Introduction
Neurologic disorders requiring surgical intervention during pregnancy are not uncommon, and many anesthesiologists eventually encounter a pregnant woman in need of a neurosurgical procedure. The anesthetic management of such patients can be complicated by the physiologic changes that occur during pregnancy. These changes might require adjustments in anesthetic management that would be inappropriate for a nonpregnant patient with the same neurosurgical condition.
Maternal well-being must remain a primary concern, but it is important to recognize that interventions which benefit the mother might have the potential to harm the fetus. Thus, the major challenge in providing anesthesia for neurosurgery performed during pregnancy is to provide an appropriate balance between competing, and sometimes contradictory, clinical goals.
Maternal physiologic changes during pregnancy
The pregnant woman undergoes a number of physiological adaptations to pregnancy. The earliest of these changes are hormonally driven, while changes that occur later in pregnancy are associated with the mechanical effects of the enlarging uterus, increased metabolic demands of the fetus, and a low resistance placental circulation.
Nervous System
Inhalation Anesthetic Requirements
Anesthetic requirements for volatile anesthetics during pregnancy, as measured by minimum alveolar concentration (MAC), are decreased by 30% from the nonpregnant state. , Higher levels of plasma endorphins and progesterone are said to account for this change. Hence, inspired anesthetic concentrations that would be appropriate in the nonpregnant patient could have exaggerated effects during pregnancy. However, the relationship between pregnancy and MAC is complicated by the findings from one study that showed no differences in electroencephalographic measures during sevoflurane anesthesia between pregnant and nonpregnant women. The authors of that study suggested that a decrease in MAC during pregnancy does not correlate with an enhanced hypnotic effect of sevoflurane on the brain. They believe that pregnant women should receive the same dose of volatile agent as a nonpregnant woman in order to prevent intraoperative awareness, and we should reconsider MAC as an indicator of the efficacy of volatile anesthetics.
Local Anesthetic Requirements
Local anesthetic requirements for neuraxial anesthesia are decreased by 30–40% during pregnancy. This reduction is in part due to the decreased volume of cerebrospinal fluid (CSF) in the lumbar subarachnoid space secondary to engorgement of the epidural veins. The decrease in local anesthetic requirements precedes the onset of significant epidural venous engorgement, however. In vitro preparations of vagus nerves obtained from pregnant rabbits show increased sensitivity to local anesthetic-induced blockade of nerve conduction. When nerves obtained from nonpregnant rabbits are bathed in a progesterone-containing solution, however, this greater sensitivity is not seen. It is, therefore, suggested that long-term but not short-term exposure to progesterone leads to changes in the neuronal membrane Na + channel that increase its sensitivity to local anesthetics.
In summary, parturients may have decreased anesthetic requirements but despite a 30% reduction in MAC, recent research indicates that it might be prudent to use the same dose of volatile agent as in a nonpregnant woman in order to avoid awareness. However, parturients appear to need reduced doses of neuraxial local anesthetics.
Respiratory System
Upper Airway Mucosal Edema
The accumulation of extracellular fluid produces soft tissue edema during pregnancy, particularly in the upper airway where marked mucosal friability can develop. Nasotracheal intubation and the insertion of nasogastric tubes should be avoided unless absolutely necessary because of the risk of significant epistaxis. Laryngeal edema can also reduce the size of the glottic aperture, leading to difficult intubation. Mallampati scores can increase during labor making endotracheal intubation more difficult, and this problem is likely to be worsened in preeclamptic patients. A smaller (6.0–7.0-mm) endotracheal tube is appropriate for most pregnant patients.
Functional Residual Capacity
By the end of the third trimester, functional residual capacity (FRC) decreases 20% from prepregnant values, whereas closing capacity remains unchanged. The FRC drops further in the supine position, a situation in which closing capacity commonly exceeds FRC. This decrease leads to closure of small airways, increased shunt fraction, and a greater potential for arterial oxygen desaturation. Additionally, because FRC represents the store of oxygen available during a period of apnea, decreases in FRC will lead to the rapid development of hypoxemia when the pregnant patient becomes apneic, as occurs during the induction of general anesthesia. Because oxygen consumption rises by as much as 60% during pregnancy, significant desaturation can occur even when intubation is performed expeditiously. This process was demonstrated in a computer model of pregnancy in which apnea was simulated after 99% denitrogenation. Desaturation to 90% occurred in approximately 5 minutes in the pregnant model, versus 7.5 minutes in the nonpregnant model. Thus, at least 2 minutes of preoxygenation and denitrogenation with a tightly fitting face mask is mandatory before the induction of general anesthesia during pregnancy.
