      • Vercauteren M.
      Do epidurals cause higher intrapartum temperatures in parturients and neonates? a Belgian experience.
      (2013)
      180Prospective cohortEpidural vs no analgesiaHyperthermia (>37.5°C)Full term
      Burgess and colleagues
      • Burgess A.P.H.
      • Katz J.E.
      • Moretti M.
      • Lakhi N.
      Risk factors for intrapartum fever in term gestations and associated maternal and neonatal sequelae.
      (2017)
      360Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)36–42 weeks
      Curtin and colleagues
      • Curtin W.M.
      • Katzman P.J.
      • Florescue H.
      • Metlay L.A.
      • Ural S.H.
      Intrapartum fever, epidural analgesia and histologic chorioamnionitis.
      (2015)
      641Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)≥37 weeks
      Dashe and colleagues
      • Dashe J.S.
      • Rogers B.B.
      • McIntire D.D.
      • Leveno K.J.
      Epidural analgesia and intrapartum fever: placental findings.
      (1999)
      149Prospective cohortEpidural vs pethidineHyperthermia (>38°C)≥2500 g
      del Arroyo and colleagues
      • del Arroyo A.G.
      • Sanchez J.
      • Patel S.
      • et al.
      Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.
      (2019)
      53Prospective cohortEpidural vs other analgesiaHyperthermia (≥38°C)≥37 weeks
      de Orange and colleagues
      • de Orange F.A.
      • Passini Jr., R.
      • Amorim M.M.
      • Almeida T.
      • Barros A.
      Combined spinal and epidural anaesthesia and maternal intrapartum temperature during vaginal delivery: a randomized clinical trial.
      (2011)
      72RCTCSE vs non-pharmacologicalHyperthermia (>38°C)Full term
      Douma and colleagues
      • Douma M.R.
      • Stienstra R.
      • Middeldorp J.M.
      • Arbous M.S.
      • Dahan A.
      Differences in maternal temperature during labour with remifentanil patient-controlled analgesia or epidural analgesia: a randomised controlled trial.
      (2015)
      116RCTEpidural vs remifentanil PCAHyperthermia (>38°C)37–42 weeks
      Evron and colleagues
      • Evron S.
      • Parameswaran R.
      • Zipori D.
      • Ezri T.
      • Sadan O.
      • Koren R.
      Activin betaA in term placenta and its correlation with placental inflammation in parturients having epidural or systemic meperidine analgesia: a randomized study.
      (2007)
      56RCTEpidural vs pethidine PCAHyperthermia (>37.5°C)Full term
      Evron and colleagues
      • Evron S.
      • Ezri T.
      • Protianov M.
      • et al.
      The effects of remifentanil or acetaminophen with epidural ropivacaine on body temperature during labor.
      (2008)
      213RCTEpidural vs remifentanil PCAHyperthermia (>38°C)Full term
      Freeman and colleagues
      • Freeman L.M.
      • Bloemenkamp K.W.
      • Franssen M.T.
      • et al.
      Patient controlled analgesia with remifentanil versus epidural analgesia in labour: randomised multicentre equivalence trial.
      (2015)
      1358RCTEpidural vs remifentanil PCAHyperthermia (>38°C)>32 weeks
      Fusi and colleagues
      • Fusi L.
      • Maresh M.J.A.
      • Steer P.J.
      • Beard R.W.
      Maternal pyrexia associated with the use of epidural analgesia in labor.
      (1989)
      40Prospective cohortEpidural vs pethidineHyperthermia (>37.5°C)>36 weeks
      Goetzl and colleagues
      • Goetzl L.
      • Cohen A.
      • Frigoletto F.
      • Ringer S.A.
      • Lang J.M.
      • Lieberman E.
      Maternal epidural use and neonatal sepsis evaluation in afebrile mothers.
      (2001)
      1109Cohort (RCT: 2° analysis)Epidural vs no epiduralHyperthermia (>37.5°C)Full term
      Gross and colleagues
      • Gross J.B.
      • Cohen A.P.
      • Lang J.M.
      • Frigoletto F.D.
      • Lieberman E.S.
      Differences in systemic opioid use do not explain increased fever incidence in parturients receiving epidural analgesia.
      (2002)
      1233Cohort (RCT: 2° analysis)Epidural vs no epiduralHyperthermia (>38°C)Full term
      Herbst and colleagues
      • Herbst A.
      • Wolner-Hanssen P.
      • Ingemarsson I.
      Risk factors for fever in labor.
      (1995)
      3109Retrospective case–controlEpidural vs no epiduralHyperthermia (>38°C)Full term
      Kaul and colleagues
      • Kaul B.
      • Vallejo M.
      • Ramanathan S.
      • Mandell G.
      Epidural labor analgesia and neonatal sepsis evaluation rate: a quality improvement study.
      (2001)
      1177Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)All deliveries
      Lieberman and colleagues
      • Lieberman E.
      • Cohen A.
      • Lang J.
      • Frigoletto F.
      • Goetzl L.
      Maternal intrapartum temperature elevation as a risk factor for cesarean delivery and assisted vaginal delivery.
      (1999)
      1233Cohort (RCT: 2° analysis)Epidural vs no epiduralHyperthermia (>37.5°C)Full term
      Logtenberg and colleagues
      • Logtenberg S.L.M.
      • Oude Rengerink K.
      • Verhoeven C.J.
      • et al.
      Labour pain with remifentanil patient-controlled analgesia versus epidural analgesia: a randomised equivalence trial.
      (2017)
      409RCTEpidural vs remifentanil PCAHyperthermia (>38°C)>32 weeks
      Lucas and colleagues
      • Lucas M.J.
      • Sharma S.K.
      • McIntire D.D.
      • et al.
      A randomized trial of labor analgesia in women with pregnancy-induced hypertension.
      (2001)
      736RCTEpidural vs pethidine PCAHyperthermia (≥38°C)All deliveries
      Maayan-Metzger and colleagues
      • Maayan-Metzger A.
      • Mazkereth R.
      • Shani A.
      • Kuint J.
      Risk factors for maternal intrapartum fever and short-term neonatal outcome.
      (2006)
      320Case–controlEpidural vs no epiduralHyperthermia (>37.8°C)>35 weeks
      Mark and colleagues
      • Mark S.P.
      • Croughan-Minihane M.S.
      • Kilpatrick S.J.
      Chorioamnionitis and uterine function.
      (2000)
      16 226Retrospective cohortEpidural vs no epiduralClinical chorioamnionitis (>37.8°C)All deliveries
      Mayer and colleagues
      • Mayer D.C.
      • Chescheir N.C.
      • Spielman F.J.
      Increased intrapartum antibiotic administration associated with epidural analgesia in labor.
      (1997)
      287Retrospective cohortEpidural vs i.v. opioidHyperthermia (>37.8°C)Full term
      Nafisi
      • Nafisi S.
      Effects of epidural lidocaine analgesia on labor and delivery: a randomized, prospective, controlled trial.
      (2006)
      395RCTEpidural vs i.v. pethidineHyperthermia (≥38°C)All deliveries
      Philip and colleagues
      • Philip J.
      • Alexander J.M.
      • Sharma S.K.
      • Leveno K.J.
      • McIntire D.D.
      • Wiley J.
      Epidural analgesia during labor and maternal fever.
      (1999)
      715RCT: 2° analysisEpidural vs pethidine PCAHyperthermia (>38°C)Full term
      Ploeckinger and colleagues
