Respiratory System and Acid-Base Balance Changes

Alveolar ventilation increases by 30% or more by mid-pregnancy. This increase results in chronic respiratory alkalosis with a Pa co ₂ of 28 to 32 mm Hg, a slightly alkaline pH (approximately 7.44), and decreased levels of bicarbonate and buffer base. Although oxygen consumption is increased, Pa o ₂ usually increases only slightly or remains within the normal range. Functional residual capacity (FRC) diminishes by approximately 20% as the uterus expands, resulting in decreased oxygen reserve and the potential for airway closure. When FRC is decreased further (e.g., from morbid obesity; perioperative intra-abdominal distention; placement of the patient in the supine, Trendelenburg, or lithotomy position; or induction of anesthesia), airway closure may be sufficient to cause hypoxemia.

Weight gain during pregnancy and capillary engorgement of the respiratory tract mucosa lead to more frequent problems with mask ventilation and tracheal intubation (see Chapter 29 ). Difficult airway management and failed intubation (a leading cause of anesthesia-related maternal death) is as much a risk during early pregnancy with nonobstetric surgery as it is during cesarean delivery. In 2015, the Obstetric Anaesthetists’ Association and the Difficult Airway Society developed a difficult airway algorithm that was designed for the unique challenges of managing an obstetric patient, including considerations of the fetal status and urgency of a cesarean delivery; this algorithm is relevant to airway management for women with a viable fetus undergoing nonobstetric surgery (see Figs. 29.12 , 29.13 , 29.14 ).

Decreased FRC, increased oxygen consumption, and diminished buffering capacity result in the rapid development of hypoxemia and acidosis during periods of hypoventilation or apnea. Moreover, induction of inhalation anesthesia occurs more rapidly during pregnancy because alveolar hyperventilation and decreased FRC allow faster equilibration of inhaled agents. Combined with the reduction in the minimum alveolar concentration (MAC), subanesthetic concentrations of analgesic and anesthetic agents can induce unconsciousness quickly and unexpectedly in the pregnant woman.

Cardiovascular System Changes

Cardiac output increases by up to 50% during pregnancy because of increases in heart rate and stroke volume; diminished systemic and pulmonary vascular resistances occur from increased production of endothelial prostacyclin, relaxin, and nitric oxide. By 8 weeks’ gestation, 57% of the increase in cardiac output, 78% of the increase in stroke volume, and 90% of the decrease in systemic vascular resistance that are typically achieved by 24 weeks’ gestation have already occurred.

During the second half of gestation, compression of the inferior vena cava by the gravid uterus reduces venous return and cardiac output; in 10% of pregnant women, these effects can precipitate significant vasovagal symptoms and signs, which are collectively known as the “supine hypotension syndrome of pregnancy.” During mid-pregnancy, patient movement from the supine to the left lateral position reduces vena caval compression, resulting in a significant increase in left ventricular ejection fraction (8%), end-diastolic volume (25%), and stroke volume. By late pregnancy, the same patient movement results in even greater increases in these parameters; for example, cardiac output increases by up to 24%. In the supine position, pregnant women may maintain upper extremity blood pressure by compensatory vasoconstriction and tachycardia; however, these effects may be attenuated by neuraxial or general anesthesia. Moreover, uteroplacental blood flow and venous return can be compromised.

Although magnetic resonance imaging (MRI) studies of vena caval compression indicate virtually no compression with 30 degrees of left lateral tilt, most surgeries cannot be performed in this position. Therefore, after 18 to 20 weeks’ gestation, some degree of left lateral tilt should be applied, acknowledging that maternal or fetal hemodynamic instability may warrant a further increase in tilt, if necessary.

Vena caval compression can result in distention of the epidural venous plexus, which increases the likelihood of intravascular injection of local anesthetic during the administration of epidural anesthesia. The reduced capacity of the epidural space most likely contributes to the enhanced spread of epidural local anesthetic solution that is observed during pregnancy.

