Effects of Regional Analgesia on LaborMost women experience significant pain during their first labor that is why obstetricians spend a considerable amount of time counseling women about their pain control options. Epidural analgesia is attractive to both patients and clinicians because it is the most effective pain control method available, is relatively safe, and has only moderate effects on the course of labor. Despite its popularity and safety, epidural analgesia is not without side effects. The most common of which are maternal fever, effects on uterine basal tone and fetal heart rate (FHR) abnormalities. Pain management should be provided whenever it is medically indicated. FHR abnormalities after labor analgesia are a daily challenge for obstetricians and anesthesiologists and a concern for patients who desire to have pain relief during childbirth. Many of us often encourage laboring patients who choose epidural analgesia to try to hold off receiving it as long as possible, or at least until cervical dilatation reaches 4 to 5 cm. Dysfunctional labor, fetal malposition, and macrosomia may all be associated with more painful labor and a higher cesarean section rate. Or could it be that regional analgesia directly or indirectly influences the progress and outcome of labor? The purpose of this document is to understand the potential for maternal and neonatal morbidity and mortality of epidural-related maternal fever, uterine tone and fetal heart rate abnormalities of regional analgesia during labor. Of the various pharmacologic methods of pain relief during labor and delivery, regional analgesia techniques -- spinal, epidural, and combined spinal epidural -- are the most flexible, effective, and least depressing to the central nervous system, allowing an alert, participating woman and an alert neonate. In obstetric patients, regional analgesia refers to a partial to complete loss of pain sensation below the T8 to T10 level. In addition, a varying degree of motor blockade may be present, depending on the agents used (1). Epidural and spinal local anesthetics may relax the pelvic musculature, leading to abnormal fetal descent and rotation or impair abdominal muscle function and reduce maternal expulsion efforts. Administered over many hours, the concentration of drug is associated with significant motor blockade. More recent regional analgesia studies have lower concentrations of bupivacaine combined with fentanyl. The practice of lower concentrations is catching on, with greater awareness that high concentrations can increase instrumental vaginal deliveries or increase number of cesarean deliveries. Epidural: It offers the most effective form of pain relief and is used by most women in the United States. In most obstetric patients, the primary indication for epidural analgesia is the patient's desire for pain relief. Medical indications for epidural analgesia during labor may include anticipated difficulty in intubation, a history of malignant hyperthermia, selected forms of cardiovascular and respiratory disease, and prevention or treatment of autonomic hyperreflexia in parturients with a high spinal cord lesion. A catheter is placed in the epidural space, allowing for continuous epidural infusion of local anesthetic agents or narcotics. The advantage of this method is that medication can be titrated over the course of labor as needed. Women randomized to traditional high-dose epidural analgesia (with 0.25% bupivacaine) were more likely to have an instrumental vaginal delivery than women randomized to low-dose (0.1% bupivacaine with fentanyl) epidural maintenance techniques, although the rate of cesarean section delivery was no different among the groups (2). Modern epidural preparations that combine a low-dose local anesthetic, such as bupivacaine, levobupivacaine, or ropivacaine, with an opioid agonist are preferred because they decrease motor blockade and result in an increased rate of spontaneous vaginal delivery (3). Spinal: Single-shot spinal analgesia provides excellent pain relief for procedures of limited duration, such as cesarean delivery, the second stage of labor, rapidly progressing labor, and post partum tubal ligation. A long acting anesthetic often is used, with or without an opioid agonist. The duration of anesthesia is approximately 30-250 minutes depending on the drugs used (4). However, because of its inability to extend the duration of action, single-shot spinal analgesia is of limited use for the management of labor. Combined Spinal Epidural: It offers the rapid onset of spinal analgesia combined with the ability to use the epidural catheter to prolong the duration of analgesia with a continuous infusion for labor, to convert to anesthesia for cesarean delivery, or to provide post-cesarean delivery pain control. This method of obstetric analgesia is increasing in popularity, especially with the advent of needle-through-needle techniques that eliminate the need for more than one skin puncture. In addition, the use of newer "atraumatic" spinal needles is associated with a dramatically