Chestnut's Obstetric Anesthesia Principles and Practice PDF - Pregnancy Physiology

2 Physiologic Changes of Pregnancy Rachel M. Kacmar, MD, Robert Gaiser, MD CHAPTER OUTLINE Body Weight and Composition, 13 The Kidneys, 21 Cardio...

2 Physiologic Changes of Pregnancy Rachel M. Kacmar, MD, Robert Gaiser, MD CHAPTER OUTLINE Body Weight and Composition, 13 The Kidneys, 21 Cardiovascular Changes, 13 Hematology, 22 Physical Examination and Cardiac Studies, 13 Blood Volume, 22 Central Hemodynamics, 14 Plasma Proteins, 23 Blood Pressure and Systemic Vascular Resistance, 16 Coagulation, 23 Aortocaval Compression, 16 Hematology and Coagulation during the Puerperium, 24 Hemodynamic Changes during Labor and the The Immune System, 25 Puerperium, 17 Nonplacental Endocrinology, 25 The Respiratory System, 17 Thyroid Function, 25 Anatomy, 17 Glucose Metabolism, 25 Airflow Mechanics, 17 Adrenal Cortical Function, 25 Lung Volumes and Capacities, 18 The Musculoskeletal System, 26 Ventilation and Blood Gases, 18 The Nervous System, 26 Metabolism and Respiration during Labor and the Sleep, 26 Puerperium, 20 Central Nervous System, 27 The Gastrointestinal System, 20 Vertebral Column, 27 Anatomy, Barrier Pressure, and Gastroesophageal Sympathetic Nervous System, 27 Reflux, 20 Anesthetic Implications, 27 Gastrointestinal Motility, 20 Positioning, 27 Gastric Acid Secretion, 21 Blood Replacement, 27 Nausea and Vomiting, 21 General Anesthesia, 28 Gastric Function during Labor and the Puerperium, 21 Neuraxial Analgesia and Anesthesia, 29 The Liver and Gallbladder, 21 Marked anatomic and physiologic changes occur during increases in blood volume and interstitial fluid (approxi- pregnancy that allow the woman to adapt to the developing mately 1 kg each), and deposition of new fat and protein fetus and its metabolic demands. The enlarging gravid uterus (approximately 4 kg). The weight gain during pregnancy places mechanical strain on the woman’s body. Greater hor- recommended by the Institute of Medicine is tiered based on monal production by the ovaries and the placenta further prepregnancy body mass index (BMI; Table 2.1) and reflects alters maternal physiology. The hallmark of successful anes- the increasing incidence of obesity.2 The expected weight thetic management of the pregnant woman is recognition of increase during the first trimester in a nonobese individual these changes and appropriate adaptation of anesthetic tech- is 1 to 2 kg, and there is a 5- to 6-kg increase in each of the niques to account for them. The physiologic alterations of last two trimesters. The recommended gain is less in obese normal pregnancy and their anesthetic implications are individuals. Excessive weight gain during pregnancy is a risk reviewed in this chapter. factor for a long-term increase in BMI.3 BODY WEIGHT AND COMPOSITION CARDIOVASCULAR CHANGES The mean maternal weight increase during pregnancy is 17% Physical Examination and Cardiac Studies of the prepregnancy weight, or approximately 12 kg.1 It results Pregnancy causes the heart to increase in size, a result of both from an increase in the size of the uterus and its contents greater blood volume and increased stretch and force of con- (uterus, 1 kg; amniotic fluid, 1 kg; fetus and placenta, 4 kg), traction.4 These changes, coupled with the elevation of the 13 14 PART II Maternal and Fetal Physiology TABLE 2.1 Recommended Weight Gain implications for women with long QT syndrome (see Chapter during Pregnancy 41). The QRS axis shifts to the right during the first trimester but may shift to the left during the third trimester.10 Depressed Rate of Weight ST segments and isoelectric low-voltage T waves in the left- Prepregnancy Gain during Second sided precordial and limb leads are common.11 Body Mass Total Weight and Third Trimester Index (kg/m2) Gain in kg (lb) in kg/wk (lb/wk) Central Hemodynamics < 18.5 12.7–18.2 (28–40) 0.45 (1) To accurately determine central hemodynamic values and/ 18.5–24.9 11.4–15.9 (25–35) 0.45 (1) or changes during pregnancy, measurements should be made 25.0–29.9 6.8–11.4 (15–25) 0.27 (0.6) with the patient in a resting position with left uterine displace- ≥ 30 5.0–9.1 (11–20) 0.23 (0.5) ment to minimize vena caval compression. Comparisons must Modified from Rasmussen KM, Yaktine AL, eds. Weight Gain be made with an appropriate control, such as prepregnancy During Pregnancy: Reexamining the Guidelines. Washington, DC: values or a matched group of nonpregnant women. If control National Academies Press; 2009. measurements are made postpartum, a sufficient interval must elapse for parameters to have returned to prepregnancy BOX 2.1 Changes in the Cardiac values; this may take 24 weeks or more.12 There is significant Examination in the Pregnant Patient heterogeneity in cardiac output measurement using different Accentuation of first heart sound (S1) and exaggerated noninvasive devices; these differences should be taken into splitting of the mitral and tricuspid components account when caring for individual patients.13 Typical systolic ejection murmur Cardiac output begins to increase by five weeks’ gestation Possible presence of third heart sound (S3) and fourth and is 35% to 40% above baseline by the end of the first tri- heart sound (S4); no clinical significance mester.8,14 It continues increasing throughout the second tri- Leftward displacement of point of maximal cardiac impulse mester to approximately 50% greater than nonpregnant values (Figs. 2.1 and 2.2).8,12,15,16 Cardiac output does not diaphragm from the expanding uterus, cause several changes change further during the third trimester.17 Some studies in the physical examination and in cardiac studies. have reported a decrease in cardiac output during the third Changes in heart sounds include accentuation of the first trimester; however, typically this is with measurements made heart sound with exaggerated splitting of the mitral and in the supine position and thus likely reflects vena caval com- tricuspid components (Box 2.1).5 The second heart sound pression rather than a true gestational decline. changes little, although the aortic-pulmonic interval tends The initial increase in cardiac output results from an to vary less with respiration during the third trimester, a increase in heart rate.8 The heart rate increases 15% to 25% finding without clinical significance. A fourth heart sound above baseline by the end of the first trimester and remains may be heard in 16% of pregnant women, although typically relatively stable for the remainder of the pregnancy.8,12,14-16,18 it disappears at term. A grade II systolic ejection murmur is Cardiac output continues to increase through the second tri- commonly heard at the left sternal border6; the murmur is mester owing to an increase in stroke volume. Stroke volume considered a benign flow murmur, attributable to cardiac increases by approximately 20% during the first trimester and enlargement from increased intravascular volume, which by 25% to 30% above baseline during the second trimes- causes dilation of the tricuspid annulus and mild tricuspid ter.8,12,14,18 The increased stroke volume correlates with regurgitation. Elevation of the diaphragm by the growing increasing estrogen levels.1 Stroke volume index decreases uterus shifts the heart anteriorly and to the left. The point of over the course of pregnancy, while cardiac index remains maximal cardiac impulse is displaced cephalad to the fourth slightly increased from prepregnancy values.17 intercostal space and left to at least the midclavicular line. Left ventricular end-diastolic volume increases during Echocardiography demonstrates left ventricular (LV) pregnancy, whereas end-systolic volume remains unchanged, hypertrophy by 12 weeks’ gestation with a 23% increase in LV resulting in a larger ejection fraction.8,12,14,15,18 Central venous, mass from the first to the third trimester7 and an overall 50% pulmonary artery diastolic, and pulmonary capillary wedge increase in mass at term.8 This eccentric hypertrophy results pressures are within the normal nonpregnant range.16 The from an increase in the size of the preexisting cardiomyocytes, apparent discrepancy between left ventricular filling pressure resembling the changes that occur from repeated, strenuous and end-diastolic volume is explained by both hypertrophy exercise.1 The annular diameters of the mitral, tricuspid, and and dilation, with the dilated ventricle accommodating a pulmonic valves increase; 94% of term pregnant women greater volume without an increase in pressure. exhibit tricuspid and pulmonic regurgitation, and 27% Myocardial contractility increases, as demonstrated exhibit mitral regurgitation.9 The aortic annulus does not by higher velocity of left ventricular circumferential fiber dilate from normal pregnancy-induced physiologic changes. shortening (Fig. 2.3).8,15,18 Tissue Doppler imaging, which The electrocardiogram typically changes, especially during is relatively independent of preload, has been used to assess the third trimester. Heart rate steadily increases during the diastolic function.19 A mild degree of diastolic dysfunction first and second trimesters, and both the PR interval and the may be seen during the third trimester compared with earlier uncorrected QT interval are shortened. This has clinical in pregnancy and nonpregnant controls.17  CHAPTER 2 Physiologic Changes of Pregnancy 15 Fig. 2.1 Central Hemodynamic Changes at Term Gestation. Changes are relative to the nonpregnant state. CO, cardiac output; SV, stroke volume; HR, heart rate; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; EF, ejection fraction; LVSWI, left ventricular stroke work index; PCWP, pulmonary capillary wedge pres- sure; PADP, pulmonary artery diastolic pressure; CVP, central venous pressure; SVR, systemic vas- cular resistance; NC, no change. (Data from Conklin KA. Maternal physiological adaptations during gesta- CO SV HR LVEDV LVESV EF LVSWI PCWP PADP CVP SVR !50% !25% !25% NC NC NC NC NC "20% tion, labor, and puerperium. Semin Anesth. 