Changes in Blood Volume and Blood Constituents

Blood volume expansion begins as early as the first trimester and ultimately achieves a 30% to 45% increase by term gestation. The smaller increase in red blood cell than plasma volume results in dilutional anemia, allowing moderate blood loss to be well tolerated. However, when accompanied by anemia from other causes, a patient’s reserve during significant hemorrhage is decreased. The need for perioperative transfusions in pregnant women with iron-deficiency anemia is reduced by the intravenous administration of iron. Hemoglobin levels increase more rapidly (2 weeks) with intravenous compared with oral (greater than 6 weeks) iron therapy. Pregnancy is associated with benign leukocytosis; thus the white blood cell count is an unreliable indicator of infection. In general, pregnancy induces a hypercoagulable state, with increases in fibrinogen; factors VII, VIII, X, and XII; and fibrin degradation products.

Pregnancy is associated with enhancement of platelet turnover, clotting, and fibrinolysis; although a wide variation in the platelet count has been observed, functionally some pregnant women with thrombocytopenia may still be hypercoagulable. Pregnancy represents a state of accelerated but compensated intravascular coagulation. Given the high risk and mortality associated with thromboembolism, thromboprophylaxis management should be applied to pregnant surgical patients (see later discussion).

Gastrointestinal System Changes

Incompetence of the lower esophageal sphincter and distortion of gastric and pyloric anatomy during pregnancy increase the risk for gastroesophageal reflux, despite similar gastric emptying rates in pregnant and nonpregnant patients. It is unclear at what gestational age the risk for aspiration becomes significant; gastroesophageal reflex starts early in the first trimester, and other mechanically induced factors become more relevant later in pregnancy. Investigators have studied the feasibility of assessing gastric contents using ultrasonography. Further study is warranted to determine if assessing gastric contents before the induction of anesthesia can be used to inform anesthetic management and reduce the risk for aspiration. It seems prudent to consider the pregnant patient as having a higher risk for aspiration from the beginning of the second trimester.

Altered Responses to Anesthesia

A 30% to 40% decrease in the MAC of volatile anesthetic agents has been observed in pregnancy, correlating with higher serum progesterone levels. Although thiopental requirements begin to decrease in early pregnancy, the effects of pregnancy on propofol requirements are conflicting and appear unrelated to progesterone levels. Higuchi et al. determined that the median effective dose (ED ₅₀ ) of propofol required to achieved loss of consciousness was unchanged in pregnancy, whereas Mongardon et al. reported that lower propofol doses were required in early pregnancy compared with the nonpregnant state. The relatively high risk for intraoperative awareness (estimated risk 1 in 670 general anesthetics) observed during cesarean delivery is attributable, in part, to the need for rapid-sequence induction of general anesthesia, omission or reduction in analgesic (opioids) and anesthetic medications, and need for urgent surgery. These circumstances are also commonly encountered during nonobstetric surgery in pregnancy.

Plasma cholinesterase levels decrease by approximately 25% from early in pregnancy until the seventh postpartum day. However, prolonged neuromuscular blockade with succinylcholine is uncommon, because the larger volume available for drug distribution offsets the impact of decreased drug hydrolysis. The anesthesia provider should monitor all forms of neuromuscular blockade with a nerve stimulator to ensure adequate muscle relaxation as well as reversal before extubation of the trachea.

Decreased protein binding associated with lower albumin and alpha-glycoprotein concentrations during pregnancy may result in a larger fraction of unbound drug, with the potential for greater drug toxicity during pregnancy. Pregnancy-associated changes in volume of distribution (caused by changes in body composition and/or plasma protein–binding capacity), metabolic activity, and hepatic or renal elimination (caused by changes in glomerular filtration rate and tubular transport processes) may contribute to changes in drug effects and metabolism, including a higher initial loading dose of any given medication. For example, in pregnant women, cefazolin clearance is approximately twice as high between 20 and 40 weeks’ gestation and acetaminophen (paracetamol) clearance is increased, compared with nonpregnant women.

Pregnant surgical patients may require drugs for which limited pharmacokinetic and pharmacodynamic information during pregnancy is available; judicious use of such agents is advisable. In addition to the altered response to systemic drugs, more extensive neuraxial and peripheral neural blockade may occur in pregnant than nonpregnant patients (see Chapter 12 ). Pregnancy may be associated with lower 48-hour postsurgical analgesic drug consumption, but this decrease has not been consistently demonstrated across studies.

