Definition and Pathophysiology

In 1868, Carl Wunderlich analyzed more than 1 million axillary temperature measurements from 25,000 patients.¹ He concluded that the average normal temperature of healthy adults was 37° C (98.6° F). However, he found a range of temperatures, with a nadir of 36.2° C between 2:00 and 8:00 AM and a zenith of 37.5° C between 4:00 and 9:00 PM. He also observed that women had slightly higher mean temperatures than men. A 1992 study using modern oral thermometers largely confirmed Wunderlich’s original data.²

Well-regulated temperature results from hypothalamic integration of afferent thermal information from the skin, spinal cord, and other sites within the central nervous system (CNS). When this integrated temperature deviates from normal, thermoregulatory responses are triggered.³ In humans, the first (and least metabolically “expensive”) response to temperature perturbations is behavioral (e.g., moving to a different environment, putting on appropriate clothing, adjusting room temperature). Such responses obviously are unavailable to an anesthetized patient, although some may be implemented by those caring for the patient. Further responses to temperature perturbations are mediated by the autonomic nervous system. Hypothermia prompts vasoconstriction in peripheral tissues to decrease skin blood flow, decrease heat loss, and retain heat in the core compartment. If vasoconstriction is not adequate to prevent hypothermia, thermoregulatory shivering is triggered to increase heat production. The CNS controls the metabolic activity of skeletal muscle, which converts chemical energy into heat by shivering.

Increased body temperature initially prompts vasodilation. This vasodilation is passive. It results from the release of sympathetic tone, and it is observed in unanesthetized adults exposed to a hot environment before any significant change in central temperature occurs. If vasodilation is not adequate to prevent hyperthermia, thermoregulatory sweating occurs, which increases evaporative heat loss.

An abnormal body temperature can result from drugs or diseases that either change thermoregulatory thresholds or impair thermoregulatory responses. Hypothalamic activity and fever may be triggered by endogenous pyrogens released from immune effector cells in response to invasion by microorganisms (Figure 37-1). Although no single endogenous pyrogen has been conclusively identified as the mediator of the febrile response, tumor necrosis factor seems capable of reproducing many components of the febrile response.⁴ Endogenous pyrogen activity appears to depend largely on increased endothelial cell production of prostaglandins. Of interest, many of these substances help mediate uterine activity and parturition.⁵ The central neural pathways leading to changes in thermoregulatory physiology are increasingly well understood and involve pathways coordinated in the preoptic area and projecting to the dorsomedial hypothalamus or to the rostral medullary raphe region.³

Clinically, temperature measurements greater than 38° C represent fever. During episodes of fever, the thermoregulatory set point is elevated and the normal thermoregulatory mechanisms are used to maintain the elevated temperature. However, there are circumstances in which an abnormally high temperature is measured in the absence of a change in thermoregulatory set point, such as when thermoregulatory responses to hyperthermia are prevented (e.g., block of sympathetically mediated sweating) or overwhelmed (e.g., immersion in hot water, malignant hyperthermia).

The fetus, by virtue of its intra-abdominal location, has a unique problem with heat elimination. The only anatomic routes for egress of heat are the fetal skin surface (through the amniotic fluid) or the uteroplacental circulation. Evidence suggests that the fetus relies on heat exchange across the uteroplacental circulation to dissipate most of its metabolic heat. The normal fetus maintains a temperature that is approximately 0.5° C to 0.75° C higher than maternal temperature.^6–8

Consequences of Maternal Fever and Infection

Maternal-fetal infection is associated with increased perinatal morbidity.^9,10 The increased morbidity is the result of many factors, including preterm delivery (perhaps related to an increased release of prostaglandins) and direct effects of the infection. Fever, irrespective of its etiology, may be harmful to the fetus, although the mechanisms of injury may differ with various causes. Conversely, some infections may be harmful without producing fever. Infection is the most common cause of fever and involves liberation of inflammatory cytokines, which are implicated in the pathogenesis of many fetal and neonatal injuries (see Chapter 10).^11,12 Noninfectious inflammatory fever, also leading to elevated cytokines, may complicate neuraxial analgesia in the absence of clinical infection (see later discussion).

Experimental evidence suggests that extreme levels of hyperthermia, independent of infection or inflammation, may have a deleterious effect on the fetus. Morishima et al.¹³ reported increased uterine activity and fetal deterioration during maternal hyperthermia produced by radiant heat in anesthetized baboons. However, the extreme degree of hyperthermia (approximately 41.7° C) employed in this study produced maternal as well as fetal deaths. Such extreme hyperthermia exceeds the modest fever that often occurs clinically; thus the clinical relevance of this study is unclear. Similarly, Cefalo and Hellegers¹⁴ demonstrated fetal deterioration at levels of hyperthermia that produced maternal cardiovascular collapse in anesthetized gravid ewes. However, the investigators also observed increased umbilical blood flow with clinically relevant, mild to moderate hyperthermia (0.5° C to 1.5° C above baseline). They suggested that increased umbilical blood flow in response to moderate degrees of hyperthermia might be beneficial to the fetus by increasing oxygen delivery and heat removal. Harris et al.¹⁵ demonstrated the preservation of fetal oxygenation and acid-base status during moderate degrees of fever (approximately 1° C above baseline) produced by the injection of bacterial pyrogen in awake pregnant ewes. However, they also observed an increase in fetal heart rate (FHR) and a greater incidence of fetal arrhythmias during fever.

Nonetheless, in humans, hot tub and sauna use in pregnancy has been linked epidemiologically to neural tube defects in the fetus with attributable risk comparable to that observed with febrile illness.¹⁶ Spontaneous abortion¹⁷ and major structural birth defects¹⁸ have similarly been associated with the frequency of use of hot tubs and saunas. Neonatal hypoxic encephalopathy has been observed after prolonged immersion in 39.7° C water during otherwise uncomplicated labor.¹⁹

Epidemiologic evidence suggests that mild maternal intrapartum fever may not be as benign as has been assumed on the basis of animal studies. Macauley et al.⁸ measured fetal scalp temperature in utero using a modified intrauterine pressure catheter. They concluded that fetal core temperature may exceed 40° C in some febrile women (Figure 37-2). Lieberman et al.²⁰ retrospectively reviewed the records of 1218 nulliparous women with singleton, term pregnancies in spontaneous labor who were afebrile on admission. They found fever (> 38° C) in 10% of the patients, nearly all of whom had received epidural analgesia. One-minute Apgar scores less than 7 and hypotonia were more common in the newborns of febrile mothers. Fever higher than 38.3° C was associated with more frequent requirement for bag-and-mask ventilation in the delivery room and need for supplemental oxygen in the nursery. There was also a nonsignificant increase in the incidence of neonatal seizures.²⁰ The same group performed a case-control study of unexplained neonatal seizures in term infants and found a strong association with intrapartum fever and seizures (odds ratio [OR], 3.4).²¹ A similar finding was reported by Perlman,²² who found a high incidence of maternal fever among a cohort of infants with a 5-minute Apgar score of 5 or less and those requiring resuscitation with chest compressions in the delivery room. The same group found a higher incidence of prolonged positive-pressure ventilation in the delivery room, tracheal intubation, admission to a neonatal intensive care unit, and 5-minute Apgar score less than 6 in febrile newborns born to women with chorioamnionitis compared with afebrile newborns born to women with chorioamnionitis.²³ Similarly, Greenwell et al.²⁴ found an association between low-grade fever (37.5° C) and adverse neonatal outcomes, including hypotonia and low 1-minute Apgar scores. More extreme fever (> 38.3° C) was also associated with low 5-minutes Apgar scores, assisted ventilation, and seizures.²⁴

