Perinatal outcomes and risk factors for epidural analgesia-associated intrapartum maternal fever: a retrospective study

doi:10.21203/rs.3.rs-1597834/v1

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Perinatal outcomes and risk factors for epidural analgesia-associated intrapartum maternal fever: a retrospective study

https://doi.org/10.21203/rs.3.rs-1597834/v1

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published 30 Apr, 2023

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Background: Epidural analgesia (EA) increases the risks of maternal fever during labor, which is associated with adverse maternal and neonatal outcomes, while the risk factors for the phenomenon of epidural-associated fever and future strategies for minimizing these effects remain unknown.

Methods: We retrospectively analyzed 325 pregnant women who attended our institution for a vaginal in-hospital delivery, including 208 voluntarily accepted EA women and 117 pregnant women who did not receive EA. During labor, 208 EA women were subgrouped into the Fever group (n = 42, an axillary temperature ≥ 37.5 °C during labor), and None-fever group (n = 166). The outcome measures include main maternal and neonatal outcomes, labor time, duration of EA, and total EA amount.

Results: 42 out of 208 women with EA presented fever during labor, higher than that in women without EA (20.19% vs. 0.85%). Maternal fever had increased risks for conversion to surgery ((Adjusted odds ratio (AOR), 4.05; 95% CI, 1.44 to 11.39)) and neonatal infections (5.13; 1.98 to 13.29) compared to the None-Fever group. While maternal fever didn’t increase the risks for assisted vaginal delivery, fetal distress and admission to neonatal intensive care unit (NICU)，it was predominantly associated with primiparity and less times of gravity. Frequent cervical examinations, duration of first stage and total labor, and duration of EA and total EA amount were positively correlated with the incidence of fever. Furthermore, after stratifying risk factors into subgroups, we found that more frequent cervical examinations (≥ 7 times) and longer duration of first stage (≥ 442.5min), total labor time (≥ 490min), EA (≥ 610.0min) increased the risks of epidural-associated fever after adjustment for potential confounding factors.

Conclusions: EA increases the risk of intrapartum epidural-associated fever, which is correlated with adverse perinatal outcomes. Nulliparity, less times of gravidity, more than 7 times of cervical examinations, more amount of EA volume, prolonged duration of EA and total labor time are the risk factors for epidural-associated fever, which provide us insights and strategies to prevent epidural-associated fever in a safer and more effective way.

Epidural analgesia

intrapartum maternal fever

perinatal outcome

labor time

Over the past 2 decades, epidural analgesia (EA) has been widely acknowledged as a safe and efficient method to relieve the pain during labor[1]. With the implementation of the “No Pain Labor & Delivery” program since 2008, EA usage rate has risen up to 50% in most hospitals in China. Despite its effectiveness as an analgesic, accumulative studies suggest that women who have receive labor epidural analgesia are more likely to develop epidural-related fever[2], which has attracted widespread attention since 30 years ago[3], reporting that it complicates up to one-third of deliveries[4]. Furthermore, epidural-related maternal fever(ERMF) during labor may lead to significant maternal or neonatal adverse effects, including higher risks of assisted vaginal delivery or cesarean delivery and an increased risk of neonatal mortality and morbidity as well[5–7].

Unfortunately, the mechanisms for epidural-associated fever is at this point not well understood. ERMF doesn’t happen among non-pregnant women or pregnant women receiving epidural or spinal anesthesia for elective cesarean delivery. Even in the absence of bacteriological evidence of vaginal, uterine, or urinary tract infection, pregnant women are more easily predisposed to development of pyrexia due to ERMF. And broad-spectrum antibiotic administration[6] or acetaminophen[8] can’t reduce the incidence of ERMF, which suggesting that ERMF is a sterile (noninfectious) inflammatory process[9]. The unidentified pathological process provokes us to lay emphasis on exploration of risk factors for the ERMF. 15–25% women receiving epidural analgesia were presented with fever[4]. Numerous studies demonstrate that maternal fever during labor is likely mediated by various circumstantial factors such as nulliparity, difficult labor, and prolonged ruptured membranes collectively contribute to its development[10].

Whether there are other risk factors for ERMF, and its consequences to the mother and baby, and future strategies for minimizing these effects remains unknown. Hence, our interest mainly lies in examining latent contributing factors such as duration of labor, frequent cervical examinations, duration of epidural analgesia, dosage of patient-controlled epidural analgesia. The study aims to investigate a number of well-characterized clinical features related to ERMF and evaluate the optimal ways to guide the clinical prevention of ERMF and provide evidence for exploring the underlying pathophysiological processes for ERMF.

