PEDIATRICS Vol. 105 No. 1 January 2000, pp. 8-13

Intrapartum Maternal Fever and Neonatal Outcome

Ellice Lieberman, MD, DrPH^*, Janet Lang, PhD, ScD, Douglas K. Richardson, MD, MBA^§, Fredric D. Frigoletto, MD, Linda J. Heffner, MD, PhD^*, and Amy Cohen, BA^*

From the ^* Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School; the  Department of Epidemiology and Biostatistics, Boston University School of Public Health; the ^§ Joint Program for Neonatology, Harvard Medical School; and the  Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

	ABSTRACT

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Objective.  Much of fever during term labor may not be infectious but rather a consequence of the use of epidural analgesia. Therefore, we investigated the association of elevated maternal intrapartum temperature with neonatal outcome when the infant does not develop an infection.

Methods.  We studied 1218 nulliparous women with singleton, term pregnancies in a vertex presentation and spontaneous labor. Women were excluded if their temperature was >99.5°F at admission for delivery, if they were diabetic or had an active genital herpes infection or if their infant developed a neonatal infection, had a congenital infection, or had a major malformation. Maximum intrapartum temperature was categorized as: 100.4°F (afebrile), 100.5°F to 101°F, and >101°F.

Results.  During labor, 123 women (10.1%) developed a fever >100.4°F; 62 (5.1%) women had a maximum temperature of 100.5°F to 101°F and 61 (5.0%) women had a maximum temperature >101°F. Of febrile women, 97.6% had received epidural analgesia for pain relief. Infants of women developing a fever >100.4°F were more likely to have a 1-minute Apgar score <7 (22.8% for >100.4°F vs 8.0% for afebrile) and to be hypotonic after delivery (4.8% for >100.4°F vs .5% for afebrile). Compared with infants of afebrile women, infants whose mothers' maximum temperature was >101°F were more likely to require bag and mask resuscitation (11.5% vs 3.0%) and to be given oxygen therapy in the nursery (8.2% vs 1.3%). We also found a higher rate of neonatal seizure with fever (3.3% vs .2%), but the number of infants with seizure was small (n = 4). All associations remained essentially the same after controlling for confounding in logistic regression analyses.

Conclusions.  Intrapartum maternal fever, particularly if >101°F, was associated with a number of apparently transient adverse effects in the newborn. Larger studies are needed to investigate the association of intrapartum fever with neonatal seizures and to determine whether any lasting injury to the fetus may occur.  Key words:  fever, epidural analgesia, neonatal outcome, neonatal seizures, labor.

Intrapartum maternal fever has been of concern to pediatricians because it may indicate a maternal infection that could affect the newborn. Recent work suggests, however, that for women with term pregnancies, much of fever developing during labor may not be infectious in origin but a consequence of the use of epidural analgesia.¹ A number of studies have demonstrated that use of epidural analgesia is associated with increases in maternal temperature or a higher rate of maternal fever.^1-6

Even when fever is not of infectious origin a high maternal body temperature may be cause for concern with regard to the fetus. In primate studies, hyperthermia in the absence of infection has been associated directly with the development of fetal hypoxia, metabolic acidosis, and hypotension.⁷ Other animal studies have demonstrated that an increase in brain temperature of even 1°C or 2°C increases the degree of brain damage resulting from an ischemic insult.^8-10 Among adults admitted with stroke, higher body temperature at admission was associated with an increase in stroke severity, infarct size and mortality.¹¹ Conversely, cooling of the newborn head during ischemia has been demonstrated to be neuroprotective in animal models^12,13 and is being investigated actively as a treatment to attenuate perinatal brain injury.¹⁴ These findings suggest that maternal intrapartum fever could be injurious to the fetus by increasing the risk of neurologic injury independent of infection. Fetal temperature may reach fever levels more often than indicated by maternal temperature, because studies in humans indicate that fetal temperature is .5°C to .9°C higher than maternal temperature.^715-19

We performed this study to investigate the association of increased maternal temperature during labor with infant outcome when the infant does not develop an infection.

