This study and others8,9,12
showing an i.rease in adverse outcomes among infants of febrile mothers in the absence of demonstrated infection suggest that increased maternal temperature, regardless of etiology, may have implications for the fetus. In our population of low-risk nulliparous women, elevated intrapartum maternal temperature (>99.5°F) among women receiving epidural analgesia was associated with a higher risk of adverse neonatal outcomes such as hypotonia, the need for assisted ventilation, low 1- and 5-minute Apgar scores, and early-onset neonatal seizures. Our data indicated a trend, with a statistically significant increase in the occurrence of these adverse outcomes with increasing maximum maternal temperature (). After adjusting for potentially confounding factors, high maternal fever >101°F was associated with a two- to sixfold increase in the occurrence of all adverse neonatal outcomes examined. Our estimates were conservative because length of labor was included as a potential confounder in our models. These findings are consistent with previous results from our institution9,12
and another study examining this issue.13
In contrast, we found no increase in adverse neonatal outcomes between women receiving and not receiving epidural in the absence of maternal temperature elevation, suggesting that epidural analgesia without accompanying maternal fever does not have an immediate effect on neonatal status.
reported that labor epidural analgesia was not associated with an increase in adverse neonatal outcomes. However, the authors did not examine whether adverse effects may have occurred more often among the subset of women who were febrile. Because approximately 15% to 20% of women become febrile, even a relatively large increase in adverse outcomes in that subgroup might not be detectable in an analysis of the overall population of women receiving epidural.
Our finding of an increase in unexplained seizures among infants of women with fever >101°F is of concern. Although the findings were based on a relatively small number of seizures (n =
8), it is consistent with other studies reporting an association of intrapartum maternal fever with neonatal encephalopathy.13,15
We also previously reported an association of unexplained seizures with epidural-related fever in a different population.9,12
Studies hypothesizing an association between neonatal encephalopathy or seizures and intrapartum maternal fever have assumed the fever resulted from infection such as chorioamnionitis.14,15,17
However, data suggest that among women delivering at term, most fever is related to epidural use rather than infection.8–10,22
In their study of low-risk women, Impey et al13
found a positive blood culture in only 1 of 16 infants (6.3%) with neonatal encephalopathy.
We also observed that 3 of 4 infants diagnosed with cerebral infarction were born to febrile mothers. Although not statistically significant, possibly because of small numbers, this finding is consistent with recent evidence suggesting an association between maternal fever and neonatal stroke in term infants.16
However, in that study, maternal fever was viewed by the authors as a marker for infection. This study did not consider the possibility that maternal fever was not the result of infection but rather related to the use of epidural. Term infants with stroke, specifically perinatal arterial stroke, are at higher risk of long-term neurologic impairment during childhood,16,23
as are neonates with seizures or encephalopathy.17,24
Previous studies have demonstrated that clinical chorioamnionitis, primarily diagnosed by the presence of intrapartum fever, is associated with a four- to ninefold increased risk of cerebral palsy in term infants.17,18
If confirmed, these findings suggest that exposure to intrapartum fever may not only increase the risk of adverse effects at birth but could potentially contribute to the development of long-term neurologic morbidity.
The exact mechanism through which epidural analgesia causes maternal fever and the mechanism through which the fever might increase the risk of adverse neonatal outcomes remains unclear. Our recent work,10
as well that of others,25–27
suggests an inflammatory response accompanying epidural-related fever. Studies have linked epidural use with elevated maternal serum levels of interleukin (IL)-625
and a higher monocyte production of IL-1β
and IL-6 in the newborn.26
Goetzl et al27
found that in the absence of neonatal infection, intrapartum epidural-related fever was associated with elevation of both maternal and fetal serum levels of IL-6 compared with women receiving epidural who did not develop fever. Cytokines released in response to inflammation or infection can act as mediators of neurologic injury and have been linked to neonatal encephalopathy and brain damage in newborns.28–30
Although available data suggest that epidural-related fever is associated with an inflammatory response, it is not yet clear whether control of the fever after it occurs would ameliorate the adverse neonatal outcomes we observed.
Because core fetal temperature in utero is approximately 0.5°C to 0.9°C higher than maternal temperature,31–33
the fetus may be exposed to higher temperatures than suggested by the degree of maternal temperature elevation. Previous animal studies have shown even small elevations in brain temperature before or during ischemia can increase the magnitude of brain injury and neuronal cell death in the fetus.34–36
There are several limitations in our study. In our low risk population, there were few women not receiving epidural who developed fever (n = 10) precluding meaningful analysis of that group. We are therefore not able to comment on the effects epidural-related fever compared with fever that occurs in the absence of epidural use.
In addition, the more frequent presence of pediatricians in the delivery room when a woman develops fever could have resulted in an increased use of resuscitative measures or assignment of lower Apgar scores. We addressed this potential bias by evaluating more serious resuscitative measures (positive pressure ventilation, bag and mask resuscitation, intubation, or chest compressions) because we believed such measures would have been used by pediatricians only when clearly necessary, and comparably applied regardless of maternal temperature status. We also evaluated 5-minute Apgar scores <7 and hypotonia lasting >15 minutes, which also represented more serious indicators of depression at birth. The higher rate of adverse outcomes among the infants of women whose maximum temperature was between 99.6 and 100.4°F, deliveries at which pediatricians would not be present, suggests the presence of pediatricians at the deliveries of febrile women is not responsible for the results we report.
Also, although we excluded infants with documented infection, one must consider the possibility that neonatal infection undiagnosed due to intrapartum maternal treatment with antibiotics contributed to the increase in adverse neonatal outcomes we observed. Our institution follows Centers for Disease Control guidelines37,38
for evaluation and treatment of neonatal sepsis. All infants born to mothers with intrapartum fever >100.4°F were evaluated for sepsis, as were infants with additional risk factors such as fetal tachycardia or rupture of membranes ≥18 hours. Among the 3209 infants in our sample, 2.2% (17 of 760) were treated with antibiotics for 3 to 7 days and 0.7% (5 of 760) for 7 days or more. Although it is plausible that some of these cases represent “presumed culture negative infection,” exclusion of these cases did not substantially alter the associations we noted.
Finally, it is plausible that in some cases undetected maternal intrapartum infection was responsible for the adverse outcomes we observed. To minimize the possibility of including women with preexisting infection, we excluded women with temperatures >99.5°F at admission. In addition, it is important to note that 20% of infants born to mothers receiving epidural analgesia experienced ≥1 adverse outcomes. Given the expected low rate of infection in low-risk infants (1–5 in 1000),39,40
it seems unlikely that infection is responsible for our findings of adverse outcomes.