decreased risk of spinal headache (5). The spinal component of combined spinal epidural may be an intrathecal narcotic plus a small amount of a local anesthetic. Failure of the spinal component occurs at a rate of 4% with combined spinal epidural, but the block can be supplemented with the epidural catheter (6). The primary clinical risk factor for developing a fever after epidural analgesia is duration of exposure to the epidural itself. As a result, the risk of epidural fever is largely confined to nulliparous patients. Most multiparous patients deliver shortly after receiving epidural analgesia, and as a result do not have a significantly increased risk of fever. In fact, randomized trials have shown only 4% of multiparas on epidural analgesia develop fever, versus 3% in controls (7). Increasing maternal age also puts patients at risk for epidural fever. But while women who develop epidural fever are significantly older (mean 25.5 ± 1.1 vs. 22.0 ± 0.9 years) this difference is not clinically useful for counseling. Similarly, other clinical indicators such as maternal temperature at epidural placement, white blood cell count, or group B streptococcus carriage do not help clinicians identify women who will subsequently develop epidural fever. Accurately counseling an individual patient on her risk is complicated by wide variations in the risk of fever in different populations. The rates of intrapartum fever with epidural analgesia in nulliparas range from 13% to 33%. Rates at the upper end of this range have been observed in large public hospitals with primarily Hispanic populations. Conversely, rates at the lower end of the spectrum have largely been observed at private hospitals with predominantly Caucasian populations. Based on conservative calculations, epidural analgesia is theoretically associated with more than 400,000 additional cases of intrapartum fevers in the US every year. The rate of fever in a low-risk nulliparous population varies by patient population and by duration of epidural analgesia -- between 5% and 9% at 4 hours, 8% to 18% at 6 hours, and 11% to 24% at 8 hours (8). The mechanism for fever is not known. Theories include thermoregulation and chorioamnionitis. More recent research suggests a non-infectious inflammatory cause. Investigators have correlated epidural analgesia in labor with higher levels of interleukin-6, a marker for maternal inflammation (9). Although we do not understand the mechanism of this cascade, the time course of the response (within 1 hour) suggests that susceptible women are different from women who remain afebrile, and that these differences are present at the time of epidural placement. Several lines of evidence suggest that women with a propensity toward an exaggerated inflammatory response are more likely to develop intrapartum fever. Women with the tumor necrosis factor (TNFα) ∆308 polymorphism, which increases levels of this pro-inflammatory cytokine, have an increased risk of intrapartum fever (24.4%) compared with controls (RR 3.3; 95% confidence interval [CI], 1.3-7.1). In addition, the degree of maternal inflammatory response after epidural analgesia is directly related to level of interleukin-6 in maternal serum obtained prior to placement of epidural analgesia for labor pain (9). This is consistent with an increase in maternal temperature within 1 hour after catheter placement. However, the most compelling evidence for an inflammatory etiology is the finding that treatment with prophylactic corticosteroids (100 mg of methylprednisolone IV every 4 hours) at the time of epidural analgesia reduces the rate of maternal fever by more than 90% (10). A connection between epidural analgesia and a progressive increase in maternal temperature was first reported in 1989. Subsequent studies estimated a mean increase in maternal temperature of 0.14ºF per hour. However, these initial studies assumed that all women responded to epidural analgesia uniformly. More recent studies suggest that is not the case. Hyperthermia appears to be an abnormal response to epidural analgesia that occurs only in a relatively small subset of women. Temperature increase can be rapid, averaging 0.33ºF per hour (11). There is no recognized limit to maternal temperature elevation after epidural analgesia and unfortunately, there is no evidence to indicate that the degree of fever can be used to safely differentiate between epidural fever and chorioamnionitis. Further, because any significant temperature elevation in labor appears to be an abnormal response, there is no biologically plausible reason for requiring more than one elevated temperature measurement in labor to establish the diagnosis of intrapartum fever. Epidural-related fever is not benign. Although there is no increased risk of neonatal sepsis, there is a statistically significant increase in neonatal sepsis evaluations. Epidural-related fever results in a statistically significant risk of maternal antibiotic treatment and a statistically significant increase in neonatal antibiotic treatment (12). Since epidural analgesia increases