	METHODS

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The base sample for this study was the 1934 nulliparous women enrolled in the active management of labor trial conducted at Brigham and Women's Hospital from May 1990 through October 1994. Approval for the study was obtained from the Human Research Committee of Brigham and Women's Hospital and informed consent was obtained from all participants. Women enrolling were assigned randomly to have their labor managed either under a protocol of active management of labor or to usual care. The active management of labor protocol specified the criteria for the diagnosis of labor, the timing and dose of oxytocin, and use of one-to-one nursing throughout the course of labor. Epidural analgesia was not part of the trial protocol. It was administered to women in both groups on request. Data were abstracted from the maternal medical record regarding the course of pregnancy and labor and from the newborn record regarding infant outcome. A complete description of the study methodology and results has been published previously.²⁰

The current analysis included women from both the active management and usual care groups but was limited to women with singleton, term pregnancies with the infant in vertex presentation, and the spontaneous onset of labor resulting in a live born infant (n = 1303). Women were excluded if they were diabetic (n = 3), had an active genital herpes infection (n = 4), if maternal temperature was never recorded (n = 30), or if a maternal temperature >99.5°F was present at admission (n = 31). In addition, 2 women were excluded because the birth weight of their infant was not recorded. Because we wished to examine the effects of intrapartum fever in the absence of infant infection, we also excluded infants with documented sepsis (n = 1), pneumonia (n = 3), or herpes infection (n = 1). Finally, we excluded the small number of infants with other congenital infection (n = 1) or major congenital malformations (n = 9) because these conditions might influence neonatal outcome independent of maternal fever. After these exclusions, 1218 mother/infant pairs remained for inclusion in the current analysis.

All maternal temperatures recorded during labor were abstracted from the medical record. Most maternal temperatures were recorded orally and the axillary temperatures were increased by one degree Fahrenheit for comparability. Maximum intrapartum temperature was classified into 3 categories: 1) afebrile (100.4°F), 2) 100.5°F to 101.0°F, and 3) >101.0°F.

The association of intrapartum fever with neonatal outcome was evaluated. Outcomes examined were 1- and 5-minute Apgar scores, resuscitation, hypotonia, seizures, and the need for oxygen therapy in the nursery. In examining resuscitation, we chose to investigate the need for bag and mask resuscitation. We were concerned that the use of lesser resuscitation measures (free flow oxygen, suction, and stimulation) might be recorded more frequently for infants of febrile mothers, because a pediatrician was more often present at the delivery, and we believed that the need for bag and mask resuscitation provided a more objective measure of neonatal status. The diagnosis of hypotonia was confirmed by review of the infant medical records by one of the authors (D.K.R) who was blind to the occurrence of intrapartum fever. The diagnosis of seizures was made only if observed by 2 individuals including an attending neonatologist or if the diagnosis was confirmed by electroencephalogram or neurology consult.

Crude rate ratios (RR) and 95% confidence intervals (CI) for the association of intrapartum fever with neonatal outcome were calculated. Logistic regression analysis was used to examine the association, controlling for the potential confounding effects of infant birth weight, epidural analgesia, length of labor, treatment with the active management of labor protocol, and method of delivery. Fever was modeled as 2 indicator variables (100.5°F to 101°F and >101°F) with afebrile women as the referent group. Adjusted odds ratios (OR) were calculated from the regression coefficients and 95% CIs from the standard errors of those coefficients.

	RESULTS

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Overall, 1218 women with term, vertex fetuses and the spontaneous onset of labor were included in the analysis. During labor, 123 women (10.1%) developed a temperature of 100.5°F during labor. Of those women, 62 (5.1%) had a maximum temperature between 100.5°F and 101°F, whereas 61 (5.0%) developed a fever of >101°F. Women who developed a fever tended to have somewhat longer gestations (2-3 days) and larger infants (113-181 g) and to have longer labors than did women who did not develop a fever. In addition, women developing a fever were far more likely to have received epidural analgesia; 97.6% of women developing a fever >100.4°F had received epidural analgesia compared with only 55.2% of those who remained afebrile during labor (Table 1). Fewer than 1% of women were febrile at the time of epidural (6/724) and the mean time from epidural to fever was 5.9 hours.