Ventilation
Significant increases in minute ventilation occur as early as the end of the first trimester. At term, minute ventilation increases by 45%, owing to an increase in tidal volume; respiratory rate is essentially unchanged. This most likely results from a progesterone-induced increase in the ventilatory response to carbon dioxide (CO 2 ); there also appears to be an effect due to pregnancy-induced changes in wakefulness. Because the increase in ventilation exceeds the increase in CO 2 production, the normal arterial partial pressure of CO 2 (Paco 2 ) diminishes to approximately 32 mmHg. The greater excretion of renal bicarbonate partially compensates for the hypocarbia, so that pH rises only slightly, to approximately 7.42 to 7.44.
Cardiovascular System
Blood Volume
Blood volume increases by 45% during pregnancy, with the majority of this increase occurring by the end of the second trimester. Because plasma volume increases to a greater extent than red blood cell mass, a dilutional anemia commonly occurs. Normal hematocrit at term ranges from 30% to 35% and is often lower in women not receiving supplemental dietary iron.
Cardiac Output
Significant increases in cardiac output (CO) occur as early as the first trimester. Capeless and Clapp demonstrated a 22% rise in CO by 8 weeks’ gestation, which represents 57% of the total change seen at 24 weeks. Cardiac output rises steadily throughout the second trimester. Maximum increases in CO occur between 28 and 32 weeks’ gestation. At term, cardiac output is approximately 50% above prepregnancy baseline.
Cardiac output can increase by an additional 60% during labor. Part of this increase is caused by the pain and apprehension associated with contractions, an increase that can be blunted with the provision of adequate analgesia. There is a further rise in CO, unaffected by analgesia, from the autotransfusion of 300–500 mL of blood from the uterus into the central circulation with each contraction. Finally, CO increases further in the immediate postpartum period, by as much as 80% above pre-labor values, because of autotransfusion from the rapidly involuting uterus as well as the augmentation of preload after relieving aortocaval compression.
Aortocaval Compression
In the supine position after 20 weeks’ gestation, the enlarged uterus can compress the inferior vena cava against the vertebral column. Collateral flow through the epidural venous plexus and paravertebral vessels can partially compensate for decreased caval blood flow, but the net return of blood to the heart can be significantly decreased, leading to reduced CO. This can decrease uterine blood flow (UBF) and impair uteroplacental oxygen delivery. Supine positioning can also produce aortic compression. If this occurs, upper extremity blood pressure might be normal but distal aortic pressure and thus uterine artery perfusion pressure could decrease. The effects of aortocaval compression are magnified in the anesthetized patient when venous return is reduced from sympathetic blockade. Therefore, the supine position must be avoided in pregnant patients undergoing anesthesia after the mid-second trimester. One study evaluated the degree of tilt necessary to minimize aortocaval compression in term, nonlaboring patients prior to cesarean delivery. CO and pulse pressure were highest at 15 degrees of left tilt, equal to full 90 degrees left lateral position.
Gastrointestinal System
Gastric Acid Production
Ectopic gastrin is produced by the placenta. However, plasma gastrin levels appear to be unchanged during pregnancy, and there appears to be no significant difference in either the volume or the acidity of gastric secretions in pregnancy.
Gastric Emptying
Contrary to common belief, gastric emptying is not significantly altered during pregnancy. Gastric emptying is slowed, however, in the presence of painful contractions, and systemic opioids administered to relieve labor pain will further slow gastric emptying.
Gastroesophageal Sphincter
The enlarging uterus causes elevation and rotation of the stomach, which interfere with the pinchcock mechanism of the gastroesophageal sphincter. This change increases the likelihood of gastroesophageal reflux, especially in the morbidly obese parturient.
Pregnancy and Aspiration Pneumonia
The changes described make it more likely that a pregnant patient will regurgitate and aspirate during anesthesia. The time frame for the development of these changes is unclear, but most anesthesiologists begin to use “full stomach” precautions after 16–18 weeks’ gestation, by which time uterine growth is such that alterations of gastroesophageal structure and function are likely to occur. Pregnant patients should, therefore, receive aspiration prophylaxis with a nonparticulate antacid and/or a combination of a histamine H 2 blocking drug and metoclopramide. Anesthetic induction is influenced by the presence of a full stomach but, as described later, techniques designed to minimize the risk of aspiration might not be ideal for the patient who has an intracranial lesion.