Risk for Teratogenicity

Although severe maternal hypoxia and hypotension pose the greatest risk to the fetus, considerable attention has focused on the role of anesthetic agents as abortifacients and teratogens. Teratogenicity has been defined as any significant postnatal change in function or form in an offspring after prenatal treatment. Concern about the potential harmful effects of anesthetic agents stems from their known effects on mammalian cells, which include reversible decreases in cell motility, prolongation of DNA synthesis, and inhibition of cell division. Despite these concerns, no data specifically link any of these cellular events with teratogenic changes. Unfortunately, prospective clinical studies of the teratogenic effects of anesthetic agents are impractical; such studies would require significant numbers of patients exposed to the drug being evaluated. Therefore, investigations of anesthetic agents have taken one of the following directions: (1) small animal studies of the reproductive effects of anesthetic agents, (2) epidemiologic surveys of operating room personnel routinely exposed to subanesthetic concentrations of inhalation agents, and (3) outcome studies in women who have undergone surgery while pregnant.

Principles of Teratogenicity

Like other toxicologic phenomena, a number of important factors influence the teratogenic potential of a substance, including species susceptibility, dose of the substance, duration and timing of exposure, and genetic predisposition ( Fig. 17.1 ). Most teratologists accept the principle that any agent can be teratogenic when given at a specific dose and time. A teratogen may cause malformations following the single administration of a high dose, or the long-term administration of a low dose; however, this does not mean that a single, short exposure of a “normal” dose (e.g., during a typical anesthetic) would incur similar risk. In addition, a small dose of a teratogen may cause an effect in susceptible early embryos, whereas a much larger dose in the fetus may prove harmless, as was shown with thalidomide. Finally, the results of studies performed predominantly in small animals (e.g., chick embryos, mice, rats) cannot necessarily be extrapolated to other species, especially humans. Only a very small minority of drugs or agents listed in catalogs of teratogenic agents are proven teratogens in humans, although many more have teratogenic effects in animals.

Toxic manifestations with increasing dosage of a teratogen. A no-effect range of dosage occurs below the threshold, at which embryotoxic effects abruptly appear. Teratogenesis and embryolethality often have similar thresholds and may increase at roughly parallel rates as dosage increases to a point at which all conceptuses are affected. Increasing dosage causes increased embryolethality, but teratogenicity appears to decrease, because many defective embryos die before term. A further increase in dosage reaches the maternal lethal range.

(Modified from Wilson JG. Environment and Birth Defects. New York: Academic Press; 1973:31.)

Manifestations of teratogenicity include death, structural abnormality, growth restriction, and functional deficiency. Depending on when it occurs, death is referred to as abortion, fetal death, or stillbirth in humans, and as fetal resorption in animals. Structural abnormalities can lead to death if they are severe, although death may occur in the absence of congenital anomalies. Growth restriction is a manifestation of teratogenesis and may relate to multiple factors, including placental insufficiency and genetic and environmental factors. Functional deficiencies include behavioral and learning abnormalities, the study of which is called behavioral teratology. The stage of gestation at which exposure occurs determines the target organs or tissues, the types of defects, and the severity of damage. Most structural abnormalities result from exposure during the period of organogenesis, which extends from approximately day 31 to day 71 after the first day of the last menstrual period. Fig. 17.2 shows the critical stages of development and the related susceptibility of different organs to teratogens. Functional deficiencies are usually associated with exposure during late pregnancy or even after birth because the human central nervous system (CNS) continues to mature until the second year of life.

Critical periods in human development. During the first 2 weeks of development, the embryo typically is not susceptible to teratogens. During these predifferentiation stages, a substance either damages all or most cells of the embryo, resulting in its death, or damages only a few cells, allowing the embryo to recover without development of defects. The dark bars denote highly sensitive periods, whereas the light bars indicate periods of lesser sensitivity. The ages shown refer to the actual ages of the embryo and fetus. Clinical estimates of gestational age represent intervals beginning with the first day of the last menstrual period. Because fertilization typically occurs 2 weeks after the first day of the last menstrual period, the reader should add 14 days to the ages shown here to convert to the estimated gestational ages that are used clinically.

(Redrawn from Moore KL. The Developing Human. 4th ed. Philadelphia: WB Saunders; 1993:156.)