Study Population

This retrospective study utilized the data available in the electronic medical record system of Maternity and Child Health Hospital of Songjiang District, Shanghai, China and was based on in-hospital deliveries from Jan to Jun 2021. The inclusion criteria were as follows: 1) women with full-term singleton pregnancy (≥ 37 weeks); 2) scheduled vaginal in-hospital delivery; 3) vertex presentation; 4) willingness to use PCEA and ability to provide informed consent; The following exclusion criteria were applied: 1) women with pre-pregnancy hypertension, diabetes before pregnancy, multiple pregnancies, and stillbirth; 2) women with previous cesarean section; 3) pre-epidural temperature ≥ 37.5 °C; 4) pregnant women with pre-epidural acute inflammatory diseases (such as genital tract acute infection, upper respiratory tract infection, etc.); 5) induction of labor with balloon and prostaglandin preparation; 6) history of myocardial infarction, heart failure, maternal hepatitis, or HIV infection; 7) taking paracetamol within 6 h before the study; 8) no suspected fetal coagulopathy; 9)hemoglobin＜8g or blood platelet＜80×10^9/L; 10)lumbar disc herniation. Based on the inclusion and exclusion criteria, 208 women underwent EA were recruited. 117 pregnant women who did not receive EA (non-EA) and gave birth at the same period were selected randomly as controls. Also, 208 EA women were subgrouped into the ERMF group (n = 42), and None-fever group (n = 166). Ethics approval was obtained from the research ethics committee at Child Health Hospital of Songjiang District and written informed consent was provided by participants before study participation.

Body temperature measurement and treatment of fever

Body temperature measurement started from the onset of labor and was conducted once an hour (Infrared ear thermometer, Braun pro4000) until delivery. Intrapartum maternal fever was defined as an axillary temperature ≥ 37.5 °C during labor. If the parturient developed a fever, prophylactic antibiotics were used and fluid replacement was also accelerated to replenish the water lost at this temperature when the axillary temperature rose to 38-38.5 °C. If the axillary temperature rose above 38.5 °C, ibuprofen was administered orally.

Patient-controlled epidural analgesia (PCEA)

An epidural catheter was introduced at L3–L4 when the contractions became regular and cervical dilation was up to 2-3 cm. Women were given test dose of analgesia including 1: 200000 adrenaline and 1.5% lidocaine after the successful puncture. After 5 min, a 10 mL bolus of ropivacaine 0.075% (lot number: H20140763; Astra Zeneca, Sweden) plus 0.5 μg/mL sufentanil (batch number: H20054171; Yichang Renfu Pharmaceutical, China) was administered. Then, the epidural catheter was connected to a Programmed intermittent epidural bolus (PIEB) pump with the following parameters: PIEB settings were a 9 mL bolus every 50 min; injection rate, 1 mL/h; PCEA (demand) dose, 8 mL; maximum dose, 30 mL/h; and lockout interval, 10 min. The analgesic level was assessed according to the patient’s sensitivity to temperature (ice) after 15 min. Additional 5 mL boluses of 0.1% ropivacaine were given for breakthrough pain and a visual analogue scale pain score < 3 at any time during labor.

Data collection and independent variables

The hospital’s electronic medical records collect data on each birth delivered in the hospital. Maternal demographic, anthropometric characteristics，and reproductive history were collected at the first prenatal visit between 9 and 14 weeks gestation. We calculated the length of gestation based on the ultrasound if the disagreement between the two methods was over one week.

Analgesic data, including the duration of EA, total amount of EA doses, and total PCEA dose were also collected. The body temperature and changes in the parturients, including intrapartum fever status were recorded. The duration of labor, frequent cervical examinations and conversions to obstetric forceps or cesarean sections were also analyzed. Maternal blood pressure and heart rate were monitored continuously during labor and the rate and volume of fluid administration were measured.

Definition of outcomes

Main complications of pregnancy including gestational hypertension, preeclampsia (PE), gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP) were coded according to the 10^th revision of the International Statistical Classification of Diseases (ICD-10) and diagnosed based on our previous article[11]. Pregnancy anemia is defined as a haemoglobin concentration (Hb) <110g/L at sea level during pregnancy[12, 13]. Neonatal infections was defined as the systemic inflammatory response syndrome caused by the infection of various pathogens (including bacteria, viruses, protozoa, etc.), which was diagnosed when neonates presented Jaundice, vomiting, fever, dyspnea or other symptoms and met any 2 of the following criteria: 1) Neonates with white blood cell count ≥ 30×10⁹/L at 6 hours-3 days old, or ≥ 20×10⁹/L at the ages ≥ 3 days old, or < 5×10⁹/L at any day of age; 2) C-reactive protein ≥ 3 mg/L within 6 hours old，or ≥ 5 mg/L between 6 ~ 24 hours old, or ≥ 10 mg/L in Neonates more than 24 hours old; 3) Positive blood culture.

