The uterus is composed of smooth muscles, which normally contract throughout gestation with variable frequencies and intensity. Prior to the onset of labor, changes occur in the uterine cervix including ingrowth of afferent C fibers and activation of biochemical signaling pathways that lead to the breakdown of collagen, changing the structural integrity of the cervix. During labor, or parturition, the contractions increase in frequency and intensity to cause thinning and dilation of the cervix allowing passage of the fetus from the uterus through the birth canal (1).

Labor is classically divided into three stages. The first stage can be considered the cervical stage during which cervical effacement and dilation occur. The second stage is the pelvic stage when the fetus descends through the pelvis. The third stage is the placental stage during which the placenta is expelled. Some authorities identify a fourth stage of labor, corresponding to the first postpartum hour, during which uterine contraction leads to volume expansion and postpartum hemorrhage is most likely to occur (2).

Pain during the first stage of labor is predominantly visceral in nature, arising from afferents in the uterine corpus and cervix during contractions (3). The uterus and cervix are supplied by afferents accompanying sympathetic nerves in the uterine and cervical plexuses; the inferior, middle, and superior hypogastric plexuses; and the aortic plexus. Small unmyelinated “C” fibers (4) transmit nociception through lumbar and lower thoracic sympathetic chains to the posterior nerve roots of the 10th, 11th, and 12th thoracic and also the 1st lumbar nerves to synapse in the dorsal horn (3). As the labor progresses, severe pain is referred to dermatomes supplied by T10 and L1. The severity of pain is related to the duration and intensity of contraction (5) but there is enormous variability among women (6,7).

Pain during the second stage of labor, is due to somatic factors added to the visceral pain of the first stage. Pressure on the parietal peritoneum, traction on uterine ligaments, urethra, bladder, rectum, lumbosacral plexus, fascia, and muscles of the pelvic floor may increase the intensity of pain. In the second stage, the direct pressure exerted by the fetal presenting part against the lumbosacral plexus may cause neuropathic pain. Stretching of the vagina and perineum results in activation of the pudendal nerve (S2 to S4) via fine, myelinated, rapidly transmitting “A delta” fibers (4). From these areas, the nociceptive impulses pass to dorsal horn cells up the spinothalamic tract to the brain where they are finally interpreted as pain.

There is some suggestion from animal models that labor pain possibly affects uterine contractility. In rodents, if the hypogastric nerve is severed, the amplitude of uterine contractility is increased, potentially increasing the rate of labor (8). It is unknown whether this feedback system is relevant in human labor.

A critical task for the obstetrical management is to determine whether labor is progressing normally and, if not, to determine the significance of the delay and what the response should be. Emmanuel Friedman’s model for labor progress and its modifications has classically been used by obstetricians to predict labor progress. His approach was straightforward: He graphed cervical dilation on the y-axis and elapsed time on the x-axis for thousands of labors (9). The original Friedman model was sigmoidal consisting of a latent phase of labor before 4 cm dilation, an active phase followed by a deceleration stage just before full cervical dilation at 10 cm. The presence of the deceleration stage has been debated, and the active and latent phases of labor have commonly been simplified as linear. Friedman’s most important contribution is his separation of the latent phase from the active phase of the first stage of labor. Many hours of regular, painful uterine contractions may take place with significant cervical effacement but little change in cervical dilation. The Friedman model was modified by Philpott as an alert line at dilation less than 1 cm/h, which represented the lowest 10 percentile rate for nulliparous patients. This has been developed into the WHO partograph, designed to predict obstructed labor in low resource environments (10).

The Friedman model has been useful for the study of labor progress in different populations. However, for the individual woman, the transition from the latent to the active phase of the first stage of labor, does not occur abruptly at an arbitrary cervical dilation but rather occurs as a change in slope of the cervical dilation curve (7,11,12). Recently, two new approaches have been applied to labor progress modeling. Zhang and colleagues have used repeated measures regression with a multi-order polynomial function (11). Flood, Reitman, and colleagues have used a bi-exponential model of labor progress to detect factors that significantly influence labor progress (7,12). Each of these methodologies has strengths and limitations that are beyond the scope of this chapter.