      • Ploeckinger B.
      • Ulm M.R.
      • Chalubinski K.
      • Gruber W.
      Epidural anaesthesia in labour: influence on surgical delivery rates, intrapartum fever and blood loss.
      (1995)
      7317Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)All deliveries
      Ramin and colleagues
      • Ramin S.M.
      • Gambling D.R.
      • Lucas M.J.
      • Sharma S.K.
      • Sidawi J.E.
      • Leveno K.J.
      Randomized trial of epidural versus intravenous analgesia during labor.
      (1995)
      1330RCTEpidural vs pethidineHyperthermia (>38°C)Full term
      Reilly and Oppenheimer
      • Reilly D.R.
      • Oppenheimer L.W.
      Fever in term labour.
      (2005)
      16 505Case–controlEpidural vs no epiduralHyperthermia (>37.5 [×2] or 38 [×1]°C)≥37 weeks
      Riley and colleagues
      • Riley L.E.
      • Celi A.C.
      • Onderdonk A.B.
      • et al.
      Association of epidural-related fever and noninfectious inflammation in term labor.
      (2011)
      200Cohort (RCT: 2° analysis)Epidural or CSE vs no epiduralHyperthermia (>38°C)≥37 weeks
      Sharma and colleagues
      • Sharma S.K.
      • Sidawi J.E.
      • Ramin S.M.
      • Lucas M.J.
      • Leveno K.J.
      • Cunningham F.G.
      Cesarean delivery: a randomized trial of epidural versus patient-controlled meperidine analgesia during labor.
      (1997)
      715RCTEpidural vs pethidine PCAHyperthermia (>38°C)Full term
      Sharma and colleagues
      • Sharma S.K.
      • Alexander J.M.
      • Messick G.
      • et al.
      Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women.
      (2002)
      459RCTEpidural vs i.v. pethidineHyperthermia (≥38°C)Full term
      Sweed and colleagues
      • Sweed N.
      • Sabry N.
      • Azab T.
      • Nour S.
      Regional versus IV analgesics in labor.
      (2011)
      60RCTEpidural vs CSE vs i.v. pethidineHyperthermia (≥38°C)Full term
      Vinson and colleagues
      • Vinson D.C.
      • Thomas R.
      • Kiser T.
      Association between epidural analgesia during labor and fever.
      (1993)
      81Cohort∗Epidural vs no epiduralHyperthermia (>37.5°C)Full term
      Wassen and colleagues
      • Wassen M.M.
      • Winkens B.
      • Dorssers E.M.
      • Marcus M.A.
      • Moonen R.M.
      • Roumen F.J.
      Neonatal sepsis is mediated by maternal fever in labour epidural analgesia.
      (2014)
      906Case–controlEpidural vs no epiduralHyperthermia (>38°C)37–42 weeks
      White and colleagues
      • White A.
      • Olson D.
      • Messacar K.
      A state-wide assessment of the association between epidural analgesia, maternal fever and neonatal antibiotics in Colorado, 2007–2012.
      (2017)
      261 457Retrospective cohortEpidural vs no epiduralHyperthermia (>38°C)≥37 weeks
      Yin and Hu
      • Yin H.
      • Hu R.
      A cohort study of the impact of epidural analgesia on maternal and neonatal outcomes.
      (2019)
      506Retrospective cohortEpidural vs no epiduralHyperthermia (>37.5°C)≥37 weeks
      Intrapartum hyperthermia and neonatal brain injury
      Alexander and colleagues
      • Alexander J.M.
      • McIntire D.M.
      • Leveno K.J.
      Chorioamnionitis and the prognosis for term infants.
      (1999)
      101 170Retrospective cohortClinical chorioamnionitisEarly-onset seizures≥2500 g
      Ashwal and colleagues
      • Ashwal E.
      • Salman L.
      • Tzur Y.
      • et al.
      Intrapartum fever and the risk for perinatal complications—the effect of fever duration and positive cultures.
      (2018)
      927Retrospective cohortHyperthermia (>38°C)Early-onset seizures37–42 weeks
      Badawi and colleagues
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      (1998)
      564Case–controlHyperthermia (>37.5°C)Neonatal encephalopathyFull term
      Bauer and colleagues
      • Bauer M.
      • Fast C.
      • Haas J.
      • Resch B.
      • Lang U.
      • Pertl B.
      Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors.
      (2009)
      339Case–controlHyperthermia (>38°C)PVL26–35 weeks
      Blume and colleagues
      • Blume H.K.
      • Li C.I.
      • Loch C.M.
      • Koepsell T.D.
      Intrapartum fever and chorioamnionitis as risks for encephalopathy in term newborns: a case-control study.
      (2008)
      6390Case–controlHyperthermia (>38°C)Neonatal encephalopathy≥37 weeks
      Dammann and colleagues
      • Dammann O.
      • Drescher J.
      • Veelken N.
      Maternal fever at birth and non-verbal intelligence at age 9 years in preterm infants.
      (2003)
      294Prospective cohortHyperthermia (>38.5°C)Cerebral palsy<37 weeks and <1500 g
      Dior and colleagues
      • Dior U.P.
      • Kogan L.
      • Calderon-Margalit R.
      • et al.
      The association of maternal intrapartum subfebrile temperature and adverse obstetric and neonatal outcomes.
      (2014)
      42 601Retrospective cohortHyperthermia (>37°C)HIE or seizures≥37 weeks and <5000 g
      Dior and colleagues
      • Dior U.P.
      • Kogan L.
      • Eventov-Friedman S.
      • et al.
      Very high intrapartum fever in term pregnancies and adverse obstetric and neonatal outcomes.
      (2016)
      43 560Retrospective cohortHyperthermia (>38°C)HIE or seizures≥37 weeks and <5000 g
      Edwards and colleagues
      • Edwards J.M.
      • Edwards L.E.
      • Swamy G.K.
      • Grotegut C.A.
      Magnesium sulfate for neuroprotection in the setting of chorioamnionitis.
      (2018)
      1944Cohort (RCT: 2° analysis)Clinical chorioamnionitisCerebral palsy at 2 yr24–31 weeks
      Ghi and colleagues
      • Ghi T.
      • Giunchi S.
      • Pilu G.
      • et al.
      Neonatal hypoxic-ischemic encephalopathy in apparently low risk pregnancies: retrospective analysis of the last five years at the University of Bologna.
      (2010)
      72Case–controlHyperthermia (>38°C)Neonatal encephalopathy≥37 weeks
      Greenwood and colleagues
      • Greenwood C.
      • Yudkin P.
      • Sellers S.
      • Impey L.
      • Doyle P.
      Why is there a modifying effect of gestational age on risk factors for cerebral palsy?.
      (2005)
      881Case–controlHyperthermia (≥38°C)Cerebral palsyAll deliveries
      Grether and Nelson
      • Grether J.K.
      • Nelson K.B.
      Maternal infection and cerebral palsy in infants of normal birth weight.
      (1997)
      475Case–controlHyperthermia (>38°C)Cerebral palsy>2500 g
      Haar and Gyamfi-Bannerman
      • Haar E.V.
      • Gyamfi-Bannerman C.
      Chorioamnionitis and neurocognitive development at age 2 years.
      (2016)
      1574Cohort (RCT: 2° analysis)Clinical chorioamnionitisBSID-II score at 2 yr oldHigh-risk preterm
      Hayes and colleagues
      • Hayes B.C.
      • McGarvey C.
      • Mulvany S.
      • et al.
      A case-control study of hypoxic-ischemic encephalopathy in newborn infants at >36 weeks gestation.