Statistical analysis

Continuous variables were expressed as means ± SD. Independent-samples t-test, non-parametric test, and chi-square tests were used to evaluate the statistical significance between the two groups. Categorical variables were represented as frequencies with proportions. We applied multilevel linear regression models to Univariate logistic regressions were used to estimate odds ratios (ORs) with a 95% confidence interval (CI) in assessing associations between EA and risk of maternal fever, and the associations between maternal fever and risks of adverse maternal and neonatal outcomes as well. The ORs for the risks of maternal fever, and adverse perinatal outcomes were calculated. Frequent cervical examinations, time of first stage, total labor time, amount of medicine, total EA duration did not conform to normal distributions; therefore, these data were stratified into quartile value subgroups. Similarly, the absolute risks were estimated for maternal fever among women who underwent EA across the range of risk factor categories.

Multivariable analyses were adjusted for potential confounders. Maternal age (≤ 24, 25-29, 30-34, or ≥ 35 years), height (≤ 154, 155-164, 165-174, ≥ 175 cm), late pregnancy BMI ranges (BMI , ≤ 24.9, 25.0 to 29.9, and ≥30 kg/m² ), parity (once, or more than twice), gravidity (once, twice, or more than three times), pregnancy complications GDM (no or yes), gestational hypertensive disease (no or yes), ICP (no or yes), cephalopelvic disproportion (no or yes), and pregnancy anemia (no or yes) were included as covariates and to assess the associations between EA and incidences of maternal fever, maternal fever and incidences of perinatal outcomes, and risk factors for the incidences of maternal fever. To reduce the bias caused by low sample capacity when calculated the association between frequent cervical examinations and risk of maternal fever, women were classified into three subgroups as follows: < 5, 5-6, and ≥ 7 times subgroup. A confidence interval that contained a one meant that there was no significant difference between the event and the control in terms of risk. All statistical analyses were performed using SPSS package version 21.0 (SPSS Inc., USA). A two-tailed P-value of less than 0.05 was used as the threshold for statistical significance.

Baseline characteristics of the study population

We enrolled 325 women with a mean (±SD) age of 29.22 (±4.20) years in the study. Women in EA group were younger, less gravid and nulliparous when compared to non-EA group. Similar BMI at delivery and rates of pregnancy complications such as GDM, gestational hypertensive disease, cephalopelvic disproportion, pregnancy anemia was presented between the non-EA and EA group (Table 1). During the study period, there were 42 (20.19%) maternal fever among 208 women underwent EA. While in non-EA group, the rate of maternal fever was only 0.85% (1/117). Compared with the non-EA group, the EA group had increased risk of the maternal fever. After adjusted for maternal age, BMI, and pregnancy complications, the odds ratio of maternal fever was 21.81 with a 95% confidence interval of 2.73 to 174.54.

Maternal fever and risks of adverse maternal and neonatal outcomes among women underwent EA

To determine the effect of epidural-associated fever, we calculated the baseline characteristics, maternal and neonatal outcomes in EA participants. Similar age, height, BMI, and gestational weeks were found among fever and no-fever group. Women with ERMF showed higher white blood cells and neutrophils, while the levels of interleukin 6 and C-reactive protein didn’t present significant difference between fever and no-fever groups (Table 2). Indeed, we found that the amount of medicine and total EA duration in fever group were obviously higher than those in none-fever group.

Furthermore, for maternal outcomes, women with ERMF presented longer first-stage labor time, total labor time, more frequent cervical examinations, and less volume of postpartum hemorrhage (Table 2). Significant higher rates and risks of conversion to surgery were also found in the fever group compared to the none-fever group (28.57% vs.7.53%; AOR, 4.05; 95% CI, 1.44 to 11.39). However, the rate and risk of forceps delivery, though slightly higher, showed no statistical difference compared with the control group (Table 3). For neonatal outcomes among women underwent EA, the Apgar score of 5-minute was lower and rates of fetal distress were higher in women with epidural-associated fever, while the risk of fetal distress was not significant after adjusted for maternal age, BMI, parity, gravidity and pregnancy complications (Table 3). In addition, compared with no fever group, the fever group higher sincreased risk of the neonatal infections (35.71% vs. 7.83%; AOR, 5.13; 95% CI, 1.98 to 13.29). No difference was found in Apgar score of 1-minute and the rate of NICU between fever and no fever groups (Table 2 and Table 3).