Even more ominous is the suggestion that maternal fever may correlate with neonatal brain injury, particularly when the fever is associated with clinical or pathologically diagnosed chorioamnionitis (see Chapter 10). In several large epidemiologic studies, otherwise unexplained cerebral palsy was two to nine times more common in infants born to mothers with intrapartum fever (> 38° C) than in those born to afebrile mothers.^25–29 An equally strong association has been observed between maternal fever and neonatal encephalopathy.³⁰ Even if not apparent at birth or in early infancy, neurologic injury related to maternal fever may appear later in childhood. Dammann et al.³¹ reported an increased risk for cognitive deficits (> 2 standard deviations below the mean on a nonverbal intelligence scale) at age 9 among children whose mothers were febrile in labor. Fever during pregnancy, not specifically in the intrapartum period, has also been linked to subsequent development of autism^32,33 and schizophrenia.³⁴

The mechanism linking neurologic injuries to maternal fever likely involves the liberation of inflammatory cytokines.^11,12,29,34 Animal models of chorioamnionitis suggest that fetal brain lesions can be induced by infection and blocked by anti-inflammatory cytokines.³⁵ Infants developing neonatal encephalopathy in the setting of maternal fever do not generally exhibit positive blood cultures, implying that it is neuroinflammation, rather than infection, that causes damage.^30,36 It remains unclear whether intrapartum temperature elevation itself can cause neurologic injury, as distinct from underlying infection or other inflammatory processes that cause both elevated inflammatory cytokines and fever.

Fever also produces significant maternal effects. Elevated temperature is associated with increased maternal heart rate, cardiac output, oxygen consumption, and catecholamine production. Evidence has linked fever after cesarean delivery to risk for uterine rupture during subsequent trial of labor after cesarean delivery.³⁷ Women who develop fever are more likely to shiver and experience uncomfortable rigors.^38–40 Not surprisingly, obstetricians fearing infection are more likely to treat febrile women with antibiotics.^41,42 Even low-grade fever may prompt obstetricians to choose instrumental vaginal or cesarean delivery over expectant labor management. Lieberman et al.⁴³ found a twofold higher incidence of operative vaginal as well as cesarean delivery in a retrospective analysis of nulliparous women who were afebrile at admission but developed fever greater than 37.5° C during labor compared with those who remained afebrile, even after controlling for birth weight, duration of labor, and analgesic choice.

Together, these studies suggest that the fetus acutely tolerates modest degrees of maternal fever. Transient neonatal depression, neonatal seizures, and other neurologic disorders may be associated with inflammatory processes that produce maternal fever, although not clearly with fever per se. Inflammatory processes resulting in fever, and perhaps severe hyperthermia itself, may be risk factors for neonatal brain injury and other abnormalities.

Infections in Pregnant Women

Fever is most often the result of an infectious process. The most common sites for infection in pregnant women are the fetal membranes, urinary tract, respiratory tract, and postpartum uterine cavity.

Sepsis and Septic Shock

Sepsis is a rare, life-threatening complication of maternal infection that complicates approximately 1 in 8000 deliveries.¹¹⁷ Sepsis is defined by the American College of Chest Physicians and Society of Critical Care Medicine as infection that precipitates the systemic inflammatory response syndrome (SIRS), characterized by two or more of the following criteria: hyperthermia, hypothermia, tachycardia, tachypnea, or leukocytosis (see Chapter 55).¹¹⁸ Pregnancy may complicate the diagnosis, because many healthy pregnant women exhibit some of these signs.¹¹⁹ Noninfectious inflammation may also lead to SIRS; in all cases the syndrome appears to be triggered by mediators released from immune effector cells, including tumor necrosis factor, interleukins, and cyclooxygenase metabolites of arachidonic acid.¹²⁰

Severe sepsis is defined as sepsis with acute organ dysfunction, hypotension, or sepsis-induced hypoperfusion,¹¹⁸ and septic shock is defined as sepsis-induced hypotension that persists despite adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities or organ dysfunction.¹¹⁸ The incidence of sepsis and sepsis-related maternal mortality appears to be rising; it was the most common cause of death (1.13 per 100,000 maternities) in the most recent (2006-2008) Confidential Enquiries into Maternal Death in the United Kingdom report.¹²¹

In pregnant women, sepsis typically is associated with gram-negative bacteremia, although it can occur in association with gram-positive aerobic and anaerobic infections.¹²² Polymicrobial etiology is common,^117,123 particularly when the source of sepsis is a pelvic infection.¹²² Group A β-hemolytic streptococcal infection appears to predominate in fatal cases or those associated with major morbidity, although Clostridium species have been implicated in deaths of several otherwise healthy women undergoing gynecologic or obstetric procedures.^124,125 Untreated pneumonia, chorioamnionitis, pyelonephritis, endometritis, wound infection, incomplete abortion, and self-induced abortion may result in maternal sepsis, severe sepsis, and septic shock; case reports have attributed iatrogenic maternal sepsis to amniocentesis,^126–129 medical abortion,¹²⁵ dental procedures, and assisted reproductive procedures.¹³⁰ Approximately 45% of cases occur postpartum.¹³¹ The clinical course is often fulminant. In a series of nearly 100 cases from The Netherlands, more than half of the patients demonstrated signs of severe sepsis within 48 hours of the first sign of infection and 39% did so within 24 hours.¹³¹

Studies have suggested that pregnancy makes laboratory animals more susceptible to infection by a number of mechanisms.¹³² For example, Beller et al.¹³³ infused E. coli B6 lipopolysaccharide (endotoxin) into both nonpregnant and pregnant minipigs. The average duration of survival for the nonpregnant animals was 16 hours, whereas the average duration of survival for the pregnant animals was only 3.5 hours. The pregnant animals suffered more pronounced cardiovascular abnormalities and metabolic acidosis than the nonpregnant animals.