      (2013)
      735Case–controlHyperthermia (>38°C)Neonatal encephalopathy≥36 weeks
      Impey and colleagues
      • Impey L.
      • Greenwood C.
      • MacQuillan K.
      • Reynolds M.
      • Sheil O.
      Fever in labour and neonatal encephalopathy: a prospective cohort study.
      (2001)
      4915Prospective cohortHyperthermia (>37.5°C)Neonatal encephalopathy36–41 weeks
      Impey and colleagues
      • Impey L.W.
      • Greenwood C.E.
      • Black R.S.
      • Yeh P.S.
      • Sheil O.
      • Doyle P.
      The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy.
      (2008)
      8299Cohort (RCT: 2° analysis)Hyperthermia (>37.5°C)Neonatal encephalopathy37–41 weeks
      Jacobsson and colleagues
      • Jacobsson B.
      • Hagberg G.
      • Hagberg B.
      • Ladfors L.
      • Niklasson A.
      • Hagberg H.
      Cerebral palsy in preterm infants: a population-based case-control study of antenatal and intrapartal risk factors.
      (2002)
      444Case–controlHyperthermia (>38°C)Cerebral palsy<37 weeks
      Kaukola and colleagues
      • Kaukola T.
      • Herva R.
      • Perhomaa M.
      • et al.
      Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants.
      (2006)
      53Prospective cohortHyperthermia (>37.8°C)PVL or IVH<32 weeks
      Lieberman and colleagues
      • Lieberman E.
      • Eichenwald E.
      • Mathur G.
      • Richardson D.
      • Heffner L.
      • Cohen A.
      Intrapartum fever and unexplained seizures in term infants.
      (2000)
      190Case–controlHyperthermia (>38°C)Early-onset seizures≥37 weeks and ≥2500 g
      Lieberman and colleagues
      • Lieberman E.
      • Lang J.
      • Richardson D.K.
      • Frigoletto F.D.
      • Heffner L.J.
      • Cohen A.
      Intrapartum maternal fever and neonatal outcome.
      (2000)
      1218Cohort (RCT: 2° analysis)Hyperthermia (>38°C)Early-onset seizureFull term
      Linder and colleagues
      • Linder N.
      • Haskin O.
      • Levit O.
      • et al.
      Risk factors for intraventricular hemorrhage in very low birth weight premature infants: a retrospective case-control study.
      (2003)
      105Case–controlClinical chorioamnionitisIVH<1500 g
      Martinez-Biarge and colleagues
      • Martinez-Biarge M.
      • Cheong J.L.
      • Diez-Sebastian J.
      • Mercuri E.
      • Dubowitz L.M.
      • Cowan F.M.
      Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period.
      (2016)
      723Case–controlHyperthermia (>38°C)HIE≥35 weeks
      Matsuda and colleagues
      • Matsuda Y.
      • Kouno S.
      • Hiroyama Y.
      • et al.
      Intrauterine infection, magnesium sulfate exposure and cerebral palsy in infants born between 26 and 30 weeks of gestation.
      (2000)
      192Case–controlClinical chorioamnionitisCerebral palsy26–30 weeks
      Nasef and colleagues
      • Nasef N.
      • Shabaan A.E.
      • Schurr P.
      • et al.
      Effect of clinical and histological chorioamnionitis on the outcome of preterm infants.
      (2013)
      274Retrospective cohortClinical chorioamnionitisCerebral palsy<30 weeks
      Nelson and colleagues
      • Nelson D.B.
      • Lucke A.M.
      • McIntire D.D.
      • Sanchez P.J.
      • Leveno K.J.
      • Chalak L.F.
      Obstetric antecedents to body-cooling treatment of the newborn infant.
      (2014)
      86 371Retrospective cohortClinical chorioamnionitisNeonatal encephalopathy≥36 weeks
      Petrova and colleagues
      • Petrova A.
      • Demissie K.
      • Rhoads G.G.
      • Smulian J.C.
      • Marcella S.
      • Ananth C.V.
      Association of maternal fever during labor with neonatal and infant morbidity and mortality.
      (2001)
      11 246 042Retrospective cohortHyperthermia (>38°C)Early-onset seizuresAll deliveries
      Redline and O'Riordan
      • Redline R.W.
      • O’Riordan M.A.
      Placental lesions associated with cerebral palsy and neurologic impairment following term birth.
      (2000)
      216Case–controlHyperthermia (>38 [×2] or 38.5 [×1]°C)Cerebral palsy≥37 weeks
      Rouse and colleagues
      • Rouse D.J.
      • Landon M.
      • Leveno K.J.
      • et al.
      The maternal-fetal medicine units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes.
      (2004)
      16 650Prospective cohortHyperthermia (≥37.8°C)HIE≥37 weeks
      Sameshima and Ikenoue
      • Sameshima H.
      • Ikenoue T.
      Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection.
      (2007)
      230Retrospective cohortClinical chorioamnionitisCerebral palsy22–32 weeks
      Schlapbach and colleagues
      • Schlapbach L.J.
      • Ersch J.
      • Adams M.
      • Bernet V.
      • Bucher H.U.
      • Latal B.
      Impact of chorioamnionitis and preeclampsia on neurodevelopmental outcome in preterm infants below 32 weeks gestational age.
      (2010)
      99Retrospective cohortClinical chorioamnionitisBSID-II score at 2 yr old25–32 weeks
      Shalak and colleagues
      • Shalak L.
      • Johnson-Welch S.
      • Perlman J.M.
      Chorioamnionitis and neonatal encephalopathy in term infants with fetal acidemia: histopathologic correlations.
      (2005)
      51Case–controlClinical chorioamnionitisNeonatal encephalopathy≥36 weeks
      Spinillo and colleagues
      • Spinillo A.
      • Capuzzo E.
      • Stronati M.
      • Ometto A.
      • De Santolo A.
      • Acciano S.
      Obstetric risk factors for periventricular leukomalacia among preterm infants.
      (1998)
      349Retrospective cohortClinical chorioamnionitisPVL25–33 weeks
      Takahashi and colleagues
      • Takahashi R.
      • Yamada M.
      • Takahashi T.
      • et al.
      Risk factors for cerebral palsy in preterm infants.
      (2005)
      180Retrospective cohortClinical chorioamnionitisCerebral palsy22–33 weeks
      Wilson-Costello and colleagues
      • Wilson-Costello D.
      • Borawski E.
      • Friedman H.
      • Redline R.
      • Fanaroff A.A.
      • Hack M.
      Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.
      (1998)
      144Case–controlClinical chorioamnionitisCerebral palsy<1500 g
      Epidural hyperthermia and neonatal brain injury
      Greenwell and colleagues
      • Greenwell E.A.
      • Wyshak G.
      • Ringer S.A.
      • Johnson L.C.
      • Rivkin M.J.
      • Lieberman E.
      Intrapartum temperature elevation, epidural use, and adverse outcome in term infants.
      (2012)
      2784Retrospective cohortHyperthermia (>37.5°C)Early-onset seizures≥37 weeks and ≥2500 g
      Törnell and colleagues
      • Törnell S.
      • Ekeus C.
      • Hultin M.
      • Hakansson S.
      • Thunberg J.
      • Hogberg U.
      Low Apgar score, neonatal encephalopathy and epidural analgesia during labour: a Swedish registry-based study.
      (2015)
      294 329Retrospective cohortHyperthermia (>38°C)Neonatal encephalopathy37–42 weeks