Renal and Hepatic Systems
Aldosterone levels rise during pregnancy, with concomitant increases in total body sodium and water. These changes can increase edema in an intracranial neoplasm and lead either to worsening signs and symptoms, or to the onset of symptoms from a previously unrecognized mass lesion. Renal blood flow and glomerular filtration rate increase by approximately 60% at term, paralleling the increase in CO. Thus, blood urea nitrogen (BUN) and serum creatinine values are usually one-half to two-thirds those seen in nonpregnant women. What would be considered normal or only mildly elevated BUN and creatinine values in nonpregnant women should be a cause for concern during pregnancy.
Slight increases in serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) are not uncommon during normal pregnancy. Plasma cholinesterase levels are decreased, but prolonged neuromuscular blockade does not occur in normal parturients receiving succinylcholine.
Epidural Vascular Changes
Epidural Venous Pressure
A generalized increase in intra-abdominal pressure as well as direct compression of the inferior vena cava leads to a rise in epidural venous pressure. This rise leads to the diversion of a portion of the venous return from the legs and pelvis into the vertebral venous system, causing engorgement of the epidural veins. It has been suggested that elevated epidural venous pressure, in association with the hemodynamic changes of pregnancy, may predispose to rupture of a preexisting pathologic region of the venous wall. Epidural veins contain no valves; therefore, abrupt pressure changes, such as produced by coughing, sneezing, or a forceful Valsalva maneuver during the second stage of labor, could be transmitted directly to the epidural veins, causing rupture.
Epidural Arterial Vessels
The epidural arterial vessels may undergo degenerative changes during pregnancy secondary to elevations of progesterone and estrogen. The arterial vessels of pregnant women have been shown to demonstrate numerous histologic changes, including fragmentation of the reticulin fibers, diminished acid mucopolysaccharide concentration, and hypertrophy and hyperplasia of smooth muscle cells. These structural changes, in combination with the hemodynamic changes of pregnancy, may predispose to rupture of an epidural artery and subsequent hematoma formation.
Maternal physiologic changes during pregnancy
The pregnant woman undergoes a number of physiological adaptations to pregnancy. The earliest of these changes are hormonally driven, while changes that occur later in pregnancy are associated with the mechanical effects of the enlarging uterus, increased metabolic demands of the fetus, and a low resistance placental circulation.
Nervous System
Inhalation Anesthetic Requirements
Anesthetic requirements for volatile anesthetics during pregnancy, as measured by minimum alveolar concentration (MAC), are decreased by 30% from the nonpregnant state. , Higher levels of plasma endorphins and progesterone are said to account for this change. Hence, inspired anesthetic concentrations that would be appropriate in the nonpregnant patient could have exaggerated effects during pregnancy. However, the relationship between pregnancy and MAC is complicated by the findings from one study that showed no differences in electroencephalographic measures during sevoflurane anesthesia between pregnant and nonpregnant women. The authors of that study suggested that a decrease in MAC during pregnancy does not correlate with an enhanced hypnotic effect of sevoflurane on the brain. They believe that pregnant women should receive the same dose of volatile agent as a nonpregnant woman in order to prevent intraoperative awareness, and we should reconsider MAC as an indicator of the efficacy of volatile anesthetics.
Local Anesthetic Requirements
Local anesthetic requirements for neuraxial anesthesia are decreased by 30–40% during pregnancy. This reduction is in part due to the decreased volume of cerebrospinal fluid (CSF) in the lumbar subarachnoid space secondary to engorgement of the epidural veins. The decrease in local anesthetic requirements precedes the onset of significant epidural venous engorgement, however. In vitro preparations of vagus nerves obtained from pregnant rabbits show increased sensitivity to local anesthetic-induced blockade of nerve conduction. When nerves obtained from nonpregnant rabbits are bathed in a progesterone-containing solution, however, this greater sensitivity is not seen. It is, therefore, suggested that long-term but not short-term exposure to progesterone leads to changes in the neuronal membrane Na + channel that increase its sensitivity to local anesthetics.