It is unclear whether pregnant women are more susceptible to sepsis than age-matched nonpregnant women. Case series of maternal sepsis have reported overall case-fatality rates of 6% and 7.7%.^122,131 This survival rate may reflect the relative youth of pregnant women and the effectiveness of surgical source control for most pelvic infections. Nonetheless, clinical studies have noted that once septic shock develops in pregnant patients, maternal mortality is as high as 30%.^134–136

The mainstay of therapy is elimination and/or aggressive treatment of the source of infection with antibiotics and, if indicated, surgical extirpation. Initial antibiotic therapy should include broad-spectrum coverage for bacteria such as E. coli, enterococcus, and anaerobic organisms. A combination of ampicillin, gentamicin, and clindamycin represents an effective regimen, as does a combination of imipenem, cilastatin, and vancomycin.¹³⁷ A 2012 review of cases from the United Kingdom Center for Maternal and Child Enquiries (CMACE) project suggested initial broad-spectrum antibiotic coverage (e.g., gentamicin with either piperacillin-tazobactam or ciprofloxacin), consultation with an infectious disease specialist as soon as possible, and appropriate adjustment of antibiotic therapy once the causative organism and antibiotic susceptibilities have been identified.¹³⁸ Local patterns of microbial resistance should be considered when selecting broad-spectrum empirical therapy. In all cases, aggressive antibiotic initiation without delay (within 1 hour of diagnosis) appears important for a favorable outcome.^121,139

Only a few reports have described the management of these seriously ill patients. Timezguid et al.¹²² summarized 66 intensive care unit admissions for sepsis between 1977 and 2008. Seventeen of 22 women with a pelvic source of infection required surgical source control, including termination of pregnancy (n = 5), uterine exploration for removal of placental fragments (n = 6), drainage of a pelvic abscess (n = 5), or hysterectomy (n = 3). Premature termination of pregnancy was more frequent in 12 cases of chorioamnionitis (83%) than in the 32 cases of extrapelvic infections (31%). Vasopressors, mechanical ventilation, and renal replacement therapy were used in 16 (25%), 19 (28%), and 4 (6%) cases, respectively.

Lee et al.¹³⁵ reviewed 10 cases of septic shock in obstetric patients between 1984 and 1986, which were caused by pelvic infections in 9 cases and mastitis in 1. Eight of the 10 women required inotropic or vasopressor infusions, or both, guided by pulmonary arterial catheterization. Two women died. The primary hemodynamic abnormalities were decreased systemic vascular resistance and depressed myocardial function.

Mabie et al.¹³⁶ reported 18 cases of pregnancy-associated septic shock that occurred during 11 years in a single institution, an incidence of 1 per 8338 deliveries. The most common causes were pyelonephritis (n = 6), chorioamnionitis (n = 3), endometritis (n = 2), and toxic shock syndrome (n = 2). Five patients (28%) died. The hemodynamic profiles of the patients in this series were similar to those described by Lee et al.¹³⁵: four of the five patients who died had mildly or severely depressed myocardial function.¹³⁶ Eight patients underwent at least one surgical procedure to control the source of infection.

In most cases, concomitant supportive therapy is required to decrease maternal and fetal morbidity. Physicians must give attention to the maintenance of maternal oxygenation, circulation, and coagulation. Most authorities suggest following the Surviving Sepsis guidelines for treatment of sepsis.^121,138,139 The guidelines recommend goal-directed therapy aiming to achieve a central venous pressure (CVP) between 8 and 12 mm Hg and a MAP of 65 mm Hg, urine output of 0.5 mL/kg/h, and mixed venous oxygen saturation 65% or higher (see Chapter 55).¹³⁹ Pregnant women were excluded from trials that evaluated this goal-directed therapy,^140,141 and unfortunately no evidence is available to confirm that this approach offers survival benefit for pregnant or recently delivered women. In nonpregnant patients with septic shock, norepinephrine is considered the first choice vasopressor and may be supplemented with epinephrine or vasopressin to maintain adequate blood pressure.¹³⁹

Evidence from nonobstetric patients receiving intensive care indicates that aggressive glycemic control may not confer a survival advantage in all critically ill patients, although some evidence suggests that avoiding hyperglycemia improves outcomes in surgical patients.¹⁴² Overly tight glycemic targets increase the risk for hypoglycemia; current guidelines recommend treatment to avoid hyperglycemia (> 180 mg/dL), hypoglycemia, and wide swings in glucose levels.¹³⁹ More intensive glucose control may be indicated in the intrapartum period to achieve optimal neonatal outcomes. Corticosteroid supplementation is indicated only when fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability.^139,143

Although the effects of maternal therapy on the fetus should be considered, treatment of the mother has first priority. Often what is best for the mother will be best for the fetus. However, in some cases, maternal sepsis may require preterm delivery, or even delivery before the age of viability, particularly if chorioamnionitis is present. Although the American College of Obstetricians and Gynecologists (ACOG) has stated that “delivery usually is not indicated in the septic pregnant patient in whom the pregnancy is not the source of infection,”¹³⁷ a multidisciplinary team should consider the mother’s response to initial therapeutic interventions, her vasopressor, oxygen and ventilatory requirements, and the gestational age and fetal well-being when considering the optimal timing and route of delivery.

Incidence

Epidural anesthesia administered for surgery—including cesarean delivery—typically results in hypothermia. This effect occurs because vasodilation produced by the sympathetic neuroblockade causes a redistribution of body heat from the core to the periphery, where it is lost to the environment.¹⁴⁴

In 1989, Fusi et al.¹⁴⁵ first observed that epidural labor analgesia was associated with progressive intrapartum maternal pyrexia. They reported that the vaginal temperatures of 18 parturients who received epidural analgesia increased approximately 1° C over 7 hours, whereas the temperatures of 15 women who received intramuscular meperidine and metoclopramide remained constant. There was no evidence of infection in any of the women. The authors suggested that epidural analgesia may cause an “imbalance between the heat-producing and heat-dissipating mechanisms.”

Fusi et al.¹⁴⁵ measured vaginal temperature; this measurement may be affected by the sympathectomy and vaginal mucosal vasodilation associated with epidural analgesia. Tympanic membrane temperature should not be affected by the local vasodilation associated with epidural analgesia, and it may provide a more accurate assessment of core temperature. Camann et al.¹⁴⁶ studied the effect of epidural analgesia on maternal oral and tympanic membrane temperature measurements in 53 laboring women. They studied three groups of patients; one group received intravenous nalbuphine, one group received epidural bupivacaine only, and one group received epidural bupivacaine with fentanyl. The patients were not randomized to receive either nalbuphine or epidural analgesia; however, the women who requested epidural analgesia were randomized to receive epidural bupivacaine only or epidural bupivacaine with fentanyl. The authors maintained ambient room temperature between 20° C to 22° C. Epidural analgesia did not affect maternal temperature during the first 4 hours of the study. At 5 hours and thereafter, the mean tympanic membrane temperatures were significantly higher in both of the epidural groups than the intravenous nalbuphine group (Figure 37-3). Among women in the bupivacaine-only group, mean tympanic temperature increased from approximately 36.6° C at 1 hour to 37.1° C at 9 hours, a rate of rise of less than 0.07° C per hour. There was no difference between the epidural bupivacaine-only and the epidural bupivacaine-fentanyl groups in maternal tympanic membrane temperature measurements.