Risk factors for ERMF

We further analyzed the risk factors which would relate to the happen of ERMF. In table 4, we can find that maternal pathogen infection and different rupture pattern of membranes didn’t increase the risks of maternal epidural-associated fever. Women who is nulliparous and with less gravidities showed higher rates of epidural-associated fever. Compared to first pregnancy, women with 2 times or more than 2 times of gravidities had lower risk of epidural-associated fever (2 times: 11.67% vs 29.65%, respectively; AOR, 0.30 [95% CI, 0.12 to 0.76]; ≥3 times: 9.52% vs 29.65%, respectively; AOR, 0.27 [95% CI, 0.08 to 0.91]).

The results form table 2 and 3 showed time- and dose-dependent correlations between EA and maternal fever during delivery. In order to define feasibility values for clinicians to prevent the epidural-associated fever, we stratified the values of frequent cervical examinations, time of first stage, total labor time, amount of medicine, and total EA duration into quartile value subgroups. The cutoff points of frequent cervical examinations at the 50^th (5 times) and 75^th (7 times) percentiles were defined according to the assayed values among women enrolled. The cutoff points of time of first stage at the 25^th (168.8 min), 50^th (260 min) and 75^th (442.5 min) percentiles were defined. The values of 25^th, 50^th, 75^th percentile for total labor time were 200.0, 285.0, and 490.0 min, respectively. For duration of EA, the values of 25^th, 50^th, 75^th percentile were 150.5, 303.5 and 610.0 min. The cutoff points of amount of medicine at the 25^th (30ml), 50^th (40ml) and 75^th (56ml) percentiles were defined.

We further analyzed the association between risk factors and epidural-associated fever in four subgroups (Table 4). The rates and risks of ERMF were positively correlated to the labor time, amount of medicine, EA duration. Women with longer labor time of first stage, total labor time and duration of EA had higher risks of ERMF vs women with less than 25^th point of those factors (labor time of first stage: 32.76% vs. 9.09%, respectively; AOR, 6.62 [95% CI, 1.23 to 35.50]; total labor time: 30.51% vs. 8.33%, respectively; AOR, 5.85 [95% CI, 1.12 to 30.49]；total EA duration: 34.62% vs. 10.00%, respectively; AOR, 3.86 [95% CI, 1.20 to 12.47]). The rates and risks of ERMF were positively correlated to the amount of medicine. However, women with more amount of medicine showed no significant increase in risk of maternal fever after adjusting the confounding factors (Table 4).

In this study, we found EA increases the risk of intrapartum fever, while epidural-associated fever increased the risks for conversion to surgery and neonatal infections but showed no increase in risks of postpartum hemorrhage and assisted vaginal delivery, fetal distress and NICU after adjustment for potential confounding factors.

Women self-selected their analgesia showed an average increase in temperature of approximately 1°C over 7 hours. The results from a few randomized controlled trials (RCTs) which compared women randomized to receive epidural or nonepidural analgesia techniques have also shown an increased incidence of fever in the epidural groups[14–16].The incidence of clinical fever, usually defined as core temperature 37.5°C or 38.0°C, in women with epidural analgesia has varied strikingly, from 1–46% basing on the different study populations[17–19]. In this study, although we have set detailed inclusion and exclusion criteria to eliminate the potential maternal factors that may lead to clinically suspected of infection, the incidence of maternal fever was still up to 20.19%, while there was less than 1% in women with who didn’t receive epidural anesthesia.

Epidural analgesia-associated fever may have significant consequences for both the mother and the fetus/neonate. Similarly, in addition to increased risk of conversion to surgery, a significant increase in neonatal infections was found in women with intrapartum maternal fever in our study. Epidemiologic investigations have shown an increase in neural-tube defects in the babies of women exposed to external heat sources in early pregnancy. Hence, we should focus on the effect of intrapartum maternal fever on the neonates or children. The study of animal models of intrauterine infection showed white matter lesions in the fetal brains[20]. While the adverse effect could be blocked with anti-inflammatory cytokines, perhaps by blocking gliosis in affected areas[21, 22]. Furthermore, long-term effect of maternal fever was also attracting our attention. Even if the manifestations are not apparent at birth, cognitive deficits later in childhood appear related to maternal intrapartum infection. Dammann et al. demonstrated that nonverbal intelligence scores 2 standard deviations below the age-adjusted mean are related to maternal fever at birth (odds ratio 3.8)[23]. Maternal fever also can increase the risks of Schizophrenia, autism, and possibly even Parkinson’s disease in later life[24–26]. In this study, we only found an significant increase in neonatal infections, long-term follow-up studies should be carried out upon those offspring whose mothers juxtaposed with intrapartum fever, especially in children with neonatal infections. The mechanisms by which epidural analgesia produces maternal hyperthermia during labor remain unclear. Several explanations such as the role of thermoregulatory factors, systemic opioid administration, and inflammation have been advanced. It was not demonstrated that maternal pathogen infection increased the risks of maternal epidural-associated fever, which also caters to the view that intrapartum fever is a result of non-inflammatory process.

