Risk Factors of Combined Spinal Epidural Analgesia on Maternal Intrapartum Fever

Risk Factors of Combined Spinal Epidural Analgesia on Maternal Intrapartum Fever | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors of Combined Spinal Epidural Analgesia on Maternal Intrapartum Fever Hanzhen Zhao, Cheng Wang, Lu Shi, Lian Tang, Jingjing Li, Yanxia Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3820500/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Combined spinal epidural analgesia (CSEA) has been commonly used as clinical labor anesthesia. Intrapartum fever induced by CSEA frequently occurs and seriously endangers maternal and fetal health. The aim of this study is to explore the risk factors of CSEA on maternal intrapartum fever. Methods A total of 200 parturient women from Suzhou Municipal Hospital were included in this study.74 parturient women with intrapartum fever during combined spinal epidural analgesia were included in fever group and 126 parturient women with normal body temperature in control group. The maternal demographic characteristics, details of labor and delivery, anesthetic scheme, fetal weight and Apgar score were collected. Logistic regression and receiver operating characteristic (ROC) curve were used to analyze the related factors of intrapartum fever during labor analgesia. Nomogram and decision curve analysis (DCA) were used to apply and evaluate the predictive model. Results Logistic multivariate analysis indicated that the times of vaginal examinations (OR 2.069,95%CI 1.587–2.696), duration of analgesia (OR 2.466,95%CI 1.741–3.492), time from rupture of membrane to delivery (OR 0.909,95%CI 0.855–0.967) and labor induced by water sac(OR 10.806,95%CI 1.384–84.035)were independent risk factors for intrapartum fever. More than 7 times of vaginal examinations, 3.35h of CSEA and 5.26h from rupture of membrane to delivery prompt for higher risk of maternal intrapartum fever. Conclusion The times of vaginal examinations, duration of analgesia, time from rupture of membrane to delivery and water sac induced labor are identified as risk factors of CESA-induced intrapartum fever. The predictive model and the nomogram based on the above risk factors contribute to evaluate and restraint intrapartum fever during labor anesthesia. Labor analgesia Combined spinal epidural analgesia Intrapartum fever Logistic regression analysis Nomogram Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Combined Spinal epidural anesthesia (CSEA) integrates the features of fast onset of spinal anesthesia and flexible prolongation of epidural anesthesia, has been widely adopted in clinical practice for analgesia during labor[ 1 ].In comparison with other labor anesthesia regimens, CSEA has demonstrated more effective on the onset-time, fewer episodes of breakthrough pain during the first stage of labor and lower drug dosage consumption[ 2 ]. From the perspective of maternal outcomes, CSEA is reflected in increased cervical dilatation, reduced motor block and has a lower risk of anesthesia failure, caesarean section rates, instrumental delivery or prolonged labor[ 3 ]. The efficient mechanism of CSEA is to directly act on the subarachnoid space, promoting the effect of anesthetic drugs on the patient's spinal nerve roots. The dosage of local anesthetic drugs used in CSEA is one-third of that in epidural anesthesia, effectively avoiding adverse reactions caused by anesthetic drugs, improving muscular flaccidity and analgesic effect[ 4 ]. Given aforementioned advantages, higher maternal satisfaction scores of CSEA were reported in clinical studies compared with epidural anesthesia[ 5 ]. Inevitably, maternal side effects induced by CSEA need to be taken seriously, such as hypotension, itching and nausea, most likely due to intrathecal opioids[ 6 ].It is worth noting that intrapartum fever has been widely observed in parturient women undergoing CSEA[ 7 ],which contradicts the theoretical view of anesthetic-induced vasodilation and heat loss[ 8 ]. The mechanisms and risk factors for intrapartum fever have not yet been reached a verdict. Maternal intrapartum fever is defined as a crucial factor with elevated body temperature during labor due to infectious or non-infectious causes[ 9 ],in which anesthesia occupies a major trigger. Anesthetics are considered to damage umbilical vein endothelium and increase the production of pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α[ 10 ]. Furthermore, anesthesia-induced sweating and hyperventilation also result in reduced heat dissipation[ 11 ]. The association between epidural labor analgesia and maternal fever was first demonstrated in 1989[ 12 ],and subsequently confirmed by numerous studies. As reported in a randomized clinical trial,14% of parturient women undergoing CSEA experienced maternal intrapartum fever and the elevation of temperature was observed after 1 h and lasted up to 6 h of analgesia [ 13 ]. A meta-analysis study evaluating the safety of various epidural analgesia regimens among parturient women, including CSEA, reported that epidural anesthesia increased the risk of fever above 38°C to more than 2 fold (RR 2.51, 95% CI 1.67–3.77)[ 7 ]. Regarding the related hazards of intrapartum fever, in addition to triggering preterm labor, maternal intrapartum fever is strongly associated with adverse fetal outcomes, such as neonatal brain damage, lower Apgar scores, more sepsis, and the potential for antibiotic treatment[ 14 ]. Given that, it is urgency to explore the associated risk factors. A retrospective study identified several risk factors for epidural-related intrapartum fever: premature rupture of membrane, vaginal examination, prolonged labor, and a long time from rupture of membrane to delivery[ 15 ]. However, analyses of CSEA-related intrapartum fever are still lacking. Proactive labor management is considered to be effective in reducing the risks associated with maternal intrapartum fever[ 16 ].The aim of this study is to explore the relevant factors to CSEA-related intrapartum fever and suggest effective clinical measures to reduce the rate of incidence. Material and Method Study Design, Setting, and Population This retrospective study was conducted at The Affiliated Suzhou Hospital of Nanjing Medical University and approved by the medical ethics committee of the aforementioned hospital. Data from 579 mothers who underwent CSEA were collected in the past 2 years. A total of 200 cases were included in the statistical analysis based on inclusion criteria, exclusion criteria and data integrity.74 cases of CSEA-related maternal intrapartum fever (intrapartum temperature more than 37.5°C) in our hospital from January 2021 to December 2022 were collected as fever group (group F), while 126 cases of women with normal temperature who underwent CSEA in the same period were collected as the control group (group C),as shown in Fig. 1 , in order to avoid the interference of environmental factors in different time periods and to ensure the rationality and accuracy of case selection. The inclusion criteria were as follows: ①Normal temperature before delivery; ②Age less than 35 years old; ③American Society of Anesthesiologists classification Ⅰ ~ Ⅱ; ④Single fetus pregnancy, full-term delivery, normal fetal head position; ⑤Normal function of the placenta, normal amniotic fluid; ⑥Use of oxytocin in all cases; ⑦No food and drug allergies; ⑧No history of alcoholism, smoking and drug abuse. The exclusion criteria were as follows: ①Temperature more than 37.5℃ before delivery; ②Failure of analgesia; ③Suffering from pregnancy comorbidities (e.g. gestational hypertension, gestational diabetes mellitus, gestational cholestasis and pre-eclampsia, etc.); ④Contraindications to analgesia for labor (e.g. maternal refusal, coagulation dysfunction, uncontrolled local and systemic infections, primary or secondary uterine inertia, increased intracranial pressure, pulmonary hypertension, upper respiratory tract oedema, etc.); ⑤Suffering from infectious diseases and metabolic diseases; ⑥Emergency labor. Data Collection The hospital number, age, height, weight, BMI, gestational age, nulliparous women, baseline temperature, amniotic fluid contamination, premature rupture of membrane, gestational diabetes mellitus, positive bacterial culture, the times of vaginal examination, duration of analgesia, time from rupture of membrane to delivery, duration of labor, the amount of bleeding, the use of oxytocin, water sac, antibiotics, fetal weight, Apgar score, etc., were recorded. Analgesia Methods When the maternal uterine opening reached 2cm, CESA was administered. Monitored the maternal vital signs during the puncture process; performed an epidural puncture in the L3 ~ 4 or L2 ~ 3 intervertebral space; injected 2 ~ 3mg of 0.125% ropivacaine through the epidural puncture needle; placed the epidural catheter to the lateral side of the head, and left the catheter in the body for 3-5cm. After 20 min of epidural anesthesia, injected 3ml of saline containing 1:200,000 adrenaline through the epidural catheter before connecting with a pump in the epidural. The response of total spinal anesthesia was observed for 3–5 min and excluded the epidural catheter placement in the blood vessel; labor analgesia management was implemented (observing the vital signs, visual simulation of the pain scores and Bromage scores); routinely observed the uterine contractions, the fetal heartbeat, and the management of the labor process; The patient-controlled epidural analgesia (PCEA) pump, containing 0.1% sufentanil and 0.125% ropivacaine, maintenance volume 6 ~ 10ml, self-control volume 6 ~ 10ml, locking time 15 ~ 20 min, was adopted in the maintenance phase of analgesia. Observed and resolved abnormalities, recorded the sheet of labor analgesia. After delivery, parturient women were observed for 2 h and returned to the ward without any abnormality. Temperature monitoring The temperature of parturient women was monitored 0.5h after delivery. Measured the temperature at 1 h intervals for 2 h by a cochlear thermometer. The diagnosis of intrapartum fever was defined as the temperature exceeded 37.5°C and physical cooling was carried out. If the body temperature exceeded 38.5°C, routine blood tests and infection tests were implemented. Parturient women who diagnosed as intrapartum fever during combined spinal epidural analgesia were designated as group F, whereas those who did not were designated as group C. Statistical Analysis SPSS version 22.0 was used to statistically analyze the data,, and the data conformity with normal distribution were expressed as x ± s, and non-conformity with normal distribution were expressed as M (P 25 , P 75 ). The t-test, rank sum test and chi-square test were used in single-factor analysis, and the analysis of risk factors was performed by two-category logistic regression