Several other investigators have documented similar patterns of temperature elevation in laboring women receiving epidural analgesia.^41,147–152 These studies typically have found the average rate of temperature increase to be approximately 0.1° C per hour of epidural analgesia, usually after a lag time of 4 to 5 hours. Other investigations have documented an increase in clinical fever in women with epidural analgesia, usually defined as temperature greater than 37.5° C or greater than 38° C (Table 37-1).* These studies have employed various study designs, most commonly observational investigations of women self-selecting the mode of analgesia. Selection bias, reflecting greater prevalence of risk factors for fever among women choosing epidural analgesia, undoubtedly has affected the results of these reports.¹⁶³ However, other study designs have confirmed the finding of greater risk for fever in women who receive epidural analgesia. In a natural experiment, in which epidural analgesia was rapidly introduced in a facility in which it was previously unavailable, clinical fever markedly increased after epidural analgesia was widely available.¹⁴⁷ In addition, eight randomized controlled trials, in which women were randomly assigned to receive epidural analgesia or parenteral opioids (or nonpharmacologic analgesia in one study¹⁵⁵), also confirmed an increase in clinical fever in women who were randomized to receive epidural analgesia.^{152,155,156,158–162} Only one study examined fever as a primary outcome.¹⁵⁵ Meta-analysis of six trials found a relative risk (RR) for fever of 3.34 (95% confidence interval, 2.63 to 4.23) for epidural compared with nonepidural or no labor analgesia.¹⁶⁴ Most trials have investigated epidural labor analgesia, but at least one trial specifically investigated combined spinal-epidural (CSE) analgesia.¹⁵⁵

Originally viewed as two separate phenomena, the slow progressive temperature rise observed by Fusi¹⁴⁵ and Camann¹⁴⁶ and the clinical fever observed in other studies may be manifestations of the same process. Two investigations have concluded that the slow rise may actually be an artifact caused by averaging the temperature curves of women who develop clinical fever with those who remain afebrile (see Figure 23-7).^165,166 Frölich et al.¹⁶⁷ compared the slope of the temperature-time curves in women before and after receiving epidural analgesia and found no difference. They examined only women who did not develop a temperature greater than 38° C, and thus their finding supports the observation that epidural analgesia affects temperature in only a subset of women who develop clinical fever. These findings imply that an understanding of the nature of the relationship between epidural analgesia and overt fever is the key to understanding hyperthermia during labor in these patients.

Etiology

The mechanisms by which epidural analgesia produces maternal hyperthermia during labor remain unclear, and at least three types of explanation are plausible: thermoregulatory factors, effects of systemic opioids in patients not receiving epidural analgesia, and inflammation.¹⁶³

Thermoregulatory factors that may play a role include ambient temperature, impaired heat dissipation, and increased heat production. Fusi et al.¹⁴⁵ attributed the maternal pyrexia to the high ambient temperature (24° C to 26° C) found in most British delivery rooms. However, other investigators have failed to find an association between ambient temperature and maternal¹⁴⁸ or fetal⁸ temperature. Alternatively, epidural analgesia may impair heat-dissipating mechanisms. Decreased sweating and the lack of hyperventilation that follow the provision of effective epidural pain relief may predispose laboring women to pyrexia.^145,146,168 In volunteers, epidural anesthesia raised the sweating threshold by 0.55° C.¹⁶⁹ Moreover, epidural analgesia attenuates the significant increase in oxygen consumption observed during uterine contractions and the even greater increase observed during expulsive efforts.¹⁷⁰ This lack of increase in ventilation in the setting of increased energy expenditure may manifest as increased temperature in the laboring patient. Finally, the high incidence of shivering among laboring women who receive epidural analgesia may predispose them to the development of fever. Gleeson et al.³⁹ found that laboring patients who shivered after the administration of epidural analgesia developed pyrexia as early as 1 hour after initiation of neuroblockade, compared with more than 4 hours after initiation neuroblockade in patients who did not shiver. Moreover, the maximum temperature was higher and the incidence of clinical fever was three times more common in the women who shivered.³⁹ Some shivering and sweating in labor has been demonstrated to be nonthermoregulatory (i.e., not accompanied by changes in core temperature or vasomotor tone).⁴⁰ However, it is not clear whether shivering is a cause or an effect of factors increasing body temperature.

Parenteral opioids administered to women for labor analgesia might suppress fever that would otherwise have been apparent. In a nonpregnant volunteer study, fever was induced by the injection of interleukin-2.¹⁷¹ Epidural analgesia with ropivacaine with or without epidural fentanyl did not affect the magnitude of the fever, but intravenous fentanyl markedly attenuated the rise in temperature.¹⁷¹ However, in one large retrospective study,¹⁷² differences in intravenous nalbuphine use did not explain the increased occurrence of fever among those receiving epidural analgesia. Evron et al.¹⁷³ randomized laboring women to receive epidural ropivacaine, intravenous remifentanil, both drugs, or epidural ropivacaine and intravenous acetaminophen. They identified fever (temperature ≥ 38° C) in 14% of the ropivacaine group, 8% in the ropivacaine and remifentanil group, 8% in the ropivacaine and acetaminophen group, and 1% in the remifentanil group. Taken together, these investigations suggest that any fever-suppressing effect of parenteral opioids is relatively weak and is seen only with µ-opioid receptor agonists.

The predominant theory to date holds that inflammation, perhaps of a noninfectious etiology, is responsible for epidural analgesia–associated fever. Several lines of evidence support this mechanism. First, women who are more likely to request epidural analgesia during labor also are more likely to have other risk factors for fever during labor. These may include nulliparity,^151,174 premature rupture of membranes,¹⁷⁵ prolonged rupture of membranes,^148,151,174 induction of labor,¹⁷⁵ unfavorable cervical examination at admission,¹⁷⁵ prostaglandin exposure,¹⁷⁵ prolonged labor,^{8,146,148,151} obesity, higher temperature on admission,¹⁵¹ early chorioamnionitis,¹⁵¹ and possibly more cervical examinations.^46,175,176

Second, women with epidural analgesia and fever more frequently demonstrate placental inflammation. In a case-control study, Vallejo et al.¹⁷⁷ compared women without epidural analgesia and with clinical chorioamnionitis (temperature ≥ 38° C and clinical manifestations) to two groups of women who received epidural analgesia, one with and the other without clinical chorioamnionitis. The diagnosis of chorioamnionitis was confirmed histologically. Not surprisingly, fever was far more common in the women with chorioamnionitis. In fact, the incidence of fever in women with epidural analgesia but without chorioamnionitis was only 1%.¹⁷⁷ Similarly, Dashe et al.¹⁵⁴ analyzed the records and placental pathology of 149 women who delivered more than 6 hours after membrane rupture. They found an increased incidence of fever (temperature ≥ 38° C) in the 54% of their subjects who received epidural analgesia. However, histologic evidence of placental inflammation was also more common among epidural analgesia–exposed women. In the absence of placental inflammation, the incidence of maternal fever was equivalent in the epidural analgesia–exposed and unexposed patients (11% and 9%, respectively).¹⁵⁴