There is enormous variability in the length of the latent phase of labor. A prolonged latent phase alone is not associated with fetal compromise or cephalopelvic disproportion. However, primary dysfunctional labor and arrest of dilation during the active phase may indicate cephalopelvic disproportion (9,13,14). Friedman’s original work suggested that an arrest of dilation during the active phase was associated with the need for cesarean delivery nearly half of the time. Later studies suggest a lower percentage, but it is clear that women who experience active-phase arrest of dilation are more likely to require abdominal delivery than women with normal labor progress during the active phase. However, obstetrical convention may contribute to these numbers. Recent work by Zhang and colleagues in a large contemporary cohort suggests that the active phase of labor may not begin until 6 cm dilation in many patients and slow progress before 6 cm dilation may not be an indication of abnormal labor progress (15). Clearly, individualization of expectations for normal labor progress would contribute to more efficient use of resources and may decrease the rate of unnecessary operative deliveries.

In modern obstetric anesthesia, regional techniques are favored because of advantages for both the mother and the newborn baby. However, conditions such as coagulopathy, serious infection, hypovolemia, and neurologic anomaly may shift the balance of risk toward general anesthesia for safe delivery.

All volatile anesthetics, including sevoflurane, desflurane, isoflurane, halothane, and ethanol, inhibit spontaneous contractility of gravid human uterine muscle in a dose-dependent manner. Uterine relaxation or atony results in increased blood loss after delivery. Therefore, large concentrations of volatile anesthetics that may cause profound uterine relaxation are best avoided during cesarean delivery (16,17). However, this well-known side effect of volatile anesthetics may be paradoxically used to achieve uterine relaxation to facilitate complicated deliveries in some instances (18,19).

Historically, parenteral ethanol was introduced by Fuchs (20) during the mid-60s as a tocolytic agent for preterm labor and, despite the alternatives available, was still in clinical use up until 1981 (21). It was reported that for ethanol to be effective, blood levels between 1.2 and 1.8 g/L were needed. However, higher blood levels may cause maternal anesthesia and respiratory depression with risk of aspiration pneumonitis. Hypotension and incontinence, although uncommon, can also occur. Most women on ethanol experienced nausea and required the routine use of an anti-emetic drug.

Sevoflurane and desflurane have gained widespread acceptance in obstetric anesthesia. Their inhibitory effects on myometrial contractility have been documented in rat (22,23), and human preparations (24,25). The degree of inhibition induced by sevoflurane and desflurane is comparable to that of halothane, whereas that induced by isoflurane is less. This might be explained by differences in their mechanism of action. The inhibitory effects of isoflurane may be related, at least in part, to its ability to modulate K_ATP channels, whereas effects of other volatile anesthetics may involve other pathways including transmembrane Ca²⁺ flux (26). The inhibitory effect of volatile anesthetics occurs in a concentration-dependent manner. The uterine contractility abolished by these volatile agents is seen only at lower concentration of anesthetics (below 1 minimum alveolar concentration [MAC]) (26) and the contractility can be restored by the administration of oxytocin.

Desflurane and sevoflurane are promising agents for use in cesarean section, because they have low blood–gas partition coefficients, allowing rapid uptake and elimination. Both agents appear to have a similar relaxant effect on the uterus to those of older agents at equivalent MACs, although their rapid clearance at the end of the operation may minimize the duration of uterine relaxation. The declining use of general anesthesia for cesarean section means that few data are available on these agents. Gambling et al. compared 1% sevoflurane with 0.5% isoflurane for elective cesarean section (27). They found no difference in cardiovascular parameters, blood loss, uterine tone, perioperative complications, emergence time, or neonatal outcome. Abboud et al. compared desflurane (3% and 6%) with enflurane 0.6% for cesarean section anesthesia (28) and found no difference in uterine contractility. The use of desflurane for cesarean sections is relatively new and knowledge about its maternal and neonatal effects is being accumulated. Karaman et al. (29) compared maternal and neonatal outcomes in women undergoing elective cesarean section with desflurane, sevoflurane, or epidural anesthesia, and found no differences among the three groups.

Volatile halogenated agents provide distinct advantages, because they can be easily titrated and reduce the risk of intraoperative awareness. However, there is little evidence to guide the specific choice of modern agent (isoflurane, sevoflurane, or desflurane) routine for cesarean delivery. In patients undergoing cesarean delivery, uterine contractility typically can be maintained with a small concentration of a volatile agent (and concurrent infusion of oxytocin), but in the presence of obstetric hemorrhage due to uterine atony, it is prudent to minimize the concentration of the volatile halogenated agent or convert to an intravenous anesthetic technique.