Since the epidural-related intrapartum fever is inevitable in many labors and the mechanism involved remains unelucidated, exploring the risk factors is therefore important for women undergoing epidural analgesia.A recent study showed a total EA duration exceeding 6.3 h was associated with an increase in the duration of maternal intrapartum fever and early measures, such as oxytocin to acelerate labor, which should be taken into consideration of maternal fever prevention.[27]. Vaginal examination performed more than 6 times was reported to elevate the risk of fever during epidural labor analgesia[28]. In our study, there was no significant difference in the general data between the Analgesia and No-Analgesia groups. The risk of maternal fever was associated with primiparity, less times of gravity. Intrapartum maternal fever was time- and dose-dependently correlated with frequent cervical examinations, time of first stage and total labor and duration of EA. Logistic regression analysis showed that parturients with more frequent of cervical examinations (≥ 7 times), longer time of first stage (≥ 442.5min), total labor time (≥ 490min), and duration of EA (≥ 610.0min) were more likely to have an incidence of fever. Our results suggested that nulliparous, less gravidity, more than 7 times of cervical examinations, and prolonged duration of EA and total labor time are the risk factors for epidural-associated fever, which provides us some insights and strategies to prevent epidural-associated fever in a safer and more effective way.

EA was associated with maternal fever, which is an important risk factor for adverse perinatal outcomes, including higher rate of cesarean section and neonatal infections. Nulliparity, less times of gravidity, more than 7 times of cervical examinations, and prolonged duration of EA and total labor time are the risk factors for epidural-associated fever. Limiting the times of cervical examinations, the duration of EA and total labor time may be the safe and effective strategies to prevent epidural-associated fever to a certain extent. However, further study is required on how the epidural-related intrapartum fever can increase the risk of neonatal infections and the mechanism involved need to be elucidated.

EA: epidural analgesia; PCEA: patient-controlled epidural analgesia; ERMF: epidural-related maternal fever; GDM: Gestational diabetes mellitus; NICU: neonatal intensive care unit; AOR: adjusted odds ratio; CI: confidence interval.

Acknowledgements

We thank our patients and the information technologist for the data collecting.

Authors’ contributions

FL and X-HL conceived the study and contributed to the design of the study. HW, L-NX, YL and X-FW contributed to data collection. HW and Z-PY contributed to the analyze and paper writing. S-YW contributed to paper modification. All authors contributed to the article and approved the submitted version.

Funding

This study was funded by the National Key Research and Development Program of China

(2018YFC1005001 to X.-H.L.), the National Natural Science Foundation of China (82071730 to X.-H.L.). Shen Kang Clinical Science and Technology Innovation Project (SHDC12019X17 to X.-H.L.). Science and Technology Commission of Songjiang District (20SJKJGG171 to F.L )
Availability of data and materials
The datasets used and analyzed during the current study available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate

All methods were carried out in accordance with relevant guidelines and regulations.
This research study was conducted retrospectively from data obtained for clinical purposes. Ethics approval was obtained from the research ethics committee at Child Health Hospital of Songjiang District and written informed consent was provided by participants before study participation.
Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Apantaku O, Mulik V: Maternal intra-partum fever. J Obstet Gynaecol2007, 27(1):12-15.
Alexander JM: Epidural analgesia for labor pain and its relationship to fever. Clin Perinatol2005, 32(3):777-787.
Fusi L, Steer PJ, Maresh MJ, Beard RW: Maternal pyrexia associated with the use of epidural analgesia in labour. Lancet1989, 1(8649):1250-1252.
Segal S: Labor epidural analgesia and maternal fever. Anesth Analg2010, 111(6):1467-1475.
Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P: The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol2008, 198(1):49 e41-46.
Sharma SK, Rogers BB, Alexander JM, McIntire DD, Leveno KJ: A randomized trial of the effects of antibiotic prophylaxis on epidural-related fever in labor. Anesth Analg2014, 118(3):604-610.
Goetzl L: Epidural fever in obstetric patients: it's a hot topic. Anesth Analg2014, 118(3):494-495.
Goetzl L, Rivers J, Evans T, Citron DR, Richardson BE, Lieberman E, Suresh MS: Prophylactic acetaminophen does not prevent epidural fever in nulliparous women: a double-blind placebo-controlled trial. J Perinatol2004, 24(8):471-475.
Riley LE, Celi AC, Onderdonk AB, Roberts DJ, Johnson LC, Tsen LC, Leffert L, Pian-Smith MCM, Heffner LJ, Haas STet al: Association of epidural-related fever and noninfectious inflammation in term labor. Obstet Gynecol2011, 117(3):588-595.
Jansen S, Lopriore E, Naaktgeboren C, Sueters M, Limpens J, van Leeuwen E, Bekker V: Epidural-Related Fever and Maternal and Neonatal Morbidity: A Systematic Review and Meta-Analysis. Neonatology2020, 117(3):259-270.
Lin XH, Wu DD, Li C, Xu YJ, Gao L, Lass G, Zhang J, Tian S, Ivanova D, Tang Let al: Maternal High Triglyceride Levels During Early Pregnancy and Risk of Preterm Delivery: A Retrospective Cohort Study. J Clin Endocrinol Metab2019, 104(4):1249-1258.
Kemppinen L, Mattila M, Ekholm E, Pallasmaa N, Torma A, Varakas L, Makikallio K: Gestational iron deficiency anemia is associated with preterm birth, fetal growth restriction, and postpartum infections. J Perinat Med2021, 49(4):431-438.
Sundararajan S, Rabe H: Prevention of iron deficiency anemia in infants and toddlers. Pediatr Res2021, 89(1):63-73.
Lucas MJ, Sharma SK, McIntire DD, Wiley J, Sidawi JE, Ramin SM, Leveno KJ, Cunningham FG: A randomized trial of labor analgesia in women with pregnancy-induced hypertension. Am J Obstet Gynecol2001, 185(4):970-975.
Ramin SM, Gambling DR, Lucas MJ, Sharma SK, Sidawi JE, Leveno KJ: Randomized trial of epidural versus intravenous analgesia during labor. Obstet Gynecol1995, 86(5):783-789.
Sharma SK, Alexander JM, Messick G, Bloom SL, McIntire DD, Wiley J, Leveno KJ: Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women. Anesthesiology2002, 96(3):546-551.
Vinson DC, Thomas R, Kiser T: Association between epidural analgesia during labor and fever. J Fam Pract1993, 36(6):617-622.
Lieberman E, Lang JM, Frigoletto F, Jr., Richardson DK, Ringer SA, Cohen A: Epidural analgesia, intrapartum fever, and neonatal sepsis evaluation. Pediatrics1997, 99(3):415-419.
Kaul B, Vallejo M, Ramanathan S, Mandell G: Epidural labor analgesia and neonatal sepsis evaluation rate: a quality improvement study. Anesth Analg2001, 93(4):986-990.
Yoon BH, Kim CJ, Romero R, Jun JK, Park KH, Choi ST, Chi JG: Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol1997, 177(4):797-802.
Rodts-Palenik S, Wyatt-Ashmead J, Pang Y, Thigpen B, Cai Z, Rhodes P, Martin JN, Granger J, Bennett WA: Maternal infection-induced white matter injury is reduced by treatment with interleukin-10. Am J Obstet Gynecol2004, 191(4):1387-1392.
Pang Y, Rodts-Palenik S, Cai Z, Bennett WA, Rhodes PG: Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury. Brain Res Dev Brain Res2005, 157(2):141-149.
Dammann O, Drescher J, Veelken N: Maternal fever at birth and non-verbal intelligence at age 9 years in preterm infants. Dev Med Child Neurol2003, 45(3):148-151.
Meyer U, Feldon J, Yee BK: A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull2009, 35(5):959-972.
Previc FH: Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Med Hypotheses2007, 68(1):46-60.
Snyder-Keller A, Stark PF: Prenatal inflammatory effects on nigrostriatal development in organotypic cultures. Brain Res2008, 1233:160-167.
Zhao BS, Li B, Wang QN, Jia JX, Song XR: Time- and dose-dependent correlations between patient-controlled epidural analgesia and intrapartum maternal fever. BMC Anesthesiol2021, 21(1):31.
Ren J, Wang T, Yang B, Jiang L, Xu L, Geng X, Liu Q: Risk Factors and Safety Analyses for Intrapartum Fever in Pregnant Women Receiving Epidural Analgesia During Labor. Med Sci Monit2021, 27:e929283.