Neonatal outcomes were examined according to maximum maternal intrapartum temperature. We examined Apgar scores, resuscitation, hypotonia, oxygen treatment in the nursery, and the occurrence of seizures. Low 1-minute Apgar scores occurred more often in the presence of intrapartum maternal fever (Fig 1). Infants whose mothers had an intrapartum fever >101°F were almost 4 times as likely to have a 1-minute Apgar score <7 than were infants of afebrile mothers (31.1% vs 8.0%; RR = 3.9; 95% CI = 2.5,5.9). The infants of women with fevers of 100.5°F to 101°F also had a somewhat higher likelihood of having a low Apgar score than those born to afebrile women (14.5% vs 8.0%; RR = 1.8; 95% CI = 1.0,3.4).

View larger version (16K): [in this window] [in a new window]   Fig. 1.   Neonatal outcomes according to maternal maximum intrapartum temperature.

By 5 minutes of life, <1% of infants had Apgar scores <7 regardless of intrapartum fever. However, the same pattern of association between maternal temperature and Apgar score is seen at 5 minutes of age, if an Apgar score of <9 is used as the point of comparison. Among infants of afebrile women, only 9.1% had an Apgar score <9 at 5 minutes, compared with 16.1% of those with 100.5°F to 101°F (RR = 1.8; 95% CI = 1.0,3.2) and 29.5% of those where the fever was >101°F (RR = 3.2; 95% CI = 2.1,5.0).

Infants of mothers whose fevers were >101°F were almost 4 times as likely to require bag and mask resuscitation immediately after delivery (11.5% vs 3.0% for infants of afebrile mothers; RR = 3.8; 95% CI = 1.8,8.3). No increase in the need for bag and mask resuscitation was noted among infants when the maternal fever was between 100.5°F and 101°F (3.2%; RR = 1.1; 95% CI = .3,4.4).

The need for oxygen therapy in the nursery was 6 times higher among infants whose mothers had a temperature >101°F (8.2% vs 1.3% for afebrile; RR = 6.4; 95% CI = 2.3,17.2) but was not higher among infants whose mothers' maximum temperature was between 100.5°F and 101°F (0% vs 1.3%).

Hypotonia was more likely to be diagnosed when maternal fever reached 100.5°F. In the absence of intrapartum fever, only .5% of infants were noted to be hypotonic compared with a 4.9% rate among infants whose mothers had a temperature of at least 100.5°F (RR = 8.9; 95% CI = 2.9,27.2). The hypotonia was relatively short-lived and by 12 hours of age all but one case had resolved, and that case was in an infant of an afebrile mother.

Logistic regression analyses were performed to examine the association of each of these infant outcomes with intrapartum fever, controlling for the potentially confounding effects of infant birth weight, epidural analgesia, length of labor, treatment with the active management of labor protocol, and method of delivery. In the multivariate model, maternal fever >101°F remained a predictor of the outcomes examined. Adjusted ORs and confidence limits are presented in Table 2.

Infants whose mothers had a fever >101°F were more likely to have a seizure in the neonatal period. Among infants whose mothers had such a high fever, 3.3% (2/61) had a seizure, compared with .2% (2/1095) of infants of afebrile women. This relation remained after adjustment for confounding in a logistic regression analysis (OR = 13.2; 95% CI = 1.1,153.9). All 4 infants had their seizures observed by >1 care provider including an attending neonatologist; all were evaluated by a neurologist and were discharged on anticonvulsant medication.

Immediate newborn outcome and the timing of the seizures differed for infants with and without fever. The 2 infants of afebrile women developing seizures both had low Apgar scores (<7 at 5 minutes) and required intervention immediately after delivery. In contrast, the 2 infants of febrile mothers were both sent to the regular nursery after having a sepsis evaluation (routine practice at our institution in the presence of maternal fever >100.4°F) and subsequently were transferred to the neonatal intensive care unit as a result of their seizures (at 14 and 21 hours of age).

All infants with seizures had extensive work-ups to evaluate the cause of their seizures. Electrolytes, calcium, magnesium, and glucose were all within normal limits. For both infants whose mother had a fever, blood cultures and cerebrospinal fluid culture results were negative as were cerebrospinal fluid culture results for herpes simplex virus and tests for herpes simplex virus using the polymerase chain reaction technique. There was also no evidence of other metabolic disease, central nervous system anomaly, chromosomal anomaly, congenital infection, or skull trauma. All infants were born by cesarean section; therefore, none had a forceps or vacuum delivery. None of the mothers were noted to be drug users. Both infants of febrile mothers did have abnormalities on neuroimaging (hypoxic-ischemic encephalopathy in 1 and infarct in the other), but the cause for the lesions remained unexplained.