In summary, parturients may have decreased anesthetic requirements but despite a 30% reduction in MAC, recent research indicates that it might be prudent to use the same dose of volatile agent as in a nonpregnant woman in order to avoid awareness. However, parturients appear to need reduced doses of neuraxial local anesthetics.
Respiratory System
Upper Airway Mucosal Edema
The accumulation of extracellular fluid produces soft tissue edema during pregnancy, particularly in the upper airway where marked mucosal friability can develop. Nasotracheal intubation and the insertion of nasogastric tubes should be avoided unless absolutely necessary because of the risk of significant epistaxis. Laryngeal edema can also reduce the size of the glottic aperture, leading to difficult intubation. Mallampati scores can increase during labor making endotracheal intubation more difficult, and this problem is likely to be worsened in preeclamptic patients. A smaller (6.0–7.0-mm) endotracheal tube is appropriate for most pregnant patients.
Functional Residual Capacity
By the end of the third trimester, functional residual capacity (FRC) decreases 20% from prepregnant values, whereas closing capacity remains unchanged. The FRC drops further in the supine position, a situation in which closing capacity commonly exceeds FRC. This decrease leads to closure of small airways, increased shunt fraction, and a greater potential for arterial oxygen desaturation. Additionally, because FRC represents the store of oxygen available during a period of apnea, decreases in FRC will lead to the rapid development of hypoxemia when the pregnant patient becomes apneic, as occurs during the induction of general anesthesia. Because oxygen consumption rises by as much as 60% during pregnancy, significant desaturation can occur even when intubation is performed expeditiously. This process was demonstrated in a computer model of pregnancy in which apnea was simulated after 99% denitrogenation. Desaturation to 90% occurred in approximately 5 minutes in the pregnant model, versus 7.5 minutes in the nonpregnant model. Thus, at least 2 minutes of preoxygenation and denitrogenation with a tightly fitting face mask is mandatory before the induction of general anesthesia during pregnancy.
Ventilation
Significant increases in minute ventilation occur as early as the end of the first trimester. At term, minute ventilation increases by 45%, owing to an increase in tidal volume; respiratory rate is essentially unchanged. This most likely results from a progesterone-induced increase in the ventilatory response to carbon dioxide (CO 2 ); there also appears to be an effect due to pregnancy-induced changes in wakefulness. Because the increase in ventilation exceeds the increase in CO 2 production, the normal arterial partial pressure of CO 2 (Paco 2 ) diminishes to approximately 32 mmHg. The greater excretion of renal bicarbonate partially compensates for the hypocarbia, so that pH rises only slightly, to approximately 7.42 to 7.44.
Cardiovascular System
Blood Volume
Blood volume increases by 45% during pregnancy, with the majority of this increase occurring by the end of the second trimester. Because plasma volume increases to a greater extent than red blood cell mass, a dilutional anemia commonly occurs. Normal hematocrit at term ranges from 30% to 35% and is often lower in women not receiving supplemental dietary iron.
Cardiac Output
Significant increases in cardiac output (CO) occur as early as the first trimester. Capeless and Clapp demonstrated a 22% rise in CO by 8 weeks’ gestation, which represents 57% of the total change seen at 24 weeks. Cardiac output rises steadily throughout the second trimester. Maximum increases in CO occur between 28 and 32 weeks’ gestation. At term, cardiac output is approximately 50% above prepregnancy baseline.
Cardiac output can increase by an additional 60% during labor. Part of this increase is caused by the pain and apprehension associated with contractions, an increase that can be blunted with the provision of adequate analgesia. There is a further rise in CO, unaffected by analgesia, from the autotransfusion of 300–500 mL of blood from the uterus into the central circulation with each contraction. Finally, CO increases further in the immediate postpartum period, by as much as 80% above pre-labor values, because of autotransfusion from the rapidly involuting uterus as well as the augmentation of preload after relieving aortocaval compression.