the clinical diagnosis of chorioamnionitis, it is not surprising to find out that women who receive epidural analgesia are more likely to have been given intrapartum antibiotics. In addition, mothers who develop an intrapartum temperature of more than 99.5ºF have a two-fold increased risk of cesarean section delivery (95% CI, 1.5-3.4) even after controlling for length of labor. The reason for this increased cesarean rate is not certain; no increase in non-reassuring fetal testing has been observed in nulliparas with fever. Maternal fever at term results in intrauterine fetal exposure to hyperthermia and can be associated with fetal systemic and central nervous system inflammation. Maternal oral temperature is most highly correlated with intrauterine temperature but underestimates it by an average of 0.8ºC. In turn, fetal core temperature is approximately 0.75ºC higher than fetal skin / intrauterine temperature. Therefore, the widely used definition of intrapartum fever (38.0ºC) is generally associated with fetal temperatures of 39.5ºC or higher. Increased brain temperature may be directly neurotoxic or may lower the threshold for hypoxic injury. In a recent study, the risk of neonatal encephalopathy with either maternal fever or fetal acidosis alone was approximately 1%. However, when both maternal fever and fetal acidosis were present, the risk of neonatal encephalopathy was 12.5% (13). Clinical chorioamnionitis at term is associated with a more than four-fold increased risk of neonatal hypoxic ischemic encephalopathy (IE) and a four- to nine-fold increase risk of cerebral palsy. Although fetal exposure to intrauterine hyperthermia and / or inflammation subsequent to epidural fever is concerning, there is no direct evidence linking epidural analgesia to adverse neonatal neurologic outcomes. Further, there is no evidence that performing a cesarean delivery in the setting of intrapartum fever protects the neonate and this practice is not recommended. At this time there are no effective and safe ways to prevent epidural fever in nulliparous patients. Several prophylactic strategies have been attempted. Acetaminophen, 650 mg, given rectally every 4 hours, has no effect on rates of fever or temperature following epidural analgesia. Similarly, antibiotic prophylaxis for group B streptococcus does not decrease the rate of subsequent intrapartum fever. However, methylprednisolone (100 mg IV every 4 hours) started immediately prior to catheter placement reduces the rate of maternal fever by more than 90%. In addition, maternal steroids at this dose significantly reduce intrauterine exposure to fetal inflammation as measured by cord blood interleukin-6 levels (9) (13). Prophylactic treatment with maternal corticosteroids is seen to be accompanied by a significant increase in symptomatic neonatal bacteremia. Due to this safety concern, there is no recommended maternal treatment to prevent fetal exposure to hyperthermia and inflammation. Although neuraxial techniques (epidural, spinal and combined spinal epidural) provide the most effective and least depressant analgesia for labor, the question of whether their use is associated with an increased risk of cesarean delivery remains controversial. Several randomized prospective studies have shown an increased risk of cesarean delivery with epidural analgesia, while others have shown no increased risk with epidural analgesia or combined spinal epidural analgesia (14). Limitations to analysis of these studies high crossover rates between study populations, substantial bias, and small numbers of patients. Less controversial is the causal role epidural analgesia plays in prolonging labor by 40-90 minutes and in the approximate two-fold increased need for oxytocin augmentation. These findings are supported by most prospective studies as well as meta-analysis. An increase risk of a second stage of labor longer than 2 hours in women with epidural analgesia likely contributes to the higher rates of operative vaginal delivery seen in most prospective studies, in which elective forceps use was not permitted, yielded a combined risk of 1.9 (95% confidence interval [CI] 1.4-2.5) of forceps delivery in women who received epidural analgesia. Excessive operative vaginal deliveries have been implicated in the increased rate of third- and fourth-degree lacerations seen in women with epidural analgesia. Reports regarding the effect of the timing of epidural analgesia on the course of labor offer conflicting results. Several retrospective studies have shown an increased risk of cesarean delivery in nulliparous women in whom epidural analgesia was administered before cervical dilatation of 4 cm or 5 cm. Another retrospective study found an increased risk of cesarean delivery with higher station at epidural placement -- but not related to cervical dilatation -- after using logistic regression to control for potential confounders (1). At this time, it appears to be possible that very early placement of epidural analgesia may increase the risk of cesarean delivery and that the risk decreases