       Study Question 1: epidural analgesia and intrapartum hyperthermia

      Of the 41 studies included, 13 were RCTs, with the remaining studies being observational studies (Table 2). This resulted in a total of 646 296 parturients being included. Twenty-five studies included singleton pregnancies at full term (≥37 weeks) in healthy women (Table 2). All study populations were hospital based. Epidural protocols varied between the studies, including the use of combined spinal–epidurals, the drugs administered, and the method of drug administration; where available, protocols are detailed in Supplementary Table 2a. The study of Fusi and colleagues
      • Fusi L.
      • Maresh M.J.A.
      • Steer P.J.
      • Beard R.W.
      Maternal pyrexia associated with the use of epidural analgesia in labor.
      was not included in the meta-analysis because there was only a graphical representation of their results. The study of Lieberman and colleagues
      • Lieberman E.
      • Cohen A.
      • Lang J.
      • Frigoletto F.
      • Goetzl L.
      Maternal intrapartum temperature elevation as a risk factor for cesarean delivery and assisted vaginal delivery.
      was excluded because of duplication of data from Goetzl and colleagues.
      • Goetzl L.
      • Cohen A.
      • Frigoletto F.
      • Ringer S.A.
      • Lang J.M.
      • Lieberman E.
      Maternal epidural use and neonatal sepsis evaluation in afebrile mothers.
      For the 39 studies included in the meta-analysis, those with an epidural had an overall odds ratio of 5.26 (95% CI: 4.98–5.56) of developing intrapartum hyperthermia, although there was considerable statistical heterogeneity (I2=76%; Fig. 2a). On subgroup analysis of the 13 RCTs, this association remained, with an odds ratio of 4.21 (95% CI: 3.49–5.09) and non-significant statistical heterogeneity (I2=23%; Fig. 2b). Funnel plots for study Question 1 can be found in Supplementary Figure 3. There was no evidence of funnel plot asymmetry in the meta-analysis as a whole (P=0.70) or in the RCT subgroup analysis (P=0.24). The GRADE quality of evidence for study Question 1 as a whole was low (Supplementary Table 4). The GRADE quality was downgraded one level for the high risk of bias and one level for considerable inconsistency, but upgraded two levels for the very large magnitude of effect. For the RCT subgroup, the GRADE quality was high (Supplementary Table 4). The GRADE quality was downgraded one level for the high risk of bias, but upgraded one level for the large magnitude of effect. The high risk of bias was attributable to lack of blinding and attrition.
      Fig 2
      Fig 2Meta-analysis of study Question 1: epidural analgesia and intrapartum hyperthermia. (a) RCTs and observational studies. (b) RCTs only (where mode of analgesia was randomised). Events: intrapartum hyperthermia. CI, confidence interval; M–H, Mantel–Haenszel.

