Maternal Physiology: Body Water Metabolism

CHAPTER 3

Maternal Physiology
Michael C. Gordon

Body Water Metabolism

42

Osmoregulation 43
Salt Metabolism 43
Renin-Angiotensin-Aldosterone System 43
Atrial and Brain Natriuretic Peptide 44

Cardiovascular System

44

Heart 44
Cardiac Output 45
Arterial Blood Pressure and Systemic
Vascular Resistance 46
Venous Pressure 47
Central Hemodynamic Assessment 47
Normal Changes That Mimic Heart
Disease 47
Effect of Labor and the Immediate
Puerperium 48

Respiratory System

49

Upper Respiratory Tract 49

Mechanical Changes 49
Lung Volume and Pulmonary Function 49
Gas Exchange 50
Sleep 51

Hematologic Changes

Urinary System

42

54

Anatomic Changes 54
Renal Hemodynamics 54
Renal Tubular Function/Excretion of Nutrients
55

Alimentary Tract
Appetite 56

KEY ABBREVIATIONS
Adrenocorticotropic Hormone
Arginine Vasopressin
Blood Urea Nitrogen
Brain Natriuretic Peptide
Carbon Dioxide
Cardiac Output
Colloidal Oncotic Pressure
Corticotropin-Releasing Hormone
Forced Expiratory Volume in
1 Second
Functional Residual Capacity
Glomerular Filtration Rate
Human Chorionic Gonadotropin
Human Placenta Lactogen
Mean Arterial Pressure
Parathyroid Hormone
Pulmonary Capillary Wedge
Pressures
Rapid Eye Movement
Renin-Angiotensin-Aldosterone
System
Stroke Volume
Systemic Vascular Resistance
Thyroid-Stimulating Hormone
Thyroxine-Binding Globulin
Total Thyroxine
Total Triiodothyronine

51

Plasma Volume and Red Blood Cell
Mass 51
Iron Metabolism in Pregnancy 52
Platelets 53
Leukocytes 53
Coagulation System 54

ACTH
AVP
BUN
BNP
CO2
CO
COP
CRH
FEV1
FRC
GFR hCG hPL
MAP
PTH
PCWPs
REM
RAAS
SV
SVR
TSH
TBG
TT4
TT3

56

Mouth 56
Stomach 56
Intestines 57
Gallbladder 57
Liver 57
Nausea and Vomiting of Pregnancy 57

Skeleton

58

Calcium Metabolism 58
Skeletal and Postural Changes 59

Endocrine Changes
Thyroid 59
Adrenal Glands 61
Pituitary Gland 62

59

Pancreas and Fuel Metabolism
Glucose 62
Proteins and Fats/Lipids 62

Eye

62

62

Major adaptations in maternal anatomy, physiology, and metabolism are required for a successful pregnancy. Hormonal changes, initiated before conception, significantly alter maternal physiology and persist through both pregnancy and the initial postpartum period. Although these adaptations are profound and affect nearly every organ system, women return to the nongravid state with minimal residual changes.1 A full understanding of physiologic changes is necessary to differentiate between normal alternations and those that are abnormal. This chapter describes maternal adaptations in pregnancy and gives specific examples of how they may affect care. Finally, although women may tire of repetitive reassurance that “it is simply normal and of no concern,” a complete understanding of physiologic changes allows each obstetrician to provide a more thorough explanation for various changes and symptoms. Many of the changes to routine laboratory values caused by pregnancy are described in the following text. For a comprehensive review of normal reference ranges for common laboratory tests by trimester, the reader is encouraged to refer to Appendix A1.

BODY WATER METABOLISM

The increase in total body water of 6.5 to 8.5 L by the end of gestation represents one of the most significant adap­ tations of pregnancy. The water content of the fetus, placenta, and amniotic fluid at term accounts for about 3.5 L.
Additional water is accounted for by expansion of the

Chapter 3 Maternal Physiology 43
142
140
PNa (mmol/L)

maternal blood volume by 1500 to 1600 mL, plasma volume by 1200 to 1300 mL, and red blood cells by 300 to 400 mL.
The remainder is attributed to extravascular fluid, intracellular fluid in the uterus and breasts, and expanded adipose tissue. As a result, pregnancy is a condition of chronic volume overload with active sodium and water retention secondary to changes in osmoregulation and the reninangiotensin system. Increase in body water content contributes to maternal weight gain, hemodilution, physiologic anemia of pregnancy, and the elevation in maternal cardiac output (CO). Inadequate plasma volume expansion has been associated with increased risks for preeclampsia and fetal growth restriction.

Salt Metabolism

Sodium metabolism is delicately balanced, facilitating a net accumulation of about 900 mEq of sodium. Sixty percent of the additional sodium is contained within the fetoplacental unit (including amniotic fluid) and is lost at birth. By 2 months postpartum, the serum sodium returns to preconceptional levels. Pregnancy increases the preference for sodium intake, but the primary mechanism

136
134
300

Osmoregulation

296
292
Posm (mOsm/kg)

Expansion in plasma volume begins shortly after conception, partially mediated by a change in maternal osmoregulation through altered secretion of arginine vasopressin
(AVP) by the posterior pituitary. Water retention exceeds sodium retention; even though an additional 900 mEq of sodium is retained during pregnancy, serum levels of sodium decrease by 3 to 4 mmol/L. This is mirrored by decreases in overall plasma osmolality of 8 to 10 mOsm/ kg, a change that is in place by 10 weeks’ gestation and continues through 1 to 2 weeks postpartum2 (Figure 3-1).
Similarly, the threshold for thirst and vasopressin release changes early in pregnancy; during gestational weeks 5 to
8, an increase in water intake occurs and results in a transient increase in urinary volume but a net increase in total body water. Initial changes in AVP regulation may be due to placental signals involving nitric oxide (NO) and the hormone relaxin.3 After 8 weeks’ gestation, the new steady state for osmolality has been established with little subsequent change in water turnover, resulting in decreased polyuria. Pregnant women perceive fluid challenges or dehydration normally with changes in thirst and AVP secre­ tion, but at a new, lower “osmostat.”3
Plasma levels of AVP remain relatively unchanged despite heightened production, owing to a threefold to fourfold increase in the metabolic clearance. Increased clearance results from a circulating vasopressinase syn­ thesized by the placenta that rapidly inactivates both
AVP and oxytocin. This enzyme increases about 300-fold to 1000-fold over the course of gestation proportional to fetal weight, with the highest concentrations occurring in multiple gestations. Increased AVP clearance can unmask subclinical forms of diabetes insipidus, presum­ ably because of an insufficient pituitary AVP reserve, and causes transient diabetes insipidus with an incidence of 2 to 6 per 1000. Typically presenting with both polydipsia and polyuria, hyperosmolality is usually mild unless the thirst mechanism is abnormal or access to water is limited.4 138

288
284
280
276
272
MP

MP

LMP

4

8

12

16

Weeks of pregnancy
FIGURE 3-1. Plasma osmolality and plasma sodium during human gestation (n = 9: mean values ± SD). LMP, Last menstrual period; MP, menstrual period. (From Davison JM, Vallotton MB, Lindheimer MD:
Plasma osmolality and urinary concentration and dilution during and after pregnancy: Evidence that the lateral recumbency inhibits maximal urinary concentration ability. Br J Obstet Gynecol 88:472,
1981.)

is enhanced tubular sodium reabsorption. Increased glomerular filtration raises the total filtered sodium load from
20,000 to about 30,000 mmol/day; sodium reabsorption must increase to prevent sodium loss. However, the adaptive rise in tubular reabsorption surpasses the increase in filtered load, resulting in an additional 2 to 6 mEq of sodium reabsorption per day. Alterations in sodium handling represent the largest renal adjustment that occurs in gestation.5 Hormonal control of sodium balance is under the opposing actions of the renin-angiotensin-aldosterone system (RAAS) and the natriuretic peptides, and both are modified during pregnancy.

Renin-Angiotensin-Aldosterone System

Normal pregnancy is characterized by a marked increase in all components of the RAAS system. In early pregnancy, reduced systemic vascular tone (attributed to gestational hormones and increased NO production) results in decreased mean arterial pressure (MAP). In turn, decreased

44 Section I Physiology
MAP activates adaptations to preserve intravascular volume through sodium retention.6 Plasma renin activity, renin substrate (angiotensinogen), and angiotensin levels are all increased a minimum of fourfold to fivefold over nonpregnant levels. Activation of these components of RAAS leads to twofold elevated levels of aldosterone by the third trimester, increasing sodium reabsorption and preventing sodium loss. Despite the elevated aldosterone levels in late pregnancy, normal homeostatic responses still occur to changes in salt balance, fluid loss, and postural stimuli. In addition to aldosterone, other hormones that may contribute to increased tubular sodium retention include deoxycorticosterone and estrogen.

Atrial and Brain Natriuretic Peptide

The myocardium releases neuropeptides that serve to maintain circulatory homeostasis. Atrial natriuretic peptide
(ANP) is secreted primarily by the atrial myocytes in response to dilation, and in response to end-diastolic pressure and volume, the ventricles secrete brain natriuretic peptide (BNP). Both peptides have similar physiologic actions, acting as diuretics, natriuretics, vasorelaxants, and overall antagonists to the RAAS. Elevated levels of ANP and BNP are found in both physiologic and pathologic conditions of volume overload and can be used to screen for congestive heart failure outside of pregnancy in symptomatic patients. Because pregnant women frequently present with dyspnea and many of the physiologic effects of conception mimic heart disease, whether pregnancy affects the levels of these hormones is clinically important.
Gestational alterations in ANP are controversial because some authors have reported higher plasma levels during different stages of pregnancy, whereas others have reported no change. In a meta-analysis by Castro and colleagues,7
ANP levels were 40% higher during gestation and 150% higher during the first postpartum week.
The circulating concentration of BNP is 20% less than that of ANP in normal individuals and has been found to be more useful in the diagnosis of congestive heart failure. Levels of BNP are reported to increase largely in the third trimester of pregnancy compared with firsttrimester levels (21.5 ± 8 pg/mL versus 15.2 ± 5 pg/mL) and are highest in pregnancies complicated by preeclampsia (37.1 ± 10 pg/mL). The levels throughout pregnancy have been found to be higher than in nonpregnant controls. In pregnancies with preeclampsia, higher levels of
BNP are associated with echocardiographic evidence of left ventricular enlargement.8 Although the levels of BNP are increased during pregnancy and with preeclampsia, the mean values are still lower than the levels used to screen for cardiac dysfunction (>75 to 100 pg/mL) and, therefore, can be used to screen for congestive heart failure.9

CARDIOVASCULAR SYSTEM

Pregnancy causes profound physiologic changes in the cardiovascular system. A series of adaptive mechanisms are activated as early as 5 weeks’ gestation to maximize oxygen delivery to maternal and fetal tissues.6 In most women, these physiologic demands are well tolerated.
However, in certain cardiac diseases, maternal morbidity and even mortality may occur.