Importantly, the placental inflammation associated with epidural analgesia–associated fever may not indicate bacterial infection. Riley et al.⁵² examined the placentas of 200 women, 150 of whom received epidural analgesia, who had participated in two previous randomized trials of the presence of birthing assistants. The authors attempted to culture bacteria from the placentas, as well as to detect bacterial DNA by the polymerase chain reaction; they also measured serum interleukin concentrations. Fever was more common in women who received epidural analgesia than in those who did not (23% versus 6%, respectively; P = .009), but the incidence of infection was low in both groups (4.7% versus 4.0%, respectively; P > .99). An admission interleukin-6 (IL-6) level greater than 11 pg/mL predicted development of fever, irrespective of analgesic choice, and IL-6 levels increased more over the course of labor in women choosing epidural analgesia, irrespective of development of fever.

A third line of evidence supporting an inflammatory mechanism of epidural analgesia–associated fever is that biomarkers of inflammation are more common in women with epidural analgesia who develop fever. Goetzl et al.¹⁷⁸ randomized women with epidural analgesia to receive acetaminophen or placebo in labor. The incidence of fever (temperature > 38° C) was identical in the two groups. They demonstrated elevated maternal serum and umbilical cord blood markers of inflammation (IL-6) in febrile women. Pathologic examination of the placenta was not reported.¹⁷⁸ As discussed earlier, Riley et al.⁵² also found higher IL-6 levels in women receiving epidural analgesia and in women developing fever regardless of whether they received epidural analgesia. In a second trial, Goetzl et al.¹⁷⁹ were able to demonstrate suppression of epidural analgesia–associated fever with high-dose maternal corticosteroid therapy (methylprednisolone 100 mg every 4 hours). Umbilical cord blood IL-6 levels were lower in corticosteroid-treated patients, indicating suppression of inflammation. However, neonatal bacteremia was significantly increased by corticosteroid exposure.¹⁷⁹ In a small and likely underpowered trial, Wang et al.¹⁸⁰ randomized low-risk parturients with epidural analgesia to receive bupivacaine and fentanyl alone or combined with epidural dexamethasone 0.2 mg/mL. They observed no difference in the incidence of overt fever or placental inflammation but a reduction in mean temperature in the dexamethasone group. Maternal and umbilical cord blood IL-6 levels were reduced in the corticosteroid group, although the differences were not significant. Fetal condition was excellent in both groups.

The mechanism by which epidural analgesia might induce inflammation in a subgroup of women remains unclear. In nonrandomized investigations, differences in patient factors among women selecting epidural analgesia may indicate confounding risk factors for inflammation. Even in randomized trials, differences in obstetric management could also confound the association, because it is not possible to blind the treatment group in trials of epidural analgesia.¹⁶³ For example, epidural analgesia is associated with greater use of oxytocin in randomized trials, and it is conceivable that women randomly assigned to receive epidural analgesia may also receive earlier artificial rupture of membranes, more frequent cervical examinations, and greater use of internal monitoring in order to titrate oxytocin administration.^52,152 Conversely, a direct action of epidural local anesthetic in stimulating inflammation has been proposed, with the effect mediated through activation of the vanilloid receptor TRPV1.¹⁸¹

Clinical Impact

Epidural analgesia–associated maternal hyperthermia has become a subject of significant controversy. As discussed earlier, maternal fever attributed to clinical chorioamnionitis and other infection is associated with adverse neonatal condition as well as more severe neurologic injuries, including seizures, encephalopathy, and cerebral palsy. However, the effect of epidural analgesia–associated fever has not been specifically elucidated. In randomized trials comparing epidural and nonepidural analgesia, neonatal condition as measured by umbilical arterial acidosis or 5-minute Apgar score is consistently better in the epidural analgesia groups and neonatal intensive care unit admission does not differ between groups.¹⁶⁴ In a large retrospective analysis, epidural analgesia with fever was associated with adverse neonatal outcomes, but in the absence of fever epidural analgesia was not.²⁴ To date, no evidence has linked noninfectious epidural analgesia–associated fever to severe neonatal adverse outcomes.

It is possible that the mother and neonate may be placed at risk indirectly as a result of the interventions triggered by the occurrence of maternal fever.^41,150 For example, antibiotic administration is more likely in the setting of maternal fever. Mayer et al.⁴¹ retrospectively analyzed the records of 300 low-risk nulliparous women who received systemic opioids, epidural analgesia, or both and identified an increased incidence of both fever (≥ 37.8° C) and antibiotic administration among the two groups who received epidural analgesia. Nonetheless, only 5 of 10 patients with culture- or pathology-proven chorioamnionitis developed fever and none had fever as the only presenting sign or symptom. The authors suggested that obstetricians seek additional evidence of infection before treating all maternal fever with antibiotics.

In another retrospective study, Lieberman et al.¹⁵⁰ reanalyzed the records of 1657 low-risk nulliparous women originally enrolled in a trial of active management of labor.¹⁸² They, too, found a higher incidence of maternal temperature (> 38° C) in parturients who received epidural analgesia compared with those who did not (15% versus 1%, respectively). Neonates in the epidural group had a higher incidence of sepsis evaluation (34% versus 10%, respectively) and antibiotic treatment (15% versus 4%, respectively) compared with neonates in the nonepidural group. The incidence of actual neonatal sepsis was very low in both groups (0.3% and 0.2%, respectively). As in all studies in which women self-select their analgesia, the women receiving epidural analgesia were already at risk for intrapartum fever. For example, they had larger infants, longer labors, and a twofold increase in the rate of induction of labor.¹⁵⁰ Moreover, the active labor management protocol mandated frequent cervical examinations and early amniotomy, which may have increased the risk for fever.¹⁸³ Of interest, two thirds of the sepsis evaluations occurred in infants of mothers who did not have intrapartum fever.^150,183

To further elucidate the relationship between epidural analgesia and neonatal sepsis evaluation, the same group reanalyzed the subcohort of women¹⁸² admitted in spontaneous labor, in whom intrapartum temperature remained below 38° C throughout labor.¹⁸⁴ Epidural analgesia was associated with both major (rupture of membranes > 24 hours, FHR > 160 beats/min) and minor criteria (maternal temperature > 37.5° C, rupture of membranes 12 to 24 hours) for sepsis evaluation. It is likely that many of the features of labor that led to sepsis evaluations also predisposed women to choose epidural analgesia.