       Study Question 2: intrapartum hyperthermia and neonatal brain injury

      Thirty-six studies were included for this study question; eight were prospective observational studies, with the remainder being retrospective observational studies (Table 2). A total of 11 866 021 subjects were included. Adverse neonatal outcomes varied significantly between studies and included short-term outcomes, such as Apgar scores, neonatal ICU admission, early-onset seizures, and neonatal encephalopathy and the long-term outcome: cerebral palsy. Supplementary Table 2b provides a narrative account of the outcome measures. Definitions for hyperthermia also varied significantly between studies (≥37.5°C up to >38.5°C), including the method of temperature measurement (Table 2; Supplementary Table 2b). Clinical chorioamnionitis, the composite of hyperthermia and at least one additional clinical sign, was the exposure in 13 studies.
      • Wilson-Costello D.
      • Borawski E.
      • Friedman H.
      • Redline R.
      • Fanaroff A.A.
      • Hack M.
      Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.
      ,
      • Alexander J.M.
      • McIntire D.M.
      • Leveno K.J.
      Chorioamnionitis and the prognosis for term infants.
      ,
      • Haar E.V.
      • Gyamfi-Bannerman C.
      Chorioamnionitis and neurocognitive development at age 2 years.
      ,
      • Kaukola T.
      • Herva R.
      • Perhomaa M.
      • et al.
      Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants.
      ,
      • Linder N.
      • Haskin O.
      • Levit O.
      • et al.
      Risk factors for intraventricular hemorrhage in very low birth weight premature infants: a retrospective case-control study.
      ,
      • Matsuda Y.
      • Kouno S.
      • Hiroyama Y.
      • et al.
      Intrauterine infection, magnesium sulfate exposure and cerebral palsy in infants born between 26 and 30 weeks of gestation.
      ,
      • Nasef N.
      • Shabaan A.E.
      • Schurr P.
      • et al.
      Effect of clinical and histological chorioamnionitis on the outcome of preterm infants.
      ,
      • Sameshima H.
      • Ikenoue T.
      Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection.
      • Schlapbach L.J.
      • Ersch J.
      • Adams M.
      • Bernet V.
      • Bucher H.U.
      • Latal B.
      Impact of chorioamnionitis and preeclampsia on neurodevelopmental outcome in preterm infants below 32 weeks gestational age.
      • Shalak L.
      • Johnson-Welch S.
      • Perlman J.M.
      Chorioamnionitis and neonatal encephalopathy in term infants with fetal acidemia: histopathologic correlations.
      • Spinillo A.
      • Capuzzo E.
      • Stronati M.
      • Ometto A.
      • De Santolo A.
      • Acciano S.
      Obstetric risk factors for periventricular leukomalacia among preterm infants.
      ,
      • Novak C.M.
      • Eke A.C.
      • Ozen M.
      • Burd I.
      • Graham E.M.
      Risk factors for neonatal hypoxic-ischemic encephalopathy in the absence of sentinel events.
      Fifteen studies included only neonates born at term or a weight >2500 g; 14 studies included only preterm neonates or those born at a low birth weight. Novak and colleagues
      • Novak C.M.
      • Eke A.C.
      • Ozen M.
      • Burd I.
      • Graham E.M.
      Risk factors for neonatal hypoxic-ischemic encephalopathy in the absence of sentinel events.
      included any neonate who required therapeutic hypothermia on arrival to neonatal intensive care, and Sameshima and Ikenoue
      • Sameshima H.
      • Ikenoue T.
      Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection.
      included singleton pregnancies diagnosed with cerebral palsy at the age of 2.
      Five studies were excluded from the meta-analysis: three had no control data,
      • Kaukola T.
      • Herva R.
      • Perhomaa M.
      • et al.
      Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurologic outcome in very preterm, extremely low birth weight infants.
      ,
      • Sameshima H.
      • Ikenoue T.
      Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection.
      ,
      • Novak C.M.
      • Eke A.C.
      • Ozen M.
      • Burd I.
      • Graham E.M.
      Risk factors for neonatal hypoxic-ischemic encephalopathy in the absence of sentinel events.
      one had no data on long-term adverse outcomes,
      • Dior U.P.
      • Kogan L.
      • Calderon-Margalit R.
      • et al.
      The association of maternal intrapartum subfebrile temperature and adverse obstetric and neonatal outcomes.
      and one had only odds ratio data available,
      • Dior U.P.
      • Kogan L.
      • Eventov-Friedman S.
      • et al.
      Very high intrapartum fever in term pregnancies and adverse obstetric and neonatal outcomes.
      and the study of Impey and colleagues
      • Impey L.
      • Greenwood C.
      • MacQuillan K.
      • Reynolds M.
      • Sheil O.
      Fever in labour and neonatal encephalopathy: a prospective cohort study.
      ,
      • Impey L.W.
      • Greenwood C.E.
      • Black R.S.
      • Yeh P.S.
      • Sheil O.
      • Doyle P.
      The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy.
      was excluded to prevent double counting of data. In the remaining 31 studies, intrapartum hyperthermia was associated with adverse neonatal neurological outcome (odds ratio: 2.48; 95% CI: 2.28–2.70), although substantial statistical heterogeneity was present (I2=74%; Fig. 3a). When studies that used clinical chorioamnionitis as the exposure were excluded, the association remained (19 studies; odds ratio: 2.79; 95% CI: 2.54–3.06; Fig. 3b). Subgroup analysis revealed that this association was present in both term (12 studies; odds ratio: 3.38; 95% CI: 2.79–4.10) and preterm (13 studies; odds ratio: 1.63; 95% CI: 1.32–2.02; Fig. 3c and d) neonates. Funnel plots for each analysis are presented in Supplementary Figure 4. There was no evidence of funnel plot asymmetry in the meta-analysis as a whole (P=0.76) or in the subgroup analyses of term (P=0.33) or preterm (P=0.19) deliveries. However, funnel plot asymmetry was present in the subgroup analysis of studies in which hyperthermia alone was the exposure (P=0.0009). The GRADE quality of evidence for study Question 2 as a whole and the term subgroup was low (Supplementary Table 4). For both questions, the GRADE quality was downgraded one level for inconsistency, but upgraded one level for the large magnitude of effect. For the hyperthermia and preterm subgroups, the GRADE quality was very low (Supplementary Table 4). For the hyperthermia subgroup, the GRADE quality was downgraded one level for substantial inconsistency and one level for publication bias, but upgraded one level for the large magnitude of effect. For the preterm subgroup, the GRADE quality was downgraded one level for the high risk of bias and one level for substantial inconsistency.
      Fig 3
      Fig 3Meta-analysis of study Question 2: intrapartum hyperthermia and neonatal brain injury. (a) All studies. (b) Studies where hyperthermia alone was the exposure. (c) Studies of neonates born at ≥37 weeks' gestation. (d) Studies of neonates born at <37 weeks' gestation. Events: neonatal brain injury. CI, confidence interval; M–H, Mantel–Haenszel.
      Fig 3
      Fig 3Meta-analysis of study Question 2: intrapartum hyperthermia and neonatal brain injury. (a) All studies. (b) Studies where hyperthermia alone was the exposure. (c) Studies of neonates born at ≥37 weeks' gestation. (d) Studies of neonates born at <37 weeks' gestation. Events: neonatal brain injury. CI, confidence interval; M–H, Mantel–Haenszel.

       Study Question 3: epidural-induced hyperthermia and neonatal brain injury

      Two studies were included for this study question, both retrospective cohort studies (Supplementary Table 2c) and both of low quality (Supplementary Table 3c; Supplementary Fig. 1c). Because of the low number of studies and diversity in outcome measures, a meta-analysis could not be performed. A total of 297 113 subjects were included. Greenwell and colleagues
      • Greenwell E.A.
      • Wyshak G.
      • Ringer S.A.
      • Johnson L.C.
      • Rivkin M.J.
      • Lieberman E.
      Intrapartum temperature elevation, epidural use, and adverse outcome in term infants.
      showed that early-onset neonatal seizures were increased in patients with an epidural and a temperature >38.3°C (P=0.008). Törnell and colleagues
      • Törnell S.
      • Ekeus C.
      • Hultin M.
      • Hakansson S.
      • Thunberg J.
      • Hogberg U.
      Low Apgar score, neonatal encephalopathy and epidural analgesia during labour: a Swedish registry-based study.
      did not perform a subgroup analysis of parturients with epidural analgesia, but did demonstrate that, when intrapartum temperature is adjusted for, epidural analgesia is not associated with a diagnosis of neonatal encephalopathy (odds ratio: 1.11; 95% CI: 0.96–1.29). The GRADE quality of evidence for study Question 3 was very low (Supplementary Table 4). The GRADE quality was downgraded one level because of the high risk of bias and one level because of the low event rate (imprecision), but upgraded one level for the presence of a dose–response gradient.

      Discussion

      This systematic review and meta-analysis reviewed the evidence linking (1) epidural analgesia and intrapartum hyperthermia, (2) intrapartum hyperthermia (all cause) and neonatal brain injury, and (3) epidural-induced hyperthermia and neonatal brain injury. The results demonstrate (1) a causal link between epidural analgesia and intrapartum hyperthermia, (2) an association between intrapartum hyperthermia (all cause) and neonatal brain injury, and (3) insufficient evidence to formally evaluate the link between epidural hyperthermia and neonatal brain injury.