1991;10: 221–234.) HR Hyperdynamic 150 SV 100 (% change from prepregnant) 125 80 Normal Cardiac output LVSWI (g m M–2) 100 75 60 Depressed 50 40 25 20 0 1s Ac 1 3r 2 2n 2n 2 La Im hr da d w t tiv d d te m 5 10 15 20 25 k ys nt e ed PCWP (mm Hg) Trimester Labor Postpartum Fig. 2.3 Left ventricular function in late phase of third-trimester nor- Fig. 2.2 Cardiac Output during Pregnancy, Labor, and the Puer- motensive pregnant patients. LVSWI, left ventricular stroke work perium. Values during pregnancy are measured at the end of the index; PCWP, pulmonary capillary wedge pressure. (Modified from first, second, and third trimesters. Values during labor are measured Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment between contractions. For each measurement, the relative contribu- of cardiac function. Am J Obstet Gynecol. 1989;161:439–442.) tions of heart rate (HR) and stroke volume (SV) to the change in cardiac output are illustrated. The increase in cardiac output during pregnancy results of moderate-intensity aerobic activity every week,26 and the in increased perfusion to the uterus, kidneys, and extremi- American College of Obstetricians and Gynecologists recom- ties. Uterine blood flow increases to meet the demands of mends 20 to 30 minutes per day27; however, most women do the developing fetus from a baseline value of approximately not achieve this goal. Pregnant women are less active, with 50 mL/min (prepregnancy) to a level at term of 700 to only half as many meeting guidelines for vigorous activity 900 mL/min.20–22 During the second half of pregnancy, the compared with nonpregnant women.28 For every two women proportion of cardiac output distributed to the uterine who exercise before pregnancy, one will not do so during circulation increases from 5% to 12%.23 Approximately 90% pregnancy. Failure to exercise increases risk for greater gesta- of this flow perfuses the intervillous space, with the balance tional weight gain.29 Exercise is safe for the fetus29,30; in a study perfusing the myometrium.21 At term, skin blood flow is of 45 women, exercise on a treadmill of moderate intensity approximately three to four times the nonpregnant level, (40% to 59% of heart rate reserve) did not affect fetal heart resulting in higher skin temperature.24 Renal plasma flow is or umbilical artery Doppler indices.30 increased by 80% at 16 to 26 weeks’ gestation but is only 50% During exercise, maximal oxygen consumption is greater above the prepregnancy baseline at term.25 in pregnancy,31 especially during cardiovascular exercise. The The U.S. Department of Health and Human Services rate of increase in minute ventilation is greater with exercise recommends that pregnant women have at least 150 minutes during pregnancy.32 Cardiac output is also greater, primarily 16 PART II Maternal and Fetal Physiology from increased stroke volume33 and oxygen delivery to the the intraosseous, vertebral, paravertebral, and epidural fetus. veins.44 However, this collateral venous return is less than would occur through the inferior vena cava, resulting in a Blood Pressure and Systemic decrease in right atrial pressure.45 Compression of the inferior Vascular Resistance vena cava occurs as early as 13 to 16 weeks’ gestation and is Positioning, gestational age, and parity affect blood pressure evident from the 50% increase in femoral venous pressure measurements. Brachial sphygmomanometry yields the observed when these women assume the supine position highest measurements in the supine position and the lowest (Fig. 2.4).46 By term, femoral venous and lower inferior vena measurements in the lateral position, especially with the cuff caval pressures are approximately 2.5 times the nonpregnant on the upper arm.34 Blood pressure increases with maternal measurements in the supine position.40,46 Vena cava volume at age, and for a given age, nulliparous women have a higher term is significantly higher with a 30-degree lateral tilt com- mean pressure than parous women.35 Systolic, diastolic, and pared with the supine position, whereas there is no difference mean blood pressure decrease during mid-pregnancy and between women in the supine position and those tilted return toward baseline as the pregnancy approaches term.36 15 degrees.43 Diastolic blood pressure decreases more than systolic blood In the supine position, the aorta may be compressed by the pressure, with early- to mid-gestational decreases of approxi- term gravid uterus. This compression could account for lower mately 20%.37 pressure in the femoral versus the brachial artery in the supine The changes in blood pressure are consistent with changes position.47,48 Angiographic studies in supine pregnant women in systemic vascular resistance, which decreases during early showed partial obstruction of the aorta at the level of the gestation, reaches its nadir (35% decline) at 20 weeks’ gesta- lumbar lordosis and enhanced compression during periods tion, and increases toward prepregnancy baseline during of maternal hypotension.49 Conversely, a comparison of late gestation. Unlike blood pressure, however, systemic magnetic resonance images of healthy women at term in the vascular resistance remains approximately 20% below the supine position compared with nonpregnant women showed nonpregnant level at term.12,16 A postulated explanation no difference in aortic volume at the level of the mid- to for the decreased systemic vascular resistance is the low- upper lumbar vertebra.43 resistance uteroplacental vascular bed as well as systemic At term, the left lateral decubitus position is associated maternal vasodilation caused by prostacyclin, estrogen, and with less enhancement of cardiac sympathetic nervous system progesterone. The lower blood pressure often persists beyond activity and less suppression of cardiac vagal activity than the pregnancy. A longitudinal study of 2304 initially normoten- supine or right lateral decubitus position.50 Women who sive women over 20 years showed that nulliparous women assume the supine position at term gestation experience a who subsequently delivered one or more infants maintained 10% to 20% decline in stroke volume and cardiac output,51,52 a blood pressure that was 1 to 2 mm Hg lower than women consistent with the decrease in right atrial filling pressure. who did not have children.37 This finding demonstrates Blood flow in the upper extremities is normal, whereas that pregnancy may create long-lasting vascular changes. uterine blood flow decreases by 20% and lower extremity Advanced maternal age has been associated with higher blood flow decreases by 50%.53 Perfusion of the uterus is less median systemic vascular resistance during pregnancy, and affected than that of the lower extremities because compres- pregnant women who smoke have demonstrated a lower sion of the vena cava does not obstruct venous outflow via the systemic vascular resistance compared with nonsmoking ovarian veins.54 The adverse hemodynamic effects of aortoca- parturients.38 val compression are reduced once the fetal head is engaged.47,48 The sitting position has also been shown to result in aortoca- Aortocaval Compression val compression, with a decrease in cardiac output of 10%.55 The extent of compression of the aorta and inferior vena Flexing the legs rotates the uterus to compress against the cava by the gravid uterus depends on positioning and ges- vena cava. Short intervals in the sitting position, such as tational age. At term, partial vena caval compression occurs occurs during epidural catheter placement, have no impact when the woman is in the lateral position, as