Subsequent work by other investigators has suggested the role of maternal temperature elevation as the key feature related to neonatal sepsis evaluations. Philip et al.¹⁵² demonstrated that women randomized to receive epidural analgesia had a higher incidence of fever (≥ 38° C) than those randomized to receive intravenous analgesia (15% versus 4%, respectively). Neonatal sepsis evaluations were also much more common in women with fever than in those without (96% versus 13%, respectively). However, within both the febrile and the afebrile cohorts, the incidence of neonatal sepsis evaluation was independent of analgesic type. The authors concluded¹⁵²:

… our results indicate that in the absence of maternal fever, epidural analgesia during labor has no bearing on the need for such neonatal management and therefore should not be considered a predictor per se for neonatal sepsis evaluations. We attribute this finding to the minimization of ascertainment bias as a result of randomization of analgesia.

Other investigators have highlighted the importance of neonatal practice style in determining the rate of sepsis evaluations. Yancey et al.¹⁴⁷ studied the rates of maternal fever and neonatal sepsis evaluation during a period in which epidural analgesia use rapidly increased from 1% to 83% after the introduction of a round-the-clock, on-demand epidural analgesia service. The incidence of fever greater than 37.5° C increased threefold, and fever greater than 38° C increased 18-fold after the introduction of epidural analgesia, although numerous indices of the patients’ admission status and intrapartum obstetric management did not change. The incidence of screening neonatal blood counts and blood cultures increased modestly (RR, 1.5 and 1.7, respectively), but there was no change in antibiotic treatment. The authors contrasted their results to those of Lieberman¹⁵⁰ and attributed the difference to neonatal practice patterns that did not require antibiotic therapy solely on the basis of maternal fever or antibiotic exposure.¹⁴⁷

Kaul et al.¹⁵⁷ also emphasized neonatologists’ practice style. They analyzed the records of 1177 nulliparous women and their neonates. Women with epidural analgesia had an increased risk for fever compared with women who received parenteral opioid analgesia (7% versus 0%, respectively), but multivariate logistic regression failed to demonstrate a significant association between epidural analgesia or maternal fever and neonatal sepsis evaluation. In contrast to Lieberman et al.,¹⁵⁰ the authors attributed the lack of effect of epidural analgesia to more stringent guidelines for neonatal sepsis evaluation that required at least one neonatal sign or symptom of infection regardless of the maternal condition.¹⁵⁷

The ability of epidural analgesia to stimulate maternal fever is likely a real phenomenon and not purely an artifact of higher-risk patients selecting epidural analgesia more frequently. Because of the growing evidence that maternal inflammation and infection, manifesting as fever, can be detrimental to the fetal brain, anesthesiologists cannot dismiss this unique physiologic effect as a mere curiosity. Further study to elucidate the link between epidural analgesia, pregnancy and labor, and fever is crucial to developing effective and safe strategies to minimize this link. In addition, attention must be paid to the indirect effects of maternal fever on the clinical decision-making of obstetricians and neonatologists to minimize unnecessary maternal and fetal interventions. In the meantime, if maternal pyrexia occurs, good clinical practice dictates that efforts be made to lower maternal temperature and identify and treat a presumed maternal infection.

Laboratory Studies

Carp and Bailey¹⁸⁵ performed a study to assess the risk for meningitis after the performance of dural puncture in bacteremic rodents. In this study, rats were made bacteremic by producing a flank abscess using E. coli bacteria. The bacteremia was similar in magnitude to that which occurs during the early phase of sepsis in humans. Cisternal dural puncture was performed after the onset of bacteremia. After 24 hours, the cisterna magna was drained surgically, and the cerebrospinal fluid (CSF) was cultured for evidence of meningitis. Of the 40 animals that underwent dural puncture during E. coli bacteremia, 12 developed meningitis (Table 37-2). None of the 40 bacteremic animals not subjected to dural puncture developed meningitis. Furthermore, dural puncture did not result in infection in the 30 animals without bacteremia. Importantly, none of the 30 bacteremic animals given a dose of gentamicin 15 minutes before dural puncture developed meningitis.

This study is consistent with earlier laboratory studies that observed the development of meningitis after the performance of dural puncture in bacteremic laboratory animals.^186,187 Although animal models of disease permit careful control of experimental conditions, these studies do not duplicate clinical conditions. Thus, there are limitations in the application of the rat study¹⁸⁵ to clinical practice. First, the level of bacteremia produced in the rats exceeded the transient, low-grade bacteremia that often occurs clinically. Also, these animals most likely had hemodynamic and metabolic changes characteristic of early sepsis. Second, although E. coli is a common cause of bacteremia in surgical and obstetric patients, it is an uncommon cause of meningitis. Third, the relative size of the dural tear produced by the 26-gauge needle used in this study is greater in rats than humans. Fourth, the cisternal site of dural puncture is not used clinically. Fifth, spinal and epidural anesthesia involves the injection of local anesthetics, and these drugs appear to be bacteriostatic.¹⁸⁸ Finally, the investigators knew the identity of the organism (E. coli) and also knew that it was susceptible to gentamicin.

In summary, this study suggests that high-grade bacteremia may increase the risk for meningitis after dural puncture. However, antibiotic therapy before dural puncture appears to reduce if not eliminate this risk.

Clinical Studies

At least six retrospective clinical studies have evaluated diagnostic lumbar puncture and the risk for meningitis.^189–194 (These studies did not evaluate the risk of neuraxial anesthesia or analgesia.) These reports provided conflicting conclusions regarding the risk for meningitis after the performance of dural puncture in bacteremic patients. Two studies suggested an association between dural puncture and meningitis.^189,192 However, both studies had serious methodologic flaws. One study was performed during an epidemic of meningitis.¹⁸⁹ Although the authors observed a high rate of meningitis after lumbar puncture, they did not evaluate a comparable control group who did not undergo lumbar puncture. Teele et al.¹⁹² reported an association between lumbar puncture and meningitis only in bacteremic children younger than 1 year of age. However, they acknowledged the possibility that clinical judgment might have prompted their pediatricians to perform diagnostic lumbar puncture in children with incipient meningitis before the CSF provided diagnostic evidence of infection.

The remaining four studies clearly did not support an association between dural puncture and meningitis.^{190,191,193,194} Shapiro et al.¹⁹⁴ concluded:

The development of bacterial meningitis in children with occult bacteremia is strongly associated with the species of bacteria that causes the infection, but not with a lumbar puncture.…Children with high-density bacteremia may appear to be more severely ill than children who have bacteremia with lower concentrations of bacteria, and therefore may be more likely to undergo a lumbar puncture.