       Study Question 1: epidural analgesia and intrapartum hyperthermia

      The overall odds ratio of 5.26 for the association between epidural analgesia and intrapartum hyperthermia is strong, especially considering the large pooled sample size of 644 969 parturients. This strong association (odds ratio: 4.21) remained in the subgroup analysis of RCTs. This fits with other reviews of this nature, which reported risk ratios between 2.51 and 3.54.11 12 Additionally, this study finds that, since the previous systematic review, the GRADE quality of evidence supporting a causal link between epidural analgesia and intrapartum hyperthermia has increased to high.
      • Jansen S.
      • Lopriore E.
      • Naaktgeboren C.
      • et al.
      Epidural-related fever and maternal and neonatal morbidity: a systematic review and meta-analysis.
      The RCT subgroup analysis demonstrates a causal link between epidural analgesia and intrapartum hyperthermia. Epidural hyperthermia is not therefore a consequence of selection bias, that is, it is not the result of parturients with a greater risk of intrapartum hyperthermia selecting epidural analgesia. Although this causal link is biologically plausible, the underlying mechanism(s) remains unclear. A potential explanation is that epidural analgesia increases the risk of intrapartum infection, but a previous systematic review indicates that this is unlikely.
      • Jansen S.
      • Lopriore E.
      • Naaktgeboren C.
      • et al.
      Epidural-related fever and maternal and neonatal morbidity: a systematic review and meta-analysis.
      The most plausible explanation is that epidural hyperthermia is a distinct condition resulting from either cholinergic sympathetic blockade, immunomodulation, or both.
      • Mullington C.J.
      • Low D.A.
      • Strutton P.H.
      • Malhotra S.
      Body temperature, cutaneous heat loss and skin blood flow during epidural anaesthesia for emergency caesarean section.
      • del Arroyo A.G.
      • Sanchez J.
      • Patel S.
      • et al.
      Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.
      • Wohlrab P.
      • Boehme S.
      • Kaun C.
      • et al.
      Ropivacaine activates multiple proapoptotic and inflammatory signaling pathways that might subsume to trigger epidural-related maternal fever.
      The cholinergic blockade mechanism is that epidural local anaesthetic blocks the sympathetic pathways responsible for the control of sweating and active vasodilation, and thus, parturients' cutaneous heat loss is limited.
      • Mullington C.J.
      • Low D.A.
      • Strutton P.H.
      • Malhotra S.
      Body temperature, cutaneous heat loss and skin blood flow during epidural anaesthesia for emergency caesarean section.
      The immunomodulation mechanism is that the local anaesthetic either stimulates the release of interleukin-6, and thus induces activity in the pro-pyrogenic inflammatory pathway or inhibits the release of interleukin-1 receptor antagonist, and thus reduces the activity in the anti-pyrogenic inflammatory pathway, or both.
      • del Arroyo A.G.
      • Sanchez J.
      • Patel S.
      • et al.
      Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.
      ,
      • Wohlrab P.
      • Boehme S.
      • Kaun C.
      • et al.
      Ropivacaine activates multiple proapoptotic and inflammatory signaling pathways that might subsume to trigger epidural-related maternal fever.
      Although not a primary focus, this systematic review found no evidence favouring one mechanism.

       Study Question 2: intrapartum hyperthermia and neonatal brain injury

      This meta-analysis includes more than 11 million parturients and found a strong association between intrapartum hyperthermia and adverse neonatal neurological outcome (odds ratio: 2.48). This association remained when studies that investigated clinical chorioamnionitis were excluded (odds ratio: 2.79). Previous systematic reviews have demonstrated an association between clinical chorioamnionitis and the development of cerebral palsy.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      ,
      • Shi Z.J.
      • Ma L.
      • Luo K.H.
      • et al.
      Chorioamnionitis in the development of cerebral palsy: a meta-analysis and systematic review.
      ,
      • Shatrov J.G.
      • Birch S.C.M.
      • Lam L.T.
      • Quinlivan J.A.
      • McIntyre S.
      • Mendz G.L.
      Chorioamnionitis and cerebral palsy: a meta-analysis.
      However, this systematic review is the first to find an association between intrapartum hyperthermia of any cause and neonatal brain injury.
      Two mechanisms have been proposed that may account for the association between intrapartum hyperthermia and neonatal brain injury: the cytokine hypothesis and the energy failure hypothesis, neither of which is fully proven.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      The cytokine hypothesis is that intrauterine infection induces an inflammatory response in the fetus, which is neurotoxic.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      The energy failure hypothesis is that, after an intrapartum insult, hyperthermia exacerbates neuronal injury by increasing the intracellular energy deficit.
      • Laptook A.R.
      • Salhab W.
      • Bhaskar B.
      Admission temperature of low birth weight infants: predictors and associated morbidities.
      Energy failure is the principle that underpins the use of therapeutic hypothermia to treat neonates with encephalopathy caused by birth asphyxia (hypoxic–ischaemic encephalopathy).
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      Superficially, at least the cytokine hypothesis appears disease-specific to chorioamnionitis, whereas the energy deficit hypothesis seems applicable to intrapartum hyperthermia of any cause. However, the proposed immunomodulation mechanism of epidural hyperthermia may link with the cytokine hypothesis.
      • del Arroyo A.G.
      • Sanchez J.
      • Patel S.
      • et al.
      Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.
      ,
      • Wohlrab P.
      • Boehme S.
      • Kaun C.
      • et al.
      Ropivacaine activates multiple proapoptotic and inflammatory signaling pathways that might subsume to trigger epidural-related maternal fever.
      The diagnosis of clinical chorioamnionitis requires intrapartum hyperthermia in addition to other clinical signs of infection, such as tachycardia (maternal and fetal), tachypnoea, leucocytosis, and foul-smelling vaginal discharge.
      American College of Obstetricians and Gynecologists
      Intrapartum management of intraamniotic infection.
      However, of these symptoms, only foul-smelling vaginal discharge cannot be attributed to the hyperthermia itself.
      • Lappen J.R.
      • Keene M.
      • Lore M.
      • Grobman W.A.
      • Gossett D.R.
      Existing models fail to predict sepsis in an obstetric population with intrauterine infection.
      Previous meta-analyses found that, whilst there is often an association between clinical chorioamnionitis and cerebral palsy, this is not seen to the same extent with histological chorioamnionitis.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      ,
      • Shi Z.J.
      • Ma L.
      • Luo K.H.
      • et al.
      Chorioamnionitis in the development of cerebral palsy: a meta-analysis and systematic review.
      ,
      • Shatrov J.G.
      • Birch S.C.M.
      • Lam L.T.
      • Quinlivan J.A.
      • McIntyre S.
      • Mendz G.L.
      Chorioamnionitis and cerebral palsy: a meta-analysis.
      This hints that it is the hyperthermia itself, rather than the underlying disease process, that has the greater impact on neonatal neurological outcome. The finding in the present meta-analysis that intrapartum hyperthermia of any cause is associated with neonatal brain injury adds weight to this argument.
      Gestational age at delivery is the greatest factor in the development of neonatal brain injury. However, this systematic review demonstrates that intrapartum hyperthermia has an impact on neonatal neurological outcome that is independent of gestational age. The aetiology of brain injury in premature neonates differs to that of their term counterparts.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      The most common form of brain injury in premature neonates is intracerebral haemorrhage caused by the fragility of immature blood vessels, whereas in term neonates, brain injury is most commonly secondary to birth asphyxia and is associated with damage to watershed areas of the brain, the basal ganglia, and the thalamus.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      ,
      • Miller S.P.
      • Ferriero D.M.
      • Leonard C.
      • et al.
      Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome.
      Consequently, it should not be assumed that intrapartum hyperthermia has a similar impact on neurological outcome in both term and preterm neonates. The subgroup analysis in the present systematic review reveals that intrapartum hyperthermia increases the risk of neonatal brain injury in both term and preterm neonates. Superficially, at least it also appears to indicate that intrapartum hyperthermia has a greater impact in term neonates (odds ratio: 3.38) than in preterm neonates (odds ratio: 1.63). This result aligns with two previous meta-analyses, which investigated clinical chorioamnionitis and cerebral palsy in term and preterm neonates and demonstrated a higher risk ratio for term neonates.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      ,
      • Shi Z.J.
      • Ma L.
      • Luo K.H.
      • et al.
      Chorioamnionitis in the development of cerebral palsy: a meta-analysis and systematic review.
      However, it should be noted that in the present meta-analysis, the absolute risk increase was greater in preterm neonates than term neonates: +4.4% and +0.6%, respectively. This disparity is attributable to the difference in the baseline incidence of brain injury in the two populations: in comparison to term neonates, the risk of neonatal brain injury is approximately 7.5-fold greater in preterm neonates.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      Therefore, it can be concluded that the impact of intrapartum hyperthermia upon neurological outcome is at least as great in preterm neonates as their term counterparts.

