Due to increased progesterone levels during the first trimester, minute ventilation is increased by almost 50% and remains so for the remainder of the pregnancy. Since anatomic dead space does not change significantly during pregnancy, at term, alveolar ventilation is increased by 70%. From 20 weeks’ gestation, the functional residual capacity (FRC), expiratory reserve volume and residual volume begin to decrease as a result of upward displacement of the diaphragm by the gravid uterus; this reaches its maximum reduction of 20% by term. Vital capacity is not appreciably changed from prepregnancy levels. The increase in minute ventilation leads to a decrease in PaCO₂ to approximately 30 mm Hg. Arterial pH remains unchanged because of a compensatory increase in renal excretion of bicarbonate ions.

The increased alveolar ventilation and reduced FRC lead to a more rapid uptake and excretion of inhaled anesthetics. The decrease in FRC in conjunction with increases in cardiac output, metabolic rate, and oxygen consumption lead to a much greater risk of arterial hypoxemia during periods of apnea or airway obstruction. This places even greater emphasis on the value of preoxygenation prior to general anesthesia. Some have suggested that FRC is increased if the patient is positioned with the head elevated 30 degree versus supine. Whether this prolongs the time to oxygen desaturation is unknown (10).

Anatomic changes to the airway include laryngeal and pharyngeal edema that can make ventilation and tracheal intubation more difficult. In addition, mucosal capillary engorgement can cause bleeding during airway manipulation. Mallampati scores have been found to increase during pregnancy. Pilkington et al. (11) found the incidence of grade 4 airways increased by 38% from the 12th to the 38th week of pregnancy. Together with inherent weight gain and enlargement of breasts, these changes render tracheal intubation more difficult, as evidenced by failed intubation as a well-recognized cause of maternal mortality (12).

Cardiac output is increased by 30% to 40% during the first trimester and 50% at term. This is primarily due to an increase in stroke volume (30% to 40%), and secondarily to an increase in heart rate (15%) (13). Further rises in cardiac output occur during labor and immediately postpartum, but these are beyond the scope of this chapter. Blood pressure normally decreases during pregnancy because of a fall in systemic vascular resistance due to the vasodilatory effects of estrogen and progesterone. Diastolic pressure is decreased to a greater extent (10% to 20%) than the systolic (0% to 15%). Near term, 10% to 15% of patients have a dramatic reduction in blood pressure in the supine position, often associated with diaphoresis, nausea, vomiting, pallor, and changes in cerebration. This is known as the supine hypotensive syndrome and is caused by compression of the inferior vena cava and aorta by the gravid uterus (14). This can begin as early as the second trimester and may lead to a reduction in renal and uteroplacental blood flow. Symptoms can be alleviated by tilting the patient on her left side to displace the uterus.

Increases in cardiac output will hasten the speed of intravenous anesthesia induction. Compression of the inferior vena cava by the gravid uterus leads to dilatation of the azygos system and the epidural veins. Epidural venous engorgement decreases the volume of the epidural and intrathecal spaces, which is why the dose of drugs used in neuraxial blockade should be decreased. In addition, it is postulated that progesterone may increase the sensitivity of nerve cells to local anesthetics since neuraxial drug requirements decrease prior to uterine enlargement (15).

Traditionally, gastric emptying was considered prolonged in the pregnant woman by the end of the first trimester (16,17). This was thought to be related to progesterone and mechanical changes as the stomach is displaced upward by the enlarging uterus. However, recent studies using acetaminophen absorption have not found a difference in gastric emptying in pregnant women. Wong et al. found no difference in gastric emptying between term women who ingested 50 mL versus 300 mL of water in both nonobese (18) and obese women (19). This is in contrast to active labor when gastric emptying is delayed (20). Although gastric emptying per se may not be delayed until the onset of labor, when the gravid uterus enters the abdominal cavity at 20 weeks’ gestation bariatric pressure is increased. In addition there is an increase in the acidity of gastric secretions (20) and a reduction in lower esophageal sphincter tone due to the influence of hormones (21). Although it is unclear when these changes are clinically relevant some consider all women at risk for aspiration of gastric content at 18 to 20 weeks (22), but certainly any woman with symptoms of acid reflux such as heartburn, a common finding in pregnancy (23), should be considered at risk.