Heart

The combination of displacement of the diaphragm and the effect of pregnancy on the shape of the rib cage
(described in the respiratory section below) displaces the heart upward and to the left. In addition, the heart rotates on its long axis, moving the apex somewhat laterally, resulting in an increased cardiac silhouette on radiographic studies, without a true change in the cardiothoracic ratio.
Associated radiographic findings include an apparent straightening of the border of the left side of the heart and increased prominence of the pulmonary conus. Therefore, the diagnosis of cardiomegaly by simple radiography should be confirmed by echocardiogram if clinically appropriate.10
Although true cardiomegaly is rare, physiologic myocardial hypertrophy of the heart is consistently observed as a result of expanded blood volume in the first half of the pregnancy and progressively increasing afterload in later gestation. These structural changes in the heart are similar to those found in response to exercise and result in
eccentric hypertrophy as opposed to concentric hypertrophy that is seen with disease states such as hypertension or aortic stenosis. The eccentric hypertrophy enables the heart to enhance its pumping capacity in response to increased demand, making the pregnant heart mechanically more efficient.11,12 Most changes begin early in the first trimester and peak by 30 to 34 weeks’ gestation. Left ventricular end-diastolic dimension increases 12% over preconceptional values by M-mode echocardiography. Concurrently, left ventricular wall mass increases by 52% (mild myocardial hypertrophy), and atrial diameters increase bilaterally, peaking at 40% above nonpregnant values.12 Pulmonary capillary wedge pressures (PCWPs) are stable, reflecting a combination of decreased pulmonary vascular resistance and increased blood volume. Twin pregnancies increase myocardial hypertrophy, atrial dilation, and end-diastolic ventricular measurements even further.13 Unlike the heart of an athlete that regresses rapidly with inactivity, the pregnant heart regresses in size less rapidly and takes up to 6 months to return to normal.14
Evaluation of left ventricular function (contractility) is difficult in pregnancy because it is strongly influenced by changes in heart rate (HR), preload, and afterload. Despite the increase in stroke volume (SV) and CO, normal pregnancy is not associated with hyperdynamic left ventricular function during the third trimester, as measured by ejection fraction, left ventricular stroke work index, or fractional shortening of the left ventricle. However, some studies have shown that contractility might be slightly increased in the first two trimesters, whereas other articles report no change throughout the pregnancy, and some report a decline toward term.12 One recent study showed that in the third trimester the cardiac systolic function declines as evidenced by a decrease in the ejection fraction and the systolic myocardial velocities compared with the first trimester. The results of this study are consistent with impaired contraction and relaxation of the left ventricle at the end of pregnancy and suggest that a decline in cardiac function at term is a feature of normal pregnancy and that an exaggeration of this decline may explain the etiology for peripartum cardiomyopathy.15
Within the past decade, clinicians and researchers have focused on abnormalities of diastolic function as important

Chapter 3 Maternal Physiology 45

Cardiac output (L/min)

8

6

5

P-P

5

8

12 16

20 24 28 32

36 48 PN

P-P

5

8

12 16

20 24 28 32

36 48 PN

P-P

5

8

12 16

20 24 28 32

36 48 PN

90

Cardiac Output

80

70

60

90
Heart rate (beats/min)

One of the most remarkable changes in pregnancy is the tremendous increase in CO. Van Oppen and coworkers reviewed 33 cross-sectional and 19 longitudinal studies and found greatly divergent results on when CO peaked, the magnitude of the rise in CO before labor, and the effect of the third trimester on CO.19 However, all of the studies agreed that CO increased significantly beginning in early pregnancy, peaking at an average of 30% to 50% above pre­ conceptional values.
In a longitudinal study by Robson and associates using Doppler echocardiography, CO increased by 50% at 34 weeks from a prepregnancy value of
4.88 L/min to 7.34 L/min19,20 (Figure 3-2). In twin gestations, CO incrementally increases an additional 20% above that of singleton pregnancies.13 Robson and associates demonstrated that, by 5 weeks’ gestation, CO has already risen by more than 10%. By 12 weeks, the rise in output is 34% to
39% above nongravid levels, accounting for about 75% of the total increase in CO during pregnancy. Although the literature is not clear regarding the exact gestation when
CO peaks, most studies point to a range between 25 and
30 weeks.20 The data on whether the CO continues to increase in the third trimester are very divergent, with equal numbers of good longitudinal studies showing a mild decrease, a slight increase, or no change.19 The differences in these studies cannot be explained by differences in investigative techniques, position of the women during measurements, or study design. This apparent discrepancy
appears to be explained by the small number of individuals in each study and the probability that the course of CO during the third trimester is determined by factors specific to the individual.19 In a recent study, Desai and coworkers reported that CO in the third trimester is significantly correlated with fetal birthweight and maternal height and weight.21
Most of the increase in CO is directed to the uterus, placenta, and breasts. In the first trimester, as in the

7

4

Stroke volume (mL)

contributors to cardiac disease and symptom severity, especially in the setting of normal or near-normal systolic function.16 In a review, diastolic dysfunction was pinpointed as a leading cause of cardiac failure in pregnancy.17
During the past 5 years, the effects of pregnancy on diastolic function have been thoroughly investigated by using pulsed-wave Doppler echocardiography.12 In young healthy women, the left ventricle is elastic; therefore, diastolic relaxation is swift, and ventricular filling occurs almost completely by early diastole with minimal contribution from the atrial kick. The E/A ratio compares the peak mitral flow velocity in early diastole (E) to the peak atrial kick velocity (A); although both velocities increase in pregnancy, the overall ratio falls because of a greater rise in the
A-wave velocity. The rise in the A value, which begins in the second trimester and increases throughout the third tri­ mester, indicates the increased importance of the atrial con­ traction in left ventricular filling during pregnancy.12 Veille and associates determined that in healthy women, pregnancy did not adversely affect baseline diastolic function, but that at maximal exercise, diastolic function was impaired. The reason for the impairment was attributed to increased left ventricular wall stiffness. The authors further speculated that this change may be the limiting factor for exercise in pregnancy.18

85

80

75

70
Gestation (wk)
FIGURE 3-2. Increase in cardiac output, stroke volume, and heart rate from the nonpregnant state throughout pregnancy. PN, Postnatal; P-P, prepregnancy. (From Hunter S, Robson S: Adaptation of the maternal heart in pregnancy. Br Heart J 68:540, 1992.)

nongravid state, the uterus receives 2% to 3% of CO and the breasts 1%. The percentage of CO going to the kidneys
(20%), skin (10%), brain (10%), and coronary arteries (5%) remains at similar nonpregnant percentages, but because of the overall increase in CO, this results in an increase in absolute blood flow of about 50%.22 By term, the uterus receives 17% (450 to 650 mL/min) and the breasts 2%, mostly at the expense of a reduction of the fraction of the
CO going to the splanchnic bed and skeletal muscle.
The absolute blood flow to the liver is not changed, but the overall percentage of CO is significantly decreased.

46 Section I Physiology
CO is the product of SV and HR (CO = SV × HR), both of which increase during pregnancy and contribute to the overall rise in CO. An initial rise in the HR occurs by 5 weeks’ gestation and continues until it peaks at 32 weeks’ gestation at 15 to 20 beats above the nongravid rate, an increase of 17%. The SV begins to rise by 8 weeks’ gestation and reaches its maximum at about 20 weeks, 20% to
30% above nonpregnant values. In the third trimester, it is primarily variations in the SV that determine whether CO increases, decreases, or remains stable, as described earlier.
CO in pregnancy depends on maternal position. In a study in 10 normal gravid women in the third trimester, using pulmonary artery catheterization, CO was noted to be highest in the knee-chest position and lateral recumbent position at 6.6 to 6.9 L/min. CO decreased by 22% to 5.4 L/min in the standing position (Figure 3-3). The decrease in CO in the supine position compared with the lateral recumbent position is 10% to 30%. In both the standing and the supine positions, decreased CO results from a fall in SV secondary to decreased blood return to the heart. In the supine position, the enlarged uterus compresses the inferior vena cava, reducing venous return; before 24 weeks, this effect is not observed. Of note, in late pregnancy, the inferior vena cava is completely occluded in the supine position, with venous return from the lower extremities occurring through the dilated paravertebral collateral circulation.23
Despite decreased CO, most supine women are not hypotensive or symptomatic because of the compensated rise in systemic vascular resistance (SVR). However, 5% to 10% of gravidas manifest supine hypotension with symptoms of dizziness, lightheadedness, nausea, and even syncope. The women who become symptomatic have a greater decrease in CO and blood pressure (BP) and a greater increase in HR when in the supine position

7.0
6.8
Cardiac output (L/min)

6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
5.0

L.LAT

R.LAT

SUP*

SIT

ST*

K-C

Position
* ϭ P Ͻ 0.05
FIGURE 3-3. Effect of position change on cardiac output during pregnancy. K-C, Knee-chest; L.LAT, left lateral; R.LAT, right lateral; SIT, sitting; ST, standing; SUP, supine. (From Clark S, Cotton D, Pivarnik
J, et al: Position change and central hemodynamic profile during normal third-trimester pregnancy and postpartum. Am J Obstet
Gynecol 164:883, 1991.)

than do asymptomatic women.24 Some investigators have proposed that the determination of whether women become symptomatic depends on the development of an adequate paravertebral collateral circulation. Interestingly, with engagement of the fetal head, less of an effect on CO is seen.23 The ability to maintain a normal BP in the supine position may be lost during epidural or spinal anesthesia because of an inability to increase SVR. Clinically, the effects of maternal position on CO are especially important when the mother is clinically hypotensive or in the setting of a non-reassuring fetal heart rate tracing. The finding of a decreased CO in the standing position may give a physiologic basis for the finding of decreased birthweight and placental infarctions in working women who stand for prolonged periods.

Arterial Blood Pressure and Systemic
Vascular Resistance

BP is the product of CO and resistance (BP = CO × SVR).
Despite the large increase in CO, the maternal BP is decreased until later in pregnancy as a result of a decrease in SVR that nadirs midpregnancy and is followed by a gradual rise until term. Even at full term, SVR remains
21% lower than prepregnancy values in pregnancies not affected by gestational hypertension or preeclampsia. The most obvious cause for the decreased SVR is progesteronemediated smooth muscle relaxation; however, the exact mechanism for the fall in SVR is poorly understood. Earlier theories that uteroplacental circulation acts as an arteriovenous shunt are unlikely. Increased NO also contributes to decreased vascular resistance by direct actions and by blunting the vascular responsiveness to vasoconstrictors such as angiotensin II and norepinephrine. During con­ ception, the expression and activity of NO synthase is elevated and the plasma level of cyclic guanosine monophosphate, a second messenger of NO and a mediator of vascular smooth muscle relaxation, is also increased.25 As a result, despite the overall increase in the RAAS, the normal gravida is refractory to the vasoconstrictive effects of angiotensin II. Gant and colleagues showed that nullipa­ rous women who later become preeclamptic retain their response to angiotensin II before the appearance of clinical signs of preeclampsia.26
Decreases in maternal BP parallel the falling SVR, with initial decreased BP manifesting at 8 weeks’ gestation or earlier. Current studies did not include preconception BP or frequent first-trimester BP sampling and, therefore, cannot determine the exact time course of hemodynamic alterations. Because BP fluctuates with menstruation and is decreased in the luteal phase, it seems reasonable that BP drops immediately in early pregnancy. The diastolic BP and the mean arterial pressure [MAP = (2 × diastolic BP + systolic BP)/3] decrease more than the systolic BP, which changes minimally. The overall decrease in diastolic BP and MAP is 5 to 10 mm Hg (Figure 3-4). The diastolic BP and the MAP nadir at midpregnancy and return to prepregnancy levels by term, and in most studies rarely exceed prepregnancy or postpartum values. However, some investigators have reported that at term, the BP is greater than in matched nonpregnant controls and believe that in the third trimester, the BP is higher than prepreg­ nant values. Current studies are very limited by the

Chapter 3 Maternal Physiology 47 absence of preconceptional values for comparison within individual patients.
The position when the BP is taken and what Korotkoff sound is used to determine the diastolic BP are important.
BP is lowest in the lateral recumbent position, and the BP of the superior arm in this position is 10 to 12 mm Hg lower than the inferior arm. In the clinic, BP should be measured in the sitting position and the Korotkoff 5 sound should be used. This is the diastolic BP when the sound disappears as opposed to the Korotkoff 4, when there is a muffling of the sound. In a study of 250 gravidas, the Korotkoff
4 sound could only be identified in 48% of patients, whereas the Korotkoff 5 sound could always be determined. The Korotkoff 4 should only be used when the
Korotkoff 5 occurs at 0 mm Hg.27 Automated BP monitors have been compared with mercury sphygmomanometry during pregnancy, and although they tended to overestimate the diastolic BP, the overall results were similar in

120

Systolic
Lying

110

BP (mm)

Sitting
100

70
Lying

Diastolic

Sitting

60

50
16

20

24

28

32

36

40

Postnatal

Weeks of pregnancy
FIGURE 3-4. Blood pressure trends (sitting and lying) during pregnancy.
Postnatal measures performed 6 weeks postpartum. (From MacGillivray I, Rose G, Rowe B: Blood pressure survey in pregnancy. Clin
Sci 37:395, 1969.)

normotensive women. Of note in patients with suspected preeclampsia, automated monitors appear increasingly inaccurate at higher BPs.

Venous Pressure

Venous pressure in the upper extremities remains unchanged in pregnancy but rises progressively in the lower extremities. Femoral venous pressure increases from values near 10 cm H2O at 10 weeks’ gestation to 25 cm
H2O near term.28 From a clinical standpoint, this increase in pressure, in addition to the obstruction of the inferior vena cava by the expanding uterus, leads to the development of edema, varicose veins, and hemorrhoids, and an increased risk for deep venous thrombosis.