analysis, and P < 0.05 was considered as statistically significant. ROC curves were made, the size of the area under the curve, the optimal cut-off value and the Youden's index (Youden's index = sensitivity + specificity-1) were calculated. On the basis of the results from the final regression analysis, a nomogram for probability was constructed and assessed by the calibration curve and clinical decision curve. R version 3.1.2 with rms statistical packages was used to perform the above operations. Results Baseline characteristics and single-factor analysis A total of 200 cases received CSEA were included in our study. The cases were divided into group F and control group C according to the presence or absence of maternal intrapartum fever, with 74 in F group (37%) and 126 in C group (63%). Baseline characteristics and single-factor analysis were displayed in Table 1 . Between group F and group C, no significant differences were found in age, BMI, duration of analgesia, fetal weight, and percentage of nulliparous women, gestational diabetes mellitus patients, positive bacterial culture, use of antibiotics ( P > 0.05). Gestational age, the proportion of artificial rupture of membrane, amniotic fluid contamination, premature rupture of membrane, urinary catheterization, and oxytocin, water sac used for induction of labor were significantly difference between two groups ( P < 0.05). Compared to control group, patients with intrapartum fever had more times of vaginal examinations, amount of bleeding and longer duration of analgesia, labor and time from rupture of membrane to delivery ( P < 0.05), as shown in Fig. 2 . Table 1 Comparison of general information and risk factors for the pregnant women in the F group and the C group. Parameter Group F(n = 74) Group C(n = 126) Z or T or χ 2 value P value Age(years) 28(26,30) 27(25,29) -1.444 0.149 Gestational age (days) 281(277,285) 278(273,282) -3.240 0.001 Body mass index (kg/m 2 ) 26.88 ± 2.36 26.43 ± 2.95 -1.128 0.261 Nulliparous women(n,%) 69(93.2%) 120(95.2%) 0.076 0.782 Baseline Temperature(℃) 36.48 ± 0.23 36.43 ± 0.15 0.005 0.942 The times of vaginal examination(n) 8(5,10) 4(3,5) -6.766 0.000 Duration of analgesia(h) 3.96(2.64,5.83) 2.21(1.50,3.04) -6.707 0.000 Duration of labor(h) 13.55(10.11,23.93) 9.58(7.32,15.24) -4.077 0.000 The time from rupture of membrane to delivery(h) 9.58(6.45,16.60) 7.64(1.28,16.47) -2.215 0.027 The amount of bleeding(mL) 250(200,275) 200(200,250) -4.030 0.000 Artificial rupture of membrane (n,%) 38(51.4%) 30(23.8%) 15.759 0.000 Amniotic fluid contamination(n,%) 19(25.7%) 15(11.9%) 6.266 0.012 Oxytocin(n,%) 68(91.9%) 97(77%) 7.176 0.007 Water Sac(n,%) 9(12.2%) 2(1.6%) 8.099 0.004 Urinary Catheterization(n,%) 30(40.5%) 15(11.9%) 21.923 0.000 Premature rupture of membranes(n,%) 6(8.1%) 33(26.2%) 9.711 0.002 Gestational diabetes mellitus(n,%) 4(5.4%) 1(0.8%) 2.396 0.122 Positive bacterial culture(n,%) 12(16.2%) 34(27.0%) 3.052 0.081 Antibiotics(n,%) 9(12.2%) 9(7.1%) 1.434 0.231 Fetal weight(g) 3425.0(3187.5,3662.5) 3350.0(3100.0,3650.0) -1.110 0.267 Stepwise multivariate Logistic regression on risk factors The risk factors of CSEA on maternal intrapartum fever were estimated by the stepwise multivariate logistic regression analysis. Statistically significant variables with P < 0.05 in the single-factor analysis were included in the logistic regression analysis as the independent variables, including gestational age, times of vaginal examinations, duration of analgesia, duration of labor, time from rupture of membrane to delivery, amount of bleeding and the percentage of artificial rupture of membrane, amniotic fluid contamination, premature rupture of membrane, urinary catheterization, use of oxytocin, water sac. As shown in Table 2 , times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and water sac were significant risk factors for CSEA on maternal intrapartum fever in the multivariate logistic regression analysis. Table 2 Multifactorial Logistic Regression Analysis of CSEA on Maternal Intrapartum Fever in the F group and the C group. Parameter P value OR 95%CI The times of vaginal examination(n) 0.000 2.069 1.587–2.696 Duration of analgesia(h) 0.000 2.466 1.741–3.492 The time from rupture of membrane to delivery(h) 0.003 0.909 0.855–0.967 Water Sac 0.023 10.806 1.384–84.035 Constant 0.000 0.002 OR, odds ratio; CI, confidence interval Evaluation of the model by ROC curve analysis For each independent risk factor of the continuous variables, we calculated the specificity and sensitivity of the logistic regression model by constructing ROC curves and calculating the AUC to estimate the predictive ability of the model. ROC curves were derived from times of vaginal examinations, duration of analgesia and the time from rupture of membrane to delivery, plotted with 1-specificity as the horizontal coordinate and sensitivity as the vertical coordinate, as shown in Fig. 3 . The AUC for general predictive model and times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery were 0.903, 0.783, 0.784, and 0.594, respectively, as shown in Table 3 . The Youden's index at the optimal cut-off value for times of vaginal examinations duration of analgesia, the time from rupture of membrane to delivery are presented in Table 4 . Table 3 Area under the curve Parameter AUC SE P value 95% CI Prediction probability 0.903 0.025 0.000 0.854-0952 The times of vaginal examination(n) 0.783 0.038 0.000 0.709–0.858 Duration of analgesia(h) 0.784 0.034 0.000 0.718–0.850 The time from rupture of membrane to delivery(h) 0.594 0.040 0.027 0.516–0.672 AUC, area under curve; SE, standard deviation; CI, confidence interval Table 4 Optimal cut-off values for parameters Parameter ≥ Sensitivity 1-Specificity Youden Index The times of vaginal examination(n) 6.50 0.622 0.056 0.566 Duration of analgesia(h) 3.35 0.608 0.183 0.425 The time from rupture of membrane to delivery(h) 5.26 0.797 0.579 0.218 Youden index = sensitivity + specificity – 1 Predictive Nomogram for risk factors A predictive nomogram was constructed by the independent associated risk factors, including times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and water sac. Summing the scores for each risk factor could calculate a total score to estimate the risk of intrapartum fever in patients received CSEA, as shown in Fig. 4 A. The calibration curve of the nomogram is presented in Fig. 4 B to describe the disparity between predicted and actual outcomes for maternal intrapartum fever. Decision curve analysis is used to determine whether the predictive model is clinically beneficial, as shown in Fig. 4 C. Based on the above results, the model constructed in this study can effectively predict the risk of CSEA on maternal intrapartum fever and has the potential to achieve clinical benefits. Discussion At present, labor analgesia is widely accepted and applied in clinical practice. Intrapartum fever during labor analgesia is considered to be induced by the destruction of the maternal thermoregulatory center and the non-infectious inflammatory response of the parturient women[ 17 ]. Epidural anesthesia has been reported and thoroughly analyzed as an induction factor in intrapartum fever [ 18 ]. However, there are still no relevant report about risk factors of intrapartum fever induced by CSEA. In our study, multivariate Logistic regression analysis and ROC curve were used to evaluate the risk factors of intrapartum fever. The results showed that intrapartum fever was related to times of vaginal examinations, duration of analgesia and the time from rupture of membrane to delivery. According to the Youden's index, more than 7 times of vaginal examinations, 3.35h of analgesia and 5.26h from rupture of membrane to delivery have higher risk on intrapartum fever. According to this, medical personnel could take measures to reduce the incidence of intrapartum fever when implementing CESA. Vaginal examination is recommended as a common method of labor assessment every 4 h during pregnancy[ 19 ]. However, it has been reported that most pregnant women underwent vaginal examinations much more frequently than aforementioned frequencies[ 20 ]. According to a retrospective study in the United States, there is no significant correlation between the increased cervix examinations and the risk of fever. [ 21 ]. On the contrary, our results indicated that intrapartum fever induced by CSEA labor analgesia was correlated with times of vaginal examinations among Chinese maternal population ( P < 0.05). The times of vaginal examinations in the fever group and the normal group was 8 (5,10) and 4 (3,5) times respectively, and significantly different. The area under the curve of times of vaginal examinations on the ROC curve was 0.783 and the cut-off value was 6.50. Similar results have been observed in epidural anesthesia-induced fever, more than 6 vaginal examinations were included as risk factors in these studies[ 15 , 18 , 22 ]. Exposure of the uterine cavity to vaginal flora is considered as the immediate cause of fever[ 23 ]. Distinguished from anesthesia-induced aseptic inflammation, chorioamnionitis due to vaginal examinations is more prone to bacterial infection[ 24 ].Especially for patients who have experienced more than 8 times examinations, the increased risk of intrapartum fever, leukocytosis, purulent cervical drainage or fetal tachycardia is inevitable [ 25 ]. The use of intrapartum ultrasound lessens could reduce the times of vaginal examinations to a certain extent, this alternative method effectively control the risk of fever and infection[ 26 ]. Aseptic procedures during vaginal examinations, such as replacing clean gloves with sterile gloves, are capable of controlling anthropogenic factor. Overall, it is necessary to improve the accuracy and efficiency of vaginal examinations to control the frequency of examinations during CSEA under all circumstances. One study found that parturient women who underwent epidural analgesia had a prolonged duration of labor and the risk of intrapartum fever increased in the meantime [ 27 ]. Compared with conventional epidural anesthesia, the average onset-time of CSEA reduces by approximately 3 minutes and more parturient women underwent CSEA reported effective pain relief 10 minutes after injection[ 28 ]. In addition, CSEA reduce the consumption of anesthetic drugs and motor weakness compared to low-dose epidural anesthesia[ 29 ]. Our results revealed that the duration of anesthesia in fever group and control group during CSEA was 3.96 (2.64, 5.83) h and 2.21 (1.05, 3.04) h, respectively, with significant difference ( P < 0.05). According to the ROC curve, AUC for the duration of analgesia was 0.784 and the cut-off value was 3.35h. That is, when the duration of analgesia was longer than 3.35h, there will be greater influence on intrapartum fever. In our study, the local anesthetics