Intravascular volume is increased by 45% during pregnancy due to an increase in plasma volume. Since this increases by a greater proportion than the red blood cell volume (55% and 30%, respectively) there is a relative anemia during pregnancy. Nevertheless a hemoglobin concentration of less than 11 g/dL is considered abnormal. Most of the coagulation factors are elevated during pregnancy and consequently pregnancy is considered a hypercoagulable state, with an increased risk of thromboembolic events (24). Platelet counts generally decrease by approximately 20% during a normal pregnancy; approximately 7% of all parturients will present with a platelet count <150,000 · mm^-3, and 0.5% to 1% will present with a platelet count <100,000 · mm^-3 (25).

Tests of liver function (serum glutamic-oxaloacetic transaminase, lactic acid dehydrogenase, alkaline phosphatase, and cholesterol) are commonly increased during pregnancy, though this does not necessarily indicate abnormal liver function. Pseudocholinesterase activity declines by as much as 20% during the first trimester and remains at this level for the remainder of the pregnancy. However, prolonged apnea is rarely a problem following a standard dose of succinylcholine and the duration of ester-linked local anesthetics are not prolonged.

The minimum alveolar concentration (MAC) for inhaled anesthetics is decreased by up to 40% during pregnancy (26)
due to the effect of progesterone and endorphins. Accordingly, the doses of inhalational agents should be reduced. Also, as mentioned earlier, smaller doses of local anesthetics are required to produce the same dermatomal level of neuraxial anesthesia in pregnant women as compared to nonpregnant women (14). This is related to progesterone and to mechanical effects from the gravid uterus pressing on the spinal and epidural space enhancing spread of local anesthetic. This observed decrease in both MAC and neuraxial requirements begins in the first trimester.

A teratogen is a substance that produces an increase in the incidence of a particular defect that cannot be attributed to chance. In order to produce a defect, the teratogen must be administered in a sufficient dose at a critical point in development. In humans this critical point is during organogenesis, which extends from 15 days to approximately 60 days gestational age. Each organ system has its own unique period of susceptibility. For example, the period of vulnerability for the heart is between days 18 and 40 and for the limbs is between days 24 and 34. However, the central nervous system does not fully develop until after birth, hence the critical time for this may extend beyond gestation.

Well-controlled randomized human studies are essentially impossible to perform in this domain due to the obvious ethical limitations and the large number of patients required to study these rare defects (27). Four approaches have been utilized to study the effects of anesthesia in the pregnant patient: (1) Animal studies, (2) limited retrospective human studies, (3) studies of chronic exposure of operating room personnel to trace concentrations of inhaled anesthetics, and (4) outcome studies of women who underwent surgery while pregnant.

Almost all anesthetic agents have been found to be teratogenic in some animal models (Table 50-2). However, the results of animal studies are of limited value because of species variation, as well as the use of agents in animal studies in far greater concentrations than those used clinically. In addition, other known teratogenic factors such as hypercarbia, hypothermia, and hypoxemia were either not measured or not controlled. Species variation is particularly important. Thalidomide has no known teratogenic effects on rats and was approved by the United States Food and Drug Administration (FDA) for use in humans. However, it later became apparent that thalidomide is teratogenic in humans (28).

The United States FDA has established a risk classification system to assist physicians weigh the risks and benefits when choosing therapeutic agents for the pregnant woman (29). To date there are only five drugs known to be teratogens, and none of them are anesthetic agents. These drugs include thalidomide, isotretinoin, coumarin (warfarin), valproic acid, and folate antagonists (30). Most anesthetic agents, including the intravenous induction agents, local anesthetics, opioids, and neuromuscular blocking drugs have been assigned a Category B or C classification (Tables 50-3 and 50-4). Indeed only the benzodiazepines have been assigned as Category D (positive evidence of risk. Investigational or post-marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the potential risk). Cocaine is in Category X, or contraindicated.

Thiopental has a long track record of safety in over approximately 70 years clinical use. Although found to be teratogenic in the chick embryo it has not been specifically studied in humans and as a result of its long track record of safety is considered safe to use during pregnancy (40).

Propofol readily crosses the placenta in almost a 1:1 fetal/maternal plasma concentration ratio (41). However, no animal or human studies have demonstrated a teratogenic effect (Category B). Interestingly, there is some controversy about its use for in vitro fertilization because of high levels of propofol in follicular fluid (42) but the same is true when thiopental is used (43) and pregnancy rates are not different between the two agents (44).