Aortocaval Compression
In the supine position after 20 weeks’ gestation, the enlarged uterus can compress the inferior vena cava against the vertebral column. Collateral flow through the epidural venous plexus and paravertebral vessels can partially compensate for decreased caval blood flow, but the net return of blood to the heart can be significantly decreased, leading to reduced CO. This can decrease uterine blood flow (UBF) and impair uteroplacental oxygen delivery. Supine positioning can also produce aortic compression. If this occurs, upper extremity blood pressure might be normal but distal aortic pressure and thus uterine artery perfusion pressure could decrease. The effects of aortocaval compression are magnified in the anesthetized patient when venous return is reduced from sympathetic blockade. Therefore, the supine position must be avoided in pregnant patients undergoing anesthesia after the mid-second trimester. One study evaluated the degree of tilt necessary to minimize aortocaval compression in term, nonlaboring patients prior to cesarean delivery. CO and pulse pressure were highest at 15 degrees of left tilt, equal to full 90 degrees left lateral position.
Gastrointestinal System
Gastric Acid Production
Ectopic gastrin is produced by the placenta. However, plasma gastrin levels appear to be unchanged during pregnancy, and there appears to be no significant difference in either the volume or the acidity of gastric secretions in pregnancy.
Gastric Emptying
Contrary to common belief, gastric emptying is not significantly altered during pregnancy. Gastric emptying is slowed, however, in the presence of painful contractions, and systemic opioids administered to relieve labor pain will further slow gastric emptying.
Gastroesophageal Sphincter
The enlarging uterus causes elevation and rotation of the stomach, which interfere with the pinchcock mechanism of the gastroesophageal sphincter. This change increases the likelihood of gastroesophageal reflux, especially in the morbidly obese parturient.
Pregnancy and Aspiration Pneumonia
The changes described make it more likely that a pregnant patient will regurgitate and aspirate during anesthesia. The time frame for the development of these changes is unclear, but most anesthesiologists begin to use “full stomach” precautions after 16–18 weeks’ gestation, by which time uterine growth is such that alterations of gastroesophageal structure and function are likely to occur. Pregnant patients should, therefore, receive aspiration prophylaxis with a nonparticulate antacid and/or a combination of a histamine H 2 blocking drug and metoclopramide. Anesthetic induction is influenced by the presence of a full stomach but, as described later, techniques designed to minimize the risk of aspiration might not be ideal for the patient who has an intracranial lesion.
Renal and Hepatic Systems
Aldosterone levels rise during pregnancy, with concomitant increases in total body sodium and water. These changes can increase edema in an intracranial neoplasm and lead either to worsening signs and symptoms, or to the onset of symptoms from a previously unrecognized mass lesion. Renal blood flow and glomerular filtration rate increase by approximately 60% at term, paralleling the increase in CO. Thus, blood urea nitrogen (BUN) and serum creatinine values are usually one-half to two-thirds those seen in nonpregnant women. What would be considered normal or only mildly elevated BUN and creatinine values in nonpregnant women should be a cause for concern during pregnancy.
Slight increases in serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) are not uncommon during normal pregnancy. Plasma cholinesterase levels are decreased, but prolonged neuromuscular blockade does not occur in normal parturients receiving succinylcholine.
Epidural Vascular Changes
Epidural Venous Pressure
A generalized increase in intra-abdominal pressure as well as direct compression of the inferior vena cava leads to a rise in epidural venous pressure. This rise leads to the diversion of a portion of the venous return from the legs and pelvis into the vertebral venous system, causing engorgement of the epidural veins. It has been suggested that elevated epidural venous pressure, in association with the hemodynamic changes of pregnancy, may predispose to rupture of a preexisting pathologic region of the venous wall. Epidural veins contain no valves; therefore, abrupt pressure changes, such as produced by coughing, sneezing, or a forceful Valsalva maneuver during the second stage of labor, could be transmitted directly to the epidural veins, causing rupture.
Epidural Arterial Vessels
The epidural arterial vessels may undergo degenerative changes during pregnancy secondary to elevations of progesterone and estrogen. The arterial vessels of pregnant women have been shown to demonstrate numerous histologic changes, including fragmentation of the reticulin fibers, diminished acid mucopolysaccharide concentration, and hypertrophy and hyperplasia of smooth muscle cells. These structural changes, in combination with the hemodynamic changes of pregnancy, may predispose to rupture of an epidural artery and subsequent hematoma formation.
Effects of anesthetic interventions on uterine blood flow
At term, normal UBF increases to 700–900 mL/min, which is approximately 10% of the total maternal blood flow. This compares to a nonpregnant UBF of 70 mL/min. The magnitude of UBF is determined by the following equation:
where UAP is uterine arterial pressure, UVP is the uterine venous pressure, and UVR is the uterine vascular resistance. Alterations in any of these parameters influence UBF and, therefore, the delivery of oxygen and nutrients to the fetus.