combination for CSEA is 0.125% ropivacaine and 0.1% sufentanil. Ropivacaine combined with sufentanil active the first stage of labor, shorten the duration of labor and had no additional effect on maternal and neonatal outcomes (including the incidence of fever, postpartum hemorrhage, fetal distress, and neonatal Apgar scores) compared with 0.167% ropivacaine alone[ 30 , 31 ]. Although combined ropivacaine and sufentanil is associated with a higher risk of pruritus due to the increasing dosage of sufentanil. However, this combination may slightly delay the onset of the sensory blockade to pinprick at T10 with less motor blockade[ 32 ]. A meta-analysis reported that the combination of bupivacaine and sufentanil was effective in a shorter duration of analgesia and the length of labor compared to ropivacaine combined with sufentanil and levobupivacaine combined with sufentanil [ 33 ]. Regarding the combination with opioids and local anesthetics, it has been reported that addition of 50µg fentanyl to epidural 0.5% bupivacaine significantly can reduce intra-operative analgesia supplementation and prolongs the duration of postoperative analgesia without altering the other characteristics of block[ 34 ]. In studies on epidural analgesia, the duration of high concentration and continuous analgesics is associated with intrapartum fever. However, a logistic regression based on analgesic pump delivery of 0.08% ropivacaine and 0.4ug/ml sufentanil found that prolonged analgesia was not a risk factor for intrapartum fever[ 15 ]. From this perspective, the concentration and selection of local anesthetics for sustained analgesia may have a greater impact on postpartum fever. On balance, it is recommended to choose appropriate combination and concentration of anesthetic drugs, shorten the duration of CSEA while ensuring anesthesia quality to reduce the risk of intrapartum fever. In addition, the intrapartum fever induced by CSEA was also correlated with the time from rupture of membrane to delivery ( P < 0.05). It has been reported in epidural analgesia [ 15 ].The risk of intrapartum fever is nine fold higher in women undergoing anesthesia whose duration of labor lasted more than 12 hours[ 12 ]. It may be due to the long labor process during labor and substantial maternal physical exertion, which reduce maternal immunity and increase the chance of infection[ 35 ]. Our results showed that in the fever group and the normal group it was 9.5h (6.45, 16.60) and 7.64h (1.28, 16.47), respectively. ROC curve indicated that the risk of intrapartum fever would increase when the time from rupture of membrane to delivery is more than 5.26h. Longer duration means a greater risk of infection, especially chorioamnionitis[ 36 ]. Premature artificial rupture of membrane leaves the fetus unprotected and increase the incidence of microbiological infection[ 37 ]. Therefore, it suggests that medical staff should conduct a comprehensive assessment when performing artificial rupture of membrane for parturient who underwent CSEA, strictly adherence to clinical indications, and avoid the extension of the time from rupture of membrane to delivery caused by human factors. Our study found that water bag induced labor was a risk factor for intrapartum fever for the first time. Water sacs are deposited between uterine wall and the fetal membrane to improve intrauterine pressure, stimulate the cervical canal and induce uterine contractions to labor[ 38 ]. The efficacy and safety of water sac induction of labor in patients with high-risk pregnancies has been widely debated[ 39 ]. In our study, we found that 12.2% of patients in the fever group were induced labor with a water sac, but only 1.6% in the control group. It was also determined in the regression analysis that the use of water sac significantly increased the risk of CSEA-induced intrapartum fever. Studies have confirmed that water sac can shorten the first stage of labor[ 40 ], the risk of infection caused by water bags as vaginal foreign bodies cannot be ruled out. Before midwifery, it is necessary to follow the contraindications of water sacs: inflammation of the reproductive tract, fever above 37.5 ℃, repeated vaginal bleeding, uterine scars, and severe cardiovascular disease. The mechanism of anesthesia-induced fever is difficult to elucidate. Some investigators have proposed that it is secondary to a decrease in hyperventilation following pain relief, a decrease in sweating due to sympathetic blockade, and a bias in the information from the temperature control center, which all combine to result in a decrease in body heat loss[ 41 ]. Even more, the temperature of the labor room, which is traditionally raised to avoid hypothermia of newborn, can also have an effect on intrapartum fever[ 42 ]. In regard to CSEA, the mental stress of labor and the surgical trauma of epidural catheter insertion induce inflammatory mediator and cytokine release, which inevitably lead to aseptic inflammation[ 43 ]. Explicit preventive measures of intrapartum fever are urgently needed to reduce risk factors and to evade the adverse outcomes. Oxytocin use is considered a risk factor of intrapartum fever in epidural analgesia[ 18 ], but it has not been confirmed in our analysis of CSEA. Interestingly, another study revealed that high-dose oxytocin reduced the risk of fever and the duration of labor[ 44 ]And oxytocin was association with a lower incidence of fever, shivering, diarrhea events and other side-effects during the third stage of labor[ 45 ]. Considering prenatal pharmacological interventions, a clinical study documented that combined epidural 0.2 mg/mL dexamethasone is effective in relieving elevated temperature and reducing serum IL-6 levels during labor[ 46 ]. However, this intervention has not been widely recognized due to the detrimental of dexamethasone on the parturient women and fetus. In addition, numerous observational studies have not found positive microbial infection in patients with anesthetic-induced intrapartum fever[ 47 ]. Besides, prophylactic antibiotics had no significant effect on increased body temperature or the incidence of placental inflammation[ 48 ]. From the perspective of anesthesia operations, the ultrasound-guided paramedian approach for CSEA increases success rate of first-time puncture and reduces maternal side effects of parturient women[ 49 ]. In terms of anesthetic dose, the mean maternal temperature was lower after 4 hours of epidural 0.075% ropivacaine compared to 0.100% ropivacaine[ 50 ]. Controversially, there were no significant differences in the effects of sultaine plus 0.068% ropivacaine or 0.100% ropivacaine on body temperature and inflammatory factors[ 51 ]. The contradictory results mentioned above increase the difficulty of preventing intrapartum fever, it is urgent to improve the sample size and to include more comprehensive risk factors. Inflammatory factors and indicators of infection on the risk of intrapartum fever also need to be taken into account. Another interesting insight is that CSEA with acupoint injection improves the efficiency of pain relief and while reduces anesthetic consumption and postpartum inflammation indicators in maternal peripheral blood and umbilical cord blood[ 52 , 53 ]. Limitations of this study is that we were unable to review the exact temperature of the labor room at the time of delivery so that we can't exclude this consideration. In addition, insufficient sample size limited our study to explore more risk factors in a broader population. Consistent anesthetic drug combinations of CSEA in our hospital resulted in a lack of inclusion in the analysis of different types of anesthetics and dosages in this study. Moreover, fetal weight was included in this study, and the results showed no significant difference between the fever group and the control group. However, there is a lack of documentation of maternal pregnancy complications and indicators of neonatal outcomes. Next step, we will include patients received CESA as many as possible for internal and external validation of the predictive model. Last but not least, the impact of observers’ subjective bias on the findings present in this study cannot be ignored. Conclusion Our study identified that times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and use of water sac are high risk factors for maternal intrapartum fever in parturient women undergoing CSEA. More comprehensive and specific epidemiological studies comparing women in high-risk and low-risk parturient women are urgency to find the exact mechanism and evidence of anesthesia-induced fever. Taking preventive measures to avoid the above risk factors is essential in controlling the development of intrapartum fever. Abbreviations CSEA, combined spinal epidural analgesia; BMI, body mass index; ROC, receiver operating characteristic; DCA, decision curve analysis; AUC, area under curve; OR, odds ratio; SE, standard deviation; CI, confidence interval. Declarations Ethics approval and consent to participate All experimental protocols were approved by the medical ethics committee of The Affiliated Suzhou Hospital of Nanjing Medical University(K-2022-008-K01). All procedures were performed according to the Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent waived by the medical ethics committee of The Affiliated Suzhou Hospital of Nanjing Medical University due to retrospective study nature. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests policy Authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Funding This work was supported by Jiangsu Pharmaceutical Association. Hospital Pharmacy Research Project (H202121). Funders had no influence on the design of the study, the data collection and analysis, and the manuscript writing. Author Contributions Statement H.Z wrote the main manuscript text ,C.W collected and provided all the data, H.Z and C.W contributes equally to this work. L. T, J.L, Y, Y provided support and guidance for the research .All authors reviewed the manuscript. Authors' information a Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Suzhou Municipal Hospital, 215002, China b Department of Anesthesiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Suzhou Municipal Hospital, 215002, China References Cook TM. Combined spinal-epidural techniques: CSE techniques. Anaesthesia. 2000;55:42–64. Guasch E, Brogly N, Gilsanz F. Combined spinal epidural for labour analgesia and caesarean section: indications and recommendations. Curr Opin Anaesthesiol. 2020;33:284–90. 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Maternal fever in labor: etiologies, consequences, and clinical management. Am J Obstet Gynecol. 2023;228:1274–82. Goetzl L, Evans T, Rivers J, et al. Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am J Obstet Gynecol. 