Consideration of the possible teratogenicity of anesthetic agents must be viewed against the naturally high occurrence of adverse pregnancy outcomes. Roberts and Lowe estimated that as many as 80% of human conceptions are ultimately lost; many are lost even before pregnancy is recognized. The rates of spontaneous miscarriage from 5 to 20 weeks’ gestation range from 11% to 22%. The incidence of congenital anomalies among humans is approximately 3%, most of which are unexplained, and of these, only 1% are attributable to exposure to drugs and environmental toxins ( Table 17.1 ). There are several criteria for determining that an agent is a human teratogen, including the following: (1) proven exposure to the agent at the critical time of development; (2) consistent findings in two or more high-quality epidemiologic studies; (3) careful delineation of the clinical cases, ideally with the identification of a specific defect or syndrome; and (4) an association that “makes biological sense.” Documentation of teratogenicity in experimental animals is important but not essential. The agents or factors that are proven human teratogens do not include anesthetic agents (which are listed as “unlikely teratogens”) or any drug routinely used during the course of anesthesia ( Box 17.1 ) (see Chapter 14 ).

TABLE 17.1

Etiology of Human Developmental Abnormalities

Causes of Developmental Defects in Humans	Percentage
Genetic transmission	15–20
Chromosomal abnormality	5
Maternal condition	4
Maternal infection	3
Maternal metabolic imbalance	1–2
Drugs/chemicals/radiation	< 1
Unknown	65–70

 

Modified from Brent RL, Beckman DA. Environmental teratogens. Bull N Y Acad Med. 1990;66:123–163.

Box 17.1

Teratogenic Agents in Humans

Radiation

• 
  

  Atomic weapons, radioiodine, therapeutic uses

Infections

• 
  

  Cytomegalovirus, Herpesvirus hominis, parvovirus B19, rubella virus, syphilis, toxoplasmosis, Venezuelan equine encephalitis virus

Maternal Metabolic Imbalance

• 
  

  Alcoholism, cretinism, diabetes, folic acid deficiency, hyperthermia, phenylketonuria, rheumatic disease and congenital heart block, virilizing tumors

Drugs and Chemicals

• 
  

  Aminopterin and methylaminopterin, androgenic hormones, busulfan, captopril, chlorobiphenyls, cocaine, warfarin anticoagulants, cyclophosphamide, diethylstilbestrol, phenytoin, enalapril, etretinate, iodides (goiter), lithium, mercury (organic), methimazole (scalp defects), penicillamine, 13-cis-retinoic acid (Accutane), tetracyclines, thalidomide, trimethadione, valproic acid

Modified from Shepard TH, Lemire RJ. Catalog of Teratogenic Agents. 13th ed. Baltimore, MD: Johns Hopkins University Press; 2010.

Nondrug Factors Encountered in the Perioperative Period

Derangements of normal physiology.

Anesthesia and surgery can cause derangements of maternal physiology that may result in hypoxia, hypercapnia, stress, and abnormalities of temperature and carbohydrate metabolism. These states can increase oxidative stress and be teratogenic themselves, or they may enhance the teratogenicity of other agents.

Severe hypoglycemia and prolonged hypoxia and hypercarbia have caused congenital anomalies in laboratory animals, but there is no evidence to support teratogenicity after brief episodes in humans. Prolonged exposure to hyperglycemia is a known teratogen causing cardiac, CNS, and skeletal abnormalities, but any organ system can be affected. Anomalies are tightly linked with duration and degree of hyperglycemia, particularly in the first trimester, but it is unlikely that a brief period of intraoperative hyperglycemia has any teratogenic effects. Although severe hypoxemia causes structural teratogenesis in animals and humans, the chronic hypoxemia experienced by mothers at high altitudes results in the delivery of infants with lower birth weights but with no increase in the rate of congenital defects. Maternal stress and anxiety have been associated with poor fetal neurocognitive development (behavioral teratogenicity). Studies following obstetric outcomes in women in war zones demonstrate that maternal emotional trauma and posttraumatic stress disorder may affect fetal growth and increase the risk for miscarriage and hypertensive disorders of pregnancy, but these studies may be confounded by the lack of infrastructure to meet basic prenatal health care needs. Hypothermia is not teratogenic, whereas hyperthermia is teratogenic in both animals and humans. Congenital anomalies, especially involving the CNS, have repeatedly been associated with maternal fever during the first half of pregnancy. It must be remembered that fetal temperature is on average 0.5° C to 1° C higher than maternal temperature. Embryonic oxidative stress from reactive oxygen species has been implicated as one of the mechanisms involved in teratogenicity of many agents.