with delayed epidural placement. After weighing this conflicting data, the American College of Obstetricians and Gynecologists (ACOG) Task Force on Cesarean Delivery Rates recommended that, when feasible, obstetric practitioners should delay the administration of epidural analgesia in nulliparous women until cervical dilatation reaches 4-5 cm and that other forms of analgesia be used that time. However, 4 cm of dilatation is an arbitrary cutoff because decreased risk with increased cervical dilatation is a continuum. Therefore, the decision of when to place epidural analgesia should be made individually with each patient, with other factors, such as parity, taken into consideration. Women in labor should not be required to reach 4-5 cm of cervical dilatation before receiving epidural analgesia. Fetal heart rate (FHR) abnormalities after labor analgesia are a daily challenge for obstetricians and anesthesiologists and a concern for patients who desire to have pain relief during childbirth. Despite great popularization of regional analgesia for labor, the causes and management of these abnormalities still remain controversial. Combined spinal epidural analgesia has come to stay because of its convenience for obstetricians, anesthesiologists, and patients. Although all the medical literature is in agreement about the fact that perinatal results in these fetuses are not worsened, more investigations are needed to better understand the effects of regional analgesia on labor progress and fetal physiology. The increasingly popular combined epidural technique with addition of opioids has been associated in various studies with a higher incidence of non-reassuring FHR tracings, and its possible causes still have no scientific confirmation. One of the hypotheses to explain it is that the effective and rapid onset pain relief provided by the method can cause a transient imbalance in maternal catecholamine level, leading to uterine hyperactivity. This hyperactivity could submit the fetus to a stress test, resulting in the observed abnormalities on fetal heart rate tracings (15). Combined spinal epidural analgesia has been associated with a significantly greater incidence of FHR abnormalities related to uterine hypertonus compared with epidural analgesia. It is also been document that the faster pain relief after analgesia, the higher the probability of uterine hypertonus and FHR changes (15). Intrapartum fever is the most common side effect of epidural analgesia. The risk is largely restricted to nulliparous patients. Maternal hyperthermia results in fetal exposure to hyperthermia and inflammation, even in the absence of documented infection. Since the rate of epidural-related fever in nulliparas receiving epidural analgesia varies widely, patients should be counseled based on the specific risks at your institution. If individualized risks are not available, it is customary to counsel nulliparous patients that if they choose epidural analgesia, their risk of fever might be between 13% and 33%. Discussion of maternal complications should focus on excess antibiotic treatment for intrapartum fever of uncertain etiology and increased risk of cesarean if any intrapartum fever develops. Discussions of neonatal complications of intrapartum fever should focus on the increase risk of neonatal sepsis evaluations. Epidural analgesia has not been associated with an increased risk of neonatal sepsis, and this information may help relieve parental anxiety. Current evidence does not provide a direct link between epidural-induced intrapartum fever and adverse neonatal neurologic complications and should not be used to counsel patients at this time. The consequences of intrapartum fetal exposure to hyperthermia and inflammation are uncertain. A woman's request for pain relief in early labor request for pain relief in early labor may be a marker for an unidentified risk factor(s) for cesarean delivery. In many studies early labor regional analgesia did not increase cesarean section rate compared to systemic opioid analgesia. This suggests the reason why early labor analgesia has been linked to a higher cesarean section rate is that early labor pain is a marker for other risk factor(s) for cesarean section. Taken together, evidence suggests that the early initiation of regional analgesia in laboring women, whether epidural or combined spinal epidural, does not adversely affect the mode of delivery compared to systemic opioid analgesia. This means that women who prefer regional analgesia can have it sooner. They need not be given systemic opioid analgesia until they have reached an arbitrary cervical dilatation for fear that early regional analgesia will increase the risk of cesarean section delivery. Acknowledgement: Women's Health and Education Center (WHEC) thanks Dr. Karen Cristine Abrão, Department of Obstetrics and Gynecology, São Paulo University, São Paulo, Brazil for the assistance in compiling the Practice Bulletin. The information is designed to aid practitioner in making decisions about appropriate obstetric and gynecologic care. |