2002;187:834–8. Department of Anaesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India, Khanna P, Jain S et al. Epidural Fever: Hiding in the Shadows. Turk J Anaesthesiol Reanim . 2020;48:350–5. Fusi L, Maresh MJA, Steer PJ, et al. MATERNAL PYREXIA ASSOCIATED WITH THE USE OF EPIDURAL ANALGESIA IN LABOUR. The Lancet. 1989;333:1250–2. De Orange FA, Passini R, Amorim MMR, et al. Combined spinal and epidural anaesthesia and maternal intrapartum temperature during vaginal delivery: a randomized clinical trial. Br J Anaesth. 2011;107:762–8. Patel S, Ciechanowicz S, Blumenfeld YJ et al. Epidural-related maternal fever: incidence, pathophysiology, outcomes, and management. American Journal of Obstetrics and Gynecology . 2023;228:S1283-S1304.e1. Ren J, Wang T, Yang B, et al. Risk Factors and Safety Analyses for Intrapartum Fever in Pregnant Women Receiving Epidural Analgesia During Labor. Med Sci Monit. 2021;27. 10.12659/MSM.929283 . Goetzl L. Epidural analgesia and maternal fever: a clinical and research update. Curr Opin Anaesthesiol. 2012;25:292–9. Hensel D, Zhang F, Carter EB et al. Severity of intrapartum fever and neonatal outcomes. American Journal of Obstetrics and Gynecology . 2022;227:513.e1-513.e8. Yuan J, Jin A, Shen J et al. Maternal intrapartum fever during epidural labour analgesia: Incidence and influencing factors. Int J of Nursing Practice. 2023;e13188. Downe S, Gyte GM, Dahlen HG, et al. Routine vaginal examinations for assessing progress of labour to improve outcomes for women and babies at term. Cochrane Database of Systematic Reviews . Published Online First: 15 July. 2013. 10.1002/14651858.CD010088.pub2 . Shepherd A, Cheyne H. The frequency and reasons for vaginal examinations in labour. Women Birth. 2013;26:49–54. Cahill AG, Duffy CR, Odibo AO, et al. Number of Cervical Examinations and Risk of Intrapartum Maternal Fever. Obstet Gynecol. 2012;119:1096–101. Curtin WM, Katzman PJ, Florescue H, et al. Intrapartum fever, epidural analgesia and histologic chorioamnionitis. J Perinatol. 2015;35:396–400. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intraamniotic infection. Am J Obstet Gynecol. 1997;176:672–7. Borders N, Lawton R, Martin SR. A Clinical Audit of the Number of Vaginal Examinations in Labor: A NOVEL Idea. J Midwifery Women’s Health. 2012;57:139–44. Gomez Slagle HB, Hoffman MK, Fonge YN, et al. Incremental risk of clinical chorioamnionitis associated with cervical examination. Am J Obstet Gynecol MFM. 2022;4:100524. Oberman M, Avrahami I, Lavi Shoseyov N, et al. Assessment of labor progress by ultrasound vs manual examination: a randomized controlled trial. Am J Obstet Gynecol MFM. 2023;5:100817. Mayer D, Chescheir N, Spielman F. Increased Intrapartum Antibiotic Administration Associated with Epidural Analgesia in Labor. Amer J Perinatol. 1997;14:83–6. Simmons SW, Taghizadeh N, Dennis AT, et al. Combined spinal-epidural versus epidural analgesia in labour. Cochrane Database of Systematic Reviews . Published Online First: 17 October. 2012. 10.1002/14651858.CD003401.pub3 . Pascual-Ramirez J, Haya J, Pérez‐López FR, et al. Effect of combined spinal–epidural analgesia versus epidural analgesia on labor and delivery duration. Intl J Gynecology & Obste. 2011;114:246–50. Zhang L, Xu C, Li Y. Impact of epidural labor analgesia using sufentanil combined with low-concentration ropivacaine on maternal and neonatal outcomes: a retrospective cohort study. BMC Anesthesiol. 2021;21:229. Wen X, Huang B, Liang X. Effect of ropivacaine and sufentanil in epidural labor analgesia. Am J Transl Res. 2021;13:7001–7. Fadlalmola HA, Elhusein AM, Albadrani MS, et al. Safety and efficacy of combined ropivacaine and sufentanil compared with ropivacaine for cesarean sections: A systematic review and meta-analysis. Afr J Reprod Health. 2023;27:95–106. Lv B, Wang W, Wang Z, et al. Efficacy and safety of local anesthetics bupivacaine, ropivacaine and levobupivacaine in combination with sufentanil in epidural anesthesia for labor and delivery: a meta-analysis. Curr Med Res Opin. 2014;30:2279–89. Parate L, Manjrekar S, Anandaswamy T, et al. The effect of addition of low dose fentanyl to epidural bupivacaine (0.5%) in patients undergoing elective caesarean section: A randomized, parallel group, double blind, placebo controlled study. J Postgrad Med. 2015;61:27. Lanier LR, Scarbrough RW, Fillingim DW, et al. Incidence of maternal and fetal complications associated with rupture of the membranes before onset of labor. Am J Obstet Gynecol. 1965;93:398–404. Batts JA, Chorioamnionitis. J Reprod Med. 1976;17:296–8. Gibson KS, Brackney K. Periviable Premature Rupture of Membranes. Obstet Gynecol Clin N Am. 2020;47:633–51. Tsakiridis I, Mamopoulos A, Athanasiadis A, et al. Induction of Labor: An Overview of Guidelines. Obstet Gynecol Surv. 2020;75:61–72. Chia HM, Tan PC, Tan SP, et al. Speculum versus digital insertion of Foley catheter for induction of labor in Nulliparas with unripe cervix: a randomized controlled trial. BMC Pregnancy Childbirth. 2020;20:330. Mi H, Sun N. Effect of Oxytocin Combined with Different Volume of Water Sac in High-Risk Term Pregnancies. Evidence-Based Complement Altern Med. 2022;2022:1–7. Glosten B, Savage M, Rooke GA, et al. Epidural anesthesia and the thermoregulatory responses to hyperthermia - preliminary observations in volunteer subjects. Acta Anaesthesiol Scand. 1998;42:442–6. Banerjee S, Steer PJ. The rise in maternal temperature associated with regional analgesia in labour is harmful and should be treated. Int J Obstet Anesth. 2003;12:280–4. Igarashi T, Hirabayashi Y, Shimizu R, et al. The Fiberscopic Findings of the Epidural Space in Pregnant Women. Anesthesiology. 2000;92:1631–6. Son M, Roy A, Stetson BT, et al. High-Dose Compared With Standard-Dose Oxytocin Regimens to Augment Labor in Nulliparous Women: A Randomized Controlled Trial. Obstet Gynecol. 2021;137:991–8. Zeng Y, Zhang Y, Zhen M, et al. Side-effects of oxytocin in postpartum hemorrhage: a systematic review and meta-analysis. Am J Transl Res. 2022;14:1934–51. Wang L-Z, Hu X-X, Liu X, et al. Influence of epidural dexamethasone on maternal temperature and serum cytokine concentration after labor epidural analgesia. Int J Gynecol Obstet. 2011;113:40–3. Sultan P, David AL, Fernando R, et al. Inflammation and Epidural-Related Maternal Fever: Proposed Mechanisms. Anesth Analgesia. 2016;122:1546–53. Sharma SK, Rogers BB, Alexander JM, et al. A Randomized Trial of the Effects of Antibiotic Prophylaxis on Epidural-Related Fever in Labor. Anesth Analgesia. 2014;118:604–10. Zhou Y, Chen W, Zhou S, et al. Comparison of different approaches to combined spinal epidural anesthesia (CSEA) under the guidance of ultrasound in cesarean delivery of obese patients: a randomized controlled trial. Eur J Med Res. 2021;26:106. Yue H-L, Shao L-J, Li J, et al. Effect of epidural analgesia with 0.075% ropivacaine versus 0.1% ropivacaine on the maternal temperature during labor: a randomized controlled study. Chin Med J (Engl). 2013;126:4301–5. Chen X, Zhang Y, Ni X, et al. Effects of labour analgesia with different concentrations of ropivacaine on maternal body temperature and inflammatory factor: A randomised controlled study. Anaesth Crit Care Pain Med. 2022;41:101030. Wu L, Zhao H, Zhang Z, et al. Combined spinal-epidural anesthesia with acupoint injection for labor anesthesia reduces IL-1β/IL-10 ratio in maternal peripheral blood, umbilical cord blood and improves the labor outcomes: A prospective randomized controlled trial. Clin Immunol. 2022;236:108935. Huang M, Fang C, Zhao H, et al. Acupoint Injection Decreases Anesthetic Cosumption during Combined Spinal-Epidural and Patient-Controlled Epidural Labor Analgesia. Chin J Integr Med. 2022;28:257–62. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3820500","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266750015,"identity":"c4e578de-3246-40df-a1b9-1e4c78f66c83","order_by":0,"name":"Hanzhen Zhao","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hanzhen","middleName":"","lastName":"Zhao","suffix":""},{"id":266750016,"identity":"73657c06-96b3-4138-97ac-2939185577a0","order_by":1,"name":"Cheng Wang","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Wang","suffix":""},{"id":266750017,"identity":"ec312fff-2e32-4c02-a93d-31c3f332c50a","order_by":2,"name":"Lu Shi","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Shi","suffix":""},{"id":266750018,"identity":"74de0e43-9890-4cba-a2a5-fa2a2783ff41","order_by":3,"name":"Lian Tang","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lian","middleName":"","lastName":"Tang","suffix":""},{"id":266750019,"identity":"ce74be50-957a-45b9-a12a-701e9b79e6c7","order_by":4,"name":"Jingjing Li","email":"","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jingjing","middleName":"","lastName":"Li","suffix":""},{"id":266750020,"identity":"a9550e65-c247-426b-8177-d7d76073d33c","order_by":5,"name":"Yanxia Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqElEQVRIiWNgGAWjYPACGx5+/gbStKTJSM44QJqWwzYGDQlEqjW4kWMm+ePPeR4DhgOMHz7mEKfF2JiH5zaPOXMDs+TMbcRpMXzMIHGbx7LhABszL5FaDA7+MDjHY3AggXgthg94Eg6QoEXyzLNiY54DyTySMw42E+cXvuPJ24AhZmfPz9988MNHYrQoHOAwgDIZG4hQDwTyDewPiFM5CkbBKBgFIxcAACc9Nng4kIUtAAAAAElFTkSuQmCC","orcid":"","institution":"The Affiliated Suzhou Hospital of Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yanxia","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2023-12-29 09:14:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3820500/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3820500/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49642606,"identity":"e947e71b-4142-4747-962f-369ac3fcb6ec","added_by":"auto","created_at":"2024-01-15 19:34:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":286972,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of data collection, exclusion and inclusion.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3820500/v1/c2d75990a53858d8ce34076e.png"},{"id":49642607,"identity":"0337389e-1a94-492a-bb7a-22e54c62fe3b","added_by":"auto","created_at":"2024-01-15 19:34:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5731499,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of risk factors between the fever group and the normal group.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e2A: The times of vaginal examination(n),2B: Duration of analgesia(h),2C: The time from rupture of membrane to delivery(h),2D: Duration of labor(h),2E: The amount of bleeding(mL). The red spots represent patients in the normal group, while the green spots represent patients in the fever group.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3820500/v1/af444555de218bbb0e4a29c9.png"},{"id":49642605,"identity":"6c5d4845-77db-48bc-9f3b-6834e4285100","added_by":"auto","created_at":"2024-01-15 19:34:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":986970,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curves for risk factors of CSEA-induced intrapartum fever.