       Study Question 3: epidural-induced hyperthermia and neonatal brain injury

      This investigation is the first to systematically review the evidence linking epidural hyperthermia and neonatal brain injury. It finds that, at present, there is insufficient evidence to answer this question. Only two studies met the inclusion criteria for this question and the GRADE quality of evidence was very low. Greenwell and colleagues
      • Greenwell E.A.
      • Wyshak G.
      • Ringer S.A.
      • Johnson L.C.
      • Rivkin M.J.
      • Lieberman E.
      Intrapartum temperature elevation, epidural use, and adverse outcome in term infants.
      showed that epidural hyperthermia increases the risk of early-onset seizures (odds ratio: 6.5), but the total number of events was low (eight). Törnell and colleagues
      • Törnell S.
      • Ekeus C.
      • Hultin M.
      • Hakansson S.
      • Thunberg J.
      • Hogberg U.
      Low Apgar score, neonatal encephalopathy and epidural analgesia during labour: a Swedish registry-based study.
      found an association between intrapartum hyperthermia of any cause and neonatal encephalopathy (odds ratio: 1.97), but they did not consider the impact of epidural hyperthermia and non-epidural-related intrapartum hyperthermia separately. Further research is required to address this knowledge gap.

       Limitations

      The results of this systematic review and meta-analysis are limited by the quality of the individual studies. However, given the nature of the study questions, higher-quality study designs are unrealistic. Study Question 1 (epidural analgesia and intrapartum hyperthermia) contains 13 unblinded RCTs. To blind subjects in this situation is impossible, and it would be unethical to prevent parturients from changing their minds about epidural use. That Evron and colleagues
      • Evron S.
      • Ezri T.
      • Protianov M.
      • et al.
      The effects of remifentanil or acetaminophen with epidural ropivacaine on body temperature during labor.
      and Nafisi
      • Nafisi S.
      Effects of epidural lidocaine analgesia on labor and delivery: a randomized, prospective, controlled trial.
      managed no patient non-adherence and that de Orange and colleagues
      • de Orange F.A.
      • Passini Jr., R.
      • Amorim M.M.
      • Almeida T.
      • Barros A.
      Combined spinal and epidural anaesthesia and maternal intrapartum temperature during vaginal delivery: a randomized clinical trial.
      only had one participant not follow the protocol in each arm of the study is remarkable. It is not possible to control whether or not a parturient develops intrapartum hyperthermia, and therefore multicentre prospective observational study designs are the optimal method of investigating study Questions 2 (intrapartum hyperthermia and neonatal brain injury) and 3 (epidural hyperthermia and neonatal brain injury). Although observational study designs are inherently at risk of selection bias, in the majority of studies, potential confounders were identified and adjusted for. Detection bias and attrition bias are also inherent risks. Detection bias is likely present in the majority of studies, as the method of temperature measurement was often unclear and observers were only blinded in one study.
      • Wilson-Costello D.
      • Borawski E.
      • Friedman H.
      • Redline R.
      • Fanaroff A.A.
      • Hack M.
      Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children.
      It is unclear to what extent attrition bias is present, as missing data were not reported in the majority of studies. However, loss to long-term follow-up was reported as 22% in one study and 20% in another.
      • Nasef N.
      • Shabaan A.E.
      • Schurr P.
      • et al.
      Effect of clinical and histological chorioamnionitis on the outcome of preterm infants.
      ,
      • Sameshima H.
      • Ikenoue T.
      Developmental effects on neonatal mortality and subsequent cerebral palsy in infants exposed to intrauterine infection.
      Considerable statistical heterogeneity was present in the meta-analysis of study Question 1 and substantial statistical heterogeneity in the meta-analysis of study Question 2. The likely sources of this heterogeneity are the definition of intrapartum hyperthermia, maternal characteristics, gestational age, and the form of neonatal brain injury. The definition of intrapartum hyperthermia ranged from >37.0 to >38.5°C.
      • Dior U.P.
      • Kogan L.
      • Calderon-Margalit R.
      • et al.
      The association of maternal intrapartum subfebrile temperature and adverse obstetric and neonatal outcomes.
      ,
      • Redline R.W.
      • O’Riordan M.A.
      Placental lesions associated with cerebral palsy and neurologic impairment following term birth.
      This lack of consistency is likely caused by geographical and temporal variations in the definition of intrapartum hyperthermia.
      American College of Obstetricians and Gynecologists
      Intrapartum management of intraamniotic infection.
      ,
      National Institute for Health and Care Excellence
      Intrapartum care for women with existing medical conditions or obstetric complications and their babies: evidence reviews for pyrexia.
      Clinical chorioamnionitis was the exposure or outcome in 15 studies (Table 2). However, this is unlikely to have been a significant factor, as there was little reduction in statistical heterogeneity in the subgroup analysis of studies, where hyperthermia alone was the exposure (Fig. 3b). The non-significant statistical heterogeneity in the subgroup meta-analysis of RCTs for study Question 1 suggests that variation in maternal characteristics was a significant factor. For example, parity may influence the incidence of hyperthermia via its impact on the duration of labour and thus the risk of epidural hyperthermia.
      • Goetzl L.
      • Rivers J.
      • Zighelboim I.
      • Wali A.
      • Badell M.
      • Suresh M.S.
      Intrapartum epidural analgesia and maternal temperature regulation.
      Variation in epidural protocols was noted between studies, but it is unclear if this was a source of statistical heterogeneity. The choice of epidural local anaesthetic has been shown to have at most a small effect on incidence of intrapartum hyperthermia, and it is unclear if the method of epidural drug delivery has an impact.
      • Fan Y.
      • Hou W.
      • Feng S.
      • et al.
      Programmed intermittent epidural bolus decreases the incidence of intra-partum fever for labor analgesia in primiparous women: a randomized controlled study.
      • Feng S.W.
      • Xu S.Q.
      • Ma L.
      • et al.
      Regular intermittent bolus provides similar incidence of maternal fever compared with continuous infusion during epidural labor analgesia.
      • Mantha V.R.
      • Vallejo M.C.
      • Ramesh V.
      • Phelps A.L.
      • Ramanathan S.
      The incidence of maternal fever during labor is less with intermittent than with continuous epidural analgesia: a randomized controlled trial.
      • Yue H.L.
      • Shao L.J.
      • Li J.
      • Wang Y.N.
      • Wang L.
      • Han R.Q.
      Effect of epidural analgesia with 0.075% ropivacaine versus 0.1% ropivacaine on the maternal temperature during labor: a randomized controlled study.
      Neonatal brain injury is more common and has a different aetiology in preterm infants, and therefore the gestational age of the individual study populations is likely to have been a contributor.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      The reduced statistical heterogeneity in the subgroup analysis of term deliveries may also reflect the more homogeneous aetiology of neonatal brain injury at term.
      • Gale C.
      • Statnikov Y.
      • Jawad S.
      • Uthaya S.N.
      • Modi N.
      Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database.
      The forms of neonatal brain injury reported include clinical diagnoses, such as neonatal encephalopathy and cerebral palsy, and radiological diagnoses, such as intraventricular haemorrhage and periventricular leucomalacia. This variation in part reflects the different methods of diagnosing and classifying brain injury at the time of birth, during the neonatal period, and later in childhood. However, they are distinct conditions, and so this variation is a likely source of statistical heterogeneity.
      The funnel plot (Supplementary Fig. 4b) shows asymmetry. The major source of this asymmetry is the study design of two outlying studies, both of which are case–control studies of neonatal brain injury with a small number of cases of intrapartum hyperthermia.
      • Dammann O.
      • Drescher J.
      • Veelken N.
      Maternal fever at birth and non-verbal intelligence at age 9 years in preterm infants.
      ,
      • Ghi T.
      • Giunchi S.
      • Pilu G.
      • et al.
      Neonatal hypoxic-ischemic encephalopathy in apparently low risk pregnancies: retrospective analysis of the last five years at the University of Bologna.
      Such study designs are prone to overestimation of the effect size.
      • Sterne J.A.C.
      • Sutton A.J.
      • Ioannidis J.P.A.
      • et al.
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
      However, this asymmetry is unlikely to affect the results of this subgroup analysis, as the two outlying studies comprise only 0.3% of the model. It is also possible that there is publication bias within this subgroup. Potential sources are inclusion of English language studies only and a lack of a grey literature search.
      • Sterne J.A.C.
      • Sutton A.J.
      • Ioannidis J.P.A.
      • et al.
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.