Diagnostic procedures.

Ionizing radiation is a human teratogen that can result in an increased, dose-related risk for malignant disease, genetic disease, congenital anomalies, and/or fetal death. The effects of radiation are often classified as being deterministic or stochastic . Deterministic effects are dose related and are observed above a certain threshold dose (e.g., pregnancy loss, growth restriction, mental retardation, organ malformation). In contrast, stochastic effects are possible at any level of exposure with no minimum threshold but with the likelihood of worsening effects at higher doses. An increased risk for childhood cancer is a stochastic effect when fetuses are exposed to ionizing radiation in utero .

Radiation is expressed as grays (Gy) or milligrays (mGy) (1 Gy = 100 rad) and is evaluated as cumulative dose (i.e., background radiation and medical diagnostic radiation) throughout the entire pregnancy. No dose of radiation is considered safe, but the type and severity of effects vary with the radiation exposure to the uterus and fetus and with the gestational age of the fetus ( Table 17.2 ). Background radiation during gestation is 1.3 to 5.8 mGy. There is no evidence that radiation exposure less than 50 mGy is associated with a teratogenic effect in either humans or animals. In contrast with the negligible risk for teratogenicity, observational studies suggest that there is a slightly higher risk for childhood cancer at radiation doses greater than or equal to 10 mGy. The relative risk for childhood malignancy after maternal abdominal radiation exposure has been estimated to be 2.28 (95% confidence interval, 1.31 to 3.97). The absorbed fetal dose for all conventional radiographic imaging inside or outside the abdomen and pelvis is negligible and is well below 50 mGy, with most falling under 5 mGy ( Table 17.3 ). However, direct radiographic examination using computed tomography or fluoroscopy of the abdomen and pelvis may result in significant fetal radiation exposure, with doses that may approach 100 mGy. Interventional radiologic procedures (e.g., cerebral angiography, cerebral embolization, endoscopic retrograde cholangiopancreatography) are frequently complex and prolonged, particularly when surgery is not an option. These procedures, especially the abdominal interventions, expose the fetus to a significant radiation dose, sometimes greater than 50 mGy; thus, professional societies have developed guidance for the use of these technologies during pregnancy ( Table 17.4 ).

TABLE 17.2

Radiation Exposure by Gestational Age and Outcomes

Radiation Dose (cGy)	Gestational Age	Fetal Effects
< 5	All stages	No fetal effects
10	< 8 weeks	Miscarriage
5–50	8–15 weeks	Growth restriction Mental retardation
5–50	16 weeks–birth	Increase childhood cancer (0.3%–6%)
> 50	16 weeks–birth > 25 weeks	Childhood cancer (> 6%) Death

 

Modified from Rimawi BH, Green V, Lindsay M. Fetal implications of diagnostic radiation exposure during pregnancy: evidence-based recommendations. Clin Obstet Gynecol. 2016;59:412–418.

TABLE 17.3

Fetal Radiation Exposure for Common Diagnostic Procedures

Procedure	Mean Exposure (mGy)	Maximum Exposure (mGy)
Conventional Radiographic Examination
Abdomen	1.4	4.2
Chest	< 0.01	< 0.01
Intravenous urogram	1.7	10
Lumbar spine	1.7	10
Pelvis	1.1	4
Skull	< 0.01	< 0.01
Thoracic spine	< 0.01	< 0.01
Fluoroscopic Examination
Barium meal (upper GI)	1.1	5.8
Barium enema	6.8	24
Computed Tomography
Abdomen	8.0	49
Head	0.06	0.96
Chest	< 0.005	< 0.005
Lumbar spine	2.4	8.6
Pelvis	25	79

 

GI, Gastrointestinal.

From Valentin J: Pregnancy and medical radiation. ICRP Publication 84. Ann ICRP . 2000;30:1–43.

TABLE 17.4

Estimated Fetal Radiation Exposure for Common Interventional Radiologic Procedures

Procedure	Estimate (mGy)	Range (mGy)
Cardiac catheter ablation	0.15–0.6 a
ERCP	3.1	0.01–55.9
TIPS creation	5.5
Pulmonary angiography	0.02–0.46
Uterine fibroid embolization	42
Cerebral angiography	0.06

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