A modification of cesarean delivery to allow various interventions during birth is called ex utero intrapartum therapy (EXIT procedure) (30). This sequence is most often employed to allow for a fetal procedure while gas exchange continues in the placenta (placental bypass). The EXIT procedure enables the prevention of postnatal asphyxia in the setting of lesions such as cystic hygroma, lymphangioma, cervical teratoma, and congenital syndromes in which securing an airway after birth can be problematic. The procedure is also used as a bridge to extracorporeal membrane oxygenation (ECMO) for a fetus with cardiopulmonary disease that is at risk for postnatal cardiac failure and resulting hypoxia. The EXIT procedure has become a widely practiced fetal intervention for a growing list of indications. The myometrial relaxant properties of volatile anesthetics are used to advantage in the EXIT procedure and similarly to facilitate fetal surgery. The EXIT procedure is conducted under general anesthesia; however, unlike normal cesarean delivery, sufficient time must be allowed after induction of anesthesia—before surgery commences—to achieve the high steady-state end-tidal concentration of the volatile halogenated agent needed to ensure uterine relaxation and to allow time for fetal anesthesia. After adequate uterine relaxation has been achieved, a uterine incision is made with the stapling device, and the fetal head and shoulders are delivered in preparation for tracheal intubation. Once the umbilical cord is clamped and the fetus delivered, the maternal anesthetic technique is changed to reduce uterine relaxation rapidly in order to avoid postpartum hemorrhage. The inspired concentration of the volatile halogenated agent is reduced or eliminated and nitrous oxide 70%, opioids, and/or a propofol infusion can be instituted (2).

Both low concentration of volatile anesthetics and nitrous oxide have been used for labor analgesia. Abboud et al. (31) compared administration of 0.25% to 1.25% enflurane in oxygen with administration of 30% to 60% nitrous oxide during the second stage of labor. Approximately 89% of the enflurane group and 76% of the nitrous oxide group rated
their analgesia as satisfactory. The rates of amnesia were similar (7% and 10%). There were no differences in blood loss, Apgar scores, or umbilical cord blood–gas measurements. Unlike the volatile anesthetics, nitrous oxide appears to have no effect on uterine contractility (32).

In addition to cesarean section, non-obstetrical surgical procedures may be required during pregnancy. Intravenous anesthetics may be used to complement volatile anesthetics or alone as total intravenous anesthesia (TIVA) techniques. The effects of these agents on uterine contractions and placental blood flow are very important to anticipate. The unexpected relaxation or contraction of myometrium can be harmful to fetus and continuing pregnancy.

The effect of general anesthesia on surgical blood loss was compared in patients anesthetized with isoflurane or propofol TIVA regimens for voluntary termination of pregnancy in the first trimester in a double-blind clinical trial (33). The mean blood loss was significantly lower in the propofol TIVA group, 148 (123 to 177) mL compared to the isoflurane group, 244 (198 to 301) mL. This difference remained significant even after controlling age, body weight, and uterus size. However, propofol has been found to decrease uterine muscle contractility in a dose-dependent manner in in vitro studies (34,35). Although propofol has not been approved by the FDA for use in pregnancy, because of the lack of availability of thiopental in the United States, it is now commonly used in clinical practice in pregnant patients and several published clinical studies attest to the safety of propofol for induction of cesarean sections (36,37,38). Propofol is rapidly distributed across the placenta, with an umbilical venous concentration/maternal venous concentration ratio of 0.65 (37).

Midazolam is a short-acting, water-soluble benzodiazepine that has few adverse hemodynamic effects and provides hypnosis and amnesia. It is used commonly in small doses (1 to 2 mg) to provide anxiolysis as an adjunct to regional anesthesia for cesarean section. While midazolam clearly crosses the placenta, at these doses, there is no evidence for a negative effect on fetal well-being (39). Although most commonly used as a premedicant prior to anesthesia, midazolam can be used in higher doses as an induction agent for cesarean delivery. The effect of midazolam on human uterine contractility has not been directly studied, but it has been shown to reduce the contractility of rat uterine muscle in in vitro preparations (40).