	DISCUSSION

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The primary concern of pediatricians regarding intrapartum fever has been that an infection is present in the mother that may be passed to the infant during labor and delivery. The risks from the maternal hyperthermia itself independent of infection have not been considered. For that reason, we specifically examined neonatal outcome in the presence of intrapartum fever when the infant did not develop an infection. Recent work suggests that most fever during term labor is not, in fact, related to infection but rather to the use of epidural analgesia.¹ In our study population, fever developed during labor in 16.6% (120/724) women receiving epidural analgesia compared with .6% (3/494) of women not receiving epidural analgesia for pain relief. Our data indicate that this intrapartum fever, even if most often not infectious, has implications for the fetus. We found that infants of women who were febrile during labor were more likely to have low 1-minute Apgar scores (<7), to require bag and mask resuscitation, to have hypotonia after delivery, and to require oxygen treatment in the nursery. For bag and mask resuscitation and the need for oxygen treatment, the effect was present only when fever was >101°F, for hypotonia the effect was present >100.4°F, whereas for Apgar, the effect seemed greater with higher fevers. The associations we noted remained after controlling for the effects of confounding factors including length of labor, birth weight, use of epidural analgesia, and method of delivery.

Most of the adverse neonatal effects we report are transient. By 5 minutes of age, Apgar scores had risen, although they were still lower among infants of febrile women. By discharge, tone was normal in all but 1 infant (born to an afebrile mother). A finding of greater concern is the increase we noted in the occurrence of seizures among the infants of women with high fever (3.3% vs .2% for afebrile). However, although the relative increase in seizures was large and the finding was statistically significant, we caution that these results are based on only 4 seizure cases and that other studies will be needed to confirm this observation. If confirmed, an increase in seizures would raise concern about the possibility of persistent effects from exposure to noninfectious intrapartum fever. In our study, we had no follow-up data on infants postdischarge.

Intrapartum maternal fever has been reported to be a risk factor for neonatal encephalopathy among term infants by Adamson et al.²¹ Those authors hypothesize that the association is related to the presence of sepsis. The encephalopathy that accompanies sepsis is thought to be related to the production of mediators, such as cytokines.²² Maternal production of cytokines in response to infection during pregnancy also has been hypothesized to be an important factor in initiating or supporting brain damage during fetal development.²³ Because the use of epidural analgesia (the major cause of noninfectious fever during labor) has been associated with higher levels of maternal serum interleukin-6 at the time of delivery,²⁴ it is plausible that epidural analgesia may trigger at least some of the same physiologic events that occur with infection.

Early neonatal seizures occurring in term infants have been associated with the occurrence of factors that increase the risk of intrapartum asphyxia.^25-26 Because animal^8-10 and human data¹¹ suggest that the effects of oxygen deprivation may be augmented by even small increases in temperature, it is possible that any effect of hypoxia during labor might be enhanced by the presence of intrapartum fever and thereby increase the risk of neurologic injury. In contrast, we did not find a higher rate of physician-diagnosed fetal distress among women with fever (4.1% for afebrile, 1.6% for 100.5°F to 101°F, 6.6% for >101°F; P = .4). Similarly, Herbst et al,²⁷ in a study of fever during labor that included infants with infection, found no increase in either fetal distress or low cord pH among febrile women.

Neonatal seizures among term infants have been demonstrated to be a risk for childhood neurologic impairment and specifically for cerebral palsy.²⁵ A recent case control study by Grether and Nelson²² suggested that maternal infection may be associated with the occurrence of unexplained cerebral palsy in infants weighing >2500 g. In their definition of infection, however, isolated fever of 100.4°F was sufficient for a woman to be classified as infected. Because they made no distinction made between infectious and noninfectious fever, it is possible that the association reported by these authors reflects, at least in part, an effect of fetal exposure to high temperature, which may occur in the presence or absence of infection.