documented on uteroplacental blood flow. by angiography.39 This finding is consistent with the 75% Some term pregnant women exhibit an increase in brach- elevation above baseline of femoral venous and lower ial artery blood pressure when they assume the supine posi- inferior vena cava pressures.40 Despite caval compression, tion, which is caused by higher systemic vascular resistance collateral circulation maintains venous return, as reflected from compression of the aorta. Up to 15% of women at term by the right ventricular filling pressure, which is unaltered experience bradycardia and a substantial decrease in blood in the lateral position.16 Intra-abdominal pressure is often pressure when supine, the so-called supine hypotension elevated in term pregnant patients regardless of BMI, syndrome.56 It may take several minutes for the brady- but is significantly lower in the lateral position compared cardia and hypotension to develop, and the bradycardia is with supine.41 usually preceded by a period of tachycardia. The syndrome In the supine position, significant and sometimes com- results from a profound decrease in venous return and plete compression of the inferior vena cava is evident at preload for which the cardiovascular system is not able term.42,43 Blood returns from the lower extremities through to compensate.  CHAPTER 2 Physiologic Changes of Pregnancy 17 32 30 Femoral Antecubital 28 26 24 Venous pressure (cm H2O) 22 20 18 16 14 12 10 8 6 4 2 Fig. 2.4 Femoral and antecubital venous pressures in the supine position throughout normal pregnancy 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 4 8 12 16 and the puerperium. (Modified from McLennan CE. Weeks of gestation Days Antecubital and femoral venous pressure in normal postpartum and toxemic pregnancy. Am J Obstet Gynecol. 1943; 45:568–591.) Hemodynamic Changes during Labor and Anatomy the Puerperium The thorax undergoes both mechanical and hormonal Cardiac output during labor (but between uterine contrac- changes during pregnancy. Relaxin (the hormone responsible tions) increases from prelabor values by approximately 10% for relaxation of the pelvic ligaments) causes relaxation of the in the early first stage, by 25% in the late first stage, and by ligamentous attachments to the lower ribs.64 The subcostal 40% in the second stage of labor.57–59 In the immediate post- angle progressively widens from approximately 69 to 104 partum period, cardiac output may be as much as 75% above degrees. The anteroposterior and transverse diameters of the predelivery measurements and 150% above prepregnancy chest wall each increase by 2 cm, resulting in an increase of 5 baseline.58 These changes result from an increase in stroke to 7 cm in the circumference of the lower rib cage. These volume caused by greater venous return and alterations in changes peak at 37 weeks’ gestation. The subcostal angle sympathetic nervous system activity. During labor, uterine remains about 20% wider than the baseline value after deliv- contractions displace 300 to 500 mL of blood from the inter- ery.65 The vertical measurement of the chest cavity decreases villous space through the ovarian venous outflow system into by as much as 4 cm as a result of the elevated position of the the central circulation (“autotransfusion”).60–62 The postpar- diaphragm. tum increase in cardiac output results from relief of vena Capillary engorgement of the larynx and the nasal and caval compression, diminished lower extremity venous pres- oropharyngeal mucosa begins early in the first trimester and sure, sustained myometrial contraction, and loss of the low- increases progressively throughout pregnancy.66 The effect of resistance placental circulation.59 Cardiac output decreases to estrogen on the nasal mucosa may cause symptoms of rhinitis just below prelabor values at 24 hours postpartum60 and and epistaxis. Nasal breathing commonly becomes difficult, returns to prepregnancy levels between 12 and 24 weeks and nasal congestion may contribute to the perceived short- postpartum12 (see Fig. 2.2). Heart rate decreases rapidly after ness of breath of pregnancy.67 delivery, reaches prepregnancy levels by 2 weeks postpartum, and is slightly below the prepregnancy rate for the next several Airflow Mechanics months.12,57 Other anatomic and functional changes of the Inspiration in the term pregnant woman is almost totally heart are also fully reversible.23,63 attributable to diaphragmatic excursion68 because of greater descent of the diaphragm from its elevated resting position and limitation of thoracic cage expansion because of its THE RESPIRATORY SYSTEM expanded resting position (Table 2.2). Both large- and small- Despite the multiple anatomic and physiologic changes that airway function are minimally altered during pregnancy. The occur during pregnancy, it is remarkable that pregnancy has a shape of flow-volume loops, the absolute flow rates at normal relatively minor impact on lung function. lung volumes,69 forced expiratory volume in 1 second (FEV1), 18 PART II Maternal and Fetal Physiology TABLE 2.2 Effects of Pregnancy on Percentage of predicted Respiratory Mechanics 110% FEV1 Parameter Changea 105% FVC Diaphragm excursion Increased 100% PEF Chest wall excursion Decreased 95% Pulmonary resistance Decreased 50% FEV1 No change 90% FEV1/FVC No change 85% Flow-volume loop No change First Second Third Closing capacity No change trimester trimester trimester FEV1, Forced expiratory volume in 1 second; FVC, forced vital Fig. 2.5 Changes in airflow mechanics during pregnancy. The magni- capacity. tude of the increase in flow rates is small. The forced expiratory a Relative to nonpregnant state. volume in one second (FEV1) is within the normal range of predictive Modified from Conklin KA. Maternal physiological adaptations during values for nonpregnant individuals. FVC, forced vital capacity; PEF, gestation, labor, and the puerperium. Semin Anesth. 1991;10:221– peak expiratory flow. (Based on data from Grindheim G, Toska K, 234. Estensen ME, Rosseland LA. Changes in pulmonary function during pregnancy: a longitudinal study. BJOG. 2012;119:94–101.) the ratio of FEV1 to forced vital capacity (FVC), and closing TABLE 2.3 Changes in Respiratory capacity are unchanged during pregnancy.70 There is no sig- Physiology at Term Gestation nificant change in respiratory muscle strength during preg- nancy despite the cephalad displacement of the diaphragm. Parameter Changea Furthermore, despite the upward displacement of the dia- Lung Volumes phragm by the gravid uterus, diaphragm excursion actually Inspiratory reserve volume +5% increases by 2 cm.71 Tidal volume +45% The peak expiratory flow (PEF) rate achieved with a Expiratory reserve volume −25% Residual volume −15% maximal effort after a maximal inspiration is often considered a surrogate for the FEV1 and can be used to monitor asthma Lung Capacities therapy. Studies of changes in PEF rate during pregnancy Inspiratory capacity +15% show conflicting results, likely reflecting differences in mea- Functional residual capacity −20% surement devices and patient position. Harirah et al.72 found Vital capacity No change that peak expiratory flow rate declined throughout gestation Total lung capacity −5% in all positions and that flow rates in the supine position were Ventilation lower than those during standing and sitting. The mean rate Minute ventilation +45% of decline was 0.65 L/min per week, and PEF rate remained Alveolar ventilation +45% below normal at 6 weeks postpartum. By contrast, Grindheim a et al.73 reported that PEF rate increased throughout preg- Relative to nonpregnant state. nancy starting at an average of 6.7 L/s in the early second tri- From Conklin KA. Maternal physiological adaptations during gestation, labor and the puerperium. Semin Anesth. 1991;10:221– mester and peaking at 7.2 L/s at term (Fig. 2.5). These authors 234. also reported that the FVC increased by 100 mL after 14 to 16 weeks’ gestation, with the change being greater in parous than in primigravid women.73 residual capacity (FRC) begins to decrease by the fifth month of pregnancy with uterine enlargement and diaphragm Lung Volumes and Capacities elevation, and is decreased by 400 to 700 mL to 80% of the Lung volumes can be measured using body plethysmography prepregnancy value at term.76,77 The overall reduction is or by inert gas techniques with slightly differing results.74 caused by a 25% reduction in expiratory reserve volume (200 By term, total lung capacity is slightly reduced,75 whereas to 300 mL) and a 15% reduction in residual volume (200 tidal volume increases by 45%, with approximately half the to 400 mL). Assumption of the supine position causes the change occurring during the first trimester (Table 2.3 and FRC to decrease further to 70% of the prepregnancy value. Fig. 2.6). The early change in tidal volume is associated with The supine FRC can be increased by 10% (approximately a transient reduction in inspiratory reserve volume. Residual 188 mL) by placing the patient in a 30-degree head-up volume tends to decrease slightly, a change that maintains position.78 vital capacity. Inspiratory capacity increases by 15% during the third trimester because of increases in tidal volume and Ventilation and Blood Gases inspiratory reserve volume.76,77 There is a corresponding During pregnancy, respiratory patterns remain relatively decrease in expiratory reserve volume.76,77 The functional unchanged. Minute ventilation increases via an increase in  CHAPTER 2 Physiologic Changes of Pregnancy 19 +5% +15% + No Change +45% -5% -25% -20% -2 -15% Fig. 2.6 Lung volumes and capacities during preg- nancy. ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capac- ity; IRV, inspiratory reserve volume; RV, residual volume; TLC, total lung capacity; TV, tidal volume; VC, vital capacity. TABLE 2.4 Blood Gas Parameters during Pregnancy TRIMESTER Parameter Nonpregnant First Second Third PaCO2 in mm Hg (kPa) 40 (5.3) 30 (4.0) 30 (4.0) 30 (4.0) PaO2 in mm Hg (kPa) 100 (13.3) 107 (14.3) 105 (14.0) 103 (13.7) pH 7.40 7.44 7.44 7.44 Bicarbonate (mEq/L) 24 21 20 20 tidal volume from 450 to 600 mL and a small increase in secondary to elevations in estrogen and progesterone levels.84 respiratory rate of 1 to 2 breaths/min.79 This occurs primar- This increase occurs despite blood and cerebrospinal fluid ily during the first 12 weeks of gestation with a minimal (CSF) alkalosis. increase thereafter. The ratio of total dead space to tidal During pregnancy, Pao2 increases to 100 to 105 mm Hg volume remains constant during pregnancy, resulting in an (13.3 to 14.0 kPa) as a result of greater alveolar ventila- increase in alveolar ventilation of 30% to 50% above baseline. tion and a decline in Paco2 (Table 2.4).85–87 As pregnancy The increase in minute ventilation results from hormonal progresses, oxygen consumption continues to increase, changes and from an increase in CO2 production at rest by and cardiac output increases to a lesser extent, resulting approximately 30% to 300 mL/min. The former is closely in a reduced mixed venous oxygen content and increased related to the blood level of progesterone,80 which acts as arteriovenous oxygen difference. After mid-gestation, preg- a direct respiratory stimulant. The progesterone-induced nant women in the supine position frequently have a Pao2 increase in chemosensitivity also results in a steeper slope and less than 100 mm Hg (13.3 kPa). This occurs because the FRC a leftward shift of the CO2-ventilatory response curve. This may be less than closing capacity, resulting in closure of small change occurs early in pregnancy and remains constant until airways during normal tidal volume ventilation.85 Moving a delivery.69 pregnant woman from the supine to the erect or lateral decu- Dyspnea is a common complaint during pregnancy, bitus position improves arterial oxygenation and reduces the affecting up to 75% of women.81 Contributing factors include alveolar-to-arterial oxygen gradient. The increased oxygen increased respiratory drive, decreased Paco2, increased tension facilitates the transfer of oxygen across the placenta oxygen consumption from the enlarging uterus and fetus, to the fetus. larger pulmonary blood volume, anemia, and nasal conges- Paco2 declines to approximately 30 mm Hg (4.0 kPa) tion. Dyspnea typically begins in the first or second trimester by 12 weeks’ gestation but does not change further during but improves as the pregnancy progresses. In a study in which the remainder of the pregnancy. Although a gradient exists 35 women were observed closely during pregnancy and between the end-tidal CO2 tension and Paco2 in nonpreg- postpartum, dyspnea was not caused by alterations in central nant women, the two measurements are equivalent during ventilatory control or respiratory mechanical factors but early pregnancy,88 at term gestation,89 and in the postpartum rather to the awareness of the increased ventilation.82 Exercise period.90 This is attributable to a reduction in alveolar has no effect on pregnancy-induced changes in ventilation dead space, which results from an increase in cardiac or alveolar gas exchange.83 The hypoxic ventilatory response output and increased basilar atelectasis during pregnancy. is increased during pregnancy to twice the normal level, The mixed venous Pco2 is 6 to 8 mm Hg (0.8 to 1.1 kPa) 20 PART II Maternal and Fetal Physiology TABLE 2.5 Changes in Gastrointestinal Physiology during Pregnancya TRIMESTER Parameter First Second Third Labor Postpartum (18 h) b Barrier pressure Decreased Decreased Decreased Decreased ? Gastric emptying No change No change No change Delayed No change Gastric acid secretion No change No change No change ? ? Proportion of women with No change No change No change Increased No change gastric volume > 25 mL Proportion of women with No change No change No change No change No change gastric pH < 2.5 a Relative to nonpregnant state. b Difference between intragastric pressure and tone of the lower esophageal high-pressure zone. below the nonpregnant level from late in the first trimester THE GASTROINTESTINAL SYSTEM until term.1 The respiratory alkalosis of pregnancy causes a compensa- Anatomy, Barrier Pressure, and tory increase in renal bicarbonate excretion and a reduction Gastroesophageal Reflux in serum bicarbonate concentration to approximately The stomach is displaced upward toward the left side of the 20 mEq/L, the base excess by 2 to 3 mEq/L, and the total diaphragm during pregnancy, and its axis is rotated approxi- buffer base by approximately 5 mEq/L.91 This compensation mately 45 degrees to the right from its normal vertical posi- is incomplete, as demonstrated by the elevation of venous,92 tion. This altered position displaces the intra-abdominal capillary,93 and arterial85 blood pH by 0.02 to 0.06 units (see segment of the esophagus into the thorax in most women, Table 2.4). The decrease in serum bicarbonate affects the causing a reduction in tone of the lower esophageal high- pregnant woman’s ability to buffer an acid load. The slight pressure zone (LEHPZ), which normally prevents the reflux respiratory alkalosis would normally shift the oxyhemoglobin of gastric contents. Progestins also may contribute to relax- saturation curve to the left, however a concurrent increase in ation of the LEHPZ.99 2,3-bisphosphoglycerate (2,3-BPG) causes the curve to shift Approximately 30% to 50% of women experience gas- slightly to the right. troesophageal reflux disease (GERD) during pregnancy.100 The prevalence of GERD is approximately 10% in the first Metabolism and Respiration during Labor and trimester, 40% in the second trimester, and 55% in the third the Puerperium trimester. In the first trimester of pregnancy, basal LEHPZ Minute ventilation in the unmedicated parturient increases pressure may not change, but the sphincter is less responsive by 70% to 140% in the first stage of labor and by 120% to physiologic stimuli that usually increase pressure.101 In to 200% in the second stage of labor compared with the second and third trimesters, LEHPZ pressure gradually prepregnancy values.94 Pain, anxiety, and coached breath- decreases to approximately 50% of basal values, reaching a ing techniques all increase minute ventilation. PaCO2 may nadir at 36 weeks’ gestation and returning to prepregnancy decrease to as low as 10 to 15 mm Hg (1.3 to 2.0 kPa). values at 1 to 4 weeks postpartum (Table 2.5). Risk factors Oxygen consumption increases above the prelabor value for GERD in pregnancy include gestational age, heartburn by 40% in the first stage and by 75% in the second stage, antecedent to pregnancy, and multiparity. Gravidity, pre- secondary to the increased metabolic demands of hyperven- pregnancy BMI, and weight gain during pregnancy do not tilation, uterine activity, and maternal expulsive efforts.94,95 correlate with the occurrence of reflux, whereas maternal age The maternal aerobic requirement for oxygen exceeds has an inverse correlation.102 oxygen consumption during labor, as is evident from the progressive elevation of blood lactate concentration, an Gastrointestinal Motility index of anaerobic metabolism.95–98 Effective neuraxial Gastric emptying is not altered during pregnancy. This has analgesia prevents these changes during the first stage of been demonstrated by studies that measured the absorption labor and mitigates the changes during the second stage of orally administered acetaminophen103–105 and by studies of labor.95,98 that assessed the emptying of a test beverage or meal by FRC increases after delivery but remains below the pre- radiographic,106 ultrasonographic,105,107 