In an editorial, Chestnut¹⁹⁵ stated, “Physicians often perform diagnostic lumbar puncture in patients with fever and/or bacteremia of unknown origin. If dural puncture during bacteremia results in meningitis, one would expect that unequivocal clinical data should exist.” However, no epidemiologic study has clearly established a causal relationship between the performance of dural puncture during bacteremia and the subsequent development of meningitis or epidural abscess. Part of the uncertainty regarding the risk of dural puncture results from awareness that processes other than meningeal integrity may help protect against the occurrence of CNS infection. For example, as many as 35% of epidural catheters used postoperatively are colonized by bacteria,¹⁹⁶ but epidural abscess is a very rare complication. Some anesthesiologists have cited anecdotal reports of meningitis after spinal anesthesia during presumed, but not documented, bacteremia as evidence that dural puncture may cause meningitis.^197–200 In one of these reports, the physicians used reusable equipment and the source of infection was traced to inadequately sterilized supplies.¹⁹⁷ The use of sterile, disposable equipment and strict attention to aseptic technique have largely eliminated these factors as a source of infection.

Some evidence points to external contamination as the source of meningitis after spinal anesthesia (see Chapter 32).^201–204 Rubin²⁰³ reported six cases of meningitis after spinal anesthesia over a 5-year period; all procedures were performed by the same anesthesiologist and the infections were all caused by the same organism. Videira et al.²⁰⁵ reported three cases of meningitis after 38,128 spinal anesthetics (1 : 12,709). In two cases, streptococci presumed to be skin or nasopharyngeal flora were cultured. The authors concluded that lapses in sterile technique may have been responsible for the meningitis. Poor attention to asepsis was also apparently responsible for three cases of meningitis reported in a 3-year period in a single hospital.²⁰⁶ In one case, the offending organism was cultured from the nose of the anesthesiologist performing the procedure. A 2012 outbreak of fungal meningitis in patients receiving otherwise uncomplicated epidural steroid injections was traced to contaminated methylprednisolone.²⁰⁷

Several reports have described the occurrence of meningitis after CSE analgesia in obstetric patients.^208–210 None of these patients was febrile during the CSE procedure. Furthermore, in the cases with positive CSF cultures, the authors concluded that contamination by skin flora was the most likely mechanism of infection. In general, evidence does not support a greater risk for meningitis with the CSE technique than with other neuraxial procedures, but rather a reporting bias involving complications of a relatively new technique.²¹¹

Large epidemiologic studies have found a very low incidence of CNS infection after the administration of neuraxial anesthesia. Dripps and Vandam²¹² prospectively studied 8460 patients who received 10,098 spinal anesthetics between 1948 and 1951. Similarly, Phillips et al.²¹³ reported the administration of spinal anesthesia to 10,440 patients between 1964 and 1966. A large number of the patients in both studies underwent obstetric or urologic procedures. Undoubtedly some patients had bacteremia during or after the performance of spinal anesthesia. However, neither study reported a single case of CNS infection.^212,213

Some evidence supports a lower frequency of infectious complications in obstetric patients than in general surgical patients. A 10-year review in Sweden of 1,260,000 spinal anesthetics and 450,000 epidural procedures (including 200,000 labor analgesia procedures) found 29 cases of meningitis and 13 epidural abscesses. Among the obstetric patients, there were no episodes of meningitis and one abscess.²¹⁴ Similarly, four reviews that included a total of more than 500,000 obstetric patients who received epidural anesthesia reported no cases of meningitis and two cases of epidural infection.^215–218 A 2009 national audit conducted in the United Kingdom gathered data on all central neuraxial procedures over a 1-year period (707,425 total cases and 320,425 obstetric cases).²¹⁹ Three cases of meningitis and 15 epidural abscesses were reported, but no meningitis and only one abscess was observed in the obstetric population.

Undoubtedly some parturients are bacteremic during the administration of epidural or spinal anesthesia, given the frequency with which parturients develop fever and infection during labor. For example, Blanco et al.⁵⁰ found a 1% incidence of bacteremia in a random sample of patients on the labor ward. Other studies have noted an incidence of bacteremia ranging from 2.3% to 12% in parturients with chorioamnionitis.^47,49,51 Unfortunately, there are no good predictive factors for identifying the subgroup of febrile patients with chorioamnionitis who are bacteremic at the time of anesthesia. The severity of fever does not reliably predict the likelihood of bacteremia in these patients.²²⁰ For example, Blanco et al.⁵⁰ reported that 86 (49%) of 176 patients with documented bacteremia had a temperature below 38.8° C. Furthermore, Bader et al.²²⁰ reported no significant difference in the mean temperatures of bacteremic and nonbacteremic patients with chorioamnionitis. Similarly, in a study of 146 women with chorioamnionitis, Goodman et al.⁵¹ found no differences in temperature, leukocytosis, or maternal symptoms between patients with positive and negative blood cultures.

Bader et al.²²⁰ retrospectively observed no cases of CNS infection after the administration of epidural or spinal anesthesia for labor and/or cesarean delivery in 279 patients with chorioamnionitis. Only 43 of these 279 women received antibiotic therapy before the administration of neuraxial anesthesia. At least three women had positive blood cultures consistent with bacteremia, and none of these three women received antibiotics before the administration of anesthesia. Similarly, Goodman et al.⁵¹ found no cases of meningitis or epidural abscess among 531 patients with chorioamnionitis (proven by culture or pathologic examination) who received epidural (n = 517) or spinal (n = 14) anesthesia. Eleven of 45 patients with fever before initiation of the neuraxial procedure, and 174 of 229 patients with preexisting leukocytosis, received no antibiotics before instrumentation of the epidural or subarachnoid space.

Together, these clinical studies suggest that meningitis and epidural abscess are rare complications of epidural or spinal anesthesia. Furthermore, bacteremia itself does not appear to increase the risk for CNS infection after the administration of neuraxial anesthesia. However, published studies of neuraxial anesthesia in patients with chorioamnionitis were small and retrospective. Given the infrequent occurrence of CNS infection among noninfected patients undergoing neuraxial anesthesia, none of these studies was sufficiently large to exclude the possibility that chorioamnionitis increases the risk for meningitis or epidural abscess. Moreover, the retrospective study design introduces the possibility of selection bias; anesthesia providers may have avoided neuraxial anesthesia in the sickest patients with chorioamnionitis.

Recommendations

In our judgment, the anesthesiologist may safely administer spinal or epidural anesthesia to healthy patients at risk for bacteremia. The anesthesiologist need not avoid administration of neuraxial anesthesia in patients at risk for transient, low-grade bacteremia after the administration of anesthesia. Moreover, appropriate antibiotic therapy may lessen the risk for meningitis or epidural abscess in patients with established infection. In our practice, we administer spinal or epidural anesthesia to patients with evidence of systemic infection, provided that appropriate antibiotic therapy has begun. Thus, it often is appropriate for the anesthesia provider to request the initiation of antibiotic therapy before administration of analgesia/anesthesia. Finally, although the choice of anesthesia must be individualized, it seems prudent to avoid spinal or epidural anesthesia in untreated patients with overt clinical signs of sepsis.