Table 1 Characteristics of study population
	Entire Population		Non-EA		EA		P Value
	n=325		n=117		n=208		P Value
Maternal age (yr), No. (%)								<0.001
≤24	42	(12.92)	15	(12.82)	27	(12.98)
25-29	139	(42.77)	45	(38.46)	94	(45.19)
30-34	109	(33.54)	33	(28.21)	76	(36.54)
≥35	35	(10.77)	24	(20.51)	11	(5.29)
Height, No. (%)								0.213
≤154	16	(4.92)	2	(1.71)	14	(6.73)
155–164	216	(66.46)	80	(68.38)	135	(64.90)
165–174	87	(26.77)	32	(27.35)	55	(26.44)
≥175	6	(1.85)	3	(2.56)	3	(1.44)
BMI at delivery (Kg/m2), No. (%)a								0.359
≤24.9	96	(29.54)	32	(27.35)	64	(30.77)
25.0-29.9	195	(60.00)	70	(59.83)	125	(60.10)
≥30	34	(10.46)	15	(12.82)	19	(9.13)
Gravidity, No. (%)								0.003
1	147	(45.23)	41	(35.04)	106	(50.96)
2	94	(28.92)	34	(29.06)	60	(28.85)
≥3	84	(25.85)	42	(35.90)	42	(20.19)
Parity, No. (%)								<0.001
1	212	(65.23)	53	(45.30)	159	(76.44)
≥2	113	(34.77)	64	(54.70)	49	(23.56)
Pregnancy complications
GDM								0.514
No	278	(85.54)	98	(83.76)	180	(86.54)
Yes	47	(14.46)	19	(16.24)	28	(13.46)
Gestational hypertensive disease								0.362
No	313	(96.31)	111	(94.87)	202	(97.12)
Yes	12	(3.69)	6	(5.13)	6	(2.88)
Intrahepatic cholestasis of pregnancy, ICP								0.659
No	301	(92.62)	107	(91.45)	194	(93.27)
Yes	24	(7.38)	10	(8.55)	14	(6.73)
Cephalopelvic disproportion,CPD								1.000
No	212	(65.23)	115	(98.29)	203	(97.60)
Yes	113	(34.77)	2	(1.71)	5	(2.40)
Pregnancy anemia								0.724
No	196	(60.31)	69	(58.97)	127	(61.06)
Yes	129	(39.69)	48	(41.03)	81	(38.94)
Maternal fever								<0.001
No	282	(86.77)	116	(99.15)	166	(79.81)
Yes	43	(13.23)	1	(0.85)	42	(20.19)
a Calculated as weight in kilograms divided by height in meters squared.

Table 2 Baseline characteristics,maternal and neonatal outcomes of EA participants.
Characteristics	None-fever	ERMF	P value
Characteristics	n=166	n=42	P value
Maternal age (yr)	28.95 ± 3.77	28.05 ± 3.68	0.898
Maternal height	161.95 ± 5.57	160.57 ± 5.14	0.149
Maternal BMI at delivery	26.51 ± 2.90	26.08 ± 2.72	0.39
Gestational weeks	39.62 ± 0.98	39.81 ± 0.82	0.248
WBC	8.71 ± 2.54	9.53 ± 2.91	0.07
N	6.47 ± 2.38	7.44 ± 2.82	0.024
N%	72.97 ± 7.09	74.73 ± 12.52	0.231
CRP (mg/L)	8.46 ± 7.45	9.81±7.39	0.296
IL-6 (pg/ml)	14.04 ± 30.66	14.74 ± 29.47	0.895
Amount of medicine (ml)	43.87 ± 20.58	52.48 ± 24.17	0.021
Total EA duration (min)	383.42 ± 369.04	630.57 ± 484.12	0.000
Time of first stage (min)	344.84 ± 198.62	549.66 ± 248.20	0.000
Time of second stage (min)	25.05 ± 21.64	33.38 ± 32.70	0.196
Time of third stage (min)	7.6 ±7.83	9.38 ± 9.01	0.275
Total labor time (min)	377.72 ± 205.99	588.62 ± 257.43	0.000
Frequent cervical examinations (Times)	5.98 ± 1.92	7.56 ± 1.96	0.000
Birth weight (g)	3406.20± 393.90	3301.67 ±363.00	0.120
Apger score (1 minute)	9.55 ± 0.68	9.40 ± 0.63	0.200
Apger score (5 minute)	9.88 ± 0.35	9.81 ± 0.40	0.070
Volume of postpartum hemorrhage (ml)	399.29 ± 124.83	293.24 ± 78.41	0.024

Table 3 Association between ERMF and risks of adverse maternal and neonatal outcomes among women underwent EA
	Entire Population		None-fever			ERMF
	n	%	n	%	OR (95% CI)	n	%	OR (95% CI)	P value	AOR (95% CI)	P value
Total number	208		166			42
Postpartum hemorrhage	6	(2.88)	6	(3.61)	1.00 (ref)	0	(0.00)	/	0.603	/
Conversion to surgery	24	(11.54)	12	(7.23)	1.00 (ref)	12	(28.57)	5.13 (2.11, 12.51)	0.000	4.05 (1.44, 11.39)	0.008
Forceps delivery	8	(3.85)	6	(3.61)	1.00 (ref)	2	(4.76)	1.33 (0.26, 6.86)	0.664	1.81(0.28, 11.59)	0.531
Fetal distress	18	(8.65)	11	(6.63)	1.00 (ref)	7	(16.67)	2.82 (1.02, 7.79)	0.060	0.54 (0.18, 1.64)	0.276
Neonatal Infections	28	(13.46)	13	(7.83)	1.00 (ref)	15	(35.71)	6.54 (2.80, 15.27)	0.000	5.13 (1.98, 13.29)	0.001
NICU admission	12	(5.77)	11	(6.63)	1.00 (ref)	1	(2.38)	0.34 (0.04, 2.74)	0.466	0.38 (0.04, 3.30)	0.377
Abbreviations: BMI, body mass index; OR, odds ratio; CI, confidence interval.
Data are shown as OR and adjusted OR (95% CI), adjusted for maternal age, BMI at delivery, gestational weeks, gravidity, parity, GDM, gestational hypertensive disease, ICP, CPD, and pregnancy anemia.