Central Hemodynamic Assessment

Clark and colleagues studied 10 carefully selected normal women at 36 to 38 weeks’ gestation and again at 11 to 13 weeks postpartum with arterial lines and Swan-Ganz catheterization to characterize the central hemodynamics of term pregnancy (Table 3-1). As described earlier, CO, HR,
SVR, and pulmonary vascular resistance change significantly with pregnancy. In addition, clinically significant decreases were noted in colloidal oncotic pressure (COP) and the COP-PCWP difference, explaining why gravid women have a greater propensity for developing pulmonary edema with changes in capillary permeability or elevations in cardiac preload. The COP can fall even further after delivery to 17 mm Hg and, if the pregnancy is complicated by preeclampsia, can reach levels as low as 14 mm Hg.29
When the PCWP is more than 4 mm Hg above the COP, the risk for pulmonary edema increases; therefore, pregnant women can experience pulmonary edema at PCWPs of
18 to 20 mm Hg, which is significantly lower than the typical nonpregnant threshold of 24 mm Hg.

Normal Changes That Mimic
Heart Disease

The physiologic adaptations of pregnancy lead to a number of changes in maternal signs and symptoms that can mimic cardiac disease and make it difficult to determine whether true disease is present. Dyspnea is common to both cardiac disease and pregnancy, but certain distinguishing features should be considered. First, the onset of pregnancy-related

TABLE 3-1 CENTRAL HEMODYNAMIC CHANGES

Cardiac output (L/min)
Heart rate (beats/min)
Systemic vascular resistance (dyne·cm·sec−5)
Pulmonary vascular resistance (dyne·cm·sec−5)
Colloid oncotic pressure (mm Hg)
Mean arterial pressure (mm Hg)
Pulmonary capillary wedge pressure (mm Hg)
Central venous pressure (mm Hg)
Left ventricular stroke work index (g·m·m−2)

11-12 WEEKS
POSTPARTUM

36-38 WEEKS’
GESTATION

CHANGE FROM
NONPREGNANT STATE

4.3 ± 0.9
71 ± 10.0
1530 ± 520
119 ± 47.0
20.8 ± 1.0
86.4 ± 7.5
3.7 ± 2.6
3.7 ± 2.6
41 ± 8

6.2 ± 1.0
83 ± 10.0
1210 ± 266
78 ± 22
18 ± 1.5
90.3 ± 5.8
3.6 ± 2.5
3.6 ± 2.5
48 ± 6

+43%*
+17%*
–21%*
–34%*
–14%*
NS
NS
NS
NS

Modified from Clark S, Cotton D, Lee W, et al: Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 161:1439, 1989.
Data are presented as mean ± standard deviation.
*P < .05.
NS, Not significant. Although data are not presented, the pulmonary artery pressures were not significantly different.

48 Section I Physiology
Wide
loud split 1st 88%
M.C.

T.C.

A2 P2
Diastolic
“flow” murmur 18%

4th occasional dyspnea usually occurs before 20 weeks, and 75% of women experience it by the third trimester. Unlike cardiac dyspnea, pregnancy-related dyspnea does not worsen sig­ nificantly with advancing gestation. Second, physiologic dyspnea is usually mild, does not stop women from per­ forming normal daily activities, and does not occur at rest.30
Other normal symptoms that can mimic cardiac disease include decreased exercise tolerance, fatigue, occasional orthopnea, syncope, and chest discomfort. The reason for this increase in cardiac symptoms is not an increase in catecholamine levels, because these levels are either unchanged or decreased in pregnancy. Symptoms that should not be attributed to pregnancy and need a more thorough investigation include hemoptysis, syncope or chest pain with exertion, progressive orthopnea, or parox­ ysmal nocturnal dyspnea. Normal physical findings that could be mistaken as evidence of cardiac disease include peripheral edema, mild tachycardia, jugular venous distention after midpregnancy, and lateral displacement of the left ventricular apex.
Pregnancy also alters normal heart sounds. At the end of the first trimester, both components of the first heart sound become louder, and there is exaggerated splitting.
The second heart sound usually remains normal with only minimal changes. Up to 80% to 90% of gravidas demonstrate a third heart sound (S3) after midpregnancy because of rapid diastolic filling. Rarely, a fourth heart sound may be auscultated, but typically phonocardiography is needed to detect this. Systolic ejection murmurs along the left sternal border develop in 96% of pregnancies, and increased blood flow across the pulmonic and aortic valves is thought to be the cause. Most commonly, these are midsystolic and less than grade 3. Diastolic murmurs have been found in up to 18% of gravidas, but their presence is uncommon enough to warrant further evaluation. A continuous murmur in the second to fourth intercostal space may be heard in the second or third trimester owing to the so-called mammary souffle caused by increased blood flow in the breast (Figure 3-5).
Troponin 1 and creatinine kinase-MB levels are tests used to assess for acute myocardial infarction. Uterine con­ tractions can lead to significant increases in the creatinine

3rd loud 84%

11
10
Cardiac output (L/min)

FIGURE 3-5. Summarization of the findings on auscultation of the heart in pregnancy. M.C., Mitral closure; T.C., tricuspid closure; A2 and P2, aortic and pulmonary elements of the second sound.
(From Cutforth R, MacDonald C: Heart sounds and murmurs in pregnancy. Am Heart J 71:741,
1966.)

Basal
During contractions

9
8
7
6
5

Յ3 cm
Before
labor

4-7 cm

Ն8 cm

1 hr

Labor

24 h

After delivery FIGURE 3-6. Changes in cardiac output during normal labor. (From
Hunter S, Robson S: Adaptation of the maternal heart in pregnancy.
Br Heart J 68:540, 1992.)

kinase-MB level, but troponin levels are not affected by pregnancy or labor.31

Effect of Labor and the Immediate
Puerperium

The profound anatomic and functional changes on cardiac function reach a crescendo during the labor process. In addition to the dramatic rise in CO with normal pregnancy, even greater increases in CO occur with labor and in the immediate puerperium. In a Doppler echocardiography study by Robson and associates of 15 uncomplicated women without epidural anesthesia, the CO between contractions increased 12% during the first stage of labor20
(Figure 3-6). This increase in CO is caused primarily by an increased SV, but HR may also increase. By the end of the first stage of labor, the CO during contractions is 51% above baseline term pregnancy values (6.99 to 10.57 L/min).

Chapter 3 Maternal Physiology 49
Increased CO is in part secondary to increased venous return from the 300- to 500-mL autotransfusion that occurs at the onset of each contraction as blood is expressed from the uterus.32,33 Paralleling increases in CO, the MAP also rises in the first stage of labor, from 82 to 91 mm Hg in early labor to 102 mm Hg by the beginning of the second stage.
MAP also increases with uterine contractions.
Much of the increase in CO and MAP is due to pain and anxiety. With epidural anesthesia, the baseline increase in
CO is reduced, but the rise observed with contractions persists.34 Maternal posture also influences hemodynamics during labor. Changing position from supine to lateral recumbent increases CO. This change is greater than the increase seen before labor and suggests that during labor,
CO may be more dependent on preload. Therefore, it is important to avoid the supine position in laboring women and to give a sufficient fluid bolus before an epidural to maintain an adequate preload.
In the immediate postpartum period (10 to 30 minutes after delivery), CO reaches its maximum, with a further rise of 10% to 20%. This increase is accompanied by a fall in the maternal HR that is likely secondary to increased SV.
Traditionally, this rise was thought to be the result of uterine autotransfusion as described earlier with contractions, but the validity of this concept is uncertain. In both vaginal and elective cesarean deliveries, the maximal increase in the CO occurs 10 to 30 minutes after delivery and returns to prelabor baseline 1 hour after delivery. The increase was 37% with epidural anesthesia and 28% with general anesthesia. Over the next 2 to 4 postpartum weeks, the cardiac hemodynamic parameters return to nearpreconceptional levels.35
The effect of pregnancy on cardiac rhythm is limited to an increase in HR and a significant increase in isolated atrial and ventricular contractions. In a Holter monitor study by Shotan and coworkers, 110 pregnant women referred for evaluation of symptoms of palpitations, dizziness, or syncope were compared with 52 healthy pregnant women.36 Symptomatic women had similar rates of isolated sinus tachycardia (9%), isolated premature atrial complexes (56%), and premature ventricular contractions
(PVCs) (49%), but increased rates of frequent PVCs greater than 10/hour (20% versus 2%, P = 0.03). A subset of patients with frequent premature atrial complexes or
PVCs had comparative Holter studies performed postpartum that revealed an 85% decrease in arrhythmia frequency (P < .05). This dramatic decline, with patients acting as their own controls, supports the arrhythmogenic effect of pregnancy. In a study of 30 healthy women placed on Holter monitors during labor, a similarly high incidence of benign arrhythmias was found (93%). Reassuringly, the prevalence of concerning arrhythmias was no higher than expected. An unexpected finding was a 35% rate of asymptomatic bradycardia, defined as a HR of less than 60 beats/ minute, in the immediate postpartum period.37 In addition, other studies have shown that women with preexisting tachyarrhythmias have an increased incidence of these rate abnormalities during pregnancy.38 Whether labor increases the rate of arrhythmias in women with cardiac disease has not been thoroughly studied, but multiple case reports suggest labor may increase arrhythmias in these women.

3.5
3.0
2.5
2.0

IC

IRV

IRV
VC

1.5

TLC

1.0
0.5
0
Ϫ0.5
Ϫ1.0

FRC

TV

TV

ERV

ERV

RV

RV

Nonpregnant

Late pregnancy

FIGURE 3-7. Lung volumes in nonpregnant and pregnant women. ERV,
Expiratory reserve; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve; RV, residual volume; TLC, total lung capacity; TV, tidal volume; VC, vital capacity. (From Cruickshank DP,
Wigton TR, Hays PM: Maternal physiology in pregnancy. In Gabbe
SG, Niebyl JR, Simpson JL [eds]: Obstetrics: Normal and Problem
Pregnancies, 3rd ed. New York, Churchill Livingstone, 1996, p 94.)

RESPIRATORY SYSTEM
Upper Respiratory Tract

During pregnancy, the mucosa of the nasopharynx becomes hyperemic and edematous with hypersecretion of mucus due to increased estrogen. These changes often lead to marked nasal stuffiness; epistaxis is also common. Placement of nasogastric tubes may cause excessive bleeding if adequate lubrication is not used.30 Polyposis of the nose and nasal sinuses develops in some individuals but regresses postpartum. Because of these changes, many gravid women complain of chronic cold symptoms.
However, the temptation to use nasal decongestants should be avoided because of risk for hypertension and rebound congestion. Mechanical Changes

The configuration of the thoracic cage changes early in pregnancy, much earlier than can be accounted for by mechanical pressure from the enlarging uterus. Relaxation of the ligamentous attachments between the ribs and sternum may be responsible. The subcostal angle increases from 68 to 103 degrees, the transverse diameter of the chest expands by 2 cm, and the chest circumference expands by 5 to 7 cm. As gestation progresses, the level of the diaphragm rises 4 cm; however, diaphragmatic excursion is not impeded and actually increases 1 to 2 cm.
Respiratory muscle function is not affected by pregnancy, and maximal inspiratory and expiratory pressures are unchanged.39 Lung Volume and Pulmonary Function

The described alterations in chest wall configuration and the diaphragm lead to changes in static lung volumes. In a review of studies with at least 15 subjects compared with nonpregnant controls, Crapo found significant changes
(Figure 3-7 and Table 3-2).30 The elevation of the

50 Section I Physiology
TABLE 3-2 LUNG VOLUMES

AND

CAPACITIES

IN

PREGNANCY
CHANGE IN
PREGNANCY

MEASUREMENT

DEFINITION

Respiratory rate (RR)
Vital capacity (VC)

Number of breaths per minute
Maximal amount of air that can be forcibly expired after maximal inspiration (IC + ERV)
Maximal amount of air that can be inspired from resting expiratory level (TV + IRV)
Amount of air inspired and expired with a normal breath
Maximal amount of air that can be inspired at end of normal inspiration
Amount of air in lungs at resting expiratory level (ERV + RV)
Maximal amount of air that can be expired from resting expiratory level
Amount of air in lungs after maximal expiration
Total amount of air in lungs at maximal inspiration (VC + RV)

Inspiratory capacity (IC)
Tidal volume (TV)
Inspiratory reserve volume (IRV)
Functional residual capacity (FRC)
Expiratory reserve volume (ERV)
Residual volume (RV)
Total lung capacity (TLC)

Unchanged
Unchanged
Increased 5% to 10%
Increased 30% to 40%
Unchanged
Decreased 20%
Decreased 15% to 20%
Decreased 20% to 25%
Decreased 5%

From Cruickshank DP, Wigton TR, Hays PM: Maternal physiology in pregnancy. In Gabbe SG, Niebyl JR, Simpson JL (eds): Obstetrics: Normal and Problem
Pregnancies, 3rd ed. New York, Churchill Livingstone, 1996, p 95.