dye dilution,108 epi- pregnancy volume for 1 to 2 weeks. Although minute ventila- gastric impedance,109 and applied potential tomographic110 tion decreases halfway toward nonpregnant values by 72 techniques. In a study of morbidly obese women at term, no hours, oxygen consumption, tidal volume, and minute venti- difference was noted between gastric emptying of 300 mL lation remain elevated until at least 6 to 8 weeks after delivery. and 50 mL of water, suggesting that fasting guidelines should The alveolar and mixed venous Pco2 values increase slowly not differ for obese versus lean parturients.111 after delivery and are still slightly below prepregnancy levels Esophageal peristalsis and intestinal transit are slowed at 6 to 8 weeks postpartum.1 during pregnancy,107,112 which has been attributed to the  CHAPTER 2 Physiologic Changes of Pregnancy 21 inhibition of gastrointestinal contractile activity by proges- terone. However, this inhibition may be an indirect action THE LIVER AND GALLBLADDER that results from a negative effect of progesterone on the Liver size, morphology, and blood flow do not change during plasma concentration of motilin, which declines during pregnancy, although the liver is displaced upward, posterior, pregnancy.107 Up to 40% of women suffer from constipation and to the right during late pregnancy. at some time during their pregnancy.113 The prevalence of Serum levels of bilirubin, alanine aminotransferase, aspar- constipation is greatest in the first two trimesters of gestation tate aminotransferase, and lactate dehydrogenase increase to and declines in the third trimester. the upper limits of the normal range during pregnancy.129 The total alkaline phosphatase activity increases twofold to four- Gastric Acid Secretion fold, mostly from production by the placenta. Excretion of Early work suggested that both basal and maximal gastric sulfobromophthalein into bile decreases, whereas the hepatic acid secretion decline in mid-gestation, reaching a nadir at 20 extraction and retention of this compound increases.130 to 30 weeks’ gestation.114 Van Thiel et al.115 demonstrated no Biliary stasis and greater secretion of bile with cholesterol difference in basal or peak gastric acid secretion in four preg- increase the risk for gallbladder disease during pregnancy.131 nant women studied in each trimester and at 1 to 4 weeks The incidence of gallstones is 5% to 12% in pregnant postpartum, although a plasma gastrin level significantly women.132 One in 1600 to 1 in 10,000 women undergo lower than postpartum levels was observed during the first cholecystectomy during pregnancy. Progesterone inhibits the trimester. Levels of gastric pH and serum gastrin concentra- contractility of gastrointestinal smooth muscle, leading to tion were compared in 100 women scheduled for elective gallbladder hypomotility.133 The size of the total bile acid pool cesarean delivery and in 100 nonpregnant women undergo- increases by about 50% during pregnancy, and the relative ing gynecologic surgery.116 The mean pH was lower in the proportions of the various bile acids change.134 The changes pregnant group (2.4 versus 3.0), but serum gastrin levels were in the composition of bile revert rapidly after delivery, even in not different despite the fact that gastrin is secreted by the patients with gallstones. placenta from 15 weeks’ gestation onward. This may reflect a dilutional effect of increased plasma volume. Other studies have shown that approximately 80% of both pregnant and THE KIDNEYS nonpregnant women have a gastric pH of 2.5 or less, approxi- Owing to an increase in total intravascular volume, both renal mately 50% have gastric volumes of 25 mL or greater, and vascular and interstitial volume increase during pregnancy. 40% to 50% exhibit both low pH and gastric volume greater These increases are reflected in enlarged kidneys, with renal than 25 mL.117 volume increased by as much as 30%.135 Vasodilation of the kidneys contributes to the overall decline in systemic vascular Nausea and Vomiting resistance during the first trimester. The collecting system, Approximately 80% of pregnant women will experience including the renal calyces, pelvis, and ureters, dilates. Hydro- nausea and vomiting during pregnancy.118 The symptoms nephrosis may occur in 80% of women by mid-pregnancy.136 typically start between 4 to 9 weeks’ gestation and may last Both the glomerular filtration rate (GFR) and the renal until 12 to 16 weeks’ gestation.119 Of these women, 1% to 5% plasma flow increase markedly during pregnancy secondary will develop symptoms that persist throughout the pregnancy, to reduced renal vascular resistance.25 The renal blood flow is known as hyperemesis gravidarum (see Chapter 16). 75% greater than nonpregnant values by 16 weeks’ gestation and is maintained until 34 weeks, when a slight decline occurs. Gastric Function during Labor and the Puerperium By the end of the first trimester, the GFR is 50% greater than Gastric emptying is slowed during labor, as shown by ultra- baseline, and this rate is maintained until the end of preg- sonographic imaging, emptying of a test meal, and the rate of nancy. The GFR does not return to prepregnancy levels until absorption of oral acetaminophen.120,121 Direct measurements 3 months postpartum. Because the GFR does not increase as show that the mean gastric volume increases.122 However, rapidly or as much as the renal blood flow, the filtration frac- in one study, postpartum gastric volume was found to be tion decreases from nonpregnant levels until the third trimes- no different in parturients who consumed water in labor ter.137 The role of nitric oxide in the renal vasodilation was compared with those who consumed an isotonic sports tested and confirmed in a rat model.138 Renin and aldosterone drink composed of mixed carbohydrates and electrolytes.123 also both increase during pregnancy.139 Gastric acid secretion may decrease during labor because Creatinine clearance is increased to 150 to 200 mL/min only 25% of parturients who are in labor have a gastric pH from the normal baseline values of 120 mL/min.140 The of 2.5 or lower.124 Gastric emptying is also delayed during increase occurs early in pregnancy, reaches a maximum by the the early postpartum period but returns to prepregnancy end of the first trimester, decreases slightly near term, and levels by 18 hours postpartum.125 Fasting gastric volume returns to the prepregnancy level by 8 to 12 weeks postpar- and pH values are similar to nonpregnant patients at 18 tum.137 These renal hemodynamic alterations are among the hours postpartum.126–128 The effects of opioids and neuraxial earliest and most dramatic maternal adaptations to preg- analgesia on gastric emptying are discussed in Chapters 23 nancy. The increased GFR results in reduced blood concen- and 28. trations of nitrogenous metabolites. The blood urea nitrogen 22 PART II Maternal and Fetal Physiology concentration decreases to 8 to 9 mg/dL by the end of the first TABLE 2.6 Hematologic Parameters at trimester and remains at that level until term.140 Serum creati- Term Gestation nine concentration is a reflection of skeletal muscle produc- tion and urinary excretion. In pregnancy, skeletal muscle Changea or Actual production of creatinine remains relatively constant, but the Parameter Measurement GFR is increased, resulting in reduced serum creatinine con- Blood volume +45%a centration. The serum creatinine concentration decreases Plasma volume +55%a progressively to 0.5 to 0.6 mg/dL by the end of pregnancy. Red blood cell volume +30%a Hemoglobin concentration (g/dL) 11.6 The serum uric acid level declines in early pregnancy because Hematocrit 35.5% of the rise in GFR, to 2.0 to 3.0 mg/dL by 24 weeks’ gesta- tion.141 Subsequently, the uric acid level begins to increase, a Relative to nonpregnant state. reaching the prepregnancy level by the end of pregnancy. Modified from Conklin KA. Maternal physiological adaptations during gestation, labor, and puerperium. Semin Anesth. 