Table 4 Risk factors for ERMF among women underwent labor EA
	Total no.	n (%)		OR	P value	Adjusted OR (95% CI)	P value
All women (n=208)
Maternal pathogen infection
No	131	22	(16.79)	1.00 (ref)		1.00 (ref)
Yes	77	20	(25.97)	1.74 (0.88, 3.45)	0.152	1.66 (0.80, 3.46)	0.174
Rupture pattern of membranes
Natural	73	10	(13.70)	1.00 (ref)		1.00 (ref)
Atificial	135	32	(23.70)	1.96 (0.90, 4.25)	0.090	1.54 (064, 3.71)	0.335
Parity
1	159	42	(26.42)	1.00 (ref)	/	1.00 (ref)	/
≥2	49	0	(0.00)	--		--
Gravidy
1	106	31	(29.25)	1.00 (ref)		1.00 (ref)
2	60	7	(11.67)	0.32 (0.13, 0.78)	0.012	0.30 (0.12, 0.76)	0.011
≥3	42	4	(9.52)	0.26 (0.08, 0.77)	0.016	0.27 (0.08, 0.91)	0.035
Frequent cervical examinations
＜5	34	2	(5.88)	1.00 (ref)		1.00 (ref)
5-6	97	12	(12.37)	2.26 (0.48,10.66)	0.303	1.89 (0.39, 9.29)	0.432
≥ 7	74	27	(36.49)	9.19 (2.04, 41.40)	0.004	7.27 (1.56, 33.99)	0.012
Missing	151	1	(0.66)	--		--
Time of first stage (min)
＜168.8	22	2	(9.09)	1.00 (ref)		1.00 (ref)
168.8-259	44	3	(6.82)	0.73 (0.11, 4.74)	0.743	0.82 (0.12, 5.79)	0.840
260-442.4	58	5	(8.62)	0.94 (0.17,5.26)	0.947	1.10 (0.18,6.68)	0.916
≥ 442.5	58	19	(32.76)	4.87 (1.03, 23.04)	0.046	6.62 (1.23, 35.50)	0.027
Missing	26	13	(50.00)	--		--
Total labor time (min)
＜200	24	2	(8.33)	1.00 (ref)		1.00 (ref)
200-284	42	3	(7.14)	0.85 (0.13, 5.46)	0.861	0.93 (0.13, 6.51)	0.861
285-489	57	6	(10.53)	1.29 (0.24,6.92)	0.763	1.41 (0.25,8.07)	0.763
≥ 490	59	18	(30.51)	4.83 (1.03, 22.75)	0.046	5.85 (1.12, 30.49)	0.036
Missing	26	13	(50.00)	--		--
Total EA duration (min)
＜150.4	50	5	(10.00)	1.00 (ref)		1.00 (ref)
150.5-303.4	53	5	(9.43)	0.94 (0.25, 3.45)	0.923	0.69 (0.17, 2.74)	0.596
303.5-609.0	52	14	(26.92)	3.32 (1.09,10.04)	0.034	2.75 (0.84,9.03)	0.095
≥ 610.0	52	18	(34.62)	4.77 (1.61, 14.11)	0.005	3.86 (1.20, 12.47)	0.024
Amount of medicine (ml)
＜30	44	4	(9.09)	1.00 (ref)		1.00 (ref)
31-39	54	10	(18.52)	2.27 (0.66,7.82)	0.193	2.02 (0.56,7.26)	0.193
40-55	57	13	(22.81)	2.96 (0.89, 9.80)	0.077	2.56 (0.74, 8.83)	0.136
≥ 56	52	15	(28.85)	4.05 (1.23, 13.32)	0.021	2.85 (0.81, 10.08)	0.104
Abbreviations: OR, odds ratio.CI,confidence interval.
Data are shown as OR and adjusted OR (95% CI), adjusted for maternal age, BMI at delivery, gestational weeks, GDM, gestational hypertensive disease, ICP, CPD, and pregnancy anemia.

No competing interests reported.

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Perinatal outcomes and risk factors for epidural analgesia-associated intrapartum maternal fever: a retrospective study

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