diaphragm decreases the volume of the lungs in the resting state, thereby reducing total lung capacity and the functional residual capacity (FRC). The FRC can be subdivided into expiratory reserve volume and residual volume, and both decrease.
Spirometric measurements assessing bronchial flow are unaltered in pregnancy. The forced expiratory volume in
1 second (FEV1) and the ratio of FEV1 to forced vital capac­ ity are both unchanged, suggesting that airway function remains stable. In addition, peak expiratory flow rates measured using a peak flow meter seem to be unaltered in pregnancy at rates of 450 ± 16 L/min.40 Harirah and associates performed a longitudinal study of the peak flow in 38 women from the first trimester until 6 weeks postpartum.41 They reported that the peak flows had a statistically significant decrease as the gestation progressed, but the amount of the decrease was minimal enough to be of questionable clinical significance. Likewise a small decrease in the peak flow was found in the supine position versus the standing or sitting position. Therefore, during gestation, both spirometry and peak flow meters can be used in diagnosing and managing respiratory illnesses, but the clinician should ensure that measurements are performed in the same maternal position.41

Gas Exchange

Increasing progesterone levels drive a state of chronic hyperventilation, as reflected by a 30% to 50% increase in tidal volume by 8 weeks’ gestation. In turn, increased tidal volume results in an overall parallel rise in minute ventila­ tion, despite a stable respiratory rate (minute ventilation = tidal volume × respiratory rate). The rise in minute ventilation, combined with a decrease in FRC, leads to a larger than expected increase in alveolar ventilation (50% to
70%). Chronic mild hyperventilation results in increased alveolar oxygen (PAO2) and decreased arterial carbon dioxide
(PaCO2) from normal levels (Table 3-3). The drop in the
PaCO2 is especially critical because it drives a more favorable carbon dioxide (CO2) gradient between the fetus and mother, facilitating CO2 transfer. The low maternal
PaCO2 results in a chronic respiratory alkalosis. Partial renal compensation occurs through increased excretion of bicarbonate, which helps maintain the pH between
7.4 and 7.45 and lowers the serum bicarbonate levels.
Early in pregnancy, the arterial oxygen (PaO2) increases

TABLE 3-3 BLOOD GAS VALUES
OF PREGNANCY

IN

THIRD TRIMESTER

PREGNANT
PaO2 (mm Hg)*
Arterial Hgb saturation
(%)†
PaCO2 (mm hg)* pH* Serum bicarbonate
(HCO3) (mmol/L)
Base deficit (mmol/L)*
Alveolar-arterial gradient
[P(A-a)O2 (mm Hg)]*

101.8 ± 1
98.5 ± 0.7%

NONPREGNANT
93.4 ± 2.04
98 ± 0.8%

30.4 ± 0.6
7.43 ± 0.006
21.7 ± 1.6

40 ± 2.5
7.43 ± 0.02
25.3 ± 1.2

3.1 ± 0.2
16.1 ± 0.9

1.06 ± 0.6
15.7 ± 0.6

*Data from Templeton A, Kelman G: Maternal blood-gases, (PAO2-PaO2), physiological shunt and VD/VT in normal pregnancy. Br J Anaesth 48:1001, 1976.
Data presented as mean ± SEM.
†
Data from McAuliffe F, Kametas N, Krampl E: Blood gases in prepregnancy at sea level and at high altitude. Br J Obstet Gynaecol 108:980, 2001. Data presented as mean ± SD.

(106 to 108 mm Hg) as the PaCO2 decreases, but by the third trimester, a slight decrease in the PaO2 (101 to 104 mm
Hg) occurs as a result of the enlarging uterus. This decrease in the PaO2 late in pregnancy is even more pronounced in the supine position, with a further drop of 5 to 10 mm Hg and an increase in the alveolar-to-arterial gradient to
26 mm Hg, and up to 25% of women exhibit a PaO2 of less than 90 mm Hg.30,42
As the minute ventilation increases, a simultaneous but smaller increase in oxygen uptake and consumption occurs. Most investigators have found maternal oxygen consumption to be 20% to 40% above nonpregnant levels.
This increase occurs as a result of the oxygen requirements of the fetus, the placenta, and the increased oxygen requirement of maternal organs. With exercise or during labor, an even greater rise in both minute ventilation and oxygen consumption takes place.30 During a contraction, oxygen consumption can triple. As a result of the increased oxygen consumption and because the functional residual capacity is decreased, there is a lowering of the maternal oxygen reserve. Therefore, the pregnant patient is more susceptible to the effects of apnea, such as during intubation when a more rapid onset of hypoxia, hypercap­ nia, and respiratory acidosis is seen.

Chapter 3 Maternal Physiology 51
TABLE 3-4 CHARACTERISTICS

OF

SLEEP

IN

PREGNANCY

STAGE OF PREGNANCY

SUBJECTIVE SYMPTOMS

OBJECTIVE (POLYSOMNOGRAPHY)*

First trimester

Increased total sleep time: ↑ naps
Increased daytime sleepiness
Increased nocturnal insomnia
Normalization of total sleep time
Increased awakenings

Increased total sleep time
Decreased stages 3 and 4 non-REM sleep

Second trimester
Third trimester

Decreased total sleep time
Increased insomnia
Increased nocturnal awakenings
Increased daytime sleepiness

Normal total sleep time
Decreased stages 3 and 4 non-REM sleep
Decreased REM sleep
Decreased total sleep time
Increased awakenings after sleep onset
Increased stage 1 non-REM sleep
Decreased stages 3 and 4 non-REM sleep
Decreased REM sleep

Modified from Santiago J, Nolledo M, Kinzler W: Sleep and sleep disorders in pregnancy. Ann Intern Med 134:396, 2001.
*Rapid eye movement (REM) sleep is important for cognitive sleep, 20% to 25% of sleep. Stages 1 and 2 non-REM sleep: light sleep, 55% of sleep. Stages 3 and 4 non-REM sleep: deep sleep, important for rest, 20% of sleep.

Sleep

Pregnancy causes both an increase in sleep disorders and significant changes in sleep profile and pattern that persist into the postpartum period.43 Pregnancy causes such significant changes that the American Sleep Disorder
Association has proposed the existence of a new term: pregnancy-associated sleep disorder. Emerging evidence indicates that sleep disturbances are associated with poor health outcomes in the general population and that sleep disturbances in pregnancy may contribute to certain complications of pregnancy. It is well known that hormones and physical discomforts affect sleep (Table 3-4). With the dramatic change in hormone levels and the significant mechanical effects that make women more uncomfortable, it is not difficult to understand why sleep is profoundly affected. Multiple authors have investigated the changes in sleep during pregnancy using questionnaires, sleep logs, and polysomnographic studies. From these studies, investigators have shown that most women (66% to 94%) report alterations in sleep that lead to the subjective perception of poor sleep quality. The disturbances in sleep begin as early as the first trimester and worsen as the pregnancy progresses.44 During the third trimester, multiple discomforts occur that can impair sleep: urinary frequency, backache, general abdominal discomfort and contractions, leg cramps, restless leg syndrome, heartburn, and fetal movement. Interestingly, no changes are seen in melatonin levels, which modulate the body’s circadian pacemaker.
In general, pregnancy is associated with a decrease in rapid eye movement (REM) sleep and a decrease in stages
3 and 4 non-REM sleep. REM sleep is important for cognitive thinking, and stages 3 and 4 non-REM sleep is the so-called deep sleep and is important for rest. In addition, with advancing gestational age, there is a decrease in sleeping efficiency and sleep continuity and an increase in awake time and daytime somnolence. By 3 months postpartum, the amount of non-REM and REM sleep recovers, but a persistent decrease in sleeping efficiency and nocturnal awakenings occur, presumably because of the newborn.43 Although pregnancy causes changes in sleep, it is important for the clinician to consider other primary sleep disorders unrelated to pregnancy such as sleep apnea. The physiologic changes of pregnancy also in­ crease the incidence of sleep-disordered breathing, which includes snoring (in up to 16% of women), upper airway

obstruction, and potentially obstructive sleep apnea. The prevalence of sleep apnea in pregnancy is unknown, but it appears to increase the risk for intrauterine growth restriction and gestational hypertension if it is associated with hypoxemia. Women with excessive daytime sleepi­ ness, loud excessive snoring, and witnessed apneas should be evaluated for obstructive sleep apnea with overnight polysomnography.45 In addition, individuals with known sleep apnea may need repeat sleep studies to determine whether changes in treatment are necessary to prevent in­ termittent hypoxia.
Although the majority of gravidas have sleep problems, most do not complain to their providers or ask for treatment. Treatment options include improving sleep habits by avoiding fluids after dinner, establishing regular sleep hours, avoiding naps and caffeine, minimizing bedroom noises, and using pillow support. Other options include relaxation techniques, managing back pain, and use of sleep medications such as diphenhydramine (Benadryl) and zolpidem (Ambien).
Another potential cause of sleep disturbances in pregnancy is the development of restless leg syndrome and periodic leg movements during sleep. Restless leg syndrome is a neurosensory disorder that typically begins in the evening and can prevent women from falling asleep.
Pregnancy can be a cause of this syndrome, and in one study up to 23% of gravidas developed some component of this syndrome in the third trimester, although the true prevalence of this disorder during pregnancy is unknown.
Although typically this syndrome is not severe enough to warrant treatment, occasionally it is a source of great discomfort to the gravid woman. Treatment options include improving sleep habits, use of an electric vibrator to the calves, and use of a benzodiazepine such as clonazepam or a dopaminergic agent such as L-dopa or carbidopa.

HEMATOLOGIC CHANGES
Plasma Volume and Red Blood Cell Mass
Maternal blood volume begins to increase at about 6 weeks’ gestation. Thereafter, it increases progressively until 30 to
34 weeks and then plateaus until delivery. The average expansion of blood volume is 40% to 50%, although individual increases range from 20% to 100%. Women with multiple pregnancies have a larger increase in blood

52 Section I Physiology
100
90
Percent increase above nonpregnant

TABLE 3-5 HEMOGLOBIN VALUES

Plasma volume
Blood volume
RBC mass

WEEKS’
GESTATION

80
70
Delivery

60
50
40

12
16
20
24
28
32
36
40

IN

PREGNANCY

MEAN
HEMOGLOBIN
(g/dL)
12.2
11.8
11.6
11.6
11.8
12.1
12.5
12.9

FIFTH PERCENTILE
HEMOGLOBIN
(g/dL)
11.0
10.6
10.5
10.5
10.7
11.0
11.4
11.9

From U.S. Department of Health and Human Services: Recommendations to prevent and control iron deficiency in the United States. MMWR Morb Mortal
Wkly Rep 47:1, 1998.

30
20
10
0

4

8

12

16

20

24

28

32

36

40 42

Weeks of pregnancy
FIGURE 3-8. Blood volume changes during pregnancy. RBC, Red blood cell. (From Scott D: Anemia during pregnancy. Obstet Gynecol Ann
1:219, 1972.)

volume than those with singletons.46 Likewise, volume expansion correlates with infant birthweight, but it is not clear whether this is a cause or an effect. The increase in blood volume results from a combined expansion of both plasma volume and red blood cell (RBC) mass. The plasma volume begins to increase by 6 weeks and expands at a steady pace until it plateaus at 30 weeks’ gestation; the overall increase is about 50% (1200 to 1300 mL). The exact etiology of the expansion of the blood volume is unknown, but the hormonal changes of gestation and the increase in
NO play important roles.
Erythrocyte mass also begins to increase at about
10 weeks’ gestation. Although the initial slope of this increase is slower than that of the plasma volume, erythrocyte mass continues to increase progressively until term without plateauing. Without iron supplementation, RBC mass increases about 18% by term, from a mean nonpregnant level of 1400 mL up to 1650 mL. Supplemental iron increases RBC mass accumulation to 400 to 450 mL, or
30%.46 Because plasma volume increases more than the
RBC mass, maternal hematocrit falls. This so-called physi­ ologic anemia of pregnancy reaches a nadir at 30 to 34 weeks. Because the RBC mass continues to increase after
30 weeks when the plasma volume expansion has plateaued, the hematocrit may rise somewhat after 30 weeks (Figure
3-8). The mean and fifth percentile hemoglobin concentrations for normal iron-supplemented pregnant women are outlined (Table 3-5). In pregnancy, erythropoietin levels increase twofold to threefold, starting at 16 weeks, and may be responsible for the moderate erythroid hyperplasia found in the bone marrow and mild elevations in the reticulocyte count. The increased blood volume is protective given the possibility of hemorrhage during pregnancy or at delivery. The larger blood volume also helps fill the expanded vascular system created by vasodilation and the large low-resistance vascular pool within the uteroplacental unit preventing hypotension.30