Factors that decrease uterine arterial pressure include hypovolemia, sympathetic blockade due to neuraxial anesthesia, aortocaval compression, anesthetic overdose, vasodilators, and excessive positive pressure ventilation. Factors that increase uterine venous pressure include vena caval compression, uterine contractions, uterine hypertonus, oxytocin overstimulation, and α-adrenergic stimulation, through adrenergically mediated increases in uterine tone. Factors that increase uterine vascular resistance include endogenous catecholamines, untreated pain or noxious stimulation (laryngoscopy and intubation, skin incision), preeclampsia, chronic hypertension, and exogenous vasoconstrictors.
Ephedrine has been considered the drug of choice for treating maternal hypotension, largely on the basis of animal studies showing decreases in UBF despite increased maternal blood pressure after the administration of high doses of pure α-adrenergic agonists. This finding has been interpreted to indicate that uterine vascular resistance is increased to a greater extent than maternal blood pressure when these agents are used. However, later studies using low doses of phenylephrine (50–100 μg) show no evidence of any deleterious effect on fetal well-being. Furthermore, there is a growing body of evidence that fetal well-being is in fact improved when phenylephrine is used to treat maternal hypotension. , The reasons for this improvement are unclear, but it has been proposed that transplacental passage of ephedrine leads to increases in fetal metabolism, resulting in a perhaps clinically insignificant, but nevertheless measurable fetal metabolic acidosis when compared to phenylephrine.
Uteroplacental drug transfer and teratogenesis
A detailed consideration of the various mechanisms (active transport, facilitated diffusion, pinocytosis) by which substances are transported across the placenta is beyond the scope of this chapter. This discussion concentrates on passive diffusion, the mechanism by which most anesthetic drugs administered to the mother reach the fetus. This process does not require the expenditure of energy. Transfer can occur either directly through the lipid membrane or through protein channels that traverse the lipid bilayer.
Determinants of Passive Diffusion
Concentration gradient is the primary determinant of the rate of transfer of drugs across the placenta. As an example, the initial rate of transfer of an inhalation anesthetic is quite rapid. As the partial pressure of the drug increases in the fetus, the rate of transfer decreases. Substances that have a low molecular weight cross the placenta more readily than those that have a higher molecular weight. Drugs with high lipid solubility readily traverse the placenta. Ionization limits placental transfer. Membrane thickness can be increased in certain pathologic states, including chronic hypertension and diabetes. The effects of these conditions on drug transfer are of less concern than the resultant limitation of the transport of oxygen and nutrients, which can lead to intrauterine growth restriction or, in severe cases, fetal demise.
Specific Drugs
Inhalation anesthetics cross the placenta freely owing to their low molecular weight and high lipid solubility. The longer the period of fetal exposure to the drug (induction-to-delivery interval), the more likely the newborn is to be depressed.
The induction drugs thiopental, etomidate, and propofol are highly lipophilic and un-ionized at physiologic pH. Placental transfer is quite rapid. Because most of the blood returning to the fetus from the umbilical vein passes through the fetal liver, extensive first-pass metabolism occurs and neonatal depression after an induction dose of these drugs is uncommon. Both depolarizing and nondepolarizing muscle relaxants are highly ionized at physiologic pH; thus, placental transfer is minimal.
Opioid drugs freely traverse the placenta because of their high lipid solubility and low molecular weight.
The muscle relaxant reversal drugs neostigmine and edrophonium are highly ionized and demonstrate minimal placental transfer.
The anticholinergic drugs atropine and scopolamine freely pass the placenta. Glycopyrrolate is highly ionized and thus crosses the placenta to a minimal degree.
The commonly used anticoagulants heparin and warfarin have remarkably different placental transfer characteristics. Heparin, a highly ionized polysaccharide molecule, does not reach the fetus. Warfarin, which is uncharged and has a molecular weight of only 330, readily passes across the placenta. Because warfarin can cause birth defects, its use is contraindicated during the period of organogenesis (see later).