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eROC curves were described as the risk factors: the times of vaginal examination, duration of analgesia, and the time from rupture of membrane to delivery, plotted with 1-specificity as the horizontal coordinate and sensitivity as the vertical coordinate.\u003c/p\u003e\n\u003cp\u003eROC: Receiver operating characteristic.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3820500/v1/7cc681a60d5d147a3ec861eb.png"},{"id":49642608,"identity":"d5a2c299-1cc4-44d0-a9a8-152189bf22b7","added_by":"auto","created_at":"2024-01-15 19:34:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3112411,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNomogram predicting CSEA-induced intrapartum fever probability and its predictive performance.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e4A: A nomogram predicting the risk of CSEA-induced intrapartum fever: the sum of the scores for each risk factor is located on the total score axis and the probabilities are determined on the risk axis.\u003c/p\u003e\n\u003cp\u003e4B: Calibration curve of the nomogram prediction: The X-axis represents the predicted probability of the nomogram and the Y-axis represents the actual probability. An ideal prediction would correspond to the dotted line.\u003c/p\u003e\n\u003cp\u003e4C: Decision curve analysis: The X-axis of the curve represents Threshold Probability and the Y-axis represents Net Benefit. The red lines represent the clinical decision value of the predictive model and its 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3820500/v1/59c76e220fbd553434404e9b.png"},{"id":65693016,"identity":"93df4afb-11fa-49e1-9c4e-70afa9c92c5d","added_by":"auto","created_at":"2024-10-01 10:39:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":20683306,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3820500/v1/906a1fe1-271a-4d85-ae42-e9db782a34ad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk Factors of Combined Spinal Epidural Analgesia on Maternal Intrapartum Fever","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCombined Spinal epidural anesthesia (CSEA) integrates the features of fast onset of spinal anesthesia and flexible prolongation of epidural anesthesia, has been widely adopted in clinical practice for analgesia during labor[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].In comparison with other labor anesthesia regimens, CSEA has demonstrated more effective on the onset-time, fewer episodes of breakthrough pain during the first stage of labor and lower drug dosage consumption[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. From the perspective of maternal outcomes, CSEA is reflected in increased cervical dilatation, reduced motor block and has a lower risk of anesthesia failure, caesarean section rates, instrumental delivery or prolonged labor[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The efficient mechanism of CSEA is to directly act on the subarachnoid space, promoting the effect of anesthetic drugs on the patient's spinal nerve roots. The dosage of local anesthetic drugs used in CSEA is one-third of that in epidural anesthesia, effectively avoiding adverse reactions caused by anesthetic drugs, improving muscular flaccidity and analgesic effect[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Given aforementioned advantages, higher maternal satisfaction scores of CSEA were reported in clinical studies compared with epidural anesthesia[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Inevitably, maternal side effects induced by CSEA need to be taken seriously, such as hypotension, itching and nausea, most likely due to intrathecal opioids[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].It is worth noting that intrapartum fever has been widely observed in parturient women undergoing CSEA[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e],which contradicts the theoretical view of anesthetic-induced vasodilation and heat loss[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The mechanisms and risk factors for intrapartum fever have not yet been reached a verdict.\u003c/p\u003e \u003cp\u003eMaternal intrapartum fever is defined as a crucial factor with elevated body temperature during labor due to infectious or non-infectious causes[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e],in which anesthesia occupies a major trigger. Anesthetics are considered to damage umbilical vein endothelium and increase the production of pro-inflammatory cytokines such as IL-6, IL-1β and TNF-α[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, anesthesia-induced sweating and hyperventilation also result in reduced heat dissipation[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The association between epidural labor analgesia and maternal fever was first demonstrated in 1989[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e],and subsequently confirmed by numerous studies. As reported in a randomized clinical trial,14% of parturient women undergoing CSEA experienced maternal intrapartum fever and the elevation of temperature was observed after 1 h and lasted up to 6 h of analgesia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A meta-analysis study evaluating the safety of various epidural analgesia regimens among parturient women, including CSEA, reported that epidural anesthesia increased the risk of fever above 38\u0026deg;C to more than 2 fold (RR 2.51, 95% CI 1.67\u0026ndash;3.77)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding the related hazards of intrapartum fever, in addition to triggering preterm labor, maternal intrapartum fever is strongly associated with adverse fetal outcomes, such as neonatal brain damage, lower Apgar scores, more sepsis, and the potential for antibiotic treatment[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Given that, it is urgency to explore the associated risk factors. A retrospective study identified several risk factors for epidural-related intrapartum fever: premature rupture of membrane, vaginal examination, prolonged labor, and a long time from rupture of membrane to delivery[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, analyses of CSEA-related intrapartum fever are still lacking. Proactive labor management is considered to be effective in reducing the risks associated with maternal intrapartum fever[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].The aim of this study is to explore the relevant factors to CSEA-related intrapartum fever and suggest effective clinical measures to reduce the rate of incidence.\u003c/p\u003e"},{"header":"Material and Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design, Setting, and Population\u003c/h2\u003e \u003cp\u003e This retrospective study was conducted at The Affiliated Suzhou Hospital of Nanjing Medical University and approved by the medical ethics committee of the aforementioned hospital.\u003c/p\u003e \u003cp\u003eData from 579 mothers who underwent CSEA were collected in the past 2 years. A total of 200 cases were included in the statistical analysis based on inclusion criteria, exclusion criteria and data integrity.74 cases of CSEA-related maternal intrapartum fever (intrapartum temperature more than 37.5\u0026deg;C) in our hospital from January 2021 to December 2022 were collected as fever group (group F), while 126 cases of women with normal temperature who underwent CSEA in the same period were collected as the control group (group C),as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, in order to avoid the interference of environmental factors in different time periods and to ensure the rationality and accuracy of case selection.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe inclusion criteria were as follows: ①Normal temperature before delivery; ②Age less than 35 years old; ③American Society of Anesthesiologists classification Ⅰ ~ Ⅱ; ④Single fetus pregnancy, full-term delivery, normal fetal head position; ⑤Normal function of the placenta, normal amniotic fluid; ⑥Use of oxytocin in all cases; ⑦No food and drug allergies; ⑧No history of alcoholism, smoking and drug abuse.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were as follows: ①Temperature more than 37.5℃ before delivery; ②Failure of analgesia; ③Suffering from pregnancy comorbidities (e.g. gestational hypertension, gestational diabetes mellitus, gestational cholestasis and pre-eclampsia, etc.); ④Contraindications to analgesia for labor (e.g. maternal refusal, coagulation dysfunction, uncontrolled local and systemic infections, primary or secondary uterine inertia, increased intracranial pressure, pulmonary hypertension, upper respiratory tract oedema, etc.); ⑤Suffering from infectious diseases and metabolic diseases; ⑥Emergency labor.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Collection\u003c/h2\u003e \u003cp\u003eThe hospital number, age, height, weight, BMI, gestational age, nulliparous women, baseline temperature, amniotic fluid contamination, premature rupture of membrane, gestational diabetes mellitus, positive bacterial culture, the times of vaginal examination, duration of analgesia, time from rupture of membrane to delivery, duration of labor, the amount of bleeding, the use of oxytocin, water sac, antibiotics, fetal weight, Apgar score, etc., were recorded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnalgesia Methods\u003c/h2\u003e \u003cp\u003eWhen the maternal uterine opening reached 2cm, CESA was administered. Monitored the maternal vital signs during the puncture process; performed an epidural puncture in the L3\u0026thinsp;~\u0026thinsp;4 or L2\u0026thinsp;~\u0026thinsp;3 intervertebral space; injected 2\u0026thinsp;~\u0026thinsp;3mg of 0.125% ropivacaine through the epidural puncture needle; placed the epidural catheter to the lateral side of the head, and left the catheter in the body for 3-5cm. After 20 min of epidural anesthesia, injected 3ml of saline containing 1:200,000 adrenaline through the epidural catheter before connecting with a pump in the epidural. The response of total spinal anesthesia was observed for 3\u0026ndash;5 min and excluded the epidural catheter placement in the blood vessel; labor analgesia management was implemented (observing the vital signs, visual simulation of the pain scores and Bromage scores); routinely observed the uterine contractions, the fetal heartbeat, and the management of the labor process; The patient-controlled epidural analgesia (PCEA) pump, containing 0.1% sufentanil and 0.125% ropivacaine, maintenance volume 6\u0026thinsp;~\u0026thinsp;10ml, self-control volume 6\u0026thinsp;~\u0026thinsp;10ml, locking time 15\u0026thinsp;~\u0026thinsp;20 min, was adopted in the maintenance phase of analgesia. Observed and resolved abnormalities, recorded the sheet of labor analgesia. After delivery, parturient women were observed for 2 h and returned to the ward without any abnormality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eTemperature monitoring\u003c/h2\u003e \u003cp\u003eThe temperature of parturient women was monitored 0.5h after delivery. Measured the temperature at 1 h intervals for 2 h by a cochlear thermometer. The diagnosis of intrapartum fever was defined as the temperature exceeded 37.5\u0026deg;C and physical cooling was carried out. If the body temperature exceeded 38.5\u0026deg;C, routine blood tests and infection tests were implemented.