Chestnut reviewed this subject and concluded¹⁹⁵:

We do not give regional [neuraxial] anesthesia in the absence of other relevant information. Rather, we provide care for febrile patients who require anesthesia for labor, delivery, or emergency surgery. When one considers the risks of infection with regional anesthesia, one should ask: What are the alternatives? What are the consequences of withholding regional anesthesia in a febrile patient? For example, what is the greater risk in a febrile parturient: meningitis or epidural abscess after spinal or epidural anesthesia, or failed intubation and aspiration during general anesthesia?

Finally, both physicians and patients should recognize that most cases of meningitis and epidural abscess occur spontaneously. Eng and Seligman¹⁹¹ concluded, “Even if an appropriate temporal sequence…is documented…one cannot differentiate spontaneous meningitis from lumbar puncture–induced meningitis in the individual patient.”

Interaction with Pregnancy

During the first 20 weeks of pregnancy, primary genital herpes infection may be associated with an increased risk for pregnancy loss,²²⁴ although contemporary cohort studies have disputed the risk for fetal death.²²⁵ However, the major obstetric concern is the potential for transmission of the virus to the infant at the time of birth. The infant may become infected in one of two ways.²²² First, infection can occur as the fetus comes in direct contact with the virus during vaginal delivery. Second, intrauterine infection can occur by ascent of the organism after rupture of membranes. Neonatal HSV infection is a life-threatening infection with the potential for permanent CNS sequelae.^{221,222,224,226} The severity of the neonatal infection may be reduced by the early initiation of antiviral therapy. Meta-analysis of seven randomized trials of antepartum antiviral therapy with acyclovir or valacyclovir demonstrated a reduction in the presence of active genital lesions at delivery (RR, 0.28) and requirement for cesarean delivery (RR, 0.30).²²⁷ However, these trials could not demonstrate a reduction in neonatal herpes infection (there were no cases in any trial), and failure of suppressive therapy to prevent such transmission has been reported.²²⁶

Retrospective studies suggest that the risk for neonatal HSV infection associated with a primary maternal infection is much greater than that associated with recurrent maternal infection or asymptomatic shedding of the virus.^{224,228–230} The risk for transmission in the setting of active recurrent herpes has been estimated at 3% and in infected women without genital lesions at delivery at 2 per 10,000.²²¹ Most likely there is a greater risk that the infant will be exposed to the virus during episodes of primary maternal infection; in recurrent herpes there is evidence that passive transfer of antibodies to HSV from the mother to the fetus is protective.

Obstetric Management

A large epidemiologic study of 58,362 women provided direct evidence that cesarean delivery dramatically reduces the overall risk for HSV transmission to the neonate when HSV cultures of the cervix and external genitalia taken at the time of labor were positive (OR, 0.14).²²⁸ Other risk factors included maternal HSV seronegativity, positive cervical culture, use of invasive obstetric monitoring, and HSV-1 (compared with HSV-2) infection.²²⁸

The ACOG has reviewed the obstetric management of parturients with HSV infections and has concluded the following²²¹:

Cesarean delivery is indicated in women with active genital lesions or prodromal symptoms, such as vulvar pain or burning at delivery, because these symptoms may indicate an impending outbreak. The incidence of neonatal disease is low when there is recurrent maternal disease, but cesarean delivery is recommended because of the potentially serious nature of the disease.…In patients with active HSV infection and ruptured membranes at or near term, a cesarean delivery should be performed as soon as the necessary personnel and equipment can be readied. There is no evidence that there is a duration of rupture of membranes beyond which the fetus does not benefit from cesarean delivery.…In pregnancies remote from term, especially in women with recurrent disease, there is increasing support for continuing the pregnancy to gain benefit from time and use of corticosteroids. There is no consensus on the gestational age at which the risks of prematurity outweigh the risks of HSV.

Of interest, the mothers of most infants infected with HSV have no history of HSV infection and no obvious lesions at the time of delivery.^221,230 Previously, it was thought that antenatal viral cultures could predict asymptomatic viral shedding at the time of delivery and reduce the incidence of neonatal infection. Unfortunately, there is little correlation between antepartum HSV culture results and viral shedding at the time of delivery, even in women with a history of previous HSV infection.²³⁰ Thus, the ACOG concluded that there was no evidence for cost-effectiveness of various antenatal screening protocols.²²¹

Anesthetic Management

There are at least five published retrospective studies of the use of neuraxial anesthesia in patients with genital HSV infection. These studies reported no serious neurologic sequelae related to the use of neuraxial anesthesia.^231–235 However, most of the patients in these studies had recurrent (secondary) infection. Two studies^232,233 were limited to patients with recurrent infection, and a third report²³¹ did not indicate whether the patients had primary or recurrent infection. Bader et al.²³⁴ reported outcomes for 169 women with genital herpes infection who underwent cesarean delivery. Five of the 169 women in this study had primary infections, and three of these women received spinal anesthesia. Of the three women, one had transient, postoperative weakness of the left leg. The authors²³⁴ stated, “None of the cases of primary infection had associated systemic symptoms; it is therefore possible that some of these cases were actually misdiagnosed recurrent infections. The safety of regional anesthesia in patients with primary HSV infection remains unclear.”

Viremia may accompany primary episodes of genital herpes infection. However, viremia rarely complicates recurrent episodes of genital herpes infection. It is unlikely that a spinal or epidural needle could introduce virus into the CNS in patients with recurrent genital herpes infection. Thus, a consensus exists that it is safe to administer spinal or epidural anesthesia to women with recurrent genital herpes infection and no systemic symptoms. There are insufficient data to allow a definitive recommendation regarding the safety of neuraxial anesthesia in patients with primary infection who may be viremic. If the anesthesia provider is confronted with a patient with primary infection, the theoretical risk for CNS infection should be weighed against the risks of alternative methods of analgesia and anesthesia.

Finally, several studies have suggested that spinal or epidural administration of morphine, commonly administered for postcesarean delivery analgesia, increases the incidence of recurrence of oral HSV infection. This phenomenon was confirmed in randomized prospective trials for both epidural²³⁶ and intrathecal²³⁷ morphine. The cause is unknown, but some investigators have speculated that pruritus and scratching play a role in reactivation of oral lesions. Boyle²³⁸ concluded that facial pruritus is a marker of the migration of morphine to the trigeminal nucleus but not the cause of HSV recrudescence. He suggested that immunologic modulation by the opioid within this ganglion is the primary cause of the viral reactivation. Substantial evidence now supports this mechanism.²³⁹ A case of HSV-1 meningitis after unintentional dural puncture and passage of an intrathecal catheter has been reported.²⁴⁰ The patient underwent cesarean delivery with spinal bupivacaine, fentanyl, and morphine; the authors suggested reactivation of HSV-1 due to morphine and the presence of the intrathecal catheter may have contributed to the infection.²⁴⁰ To our knowledge, there are no reports suggesting that epidural or intrathecal administration of opioids increases the risk for recurrent genital herpes infection or neonatal herpes infection.