Of the antihypertensive drugs, all of the β-blocking drugs that have been studied cross the placenta. Labetalol, which is both effective for the mother and safe for the fetus, is the drug of choice for treatment of maternal hypertension. High-dose infusions of esmolol have been reported to cause persistent fetal bradycardia lasting up to 30 minutes after the termination of the infusion. The effect of a single dose is not known, but there are numerous case reports of its safe use as a bolus during anesthetic induction. Sodium nitroprusside (SNP) freely passes the placenta, a characteristic that has implications for fetal toxicity (see later).
Anesthesia during Pregnancy and the Risk of Birth Defects
Principles of Teratology
It is an established principle that any substance, if administered in large enough quantities for a prolonged period of time during critical periods of gestation, can produce fetal injury ranging from growth restriction to major structural anomalies to death. Thus, it should be a goal of anesthesiologists caring for pregnant women to minimize the fetal exposure to potentially toxic substances. Nevertheless, fears regarding the potential for injury should be tempered by the following considerations:
- •
Most anesthetics are administered for such a brief period that the potential for toxicity is minimal.
- •
There is no convincing human evidence that any commonly used anesthetic is dangerous to the fetus.
- •
Maternal hypotension and hypoxemia pose a much greater risk to the fetus than any of the anesthetic drugs.
- •
Maternal well-being must be a paramount concern. If avoiding a potentially teratogenic drug leads to poor maternal outcome or maternal death, fetal outcome will be equally compromised.
- •
Anesthetic neurotoxicity to the developing brain is of concern and the focus of ongoing research. 32
Evaluation of Teratogenic Potential
There are ethical and logistical difficulties inherent in large-scale prospective studies of the teratogenic effects of anesthetics in humans. Hence, there is more reliance on indirect evidence to evaluate the teratogenic potential of these drugs. The principal investigative tools used are small animal studies, retrospective studies of the offspring of women who received anesthesia during pregnancy, and, in the case of inhalation anesthetics, studies of operating room personnel who were exposed to low-level waste anesthetic gases during pregnancy. In the discussion of specific drugs that follows, reference is made to the studies supporting or opposing their teratogenic potential.
Specific Anesthetic Drugs
Animal studies of inhalation anesthetics have demonstrated conflicting results. , Their reproductive effects appear to be dose-related. These effects are more likely to come from the physiologic disturbances (hypothermia, hypoventilation, poor feeding) produced by the anesthetic state rather than the anesthetic drug itself. When animals are exposed to inspired concentrations of inhalational anesthetics that do not impair feeding behavior or level of consciousness, reproductive effects are minimal.
Nitrous oxide has clearly been shown to increase the incidence of structural abnormalities and fetal loss in rats; the timing of exposure appears to determine the extent of the effect. This effect was initially thought to be the result of inhibition of the enzyme methionine synthetase and subsequent decreases in the levels of methionine and tetrahydrofolate. The mechanism has been called into question, however, because maximal inhibition of methionine synthetase activity occurs at levels of anesthetic exposure that do not have teratogenic effects. Later evidence suggests that the fetal effects of nitrous oxide are from α-adrenergic stimulation and subsequent decreases in UBF. These effects can be reversed by the simultaneous administration of a potent inhalation drug. Studies of operating room personnel exposed to trace levels of nitrous oxide and of women receiving nitrous oxide anesthesia have not shown any teratogenic effect. The reader is referred to the detailed reviews by Burm and Weimann of the reproductive toxicology of nitrous oxide.
Muscle relaxants do not have any teratogenic effect at clinically appropriate doses. Opioids have not been shown to be teratogenic in either human or animal studies.
Several retrospective human studies have suggested that long-term benzodiazepine therapy during pregnancy increases the incidence of cleft lip and cleft palate. These studies have been faulted for failure to control for concomitant exposure to other potentially teratogenic substances. There is little evidence to suggest that a single dose of a benzodiazepine during pregnancy poses any risk to the fetus.
There is no human evidence suggesting that clinically useful local anesthetics are teratogenic. Chronic cocaine abuse has been linked to birth defects; this is likely to be secondary to its effects on uteroplacental perfusion.
Warfarin therapy during pregnancy has been correlated with ophthalmologic, skeletal, and central nervous system abnormalities, presumably from microhemorrhages during organogenesis. Because heparin does not cross the placenta, it is the drug of choice in women requiring anticoagulation during pregnancy.
In summary no anesthetic agents are documented teratogens in humans, including nitrous oxide and the benzodiazepines, but anesthetic neurotoxicity to the developing brain is of concern and the focus of ongoing research.
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