\u003c/p\u003e \u003cp\u003eParturient women who diagnosed as intrapartum fever during combined spinal epidural analgesia were designated as group F, whereas those who did not were designated as group C.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eSPSS version 22.0 was used to statistically analyze the data,, and the data conformity with normal distribution were expressed as x\u0026thinsp;\u0026plusmn;\u0026thinsp;s, and non-conformity with normal distribution were expressed as M (P\u003csub\u003e25\u003c/sub\u003e, P\u003csub\u003e75\u003c/sub\u003e). The t-test, rank sum test and chi-square test were used in single-factor analysis, and the analysis of risk factors was performed by two-category logistic regression analysis, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant. ROC curves were made, the size of the area under the curve, the optimal cut-off value and the Youden's index (Youden's index\u0026thinsp;=\u0026thinsp;sensitivity\u0026thinsp;+\u0026thinsp;specificity-1) were calculated. On the basis of the results from the final regression analysis, a nomogram for probability was constructed and assessed by the calibration curve and clinical decision curve. R version 3.1.2 with \u003cem\u003erms\u003c/em\u003e statistical packages was used to perform the above operations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics and single-factor analysis\u003c/h2\u003e \u003cp\u003eA total of 200 cases received CSEA were included in our study. The cases were divided into group F and control group C according to the presence or absence of maternal intrapartum fever, with 74 in F group (37%) and 126 in C group (63%).\u003c/p\u003e \u003cp\u003eBaseline characteristics and single-factor analysis were displayed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Between group F and group C, no significant differences were found in age, BMI, duration of analgesia, fetal weight, and percentage of nulliparous women, gestational diabetes mellitus patients, positive bacterial culture, use of antibiotics (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Gestational age, the proportion of artificial rupture of membrane, amniotic fluid contamination, premature rupture of membrane, urinary catheterization, and oxytocin, water sac used for induction of labor were significantly difference between two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Compared to control group, patients with intrapartum fever had more times of vaginal examinations, amount of bleeding and longer duration of analgesia, labor and time from rupture of membrane to delivery (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eComparison of general information and risk factors for the pregnant women in the F group and the C group.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup F(n\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup C(n\u0026thinsp;=\u0026thinsp;126)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ or T or χ\u003csup\u003e2\u003c/sup\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(26,30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(25,29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e281(277,285)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e278(273,282)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.261\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparous women(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69(93.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120(95.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.782\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline Temperature(℃)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe times of vaginal examination(n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(5,10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(3,5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-6.766\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of analgesia(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.96(2.64,5.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.21(1.50,3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-6.707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of labor(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.55(10.11,23.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.58(7.32,15.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe time from rupture of membrane to delivery(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.58(6.45,16.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.64(1.28,16.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe amount of bleeding(mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e250(200,275)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200(200,250)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArtificial rupture of membrane (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38(51.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30(23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.759\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmniotic fluid contamination(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19(25.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(11.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxytocin(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68(91.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97(77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWater Sac(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary Catheterization(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30(40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(11.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21.923\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremature rupture of membranes(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33(26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational diabetes mellitus(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive bacterial culture(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34(27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.081\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics(n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal weight(g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3425.0(3187.5,3662.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3350.0(3100.0,3650.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-1.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStepwise multivariate Logistic regression on risk factors\u003c/h3\u003e\n\u003cp\u003eThe risk factors of CSEA on maternal intrapartum fever were estimated by the stepwise multivariate logistic regression analysis. Statistically significant variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the single-factor analysis were included in the logistic regression analysis as the independent variables, including gestational age, times of vaginal examinations, duration of analgesia, duration of labor, time from rupture of membrane to delivery, amount of bleeding and the percentage of artificial rupture of membrane, amniotic fluid contamination, premature rupture of membrane, urinary catheterization, use of oxytocin, water sac.\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and water sac were significant risk factors for CSEA on maternal intrapartum fever in the multivariate logistic regression analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultifactorial Logistic Regression Analysis of CSEA on Maternal Intrapartum Fever in the F group and the C group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe times of vaginal examination(n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.587\u0026ndash;2.696\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of analgesia(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.741\u0026ndash;3.492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe time from rupture of membrane to delivery(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.855\u0026ndash;0.967\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWater Sac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.806\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.384\u0026ndash;84.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eOR, odds ratio; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of the model by ROC curve analysis\u003c/h2\u003e \u003cp\u003eFor each independent risk factor of the continuous variables, we calculated the specificity and sensitivity of the logistic regression model by constructing ROC curves and calculating the AUC to estimate the predictive ability of the model.\u003c/p\u003e \u003cp\u003eROC curves were derived from times of vaginal examinations, duration of analgesia and the time from rupture of membrane to delivery, plotted with 1-specificity as the horizontal coordinate and sensitivity as the vertical coordinate, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The AUC for general predictive model and times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery were 0.903, 0.783, 0.784, and 0.594, respectively, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The Youden's index at the optimal cut-off value for times of vaginal examinations duration of analgesia, the time from rupture of membrane to delivery are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eArea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAUC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrediction probability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.903\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.854-0952\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe times of vaginal examination(n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.783\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.709\u0026ndash;0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of analgesia(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.718\u0026ndash;0.850\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe time from rupture of membrane to delivery(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.516\u0026ndash;0.672\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAUC, area under curve; SE, standard deviation; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOptimal cut-off values for parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1-Specificity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYouden Index\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe times of vaginal examination(n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.622\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.566\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of analgesia(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.425\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe time from rupture of membrane to delivery(h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.797\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.218\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eYouden index\u0026thinsp;=\u0026thinsp;sensitivity\u0026thinsp;+\u0026thinsp;specificity \u0026ndash; 1\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePredictive Nomogram for risk factors\u003c/h2\u003e \u003cp\u003eA predictive nomogram was constructed by the independent associated risk factors, including times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and water sac. Summing the scores for each risk factor could calculate a total score to estimate the risk of intrapartum fever in patients received CSEA, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA. The calibration curve of the nomogram is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB to describe the disparity between predicted and actual outcomes for maternal intrapartum fever. Decision curve analysis is used to determine whether the predictive model is clinically beneficial, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the above results, the model constructed in this study can effectively predict the risk of CSEA on maternal intrapartum fever and has the potential to achieve clinical benefits.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAt present, labor analgesia is widely accepted and applied in clinical practice. Intrapartum fever during labor analgesia is considered to be induced by the destruction of the maternal thermoregulatory center and the non-infectious inflammatory response of the parturient women[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Epidural anesthesia has been reported and thoroughly analyzed as an induction factor in intrapartum fever [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, there are still no relevant report about risk factors of intrapartum fever induced by CSEA.\u003c/p\u003e \u003cp\u003eIn our study, multivariate Logistic regression analysis and ROC curve were used to evaluate the risk factors of intrapartum fever. The results showed that intrapartum fever was related to times of vaginal examinations, duration of analgesia and the time from rupture of membrane to delivery. According to the Youden's index, more than 7 times of vaginal examinations, 3.35h of analgesia and 5.26h from rupture of membrane to delivery have higher risk on intrapartum fever. According to this, medical personnel could take measures to reduce the incidence of intrapartum fever when implementing CESA.\u003c/p\u003e \u003cp\u003eVaginal examination is recommended as a common method of labor assessment every 4 h during pregnancy[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, it has been reported that most pregnant women underwent vaginal examinations much more frequently than aforementioned frequencies[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. According to a retrospective study in the United States, there is no significant correlation between the increased cervix examinations and the risk of fever. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. On the contrary, our results indicated that intrapartum fever induced by CSEA labor analgesia was correlated with times of vaginal examinations among Chinese maternal population (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The times of vaginal examinations in the fever group and the normal group was 8 (5,10) and 4 (3,5) times respectively, and significantly different. The area under the curve of times of vaginal examinations on the ROC curve was 0.783 and the cut-off value was 6.50. Similar results have been observed in epidural anesthesia-induced fever, more than 6 vaginal examinations were included as risk factors in these studies[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Exposure of the uterine cavity to vaginal flora is considered as the immediate cause of fever[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Distinguished from anesthesia-induced aseptic inflammation, chorioamnionitis due to vaginal examinations is more prone to bacterial infection[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].Especially for patients who have experienced more than 8 times examinations, the increased risk of intrapartum fever, leukocytosis, purulent cervical drainage or fetal tachycardia is inevitable [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The use of intrapartum ultrasound lessens could reduce the times of vaginal examinations to a certain extent, this alternative method effectively control the risk of fever and infection[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Aseptic procedures during vaginal examinations, such as replacing clean gloves with sterile gloves, are capable of controlling anthropogenic factor. Overall, it is necessary to improve the accuracy and efficiency of vaginal examinations to control the frequency of examinations during CSEA under all circumstances.\u003c/p\u003e \u003cp\u003eOne study found that parturient women who underwent epidural analgesia had a prolonged duration of labor and the risk of intrapartum fever increased in the meantime [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Compared with conventional epidural anesthesia, the average onset-time of CSEA reduces by approximately 3 minutes and more parturient women underwent CSEA reported effective pain relief 10 minutes after injection[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In addition, CSEA reduce the consumption of anesthetic drugs and motor weakness compared to low-dose epidural anesthesia[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Our results revealed that the duration of anesthesia in fever group and control group during CSEA was 3.96 (2.64, 5.83) h and 2.21 (1.05, 3.04) h, respectively, with significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). According to the ROC curve, AUC for the duration of analgesia was 0.784 and the cut-off value was 3.35h. That is, when the duration of analgesia was longer than 3.35h, there will be greater influence on intrapartum fever. In our study, the local anesthetics combination for CSEA is 0.125% ropivacaine and 0.1% sufentanil. Ropivacaine combined with sufentanil active the first stage of labor, shorten the duration of labor and had no additional effect on maternal and neonatal outcomes (including the incidence of fever, postpartum hemorrhage, fetal distress, and neonatal Apgar scores) compared with 0.167% ropivacaine alone[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Although combined ropivacaine and sufentanil is associated with a higher risk of pruritus due to the increasing dosage of sufentanil. However, this combination may slightly delay the onset of the sensory blockade to pinprick at T10 with less motor blockade[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. A meta-analysis reported that the combination of bupivacaine and sufentanil was effective in a shorter duration of analgesia and the length of labor compared to ropivacaine combined with sufentanil and levobupivacaine combined with sufentanil [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Regarding the combination with opioids and local anesthetics, it has been reported that addition of 50\u0026micro;g fentanyl to epidural 0.5% bupivacaine significantly can reduce intra-operative analgesia supplementation and prolongs the duration of postoperative analgesia without altering the other characteristics of block[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In studies on epidural analgesia, the duration of high concentration and continuous analgesics is associated with intrapartum fever. However, a logistic regression based on analgesic pump delivery of 0.08% ropivacaine and 0.4ug/ml sufentanil found that prolonged analgesia was not a risk factor for intrapartum fever[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. From this perspective, the concentration and selection of local anesthetics for sustained analgesia may have a greater impact on postpartum fever. On balance, it is recommended to choose appropriate combination and concentration of anesthetic drugs, shorten the duration of CSEA while ensuring anesthesia quality to reduce the risk of intrapartum fever.\u003c/p\u003e \u003cp\u003eIn addition, the intrapartum fever induced by CSEA was also correlated with the time from rupture of membrane to delivery (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). It has been reported in epidural analgesia [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].The risk of intrapartum fever is nine fold higher in women undergoing anesthesia whose duration of labor lasted more than 12 hours[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It may be due to the long labor process during labor and substantial maternal physical exertion, which reduce maternal immunity and increase the chance of infection[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Our results showed that in the fever group and the normal group it was 9.5h (6.45, 16.60) and 7.64h (1.28, 16.47), respectively. ROC curve indicated that the risk of intrapartum fever would increase when the time from rupture of membrane to delivery is more than 5.26h. Longer duration means a greater risk of infection, especially chorioamnionitis[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Premature artificial rupture of membrane leaves the fetus unprotected and increase the incidence of microbiological infection[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Therefore, it suggests that medical staff should conduct a comprehensive assessment when performing artificial rupture of membrane for parturient who underwent CSEA, strictly adherence to clinical indications, and avoid the extension of the time from rupture of membrane to delivery caused by human factors.