Vaginal delivery of a singleton infant at term is associated with a mean blood loss of 500 mL; an uncomplicated cesar­ ean birth, about 1000 mL; and a cesarean hysterectomy,
1500 mL.46,47 In a normal delivery, almost all of the blood loss occurs in the first hour. Pritchard and colleagues found that over the subsequent 72 hours, only 80 mL of blood is lost.47 In the nonpregnant state, blood loss results in an immediate fall in blood volume with a slow re-expansion through volume redistribution; by 24 hours, the blood volume approaches the prehemorrhage level. Isovolemia is maintained with a drop in hematocrit proportional to the blood loss. Gravid women respond to blood loss in a different fashion. In pregnancy, the blood volume drops after postpartum bleeding, but there is no re-expansion to the prelabor level, and there is less of a change in the hemato­ crit. Indeed, instead of volume redistribution, an overall diuresis of the expanded water volume occurs postpartum.
After delivery with average blood loss, the hematocrit drops moderately for 3 to 4 days, followed by an increase.
By days 5 to 7, the postpartum hematocrit is similar to the prelabor hematocrit. If the postpartum hematocrit is lower than the prelabor hematocrit, either that the blood loss was larger than appreciated, or the hypervolemia of pregnancy was less than normal, as in preeclampsia.47

Iron Metabolism in Pregnancy

Iron absorption from the duodenum is limited to its ferrous
(divalent) state, the form found in iron supplements. Ferric
(trivalent) iron from vegetable food sources must first be converted to the divalent state by the enzyme ferric reductase. If body iron stores are normal, only about 10% of ingested iron is absorbed, most of which remains in the mucosal cells or enterocytes until sloughing leads to excretion in the feces (1 mg/day). Under conditions of increased iron needs, the fraction of iron absorbed increases. After absorption, iron is released from the enterocytes into the circulation, where it is carried bound to transferrin to the liver, spleen, muscle, and bone marrow. In those sites, iron is freed from transferrin and incorporated into hemoglobin
(75% of iron) and myoglobin or stored as ferritin and hemosiderin. Menstruating women have about half the iron stores of men, with total body iron of 2 to 2.5 g and iron stores of only 300 mg. Before pregnancy, 8% to 10% of women in Western nations have iron deficiency.

Chapter 3 Maternal Physiology 53
25

Nonpregnant women
Pregnant women

Percentage of women

20

15

10

5

Ͼ500

475-499

450-474

425-449

400-424

375-399

350-374

325-349

300-324

275-299

250-274

225-249

200-224

175-199

150-174

125-149

100-124

75-99

50-74

Ͻ50

0

Platelet count (g/L)
FIGURE 3-9. Histogram of platelet count of pregnant women in the third trimester (n = 6770) compared with nonpregnant women (n = 287).
(From Boehlen F, Hohlfield P, Extermann P: Platelet count at term pregnancy: a reappraisal of the threshold. Obstet Gynecol 95:29, 2000.)

The iron requirements of gestation are about 1000 mg.
This includes 500 mg used to increase the maternal RBC mass (1 mL of erythrocytes contains 1.1 mg iron), 300 mg transported to the fetus, and 200 mg to compensate for the normal daily iron losses by the mother.48 Thus, the normal expectant woman needs to absorb an average of 3.5 mg/ day of iron. In actuality, the iron requirements are not constant but increase remarkably during the pregnancy from 0.8 mg/day in the first trimester to 6 to 7 mg/day in the third trimester. The fetus receives its iron through active transport, primarily during the last trimester. Adequate iron transport to the fetus is maintained despite severe maternal iron deficiency. Thus, there is no correlation between maternal and fetal hemoglobin concen­ trations. For a review on use of supplemental iron in pregnancy, see Chapter 42.

Platelets

Before the introduction of automated analyzers, studies of platelet counts during pregnancy reported conflicting results, with some showing a decrease, an increase, or no change with gestation. Unfortunately, even with the availability of automated cell counters, the data on the change in platelet count during pregnancy are still somewhat unclear. Two studies have used true longitudinal methods with serial measurements in the same women. Pitkin and colleagues measured platelet counts in 23 women every
4 weeks and found that the counts dropped from 322 ±
75 × 103/mm3 in the first trimester to 278 ± 75 × 103/mm3 in the third trimester.49 Similarly, O’Brien, in a study of
30 women, found a progressive decline in platelet counts.50
Therefore, most recent studies show a decline in the platelet count during gestation possibly caused by increased destruction or hemodilution. In addition to the mild decrease in the mean platelet count, Burrows and
Kelton have demonstrated that in the third trimester, about
8% of gravidas develop gestational thrombocytopenia, with

platelet counts between 70,000 and 150,000/mm3.51 Gesta­ tional thrombocytopenia is not associated with an increase in pregnancy complications, and platelet counts return to normal by 1 to 2 weeks postpartum. Gestational thrombocytopenia is thought to be due to accelerated platelet consumption similar to that seen in normal pregnancy, but more marked in this subset of women.51 Consistent with these findings, Boehlen and associates compared platelet counts during the third trimester of pregnancy with those in nonpregnant controls. They showed a shift to a lower mean platelet count and an overall shift to the left of the
“platelet curve” in the pregnant women (Figure 3-9). This study found that only 2.5% of nonpregnant women have platelet counts less than 150,000/mm3 (the traditional value used outside of pregnancy as the cut-off for normal) versus 11.5% of gravid women. A platelet count of less than
116,000/mm3 occurred in 2.5% of gravid women; therefore, these investigators recommended using this value as the lower limit for normal in the third trimester. In addition, they suggested that workups for the etiology of decreased platelet count were unneeded at values above this level.

Leukocytes

The peripheral white blood cell (WBC) count rises progressively during pregnancy. During the first trimester, the mean WBC count is 8000/mm3, with a normal range of
5110 to 9900/mm3. During the second and third trimesters, the mean is 8500/mm3, with a range of 5600 to 12,200/ mm3.49 In labor, the count may rise to 20,000 to 30,000/ mm3, and counts are highly correlated with labor progression as determined by cervical dilation.52 Because of the normal increase of WBCs in labor, the WBC count should not be used clinically in determining the presence of infection. The increase in the WBC count is largely due to increases in circulating segmented neutrophils and granulocytes whose absolute number is nearly doubled at term.
The reason for the increased leukocytosis is unclear, but

54 Section I Physiology it may be caused by the elevated estrogen and cortisol levels. Leukocyte levels return to normal within 1 to 2 weeks of delivery.

Coagulation System

Pregnancy places women at a fivefold to sixfold increased risk for thromboembolic disease (see Chapter 43). This greater risk is caused by increased venous stasis, vessel wall injury, and changes in the coagulation cascade that lead to hypercoagulability. The increase in venous status in the lower extremities is due to compression of the inferior vena cava and the pelvic veins by the enlarging uterus. The hypercoagulability is caused by an increase in several procoagulants, a decrease in the natural inhibitors of coagulation, and a reduction in fibrinolytic activity.
These physiologic changes provide defense against peripar­ tum hemorrhage.
Most of the procoagulant factors from the coagulation cascade are markedly increased, including factors I, VII,
VIII, IX, and X. Factors II, V, and XII are unchanged or mildly increased, and levels of factors XI and XIII decline.1,53 Plasma fibrinogen (factor I) levels begin to increase in the first trimester and peak in the third trimester at levels 50% higher than before pregnancy. The rise in fibrinogen is associated with an increase in the erythrocyte sedimentation rate. In addition, pregnancy causes a decrease in the fibrinolytic system with reduced levels of available circulating plasminogen activator, a twofold to threefold increase in plasminogen activator inhibitor-1
(PAI-1), and a 25-fold increase in PAI-2.1 The placenta produces PAI-1 and is the primary source of PAI-2.
Pregnancy has been shown to cause a progressive and significant decrease in the levels of total and free protein S from early in pregnancy but to have no effect on the levels of protein C and antithrombin III.54,55 The activated protein C (APC)-to-sensitivity (S) ratio, the ratio of the clotting time in the presence and the absence of APC, declines during pregnancy. The APC/S ratio is considered abnormal if less than 2.6. In a study of 239 women,54 the
APC/S ratio decreased from a mean of 3.12 in the first trimester to 2.63 by the third trimester. By the third trimester, 38% of women were found to have an acquired
APC resistance, with APC/S ratio values below 2.6.54
Whether the changes in the protein S level and the APC/S ratio are responsible for some of the hypercoagulability of pregnancy is unknown. If a workup for thrombophilias is performed during gestation, the clinician should use caution when attempting to interpret these levels if they are abnormal. Ideally the clinician should order DNA testing for the Leiden mutation instead of testing for APC. For protein S screening during pregnancy, the free protein S antigen level should be tested with normal levels in the second and third trimesters being identified as greater than
30% and 24%.56
Most coagulation testing is unaffected by pregnancy.
The prothrombin time, activated partial thromboplastin time, and thrombin time all fall slightly but remain within the limits of normal nonpregnant values, whereas the bleeding time and whole blood clotting times are unchanged. Testing for von Willebrand disease is affected in pregnancy because levels of factor VIII, von Willebrand factor activity and antigen, and ristocetin cofactor all

increase. Levels of coagulation factors normalize 2 weeks postpartum. Researchers have found evidence to support the theory that, during pregnancy, a state of low-level intravascular coagulation occurs. Low concentrations of fibrin degradation products (markers of fibrinolysis), elevated levels of fibrinopeptide A (a marker for increased clotting), and increased levels of platelet factor-4 and β-thromboglobulin
(markers of increased platelet activity) have been found in maternal blood.57 The most likely cause for these findings involves localized physiologic changes needed for maintenance of the uterine-placental interface.

URINARY SYSTEM
Anatomic Changes

The kidneys enlarge during pregnancy, with the length as measured by intravenous pyelography increasing about
1 cm. This growth in size and weight is due to increased renal vasculature, interstitial volume, and urinary dead space. The increase in urinary dead space is attributed to dilation of the renal pelvis, calyces, and ureters. Pelvicali­ ceal dilation by term averages 15 mm (range, 5 to 25 mm) on the right and 5 mm (range, 3 to 8 mm) on the left.58
The well-known dilation of the ureters and renal pelves begins by the second month of pregnancy and is maximal by the middle of the second trimester, when ureteric diameter may be as much as 2 cm. The right ureter is almost invariably dilated more than the left, and the dilation usually cannot be demonstrated below the pelvic brim. These findings have led some investigators to argue that the dilation is caused entirely by mechanical compression of the ureters by the enlarging uterus and ovarian venous plexus.
However, the early onset of ureteral dilation suggests that smooth muscle relaxation caused by progesterone plays an additional role. Also supporting the role of progesterone is the finding of ureteral dilation in women with renal transplant and pelvic kidney.59 By 6 weeks postpartum, ureteral dilation resolves.58 A clinical consequence of ureterocalyceal dilation is an increased incidence of pyelonephritis among gravidas with asymptomatic bacteriuria. In addi­ tion, the ureterocalyceal dilation makes interpretation of urinary radiographs more difficult when evaluating possi­ ble urinary tract obstruction or nephrolithiasis.
Anatomic changes are also observed in the bladder.
From midpregnancy on, an elevation in the bladder trigone occurs, with increased vascular tortuosity throughout the bladder. This can cause an increased incidence of microhematuria. Three percent of gravidas have idiopathic hematuria, defined as greater than 1+ on a urine dipstick, and up to 16% have microscopic hematuria. Because of the increasing size of the pregnancy, a decrease in bladder capacity develops with an increase in urinary frequency, urgency, and incontinence.