1991;10:221–234. Tubular reabsorption of urate accounts for this restored uric acid level during the third trimester. Total protein excretion and urinary albumin excretion are 50 higher than nonpregnant levels. Average 24-hour total protein RBC and albumin excretion are 200 mg and 12 mg, respectively Plasma (% change from prepregnant) (upper limits are 300 mg and 20 mg, respectively).142,143 Pro- 40 teinuria (> 300 mg/24 h) has been described without the diagnosis of preeclampsia.144 However, women with isolated Blood volume 30 proteinuria are more likely to progress to preeclampsia than women with isolated hypertension. The protein-to-creatinine (P:C) ratio in a random urine sample correlates well with a 20 24-hour urine protein measurement, and a value of greater than 0.3 has been defined as the threshold for diagnosing preeclampsia.145 The degree of proteinuria in normal preg- 10 * nancy correlates with gestation. Baba et al.146 suggested that in normotensive patients, a P:C ratio of > 0.75 may be the 0 “rule-in” threshold for significant proteinuria.146 Women 1st 2nd 3rd 1 hr 1 wk 6 wk with twin pregnancies have greater protein excretion com- Trimester Postpartum pared with those with singleton pregnancies.147 Glucose is filtered and almost completely absorbed in the Fig. 2.7 Blood Volume during Pregnancy and the Puerperium. proximal tubule. In the nonpregnant state, a small amount of Values during pregnancy measured at the end of the first, second, glucose is excreted. Pregnancy imposes a change in the glucose and third trimesters. Postpartum values measured after a vaginal delivery. The values for red blood cell volume (RBC) and plasma resorptive capacity of the proximal tubules, so all pregnant volume (Plasma) do not represent the actual percentage of change in women exhibit an elevation of glucose excretion. Of pregnant these parameters but rather reflect the relative contribution of each women who have normal glucose tolerance to an oral load to the change in blood volume. The asterisk indicates that RBC and normal glucose excretion when not pregnant, approxi- volume is below the prepregnancy volume at the end of the first mately half will exhibit a doubling of glucose excretion. Most trimester. of the remainder have increases of 3 to 10 times the nonpreg- nant amount, and a small proportion (< 10%) excrete as 30% above the prepregnancy level at term.150,152,153 The red much as 20 times the nonpregnant amount.148 Overall, the blood cell volume increases in response to elevated erythro- amount of glucose excreted in the third trimester is several poietin concentration154 and the erythropoietic effects of times greater than that in the nonpregnant state. The normal progesterone, prolactin, and placental lactogen. The increase nonpregnant pattern of glucose excretion is reestablished in plasma volume exceeds the increase in red blood cell within 1 week after delivery. volume, resulting in the physiologic anemia of pregnancy. Hemoglobin concentration (hematocrit), which typically HEMATOLOGY ranges from 12.0 to 15.8 g/dL (35.4% to 44.4%) in the non- pregnant woman, decreases to 11.6 to 13.9 g/dL (31% to Blood Volume 41%) in the first trimester, 9.7 to 14.8 g/dL (30% to 39%) in Maternal plasma volume expansion begins as early as 6 weeks’ the second trimester, and 9.5 to 15.0 g/dL (28% to 40%) in gestation and continues until it reaches a net increase of the third trimester (Fig. 2.8).150,152,153,155 Women who do not approximately 50% by 34 weeks’ gestation (Table 2.6, Fig. receive iron supplements during pregnancy have greater 2.7).149–152 After 34 weeks’ gestation, the plasma volume stabi- decreases in hemoglobin concentration and hematocrit.152 lizes or decreases slightly. Red blood cell volume decreases The increase in plasma volume results from fetal and mater- during the first 8 weeks of pregnancy, increases to the pre- nal hormone production, and several systems may play a role. pregnancy level by 16 weeks, and undergoes a further rise to The maternal concentrations of estrogen and progesterone  CHAPTER 2 Physiologic Changes of Pregnancy 23 increase nearly 100-fold during pregnancy. Estrogens increase first trimester, 2.6–4.5 g/dL in the second trimester, and plasma renin activity, enhancing renal sodium absorption 2.3–4.2 g/dL in the third trimester (Table 2.7).155,158,159 The and water retention via the renin-angiotensin-aldosterone globulin level decreases by 10% in the first trimester and system. Fetal adrenal production of the estrogen precursor then increases throughout the remainder of pregnancy to dehydroepiandrosterone may be the underlying control 10% above the prepregnancy value at term.158 The albumin- mechanism. Progesterone also enhances aldosterone produc- globulin ratio decreases during pregnancy from 1.4 to 0.9, tion. These changes result in marked increases in plasma and the total plasma protein concentration decreases from renin activity and aldosterone level as well as in retention 7.8 to 7.0 g/dL.159 Maternal colloid osmotic pressure decreases of approximately 900 mEq of sodium and 7000 mL of total by approximately 5 mm Hg during pregnancy.16,160,161 The body water. The concentration of plasma adrenomedullin, a plasma cholinesterase concentration falls by approximately potent vasodilating peptide, increases during pregnancy and 25% during the first trimester and remains at that level until correlates significantly with blood volume.156 the end of pregnancy.162 Blood volume is positively correlated with the size of the fetus in singleton pregnancies and is greater in multiple gesta- Coagulation tions.151 The physiologic hypervolemia facilitates delivery of Pregnancy is associated with enhanced platelet turnover, nutrients to the fetus, protects the mother from hypotension, clotting, and fibrinolysis (Box 2.2). Thus, pregnancy repre- and reduces the risks associated with hemorrhage at deliv- sents a state of accelerated but compensated intravascular ery.153,157 The decrease in blood viscosity from the lower coagulation. hematocrit creates lower resistance to blood flow, which may be an essential component of maintaining the patency of the BOX 2.2 Changes in Coagulation and uteroplacental vascular bed. Fibrinolytic Parameters at Term Gestationa Increased Factor Concentrations Plasma Proteins Factor I (fibrinogen) Plasma albumin concentration decreases from a nonpreg- Factor VII (proconvertin) nant range of 4.1–5.3 g/dL to ranges of 3.1–5.1 g/dL in the Factor VIII (antihemophilic factor) Factor IX (Christmas factor) Factor X (Stuart-Prower factor) Percentage decrease from nonpregnant values Factor XII (Hageman factor) 0% Unchanged Factor Concentrations !5% Hemoglobin Factor II (prothrombin) Factor V (proaccelerin) !10% Hematocrit !15% Decreased Factor Concentrations Factor XI (thromboplastin antecedent) !20% Factor XIII (fibrin-stabilizing factor) !25% Other Parameters !30% Prothrombin time: shortened 20% !35% Partial thromboplastin time: shortened 20% First Second Third Thromboelastography: hypercoagulable trimester trimester trimester Fibrinopeptide A: increased Fig. 2.8 The Decrease in Both Hemoglobin Concentration and Antithrombin III: decreased Hematocrit during Pregnancy Underlies the Physiologic Anemia Platelet count: no change or decreased of Pregnancy. The decrease is greater for hematocrit, and the great- Fibrin degradation products: increased est decreases occur during the third trimester. (Based on data from Plasminogen: increased Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and Plasminogen activator inhibitor-II: increased laboratory studies: a reference table for clinicians. Obstet Gynecol. a 2009;114:1326–1331.) Relative to nonpregnant state. TABLE 2.7 Plasma Protein Values during Pregnancy TRIMESTER Protein Nonpregnant First Second Third Total protein (g/dL) 7.8 6.9 6.9 7.0 Albumin (g/dL) 4.5 3.9 3.6 3.3 Globulin (g/dL) 3.3 3.0 3.3 3.7 Albumin/globulin ratio 1.4 1.3 1.1 0.9 Plasma cholinesterase −25% −25% −25% Colloid osmotic pressure (mm Hg) 27 25 23 22 24 PART II Maternal and Fetal Physiology Increases in platelet factor 4 and beta-thromboglobulin signal elevated platelet activation, and the progressive increase in platelet distribution width and platelet volume are consistent with greater platelet consumption during pregnancy.163–165 Platelet aggregation in response to collagen, epinephrine, adenosine diphosphate, and arachidonic acid is increased.166 Some investigators have noted a decrease in platelet count,165,167 whereas others have noted no change,163,164 suggesting that increased platelet production compensates for greater activation. The platelet count usually decreases during the third trimester, with an estimated 8% of pregnant women having a platelet count less than 150,000/mm3 and 0.9% of Group I pregnant women having a platelet count less than 100,000/ Group II mm3.164,168 The most common causes of thrombocytopenia Group III are gestational thrombocytopenia, hypertensive disorders of pregnancy, and idiopathic thrombocytopenia. The decrease Fig. 2.9 Comparative thromboelastographs in nonpregnant (Group I), nonlaboring term pregnant (Group II), and laboring (Group III) women. in platelet count in the third trimester is caused by increased (From Steer PL, Krantz HB. Thromboelastrography and Sonoclot destruction and hemodilution.169 Gestational thrombocyto- analysis in the healthy parturient. J Clin Anesth. 