Our study had some limitations. For example, it is possible that because pediatricians are more frequently present in the delivery room when maternal fever occurs, lower Apgar scores could result if pediatricians assign scores differently than nurses and more frequent resuscitations could result if they have a lower threshold for intervention. Also, differences could result if knowledge of maternal fever influences pediatric treatments or diagnoses. To address these issues, we evaluated only resuscitative efforts requiring a bag and mask. Because it can have side effects such as iatrogenic pnemothorax, bag and mask resuscitation would be less likely performed on a discretionary basis, thereby providing a more objective measure of neonatal status. Similarly, although our primary report was for Apgar scores <7, we also determined the proportion of infants with 1-minute Apgar scores <5, because such serious depression also may represent a more objective standard (2.8% for afebrile, 4.8% for 100.5°F to 101°F, and 9.8% for >101°F). In addition, the diagnosis of hypotonia was confirmed by a neonatologist who reviewed the medical records blind to the presence of maternal fever, and the diagnosis of seizure required that specific medical criteria be present in the infant's medical record.

In addition, although we excluded infants with evidence of neonatal infection, we cannot rule out the possibility that some infants included in our analysis had an infection that was undetected by blood culture because of intrapartum maternal treatment with antibiotics or because specific culture techniques are required for some organisms. It has also been suggested that maternal intrapartum infection itself may be associated with adverse neonatal outcome.²² Although most of the maternal fever in our population is likely to be noninfectious in origin, a small percent of term, low-risk women (<1%) develop fever in labor without epidural use. Therefore, it is possible that some of the outcomes we observed occurred in the infants of women who had an infection. During labor, it is difficult to know whether a fever is of infectious origin because traditional markers are not useful. White blood cell counts tend to be elevated^28-29 and have been noted to be a poor marker for infection.³⁰ Placental pathology was not obtained routinely.

In evaluating the possibility that maternal infection was responsible for our findings, however, it is important to note that in our study population, 98% of fever occurred among women who had received epidural analgesia and >18% of infants of women receiving epidural had at least one of the adverse outcomes we investigated. Therefore, for the association we observe to be caused by maternal infection, rather than intrapartum fever alone, the use of epidural would need to be associated with a dramatic increase in the risk of infection. Such an increase would be contrary to substantial data that indicate that the fever associated with epidural use results from altered thermoregulation rather than from infection.^2,531-32

For the small number of infants with seizures in our study, the possible role of infection must be considered specifically. We do not believe that undetected meningitis is a likely explanation for this finding because these infants were evaluated extensively in a tertiary care intensive care unit and neonatologists did not conclude that there was an infection present. We cannot rule out the possibility that the seizures in the epidural group occurred in the infants of the few women whose fever was independent of epidural and thus more likely due to infection. Although this possibility must be born in mind, it is equally important to consider the seizure results in the context of the other outcomes reported in this study. The increased risk of low Apgar, bag and mask resuscitation, and hypotonia suggests a cluster of neonatal consequences that may result from maternal fever during labor. Larger studies are needed to investigate the association of intrapartum fever with neonatal seizures and to determine whether any lasting injury to the fetus may occur.

The association of epidural use with an increase in intrapartum temperature and a higher rate of intrapartum fever is well documented.^1-6 In our population of term deliveries, 98% of intrapartum fever occurred among women receiving epidural analgesia. We have demonstrated previously that this epidural-related fever is associated with an increase in both neonatal sepsis evaluations and neonatal antibiotic administration (although there was not a higher rate of documented sepsis associated with epidural use).¹ More recently, we also have demonstrated that even modest temperature elevation during labor is associated with an increased risk of cesarean section and operative vaginal delivery.³³ In the current study, intrapartum maternal fever, particularly if >101°F, was associated with a number of adverse outcomes in the newborn. Studies are needed to evaluate whether prevention or reduction of maternal temperature using antipyretics or other means can prevent these outcomes.

	ACKNOWLEDGMENT

This work was supported by Grant R01-HD26813 from the National Institute of Child Health and Human Development.

	FOOTNOTES

Received for publication Jul 6, 1998; accepted Apr 19, 1999.

Reprint requests to (E.L.) Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115. E-mail: eslieberma{at}bics.bwh.harvard.edu

	ABBREVIATIONS

RR, rate ratio; CI, 95% confidence interval; OR, odds ratio.

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