\u003c/p\u003e \u003cp\u003eOur study found that water bag induced labor was a risk factor for intrapartum fever for the first time. Water sacs are deposited between uterine wall and the fetal membrane to improve intrauterine pressure, stimulate the cervical canal and induce uterine contractions to labor[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The efficacy and safety of water sac induction of labor in patients with high-risk pregnancies has been widely debated[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In our study, we found that 12.2% of patients in the fever group were induced labor with a water sac, but only 1.6% in the control group. It was also determined in the regression analysis that the use of water sac significantly increased the risk of CSEA-induced intrapartum fever. Studies have confirmed that water sac can shorten the first stage of labor[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], the risk of infection caused by water bags as vaginal foreign bodies cannot be ruled out. Before midwifery, it is necessary to follow the contraindications of water sacs: inflammation of the reproductive tract, fever above 37.5 ℃, repeated vaginal bleeding, uterine scars, and severe cardiovascular disease.\u003c/p\u003e \u003cp\u003eThe mechanism of anesthesia-induced fever is difficult to elucidate. Some investigators have proposed that it is secondary to a decrease in hyperventilation following pain relief, a decrease in sweating due to sympathetic blockade, and a bias in the information from the temperature control center, which all combine to result in a decrease in body heat loss[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Even more, the temperature of the labor room, which is traditionally raised to avoid hypothermia of newborn, can also have an effect on intrapartum fever[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In regard to CSEA, the mental stress of labor and the surgical trauma of epidural catheter insertion induce inflammatory mediator and cytokine release, which inevitably lead to aseptic inflammation[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExplicit preventive measures of intrapartum fever are urgently needed to reduce risk factors and to evade the adverse outcomes. Oxytocin use is considered a risk factor of intrapartum fever in epidural analgesia[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], but it has not been confirmed in our analysis of CSEA. Interestingly, another study revealed that high-dose oxytocin reduced the risk of fever and the duration of labor[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]And oxytocin was association with a lower incidence of fever, shivering, diarrhea events and other side-effects during the third stage of labor[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Considering prenatal pharmacological interventions, a clinical study documented that combined epidural 0.2 mg/mL dexamethasone is effective in relieving elevated temperature and reducing serum IL-6 levels during labor[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. However, this intervention has not been widely recognized due to the detrimental of dexamethasone on the parturient women and fetus. In addition, numerous observational studies have not found positive microbial infection in patients with anesthetic-induced intrapartum fever[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Besides, prophylactic antibiotics had no significant effect on increased body temperature or the incidence of placental inflammation[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. From the perspective of anesthesia operations, the ultrasound-guided paramedian approach for CSEA increases success rate of first-time puncture and reduces maternal side effects of parturient women[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. In terms of anesthetic dose, the mean maternal temperature was lower after 4 hours of epidural 0.075% ropivacaine compared to 0.100% ropivacaine[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Controversially, there were no significant differences in the effects of sultaine plus 0.068% ropivacaine or 0.100% ropivacaine on body temperature and inflammatory factors[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. The contradictory results mentioned above increase the difficulty of preventing intrapartum fever, it is urgent to improve the sample size and to include more comprehensive risk factors. Inflammatory factors and indicators of infection on the risk of intrapartum fever also need to be taken into account. Another interesting insight is that CSEA with acupoint injection improves the efficiency of pain relief and while reduces anesthetic consumption and postpartum inflammation indicators in maternal peripheral blood and umbilical cord blood[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLimitations of this study is that we were unable to review the exact temperature of the labor room at the time of delivery so that we can't exclude this consideration. In addition, insufficient sample size limited our study to explore more risk factors in a broader population. Consistent anesthetic drug combinations of CSEA in our hospital resulted in a lack of inclusion in the analysis of different types of anesthetics and dosages in this study. Moreover, fetal weight was included in this study, and the results showed no significant difference between the fever group and the control group. However, there is a lack of documentation of maternal pregnancy complications and indicators of neonatal outcomes. Next step, we will include patients received CESA as many as possible for internal and external validation of the predictive model. Last but not least, the impact of observers\u0026rsquo; subjective bias on the findings present in this study cannot be ignored.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study identified that times of vaginal examinations, duration of analgesia, the time from rupture of membrane to delivery and use of water sac are high risk factors for maternal intrapartum fever in parturient women undergoing CSEA. More comprehensive and specific epidemiological studies comparing women in high-risk and low-risk parturient women are urgency to find the exact mechanism and evidence of anesthesia-induced fever. Taking preventive measures to avoid the above risk factors is essential in controlling the development of intrapartum fever.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCSEA, combined spinal epidural analgesia; BMI, body mass index; ROC, receiver operating characteristic; DCA, decision curve analysis; AUC, area under curve; OR, odds ratio; SE, standard deviation; CI, confidence interval.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll experimental protocols were approved by the medical ethics committee of The Affiliated Suzhou Hospital of Nanjing Medical University(K-2022-008-K01). All procedures were performed according to the Declaration of Helsinki. All methods were carried out in accordance with relevant guidelines and regulations.\u0026nbsp;Informed consent waived by the medical ethics committee of The Affiliated Suzhou Hospital of Nanjing Medical University due to retrospective study nature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Jiangsu Pharmaceutical Association. Hospital Pharmacy Research Project (H202121). Funders had no influence on the design of the study, the data collection and analysis, and the manuscript writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.Z wrote the main manuscript text ,C.W collected and provided all the data, H.Z and C.W contributes equally to this work. L. T, J.L, Y, Y provided support and guidance for the research .All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Suzhou Municipal Hospital, 215002, China\u003c/p\u003e\n\u003cp\u003eb Department of Anesthesiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Suzhou Municipal Hospital, 215002, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCook TM. Combined spinal-epidural techniques: CSE techniques. Anaesthesia. 2000;55:42\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuasch E, Brogly N, Gilsanz F. Combined spinal epidural for labour analgesia and caesarean section: indications and recommendations. 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Chin J Integr Med. 2022;28:257\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Labor analgesia, Combined spinal epidural analgesia, Intrapartum fever, Logistic regression analysis, Nomogram","lastPublishedDoi":"10.21203/rs.3.rs-3820500/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3820500/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eCombined spinal epidural analgesia (CSEA) has been commonly used as clinical labor anesthesia. Intrapartum fever induced by CSEA frequently occurs and seriously endangers maternal and fetal health. The aim of this study is to explore the risk factors of CSEA on maternal intrapartum fever.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 200 parturient women from Suzhou Municipal Hospital were included in this study.74 parturient women with intrapartum fever during combined spinal epidural analgesia were included in fever group and 126 parturient women with normal body temperature in control group. The maternal demographic characteristics, details of labor and delivery, anesthetic scheme, fetal weight and Apgar score were collected. Logistic regression and receiver operating characteristic (ROC) curve were used to analyze the related factors of intrapartum fever during labor analgesia. Nomogram and decision curve analysis (DCA) were used to apply and evaluate the predictive model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eLogistic multivariate analysis indicated that the times of vaginal examinations (OR 2.069,95%CI 1.587\u0026ndash;2.696), duration of analgesia (OR 2.466,95%CI 1.741\u0026ndash;3.492), time from rupture of membrane to delivery (OR 0.909,95%CI 0.855\u0026ndash;0.967) and labor induced by water sac(OR 10.806,95%CI 1.384\u0026ndash;84.035)were independent risk factors for intrapartum fever. More than 7 times of vaginal examinations, 3.35h of CSEA and 5.26h from rupture of membrane to delivery prompt for higher risk of maternal intrapartum fever.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe times of vaginal examinations, duration of analgesia, time from rupture of membrane to delivery and water sac induced labor are identified as risk factors of CESA-induced intrapartum fever. The predictive model and the nomogram based on the above risk factors contribute to evaluate and restraint intrapartum fever during labor anesthesia.\u003c/p\u003e","manuscriptTitle":"Risk Factors of Combined Spinal Epidural Analgesia on Maternal Intrapartum Fever","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-15 19:34:32","doi":"10.21203/rs.3.rs-3820500/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"47c17f4c-1d2e-4c2e-a39d-409060e209e4","owner":[],"postedDate":"January 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-01T10:38:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-15 19:34:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3820500","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3820500","identity":"rs-3820500","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}