       Clinical implications

      This systematic review and meta-analysis evaluates the evidence pertaining to an important clinical question: does epidural hyperthermia increase the risk of neonatal brain injury? It finds that, currently, there is insufficient evidence to answer this question. However, the findings that epidural analgesia is a cause of intrapartum hyperthermia and that intrapartum hyperthermia of any cause is associated with neonatal brain injury highlight the need for further investigation. Although chorioamnionitis is a risk factor for neonatal brain injury, it cannot be assumed that epidural hyperthermia has a similar impact on the neonatal brain.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      Study Question 1 demonstrates that chorioamnionitis and epidural hyperthermia are distinct conditions, and it is not known if the mechanism by which chorioamnionitis increases the risk of neonatal brain injury is common to both conditions.
      • Wu Y.W.
      • Colford J.M.
      Chorioamnionitis as a risk factor for cerebral palsy—a meta-analysis.
      ,
      • Laptook A.R.
      • Salhab W.
      • Bhaskar B.
      Admission temperature of low birth weight infants: predictors and associated morbidities.
      In contrast, it is well recognised that epidural analgesia has many benefits, including being the most effective form of labour analgesia, reducing the need for general anaesthesia and improving outcome in high-risk parturients.
      • Anim-Somuah M.
      • Smyth R.M.
      • Cyna A.M.
      • Cuthbert A.
      Epidural versus non-epidural or no analgesia for pain management in labour.
      ,
      • Leslie D.
      • Collis R.E.
      Hypertension in pregnancy.
      ,
      • Boyle R.K.
      Anaesthesia in parturients with heart disease: a five year review in an Australian tertiary hospital.
      Consequently, if unnecessary harm is to be avoided, it is crucial that the association between epidural hyperthermia and neonatal brain injury is investigated with high-quality research, before any changes in clinical practice. Given the nature of the question, it is likely that prospective multicentre observational studies are the optimum approach. However, mechanistic studies may also prove informative. For example, developing a technique to accurately differentiate epidural-induced hyperthermia from intrapartum infection will help elucidate the true relationship between epidural-induced hyperthermia and neonatal neurological outcome.

       Conclusion

      This systematic review and meta-analysis shows a causal link between epidural analgesia and intrapartum hyperthermia. It also reveals a strong association between intrapartum hyperthermia of any cause, not simply chorioamnionitis, and the development of neonatal brain injury. However, there was insufficient evidence to evaluate the link between epidural-induced hyperthermia and neonatal brain injury. Consequently, further research is required to determine whether or not epidural-induced hyperthermia is a modifiable risk factor for neonatal brain injury.

      Authors' contributions

      Study design: SM, CJM
      Literature search: SM, JK
      Data collection: SM, JK
      Quality review: all authors
      Statistical analysis: SM
      Manuscript preparation: SM, CJM
      Manuscript revision: all authors

      Acknowledgements

      The authors thank L. Blake (University of Arkansas for Medical Sciences, Little Rock, AR, USA) for her assistance in retrieving full-text versions of articles.

      Declarations of interest

      The authors declare that they have no conflict of interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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      • Accurate core temperature measurement during Caesarean delivery. Comment on Br J Anaesth 2021; 126: 500–15
        British Journal of AnaesthesiaVol. 127Issue 6
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          Editor—We would like to congratulate Morton and colleagues1 for their thoughtful and comprehensive review of an important issue. Of particular note are the associations between epidural analgesia and development of intrapartum hyperthermia amongst reviewed RCTs (odds ratio [OR]: 4.22; 95% confidence interval [CI]: 3.48–5.09) (high GRADE quality of evidence), and the association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54–2.3.06) (low GRADE quality of evidence).
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