Renal Hemodynamics

Renal plasma flow (RPF) increases markedly from early in gestation and may actually initially begin to increase during the luteal phase before implantation.60 Dunlop showed convincingly that the effective RPF rises 75% over nonpregnant levels by 16 weeks’ gestation (Table 3-6). The increase is maintained until 34 weeks’ gestation, when a

Chapter 3 Maternal Physiology 55
TABLE 3-6 SERIAL CHANGEs

IN

RENAL HEMODYNAMICS
SEATED POSITION (n = 25)*

Effective renal plasma flow (mL/min)
Glomerular filtration rate (mL/min)
Filtration fraction

LEFT LATERAL
RECUMBENT
POSITION (n = 17)†

Nonpregnant

16 wk

26 wk

36 wk

29 wk

37 wk

480 ± 72
99 ± 18
0.21

840 ± 145
149 ± 17
0.18

891 ± 279
152 ± 18
0.18

771 ± 175
150 ± 32
0.20

748 ± 85
145 ± 19
0.19

677 ± 82
138 ± 22
0.21

*Data from Dunlop W: Serial changes in renal haemodynamics during normal pregnancy. Br J Obstet Gynaecol 88:1, 1981.
†
Data from Ezimokhai M, Davison J, Philips P, et al: Nonpostural serial changes in renal function during the third trimester of normal human pregnancy. Br J Obstet
Gynaecol 88:465, 1981.

decline in RPF of about 25% occurs. The fall in RPF has been demonstrated in subjects studied serially in the sitting and the left lateral recumbent positions. Like RPF, glomerular filtration rate (GFR), as measured by inulin clearance, increases by 5 to 7 weeks. By the end of the first trimester, GFR is 50% higher than in the nonpregnant state, and this is maintained until the end of pregnancy.
Three months postpartum, GFR values have declined to normal levels.61 This renal hyperfiltration seen in pregnancy is a result of the increase in the RPF. Because the
RPF increases more than the GFR early in pregnancy, the filtration fraction falls from nonpregnant levels until the late third trimester. At this time, because of the decline in RPF, the filtration fraction returns to preconceptional values. Clinically, GFR is not determined by measuring the clearance of infused inulin (inulin is filtered by the glomerulus and is unaffected by the tubules), but rather by measuring endogenous creatinine clearance. This test gives a less precise measure of GFR because creatinine is secreted by the tubules to a variable extent. Therefore, endogenous creatinine clearance is usually higher than the actual GFR. The creatinine clearance in pregnancy is greatly increased to values of 150 to 200 mL/min (normal,
120 mL/min). As with GFR, the increase in creatinine clearance occurs by 5 to 7 weeks’ gestation and normally is maintained until the third trimester. GFR is best estimated in pregnancy using a 24-hour urine collection for creatinine clearance. Formulas that are used in patients with renal disease that estimate the GFR using serum col­ lections and clinical parameters (which avoid a 24-hour urine collection) are inaccurate in pregnancy and underes­ timate the GFR.
The increase in the RPF and GFR precede the increase in blood volume and may be induced by a reduction in the preglomerular and postglomerular arteriolar resistance.
Importantly, the increase in hyperfiltration occurs without an increase in glomerular pressure, which if it occurred, could have the potential for injury to a women’s kidney with long-term consequences.60 Recently, the mechanisms underlying the marked increase in RPF and GFR has been carefully studied. Although numerous factors are involved in this process, NO has been demonstrated to play a critical role in the decrease in renal resistance and the subsequent renal hyperemia. During pregnancy, the activation and expression of the NO synthase is enhanced in the kidneys, and inhibition of NO synthase isoforms has been shown to attenuate the hemodynamic changes within the gravid

kidney.25 Finally, the hormone relaxin appears to be important by initiating or activating some of the effects of NO on the kidney. Failure of this crucial adaptation to occur is associated with adverse outcomes such as preeclampsia and fetal growth restriction.7
The clinical consequences of glomerular hyperfiltration are a reduction in maternal plasma levels of creatinine, blood urea nitrogen (BUN), and uric acid. Serum creatinine decreases from a nonpregnant level of 0.8 mg/dL to 0.5 mg/ dL by term. Likewise, BUN falls from nonpregnant levels of 13 to 9 mg/dL by term.5 Serum uric acid declines in early pregnancy because of the rise in GFR, reaching a nadir by 24 weeks with levels of 2 to 3 mg/dL.62 After
24 weeks, the uric acid level begins to rise, and by the end of pregnancy, the levels in most women are essentially the same as before conception. The rise in uric acid levels is caused by increased renal tubular absorption of urate and increased fetal uric acid production. Patients with pre­ eclampsia have elevated uric acid level concentrations; however, because uric acid levels normally rise during the third trimester, over-reliance on this test should be avoided in the diagnosis and management of preeclampsia.62
During pregnancy, urine volume is increased, and nocturia is more common. In the standing position, sodium and water are retained, and therefore, during the daytime, gravidas tend to retain an increased amount of water. At night while in the lateral recumbent position, this added water is excreted, resulting in nocturia. Later in gestation, the renal function is affected by position, and the GFR and renal hemodynamics are decreased with changes from lateral recumbency to supine or standing.63

Renal Tubular Function/Excretion of Nutrients

Despite high levels of aldosterone, which would be expected to result in enhanced urinary excretion of potassium, gravid women retain about 350 mmol of potassium.
Most of the excess potassium is stored in the fetus and placenta. The mean potassium concentrations in maternal blood are just slightly below nonpregnant levels. The kidney’s ability to conserve potassium has been attributed to increased progesterone levels.64 For information on the changes of sodium, see the section on body water metabolism earlier in this chapter.
Glucose excretion increases in almost all pregnant women, and glycosuria is common. Nonpregnant urinary excretion of glucose is less than 100 mg/day, but 90% of gravidas with normal blood glucose levels excrete 1 to 10 g

56 Section I Physiology
TABLE 3-7 COMPARISON OF 24-HOUR URINARY VOLUME
PROTEIN AND ALBUMIN EXCRETION

Protein
(mg/24 hr)
Albumin
(mg/24 hr)

20 WEEKS
(n = 95)

20 WEEKS
(n = 175)

SIGNIFICANCE

98.1 ± 62.3

121.8 ± 71

P = .007

12.2 ± 8.5

P = .012

9.7 ± 6.2

From Higby K, Suiter C, Phelps J, et al: Normal values of urinary albumin and total protein excretion during pregnancy. Am J Obstet Gynecol 171:984, 1994.
Values are expressed as mean ± SD.

of glucose per day.65 This glycosuria is intermittent and not necessarily related to blood glucose levels or the stage of gestation. Glucose is freely filtered by the glomerulus, and with the 50% increase in GFR, a greater load of glucose is presented to the proximal tubules. There may be a change in the reabsorptive capability of the proximal tubules themselves, but the old concept of pregnancy leading to an overwhelming of the maximal tubular reabsorptive capacity for glucose is misleading and oversimplified.65
The exact mechanisms underlying the altered handling of glucose by the proximal tubules remains obscure. Even though glycosuria is common, gravidas with repetitive gly­ cosuria should be screened for diabetes mellitus if not already tested.
Urinary protein and albumin excretion increases during pregnancy, with an upper limit of 300 mg of proteinuria and
30 mg of albuminuria in a 24-hour period.63 The amount of proteinuria and albuminuria increases both when compared with nonpregnant levels and as the pregnancy advances. Higby and associates collected 24-hour urine samples from 270 women over the course of pregnancy and determined the amount of proteinuria and albuminuria.
These investigators found that the amount of protein and albumin excreted in urine did not increase significantly by trimester but did increase significantly when compared between the first and second half of pregnancy (Table 3-7).
They observed that in women without preeclampsia, under­ lying renal disease, or urinary tract infections, the mean
24-hour urine protein across pregnancy is 116.9 mg, with a
95% upper confidence limit of 260 mg. They also noted that patients do not normally have microalbuminuria, defined as urinary albumin excretion greater than 30 mg/dL. In women with preexisting proteinuria, the amount of protein­ uria increases in both the second and third trimesters, and potentially in the first trimester. In a study of women with diabetic nephropathy, the amount of proteinuria increased from a mean of 1.74 ± 1.33 g per 24 hours in the first trimester to a mean of 4.82 ± 4.7 g per 24 hours in the third trimester, even in the absence of preeclampsia.66 The increase in the renal excretion of proteins is due to a physiologic impairment of the proximal tubular function within the kidney and the increase in the GFR.63
Other changes in tubular function include an increase in the excretion of amino acids in the urine and an increase in calcium excretion (see Chapter 40). Also, the kidney responds to the respiratory alkalosis of pregnancy by enhanced excretion of bicarbonate; however, renal handling of acid excretion is unchanged.

ALIMENTARY TRACT
Appetite

Most women experience an increase in appetite throughout pregnancy. In the absence of nausea or “morning sickness,” women eating according to appetite will increase food intake by about 200 kcal/day by the end of the first trimester. The recommended dietary allowance calls for an additional 300 kcal/day, although in reality most women make up for this with decreased activity. Energy requirements vary depending on the population studied, and a greater increase may be necessary for pregnant teenagers and women with high levels of physical activity. Extensive folklore exists about dietary cravings and aversions during gestation. Many of these are undoubtedly due to an individual’s perception of which foods aggravate or ameliorate such symptoms as nausea and heartburn. The sense of taste may be blunted in some women, leading to an increased desire for highly seasoned food. Pica, a bizarre craving for strange foods, is relatively common among gravidas, and a history of pica should be sought in those with poor weight gain or refractory anemia. Examples of pica include the consumption of clay, starch, toothpaste, and ice.

Mouth

The pH and the production of saliva are probably unchanged during pregnancy. Ptyalism, an unusual complication of pregnancy, most often occurs in women suffering from nausea and may be associated with the loss of
1 to 2 L of saliva per day. Most authorities believe ptyalism actually represents inability of the nauseated woman to swallow normal amounts of saliva rather than a true increase in the production of saliva. A decrease in the ingestion of starchy foods may help decrease the amount of saliva. No evidence exists that pregnancy causes or accelerates the course of dental caries. However, the gums swell and may bleed after tooth brushing, giving rise to the so-called gingivitis of pregnancy. At times, a tumorous gingivitis may occur, presenting as a violaceous pedunculated lesion at the gum line that may bleed profusely. Called epulis gra­ vidarum or pyogenic granulomas, these lesions consist of granulation tissue and an inflammatory infiltrate (see
Chapter 48).

Stomach

The tone and motility of the stomach are decreased, probably because of the smooth muscle–relaxing effects of progesterone and estrogen. Nevertheless, scientific evidence regarding delayed gastric emptying is inconclusive.67
Macfie and colleagues, using acetaminophen absorption as an indirect measure of gastric emptying, failed to demonstrate a delay in gastric emptying when comparing 15 nonpregnant controls with 15 women in each trimester.67 In addition, a recent study showed no delay in gastric emptying in parturients at term who ingested 300 mL of water following an overnight fast.68 However, an increased delay is seen in labor, with the etiology ascribed to the pain and stress of labor.
Pregnancy causes a decreased risk for peptic ulcer disease but, at the same time, causes an increase in gastroeso­ phageal reflux disease and dyspepsia in 30% to 50% of

Chapter 3 Maternal Physiology 57 individuals.69 This apparent paradox can be partially explained by physiologic changes of the stomach and lower esophagus. The increase in gastroesophageal reflux disease is multifactorial and is attributed to esophageal dysmotility caused by gestational hormones, gastric compression from the enlarged uterus, and a decrease in the pressure of the gastroesophageal sphincter. The decrease in the tone of the gastroesophageal sphincter is caused by progesterone, and estrogen may lead to increased reflux of stomach acids into the esophagus and may be the predominant cause of reflux symptoms. Theories proposed to explain the decreased incidence of peptic ulcer disease include increased placental histaminase synthesis with lower maternal histamine levels; increased gastric mucin production leading to protection of the gastric mucosa; reduced gastric acid secretion; and enhanced immunologic tolerance of Helicobacter pylori, the infectious agent that causes peptic ulcer disease69 (see Chapter 45).

Intestines

Perturbations in the motility of the small intestines and colon are common in pregnancy, resulting in an increased incidence of constipation in some and diarrhea in others. Up to 34% of women in one study noted an increased frequency of bowel movements, perhaps related to increased prostaglandin synthesis.70 The prevalence of constipation appears to be higher in early pregnancy, with
35% to 39% of women having constipation in the first and second trimester and only 21% in the last trimester.71 The motility of the small intestines is reduced in pregnancy, with increased oral-cecal transit times. No studies on the colonic transit time have been performed, but limited information suggests reduced colonic motility.70 Although progesterone has been thought to be the primary cause of the decrease in gastrointestinal motility, newer studies show the actual etiology may be due to estrogen. Estrogen causes an increased release of NO from nerves that innervate the gastrointestinal tract that then results in relaxation of the gastrointestinal tract musculature. Absorption of nutrients from the small bowel (with the exception of increased iron and calcium absorption) is unchanged, but the increased transit time allows for more efficient absorption. Parry and colleagues demonstrated an increase in both water and sodium absorption in the colon.72
The enlarging uterus displaces the intestines and, most importantly, moves the position of the appendix. Thus, the presentation, physical signs, and type of surgical incision are affected in the management of appendicitis. Portal venous pressure is increased, leading to dilation wherever there is portosystemic venous anastomosis. This includes the gastroesophageal junction and the hemorrhoidal veins, which results in the common complaint of hemorrhoids.