1993;5:419–424.) penia is an exaggerated normal response. The concentrations of most coagulation factors, including fibrinogen (factor I), proconvertin (factor VII), antihe- mophilic factor (factor VIII), Christmas factor (factor IX), D-dimer values increase across gestation and remain higher Stuart-Prower factor (factor X), and Hageman factor (factor than prepregnancy values in the postpartum period.182,183 The XII), increase during pregnancy. The increase in factor marked elevation in the plasminogen concentration also is VIII is generally more marked in the third trimester. The consistent with enhanced fibrinolysis.184 concentrations of some factors increase by more than 100% (factors VII, VIII, IX, and fibrinogen).169–172 Prothrombin Hematology and Coagulation during (factor II) and proaccelerin (factor V) concentrations do the Puerperium not change, whereas the concentrations of thromboplastin Blood loss during normal vaginal delivery and the early puer- antecedent (factor XI) and fibrin-stabilizing factor (factor perium is approximately 600 mL.185 The normal physiologic XIII) decrease.171–173 An increase in most factor concentra- changes of pregnancy allow the healthy parturient to com- tions, shortening of the prothrombin time (PT) and activated pensate for this loss. However, blood loss after either vaginal partial thromboplastin time (aPTT),170 an increase in fibrino- or cesarean delivery is often underestimated, and the discrep- peptide A concentration, and a decrease in antithrombin III ancy between actual and estimated blood loss is greater with concentration suggest activation of the clotting system (PT increasing blood loss (see Chapter 37).186 decreases from a nonpregnant range of 12.7–15.4 seconds to Blood volume decreases to 125% of the prepregnancy level a range of 9.6–12.9 seconds in the third trimester, and aPTT during the first postpartum week,185 followed by a more decreases from a range of 26.3–39.4 seconds in nonpregnant gradual decline to 110% of the prepregnancy level at 6 to 9 women to a range of 24.7–35.0 seconds in the third trimes- weeks postpartum (see Fig. 2.7). The hemoglobin concentra- ter).174 Protein S activity decreases steadily during pregnancy, tion and hematocrit decrease during the first 3 days postpar- reaching the lowest values at delivery.175 tum, increase gradually during the next 3 days (because of a Thromboelastrography (TEG) demonstrates evidence of reduction in plasma volume), and continue to increase to hypercoagulability in pregnancy. These changes (decrease in prepregnancy measurements by 3 weeks postpartum.187 R and K values, increase in the α angle and maximum ampli- Cesarean delivery results in a blood loss of approximately tude [MA], and decrease in measures of lysis) are observed as 1000 mL within the first few hours of delivery.185 The hema- early as 10 to 12 weeks’ gestation and are even greater during tocrit in the immediate postpartum period is lower after labor (Fig. 2.9).176–178 Compared with samples taken during cesarean delivery than after vaginal delivery because of the labor, TEG has demonstrated increased lysis in the postpar- greater blood loss during cesarean delivery.185 tum period, possibly caused by the loss of placental expression Albumin and total protein concentrations and colloid of plasminogen activator inhibitor-2.179 In vitro, exogenous osmotic pressure decline after delivery and gradually return oxytocin decreases R and K values, while increasing the α to prepregnancy levels by 6 weeks postpartum.160 The plasma angle.180 The in vivo effects of exogenous oxytocin are not cholinesterase value decreases below the predelivery level by known. Rotational thromboelastometry (ROTEM) during the first postpartum day and remains at that decreased level pregnancy does not demonstrate significant changes from the during the next week.162 Globulin concentrations are elevated nonpregnant state compared with term parturients.181 throughout the first postpartum week.158 The greater concentration of fibrin degradation products Beginning with delivery and during the first postpartum signals increased fibrinolytic activity during gestation.163 day, there is a rapid decrease in the platelet count and in the  CHAPTER 2 Physiologic Changes of Pregnancy 25 concentrations of fibrinogen, factor VIII, and plasminogen women with a history of pregnancy have higher baseline IgE and an increase in antifibrinolytic activity.188 Clotting times and experience a slower decline in IgE levels as they age.197 remain shortened during the first postpartum day,189 and TEG remains consistent with a hypercoagulable state, NONPLACENTAL ENDOCRINOLOGY although lysis may increase.179,180 During the first 3 to 5 days postpartum, increases are noted in the fibrinogen concentra- Thyroid Function tion and platelet count, changes that may account for the The thyroid gland enlarges by 50% to 70% during pregnancy greater incidence of thrombotic complications during the because of follicular hyperplasia and greater vascularity. The puerperium.189 The coagulation profile returns to the non- estrogen-induced increase in thyroid-binding globulin results pregnant state by 2 weeks postpartum.188 in a 50% increase in total triiodothyronine (T3) and thyroxine (T4) concentrations during the first trimester, which are maintained until term.198 The concentrations of free T3 and THE IMMUNE SYSTEM T4 do not change. The concentration of thyroid-stimulating The blood leukocyte count increases progressively during hormone (TSH) decreases during the first trimester but pregnancy from the prepregnancy level of approximately returns to the nonpregnant level shortly thereafter and 6000/mm3 to between 9000 and 11,000/mm3.167 This change undergoes no further change during the remainder of preg- reflects an increase in the number of polymorphonuclear nancy. The fetal thyroid gland cannot produce thyroid cells, with the appearance of immature granulocytic forms hormone until the end of the first trimester and relies solely (myelocytes and metamyelocytes) in most pregnant women. on maternal T4 production during this critical time of devel- The proportion of immature forms decreases during the last opment and organogenesis. 2 months of pregnancy. The lymphocyte, eosinophil, and Approximately 4% to 7% of women of childbearing age basophil counts decrease, whereas the monocyte count does are either hypothyroid or at risk for hypothyroidism during not change. The leukocyte count increases to approximately pregnancy.199 Only 20% to 30% of affected women demon- 13,000/mm3 during labor and increases further to an average strate symptoms of hypothyroidism, likely because symptoms of 15,000/mm3 on the first postpartum day.187 By the sixth of hypothyroidism mimic features of pregnancy.200 In a large postpartum day, the leukocyte count decreases to an average study of 502,036 pregnant women, 15% of tested women had of 9250/mm3, although the count is still above normal at 6 gestational hypothyroidism, with 33% of these women weeks postpartum. demonstrating symptoms.201 Based on these results, many Despite an increased concentration, polymorphonuclear physicians advocate universal screening, which appears to be leukocyte function is impaired during pregnancy, as evi- cost-effective, given the risk for decreased intelligence in the denced by depressed neutrophil chemotaxis and adherence.190 offspring, miscarriage, and postpartum bleeding if hypothy- This impairment may account for the greater incidence of roidism is left untreated.202 infection during pregnancy and improved symptoms in some pregnant women with autoimmune diseases (e.g., rheuma- Glucose Metabolism toid arthritis). Levels of immunoglobulins A, G, and M are Mean blood glucose concentration remains within the normal unchanged during gestation, but humoral antibody titers to range during pregnancy, although the concentration may be certain viruses (e.g., herpes simplex, measles, influenza type lower in some women during the third trimester compared A) are decreased.191 with nonpregnant individuals.203 This finding is explained by During pregnancy, the uterine mucosa is characterized by the greater glucose demand of the fetus and the placenta. The a large number of maternal immune cells found in close relative hypoglycemic state results in fasting hypoinsulinemia. contact with the trophoblast. The fetal expression of paternal Pregnant women also exhibit exaggerated starvation ketosis. antigens requires adaptations in the maternal immune system Pregnant women are relatively insulin resistant because of so that the fetus is not perceived by the mother as “foreign.”192,193 hormones such as placental lactogen secreted by the pla- This “immune tolerance” occurs because of a lack of fetal centa.204 The blood glucose levels after a carbohydrate load antigen expression, because of separation of the mother from are greater in pregnant women than in nonpregnant women, the fetus, or from a functional suppression of the maternal despite a hyperinsulinemic response. These changes