Ketamine is useful as an analgesic and/or sedative supplement to general or regional anesthesia for obstetric surgery. It causes limited cardiovascular and respiratory depression in the mother and may reduce opioid side effects in the newborn (41,42). Ketamine’s analgesic effects are likely related to antagonism of the N-methyl-D-aspartate (NMDA) receptor. Animal studies suggest that the use of ketamine is not associated with a reduction in uterine blood flow (43,44,45). Ketamine is associated with dose-dependent increases in uterine tone in vitro, but a single induction dose does not increase uterine tone at term gestation (46). Ketamine is suitable for induction of general anesthesia for cesarean section and has compared favorably with thiopental in terms of maternal hemodynamics, wakefulness, and neonatal outcome (47,48,49). It rapidly crosses the placenta but neonatal depression is not observed with doses less than 1 mg/kg (41,50). However, the emergence delirium and hallucinations experienced with ketamine, particularly in the unpremedicated patient, limit the routine use of ketamine as an induction agent for cesarean delivery (51). If ketamine is used, a benzodiazepine should be administered to decrease the incidence of these psychomimetic effects (52).

Although many different systemic opioids have been used for labor analgesia, little scientific evidence suggests that one drug is intrinsically better than another for this purpose; most often the selection of an opioid is based on institutional tradition and/or pharmacokinetics. Ex vivo studies on isolated human pregnant uterine muscle strips demonstrate that opioids such as fentanyl, meperidine, remifentanil, and alfentanil may directly inhibit uterine contractility, though at concentrations higher than those used for analgesia (40,53,54). At analgesic concentrations, they do not have a significant effect on spontaneous contractions of gravid human uterine muscle. Interestingly, morphine and sufentanil had no effect on uterine contractility even at much higher than clinically relevant levels (53). Prospective comparison of the effects of neuraxial analgesia and parenteral opioid analgesia on cesarean delivery rates showed that there was no difference in the rate of cesarean delivery for dystocia (55,56). A meta-analysis of trials that randomized patients to receiving neuraxial analgesia or parenteral opioids suggested that patients receiving neuraxial analgesia had slightly longer labor, but, also higher satisfaction and better neonatal outcome. A low umbilical artery pH (<7.15 or 7.20) was recorded more commonly among neonates born after parenteral opioids than after epidural analgesia (57).

Neuraxial anesthesia and analgesia has become increasingly popular for obstetrics. The foremost reason is evidence that it is safer than general anesthesia for most pregnant women. The most common anesthesia-related contribution to maternal mortality is inability to secure a difficult airway, the incidence of which has been increasing in pregnancy (58,59). Maternal mortality significantly decreased during the period between 1991 and 2002 compared to 1979 and 1990, potentially partially as a result of increased use of neuraxial anesthesia for cesarean deliveries (60,61).

Due to the smaller amount of drug required for spinal anesthesia and the resulting reduction in systemic exposure, there is little direct effect of spinal anesthetic medication on the uterus/fetus or neonate (62). Hypotension and increased uterine tone that can be side effects of neuraxial anesthesia can potentially adversely affect placental blood flow. Since uterine blood flow is not autoregulated, uteroplacental perfusion is directly dependent on maternal perfusion pressure. Untreated reduction in maternal blood pressure may not be very well tolerated by the fetus. A meta-analysis of studies comparing spinal and epidural anesthesia for cesarean delivery revealed that the severity of hypotension is greater with spinal anesthesia (63). Another review that compared different modes of anesthesia found that spinal anesthesia compared to both general and epidural anesthesia was associated with lower umbilical pH and higher base deficit (64). There is no evidence, however, that this statistical difference in fetal acid–base status results in clinically different neonatal outcome. It should also be noted that none of the reviews mentioned considered treatment of sympathectomy with modern methods that include administration of phenylephrine infusion.

When a spinal dose was first added to epidural analgesia for labor, as part of a combined spinal–epidural technique, an increase in the incidence of transient fetal heart rate abnormalities was observed. In some settings these were clearly related to maternal hypotension but in many cases maternal blood pressure was largely unchanged while the rate of uterine contractility was noted to increase, including case reports of uterine hyperactivity (65). This hypothesis has been
recently supported by the results of a randomized clinical trial in patients who had intrauterine pressure catheters (66). The uterus expresses β2-adrenergic receptors that are activated by endogenous epinephrine to result in tonic uterine relaxation. Systemic epinephrine concentrations are rapidly reduced after neuraxial anesthesia. When that tonic break on uterine tone is released in the setting of neuraxial anesthesia, the baseline contractile activity increases. Treatment with intramuscular ephedrine (25 mg) prior to combined spinal–epidural analgesia has been shown to reduce the incidence of late and variable fetal decelerations independent of maternal blood pressure (67). A direct relationship to uterine tone cannot be inferred however as the patients who were studied did not have intrauterine pressure catheters in place.