Gallbladder

The function of the gallbladder is markedly altered because of the effects of progesterone. After the first trimester, the fasting and residual volumes are twice as great, and the rate at which the gallbladder empties is much slower. In addition, the biliary cholesterol saturation is increased, and the chenodeoxycholic acid level is decreased.73 This change in the composition of the bile fluid favors the formation of cholesterol crystals, and with

incomplete emptying of the gallbladder, the crystals are retained, and gallstone formation is enhanced. During pregnancy, biliary sludge develops in about one third of women, and by the time of delivery 10% to 12% of women have gallstones on ultrasonographic examination. Postpar­ tum, biliary sludge disappears in virtually all women, but only about one third of small stones disappear.

Liver

The size and histology of the liver are unchanged in pregnancy. However, many clinical and laboratory signs usually associated with liver disease are present. Spider angiomas and palmar erythema, caused by elevated estrogen levels, are normal and disappear soon after delivery. The serum albumin and total protein levels fall progressively during gestation. By term, albumin levels are 25% lower than non­ pregnant levels. Despite an overall increase in total body protein, decreases in total protein and albumin concentrations occur as a result of hemodilution. In addition, serum alkaline phosphatase activity rises during the third trimes­ ter to levels two to four times those of nongravid women.
Most of this increase is caused by placental production of the heat-stable isoenzyme and not from the liver.1 The serum concentrations of many proteins produced by the liver increase. These include elevations in fibrinogen, ceruloplasmin, transferrin, and the binding proteins for corticosteroids, sex steroids, and thyroid hormones.1
With the exception of alkaline phosphatase, the other
“liver function tests” are unaffected by pregnancy, including serum levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase,
5′-nucleotidase, creatinine phosphokinase, and lactate dehydrogenase. In some studies, the mean levels of ALT and AST are mildly elevated but still within normal values.74 Levels of creatinine phosphokinase and lactate dehydrogenase can increase with labor. Finally, pregnancy may cause some changes in bile acid production and secretion. Pregnancy may be associated with mild subclinical cholestasis resulting from the high concentrations of estrogen. Reports on serum bile acid concentrations are conflicting, with some studies showing an increase and others no change. The fasting levels are unchanged, and the measure­ ment of a fasting level appears to be the best test for diag­ nosing cholestasis of pregnancy.74 Cholestasis results from elevated levels of bile acids and is associated with significant pruritus, usually mild increases of ALT/AST, and an increased risk for poor fetal outcomes (see Chapter 45).

Nausea and Vomiting of Pregnancy

Nausea and vomiting, or “morning sickness,” complicate up to 70% of pregnancies. Typical onset is between 4 and
8 weeks’ gestation, with improvement before 16 weeks; however, 10% to 25% of women still experience symptoms at 20 to 22 weeks’ gestation, and some women experience symptoms throughout the gestation.75 Although the symptoms are often distressing, simple morning sickness seldom leads to significant weight loss, ketonemia, or electrolyte disturbances. The cause is not well understood, although relaxation of the smooth muscle of the stomach probably plays a role. Elevated levels of human chorionic gonadotropin (hCG) may be involved, although a good correlation between maternal hCG concentrations and the degree of

58 Section I Physiology

SKELETON
Calcium Metabolism

Pregnancy was initially thought to be a state of “physiologic hyperparathyroidism” with maternal skeletal calcium loss needed to supply the fetus with calcium. It was thought that this could result in long-term maternal bone loss. It is now evident that most fetal calcium needs are met through a series of physiologic changes in calcium metabolism without long-term consequences to the maternal skeleton.77
This allows the fetus to accumulate 21 g (range, 13 to 33 g) of calcium, 80% of this amount during the third trimester, when fetal skeletal mineralization is at its peak. Calcium is

actively transported across the placenta. Surprisingly, calcium is excreted in greater amounts by the maternal kidneys so that, by term, calciuria is doubled.
Maternal total calcium levels decline throughout preg­ nancy. The fall in total calcium is caused by the reduced serum albumin levels that result in a decrease in the albumin-bound fraction of calcium. However, the physio­ logically important fraction, serum ionized calcium, is unchanged and constant77 (Figure 3-10). Therefore, the actual maternal serum calcium levels are maintained and the fetal calcium needs are met mainly through increased intestinal calcium absorption. Calcium is absorbed through the small intestines, and its absorption is doubled by 12 weeks’ gestation, with maximal absorption in the third trimester.77,78 The early increase in absorption may allow the maternal skeleton to store calcium in advance of the

Total Calcium
(mmol/L)

2.7

2.1
Ionized Calcium
(mmol/L)

1.6

0.9

PTH
(pmol/L)

5.0

0.0

1,25-D
(pmol/L)

300

0.0
100
Calcitonin
(ng/L)

nausea and vomiting has not been observed. Similarly, minimal data exist to show the etiology is associated with higher levels of estrogen or progesterone. Interestingly, pregnancies complicated by nausea and vomiting generally have a more favorable outcome than do those without such symptoms.75 Treatment is largely supportive, consisting of reassurance, avoidance of foods found to trigger nausea, and frequent small meals. Eating dry toast or crackers before getting out of bed may be beneficial. Recently, the
American College of Obstetricians and Gynecologists
(ACOG) stated that the use of either vitamin B6 alone or in combination with doxylamine (Unisom) is safe and effective and should be considered a first line of medical treatment.
A recent review of alternative therapies to antiemetic drugs found that acupressure, wristbands, or treatment with ginger root may be helpful.
Hyperemesis gravidarum is a more pernicious form of nausea and vomiting associated with weight loss, ketone­ mia, electrolyte imbalance, and dehydration. It occurs in
1% to 3% of women, with persistence often throughout pregnancy, and rarely can result in significant complications, including Wernicke encephalopathy, rhabdomyolysis, acute renal failure, and esophageal rupture. For these patients, the clinician must rule out other diseases such as pancreatitis, cholecystitis, hepatitis, and psychiatric disease. Hospitalization with intravenous replacement of fluids and electrolytes is often needed. Options of anti­ emetics include the phenothiazines: promethazine (Phen­ ergan), chlorpromazine (Thorazine), and prochlorperazine
(Compazine) or metoclopramide (Reglan), or ondansetron
(Zofran).76 On admission to the hospital, the patient should be given intravenous hydration and tried on one of the above-mentioned medications (intravenously or intramus­ cularly initially). Care must be taken not to combine the phenothiazines with metoclopramide because of the additive risks for causing extrapyramidal reactions. Chlorpromazine given rectally (25 to 50 mg every 8 hours) may be highly effective in the more refractory cases. Recently, use of oral methylprednisolone, 16 mg three times daily for
3 days and then tapered over 2 weeks, has been shown to be more effective than promethazine, but multiple subsequent studies failed to demonstrate benefit from the use of steroids.76 Unfortunately, no single therapy works in all women, and occasionally, multiple different medications must be tried before finding the one that is effective.
Because of potential risks, parenteral caloric replacement should only be used after failure of multiple antiemetic treatments and attempts at enteral tube feedings.

0.0
1st

2nd

3rd

Trimesters of pregnancy
FIGURE 3-10. The longitudinal changes in calcium and calcitropic hormone levels that occur during human pregnancy. Normal adult ranges are indicated by the shaded areas. 1,25-D, 1,25-dihydroxyvitamin
D; PTH, parathyroid hormone. (From Kovacs C, Kronenberg H:
Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev 18:832, 1997.)

Chapter 3 Maternal Physiology 59 peak third-trimester fetal demands. Although most fetal calcium needs are met by increased absorption of calcium, accumulating data confirm that at least some calcium resorption from maternal bone occurs to help meet the increased fetal demands in the third trimester. These data are compatible with the hypothesis that physiologic mechanisms exist to ensure an adequate supply of calcium for fetal growth and milk production without sole reliance on the maternal diet.78 Maternal serum phosphate levels are similarly unchanged.77
Older studies showed an increase in maternal parathyroid hormone (PTH) levels. These studies used less sensitive PTH assays that measured multiple different fragments of PTH, most of which are biologically inactive.
In five recent prospective studies, all using newer assays, maternal levels of PTH were not elevated and actually remained in the low-normal range throughout gestation.77
Therefore, pregnancy is not associated with relative hyperparathyroidism (see Chapter 40).
Vitamin D is a prohormone that is derived from cholesterol and occurs in two main nutritional forms: D3
(cholecalciferol), which is generated in the skin, and D2
(ergocalciferol), which is derived from plants and absorbed in the gut. Serum levels of 25-hydroxyvitamin D (25[OH]
D) increase in proportion to vitamin D synthesis and intake. Levels of 25[OH]D represent the best indicator of vitamin D status.79 25[OH]D is furthered metabolized to
1,25-dihydroxyvitamin D or active vitamin D. Levels of
1,25-dihydroxyvitamin D increase overall in pregnancy, with prepregnancy levels doubling in the first trimester and peaking in the third trimester. Levels of 25[OH]D do not change in pregnancy unless vitamin D intake or synthesis is changed. The increase in 1,25-dihydroxyvitamin D is secondary to increased production by the maternal kidneys and potentially the fetoplacental unit and is independent of PTH control. The increase in 1,25-dihydroxyvitamin D is directly responsible for most of the increase in intestinal calcium absorption.77 Recently, a great deal of interest in vitamin D deficiency in pregnancy has occurred, with esti­ mated prevalence of 5% to 50% in the United States. Con­ troversy exists over the recommendations to institute universal screening during pregnancy by measuring serum levels of 25[OH]D. Levels less than 32 ng/mL indicate vitamin D deficiency, with recommendations to increase vitamin D supplementation if such a deficiency is diag­ nosed.79 Calcitonin levels also rise by 20% and may help protect the maternal skeleton from excess bone loss.77

Skeletal and Postural Changes

The effect of pregnancy on bone metabolism is complex, and evidence of maternal bone loss during pregnancy has been inconsistent, with various studies reporting bone loss, no change, and even gain. Whether pregnancy causes bone loss is not the important question; instead, the critical question is whether pregnancy and lactation have a longterm risk for causing osteoporosis later in life.80 In a recent review of 23 studies, Ensom and colleagues80 concluded that pregnancy is a period of high bone turnover and remod­ eling. Both pregnancy and lactation cause reversible bone loss, and this loss is increased in women who breastfeed for longer intervals. Studies do not support an association between parity and osteoporosis later in life. Additionally,

in a comparison of female twins discordant for parity, pregnancy and lactation were found to have no detrimental effect on long-term bone loss.
Bone turnover appears to be low in the first half of gestation and then increases in the third trimester, corresponding to the peak rate of fetal calcium needs, and may represent turnover of previously stored skeletal calcium.77
Markers of both bone resorption (hydroxyproline and tartrate-resistant acid phosphatase) and bone formation
(alkaline phosphatase and procollagen peptides) are increased during gestation.78 In the only study of bone biopsies performed in pregnancy, Shahtaheri and associates observed a change in the microarchitectural pattern of bone, but no change in overall bone mass was found. This change in the microarchitectural pattern seems to result in a framework more resistant to the bending forces and biomechanical stresses needed to carry a growing fetus.81 In support of this study, multiple recent studies have shown that bone loss occurs only in the trabecular bone and not cortical bone. Promislow and coworkers measured bone mineral density twice during pregnancies using dualenergy x-ray absorptiometry and showed the mean loss of trabecular bone was 1.9% per 20 weeks’ gestation.82
However, women placed on bedrest had significantly greater bone loss. In comparison, the mean bone loss in postmenopausal women rarely exceeds 2% per year. Older studies indicate that the cortical bone thickness of long bones may even increase with pregnancy.
Although bone loss occurs in pregnancy, the occurrence of osteoporosis during or soon after pregnancy is rare.
Whether additional calcium intake during pregnancy and lactation prevents bone loss is controversial. Most current studies indicate that calcium supplementation does not decrease the amount of bone loss, but Promislow and coworkers82 found that maternal intake of 2 g per day or greater was modestly protective. This is greater than the recommended dietary allowance of 1000 to 1300 mg/day during pregnancy and lactation.78
Pregnancy results in a progressively increasing anterior convexity of the lumbar spine (lordosis). This compensatory mechanism keeps the woman’s center of gravity over her legs and prevents the enlarging uterus from shifting the center of gravity anteriorly. The unfortunate side effect of this necessary alteration is low back pain in two thirds of women, with the pain described as severe in one third.
The ligaments of the pubic symphysis and sacroiliac joints loosen, probably from the effects of the hormone relaxin, the levels of which increase 10-fold in pregnancy. Marked widening of the pubic symphysis occurs by 28 to 32 weeks’ gestation, with the width increasing from 3 to 4 mm to 7.7 to 7.9 mm. This commonly results in pain near the symphysis that is referred down the inner thigh with standing and may result in a maternal sensation of snapping or movement of the bones with walking.