resolve lymphocytes.194 During the first trimester of pregnancy, T within 24 hours of delivery. lymphocytes express granulysin, a novel cytolytic protein that provides a protective role at the maternal-fetal interface.195 Adrenal Cortical Function Human T cells may be classified into T-helper cells types 1 The concentration of corticosteroid-binding globulin (CBG) and 2 (Th1 and Th2) on the basis of their cytokine produc- doubles during gestation as a result of an estrogen-induced tion. Successful pregnancy is associated with a predominant enhancement of hepatic synthesis.205 The elevated CBG value Th2 cytokine profile. Th1 cytokines are detrimental to preg- results in a 100% increase in the plasma cortisol concentra- nancy. These cells also produce natural antimicrobial agents tion at the end of the first trimester and a 200% increase at within the uterus, which are important for prevention of term. The concentration of unbound, metabolically active uterine infection during pregnancy.196 Maternal immuno- cortisol at the end of the third trimester is two and one-half globulin E (IgE) production increases with pregnancy, and times the nonpregnant level. The increase in free cortisol 26 PART II Maternal and Fetal Physiology results from greater production and reduced clearance. An increase in CBG concentration and a decrease in the serum albumin level affect the protein binding of corticosteroids. CBG binding capacity usually saturates at low concentrations of glucocorticoids. Clearance of betamethasone is greater during pregnancy, possibly because the drug is metabolized by placental enzymes.206 THE MUSCULOSKELETAL SYSTEM Back pain during pregnancy is common. In a cohort study of 200 consecutive women without back pain at the start of pregnancy, 19% complained of backache at 12 weeks’ gestation, and the incidence increased to 47% at 24 weeks’ gestation, peaking at 49% at 36 weeks’ gestation and declining to 9.4% after delivery.207 In another study that showed a relatively high prevalence of low back pain during pregnancy, only 32% of women reported this to their phy- sician and only 25% of providers recommended specific therapy.208 The etiology of the back pain is multifactorial (see Chapter 12 Weeks 24 Weeks 36 Weeks 47). One theory is that the enlarging uterus results in exagger- Fig. 2.10 Changes in Posture during Pregnancy. The first and the ated lumbar lordosis, placing mechanical strain on the lower subsequent dotted-line figures represent a woman’s posture before back. The hormonal changes of pregnancy may also play a growth of the uterus and its contents have affected the center of role. Relaxin, a polypeptide hormone of the insulin-like gravity. The second and third solid figures show that as the uterus enlarges and the abdomen protrudes, the lumbar lordosis is enhanced growth factor family, is associated with remodeling of colla- and the shoulders slump and move posteriorly. (Modified from Beck gen fibers and pelvic connective tissue, permitting the afore- AC, Rosenthal AH. Obstetrical Practice. Baltimore, MD: Williams & mentioned lordosis. The primary source of circulating relaxin Wilkins; 1955:146.) is the corpus luteum; the placenta is a secondary source. Serum relaxin level in early pregnancy is positively correlated with the presence of back pain.209 During pregnancy, gait also tunnel syndrome during pregnancy by changing the nature of changes and there is an increase in anterior tilt of the pelvis to the connective tissue so that more fluid is absorbed.214 maintain body stability,210 which may cause further stress on The human fetus requires approximately 30 g of calcium the vertebral column, leading to increased pain. for skeletal development by the time of term delivery.215 Women who have low back pain in pregnancy have a very Although intestinal absorption of calcium by the mother high risk for a new episode during a subsequent pregnancy.211 increases from as early as 12 weeks’ gestation to meet this In the majority of patients, low back pain during pregnancy increased demand, it is insufficient to meet fetal demand and responds to activity and postural modification. Exercises to thus the maternal skeleton undergoes calcium resorption.216 increase the strength of the abdominal and back muscles are This does not cause long-term changes in skeletal calcium helpful. Scheduled rest periods with elevation of the feet to content or strength. Pregnant women with a twin gestation flex the hips and decrease the lumbar lordosis help relieve have a much higher calcium requirement. Compared with muscle spasm and pain.212 singleton pregnancies, there is a larger increase in maternal The enhancement of the lumbar lordosis during preg- bone resorption in twin gestation.217 nancy alters the center of gravity over the lower extremities (Fig. 2.10) and may lead to other mechanical problems. Exag- THE NERVOUS SYSTEM gerated lumbar lordosis tends to stretch the lateral femoral cutaneous nerve, possibly resulting in meralgia paresthetica, Sleep with paresthesia or sensory loss over the anterolateral thigh. Sleep disturbances from mechanical and hormonal factors Anterior flexion of the neck and slumping of the shoulders occur commonly during pregnancy. Latency and duration of usually accompany the enhanced lordosis, sometimes leading rapid eye movement (REM) sleep are influenced by changes to a brachial plexus neuropathy. in progesterone and estrogen concentrations. Pregnant Mobility of the sacroiliac, sacrococcygeal, and pubic joints women have more complaints of insomnia and daytime increases during pregnancy in preparation for passage of the sleepiness. The American Academy of Sleep Medicine defined fetus. A widening of the pubic symphysis is evident by 30 pregnancy-associated sleep disorder as the occurrence of weeks’ gestation. These changes are attributable to relaxin and insomnia or excessive sleepiness that develops in the course of the biomechanical strain of pregnancy on the ligaments.213 pregnancy.218 In a cohort study of 189 healthy nulliparous Relaxin may also contribute to the greater incidence of carpal women, Facco et al. reported that mean (± SD) sleep duration  CHAPTER 2 Physiologic Changes of Pregnancy 27 Cerebral blood flow and CSF of parturients,226 and opioid antagonists abolish 60 pregnancy-induced analgesia to visceral stimulation in (mL/min/100 g of brain) experimental animals.227 50 Cerebral blood flow 40 Vertebral Column 30 Anatomic and mechanical changes occur to the vertebral column during pregnancy. The epidural space can be regarded 20 as a rigid tube that contains two fluid-filled distensible tubes, 10 the dural sac and the epidural veins. The volume of epidural 0 fat and the epidural venous plexus enlarge during pregnancy, Nonpregnant First Second Third and spinal CSF volume is reduced.42 trimester trimester trimester In the lateral position, lumbar epidural pressure is positive Fig. 2.11 Cerebral Blood Flow during Pregnancy. Cerebral blood in term pregnant women but negative in more than 90% of flow increases as pregnancy progresses and is attributable to nonpregnant women.228 Turning a parturient from the lateral vasodilation from the hormonal changes of pregnancy. This increase to the supine position increases the epidural pressure. Epi- in cerebral blood flow explains the increased risk for complications in patients with intracranial pathology as pregnancy progresses. (Based dural pressure also increases during labor because of increased on data from Nevo O, Soustiel JF, Thaler I. Maternal cerebral blood diversion of venous blood through the vertebral plexus sec- flow during normal pregnancy: a cross-sectional study. Am J Obstet ondary to either enhanced compression of the inferior vena Gynecol. 2010;203:475.e1–6.) cava in the supine position or greater intra-abdominal pres- sure during pain and pushing. The epidural pressure returns to the nonpregnant level by 6 to 12 hours postpartum. was shorter in the third trimester (7.0 ± 1.2 hours) compared Despite compression of the dural sac by the epidural veins, with the baseline period between 6 and 20 weeks’ gestation the CSF pressure in pregnant women is the same as in non- (7.4 ± 1.2 hours).219 pregnant women.229 Uterine contractions and pushing during Sleep characteristics change as pregnancy progresses.220 labor result in an increase in CSF pressure that is secondary to Early pregnancy is characterized by increased total sleep time acute increases in epidural vein distention. and decreased stage 3 and 4 non-REM sleep, whereas late pregnancy is characterized by decreased total sleep time, Sympathetic Nervous System increased waking after sleep onset, and decreased REM Dependence on the sympathetic nervous system for mainte- sleep.220 Sleep may be poor for up to 3 months postpartum.221 nance of hemodynamic stabilit