ENDOCRINE CHANGES
Thyroid

Thyroid diseases are common in women of childbearing age
(see Chapter 40). However, normal pregnancy symptoms mirror those of thyroid disease, making it difficult to know when screening for thyroid disease is appropriate. In

60 Section I Physiology addition, the physiologic effects of pregnancy frequently make the interpretation of thyroid tests difficult. Therefore, it is important for the obstetrician to be familiar with the normal changes in thyroid function that occur. Recent data have shown that the correct and timely diagnosis and treatment of thyroid disease is important to prevent both maternal and fetal complications.
Despite alterations in thyroid morphology, histology, and laboratory indices, pregnant women remain euthyroid.
The thyroid gland increases in size, but not as much as was commonly believed. If adequate iodine intake is main­ tained, the size of the thyroid gland remains unchanged or undergoes a small increase in size that can be detected only by ultrasound.83 The World Health Organization recommends that iodine intake be increased in pregnancy from
100 mg/day to 150 to 200 mg/day. In an iodine-deficient state, the thyroid gland is up to 25% larger, and goiters occur in 10% of women.84 Histologically, during pregnancy an increase in thyroid vascularity occurs with evidence of follicular hyperplasia. The development of a clinically apparent goiter during pregnancy is abnormal and should be evaluated.
During pregnancy, serum iodide levels fall because of increased renal loss. In addition, in the latter half of pregnancy, iodine is also transferred to the fetus, further decreasing maternal levels.84 However, at least one investigator has reported that in iodine-sufficient regions, the concentration of iodide does not decrease.85 These alterations cause the thyroid to synthesize and secrete thyroid hormone actively.84 Although there is increased uptake of iodine by the thyroid, pregnant women remain euthyroid by laboratory evaluation.
Total thyroxine (TT4) and total triiodothyronine (TT3) levels begin to increase in the first trimester and peak at midgestation as a result of increased production of thyroidbinding globulin (TBG). The increase in TBG is seen in the first trimester and plateaus at 12 to 14 weeks. The concentration of TT4 increases in parallel with the TBG from a normal range of 5 to 12 mg/dL in nonpregnant women to 9 to 16 mg/dL during pregnancy (increases by a factor of about 1.5). Only a small amount of TT4 and
TT3 is unbound, but these free fractions (normally about
0.04% for T4 and 0.5% for T3) are the major determinants of whether an individual is euthyroid. The extent of change in free T4 and T3 levels during pregnancy has been controversial, and the discrepancies in past studies have been attributed to the techniques used to measure the free hormone levels. The current best evidence is that the free
T4 levels rise slightly in the first trimester and then decrease so that by delivery, the free T4 levels are 10% to 15% lower than in nonpregnant women. However, these changes are small, and in most gravidas, free T4 concentrations remain within the normal nonpregnant range84 (Figure 3-11). In clinical practice, the free T4 level can be measured using either the free thyroxine index (FTI) or estimates of free
T4. These tests use immunoassays that do not measure the free T4 directly and may be less accurate in pregnancy because they are TBG dependent. Lee and colleagues showed that the FTI is a more accurate method for mea­ suring free T4 and that the currently used estimates for free T4 may incorrectly diagnose women as hypothyroid in the second and third trimesters; however, other authors

TBG
Total T4 hCG Free T4

10

TSH

20

30

40

Week of pregnancy
FIGURE 3-11. Relative changes in maternal thyroid function during pregnancy. hCG, Human chorionic gonadotropin; T4, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone. (From
Burrow G, Fisher D, Larsen P: Maternal and fetal thyroid function.
N Engl J Med 331:1072, 1994.)

have shown that these free T4 estimates are accurate.86,87
Free T3 levels follow a similar pattern as free T4 levels.
Thyroid-stimulating hormone (TSH) concentrations decrease transiently in the first trimester and then rise to prepregnant levels by the end of this trimester. TSH levels then remain stable throughout the remainder of gestation.84
The transient decrease in TSH coincides with the firsttrimester increase in free T4 levels, and both appear to be caused by the thyrotropic effects of hCG. Women with higher peak hCG levels have more TSH suppression.
TSH and hCG are structurally very similar, and they share a common α-subunit and have a similar β-unit. Glinoer and colleagues estimated that a 10,000-IU/L increment in circulating hCG corresponds to a mean free T4 increment of 0.6 pmol/L (0.1 ng/dL) and, in turn, lowers TSH by
0.1 mIU/L.84,88 These investigators measured TSH levels during successive trimesters of pregnancy in a large group of women and found that TSH was suppressed below normal in 18% in the first trimester, 5% during the second trimester, and 2% in the third trimester. In the first two trimesters, the mean hCG level was higher in women with suppressed TSH levels.88 It appears that hCG has some thyrotropic activity, but conflicting data on the exact role of hCG in maternal thyroid function remain.84 In some women, the thyrotropic effects of hCG can cause a transient form of hyperthyroidism called gestational transient thyrotoxicosis.
The influence of maternal thyroid physiology on the fetus appears much more complex than was previously thought. Whereas the maternal thyroid does not directly control fetal thyroid function, the systems interact by means of the placenta, which regulates the transfer of iodine and a small but important amount of thyroxine to the fetus. It was previously thought that little if any transplacental passage of T4 and T3 occurred. It is now

Chapter 3 Maternal Physiology 61 recognized that T4 crosses the placenta and that, in fact, in early pregnancy, the fetus is critically dependent on the maternal T4 supply for normal neurologic development.89
However, as a result of the deiodinase activity of the placenta, a large percentage of T4 is broken down before transfer to the fetus. The human fetus cannot synthesize thyroid hormones until after 12 weeks’ gestation, and any fetal requirement before this time is totally dependent on maternal transfer. Even after the fetal thyroid is functional, the fetus continues to rely to some extent on a maternal supply of thyroxine.
Neonates with thyroid agenesis or a total defect in thyroid hormone synthesis have umbilical cord thyroxine levels between 20% and 50% of those in normal infants, demonstrating that the placenta is not impermeable to T4.
Further evidence that the fetus is dependent on the maternal thyroid for normal development has been published.
In women living in iodine-deficient areas, maternal hypothyroidism is associated with neonatal hypothyroidism and defects in long-term neurologic function and mental retardation termed endemic cretinism. These abnormalities can be prevented if maternal iodine intake is initiated at the beginning of the second trimester.90 Haddow and cowork­ ers91 have found that maternal hypothyroidism during pregnancy results in slightly lower IQ scores in children tested at ages 7 to 9 years. These findings have resulted in controversy over whether all pregnant women should be screened for subclinical hypothyroidism, which has an inci­ dence of 2% to 5%. Position statements from various orga­ nizations are currently contradictory. The Endocrine
Society recommends universal screening. ACOG opposes routine screening in pregnancy (Committee Opinion No.
381). Like T4, thyrotropin-releasing hormone crosses the placenta; TSH does not.
Because iodine is actively transported across the placenta and the concentration of iodide in the fetal blood is 75% that of the maternal blood, the fetus is susceptible to iodine-induced goiters when the mother is given pharmacologic amounts of iodine. Similarly, radio­ active iodine crosses the placenta and, if given after
12 weeks’ gestation when the fetal thyroid is able to con­ centrate iodine, profound adverse effects can occur. These include fetal hypothyroidism, mental retardation, attention deficit disorder, and a 1% to 2% increase in the lifetime cancer risk.

Adrenal Glands

Increased steroid production is essential in pregnancy to meet the need for an increase in maternal production of estrogen and cortisol and the fetal need for reproductive and somatic growth development. Pregnancy is associated with marked changes in adrenocortical function, with increased serum levels of aldosterone, deoxycorticosterone, corticosteroid-binding globulin (CBG), adrenocortico­ tropic hormone (ACTH), cortisol, and free cortisol and causes a state of “physiologic” hypercorticolism92,93 (see
Chapter 41 and Appendix A1). Although the combined weight of the adrenal glands does not increase significantly, expansion of the zona fasciculata, which primarily produces glucocorticoids, is observed. The plasma concentration of CBG doubles (because of hepatic stimulation by estrogen) by the end of the sixth month of gestation

compared with nonpregnant values, resulting in elevated levels of total plasma cortisol. The levels of total cortisol rise after the first trimester and by the end of pregnancy are nearly three times higher than nonpregnant values and reach values that are in the range seen in Cushing syn­ drome. The diurnal variations in cortisol levels may be partly blunted but are maintained, with the highest values in the morning.
Only free cortisol, the fraction of cortisol not bound to
CBG, is metabolically active, but direct measurements are difficult to perform. However, urinary free cortisol concentrations, the free cortisol index, and salivary cortisol concentrations, all of which reflect active free cortisol levels, are elevated after the first trimester.93,94 In a study of 21 uncomplicated pregnancies, Goland and associates found that the urinary free cortisol concentration doubled from the first to the third trimester.93 Although the increase in total cortisol concentrations can be explained by the increase in CBG, this does not explain the higher free cortisol levels. The elevation in free cortisol levels seems to be caused in part by a marked increase in corticotropinreleasing hormone (CRH) during pregnancy, which, in turn, stimulates the production of ACTH in the pituitary and from the placenta. Outside of pregnancy, CRH is mainly secreted from the hypothalamus. During pregnancy, CRH is also produced by the placenta and fetal membranes and is secreted into the maternal circulation.
First-trimester values of CRH are similar to prepregnant levels, followed by an exponential rise in CRH during the third trimester predominantly as a result of the placental production.93 Goland and associates have shown that CRH and ACTH concentrations continue to rise in the third trimester despite the increased levels of total and free cortisol levels, supporting the theory that an increase in
CRH drives the increased levels of cortisol seen in pregnancy. Furthermore, significant correlation is observed between the rise in CRH levels and maternal ACTH and urinary free cortisol concentrations.93 Other possible causes for the hypercortisolism include delayed plasma clearance of cortisol as a result of changes in renal clearance, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors such as vasopressin and CRH.92,95
Although the levels of cortisol are increased to concentrations observed in Cushing’s syndrome, little clinical evidence is present for hypercortisolism during pregnancy with the exception of weight gain, striae, hyperglycemia, and tiredness. However, the diagnosis of Cushing syn­ drome during pregnancy is difficult because of these changes. The hypothalamic-pituitary axis response to exogenous glucocorticoids is blunted during normal preg­ nancy and makes interpretations of dexamethasone sup­ pression tests for adrenal excess problematic.95 In addition, pregnancy causes an enhanced adrenal responsiveness to higher-dose ACTH stimulation tests using 250 mcg of cosyntropin, making the diagnosis of adrenal insufficiency also difficult.
Deoxycorticosterone (DOC), like aldosterone, is a potent mineralocorticoid. Marked elevations in the maternal concentrations of DOC are present by midgestation, reaching peak levels in the third trimester. In contrast to the nonpregnant state, plasma DOC levels in the third

62 Section I Physiology trimester do not respond to ACTH stimulation, dexamethasone suppression, or salt intake.92 These findings suggest that an autonomous source of DOC, specifically the fetoplacental unit, may be responsible for the increased levels. Dehydroepiandrosterone sulfate levels are decreased in gestation because of a marked rise in the metabolic clearance of this adrenal androgenic steroid.
Maternal concentrations of testosterone and androstenedione are slightly higher; testosterone is increased because of an elevation in sex hormone-binding protein, and androstenedione is increased because of an increase in its synthesis. Pregnancy taxes maternal insulin and carbohydrate physiology, and in all pregnancies, some deterioration in glucose tolerance occurs. In most women, only mild changes take place. In others, pregnancy is sufficiently diabetogenic to result in gestational diabetes mellitus. Overall, pregnancy results in fasting hypoglycemia, postprandial hyperglyce­ mia, and hyperinsulinemia.99 To accommodate the increased demand for insulin, hypertrophy and hyperplasia of the β cells (insulin producing) occur within the islets of
Langerhans in the maternal pancreas. For a complete review of the physiologic changes in glucose metabolism, refer to Chapter 39.

Pituitary Gland

Proteins and Fats/Lipids

The pituitary gland enlarges in pregnancy, principally because of proliferation of prolactin-producing cells in the anterior pituitary (see Chapter 41). Gonzalez and colleagues demonstrated that the mean pituitary volume increased by 36% at term.96 The enlargement of the pitu­ itary gland makes it more susceptible to alterations in blood supply and increases the risk for postpartum infarction
(Sheehan syndrome) should a large maternal blood loss occur. Anterior pituitary hormone levels are significantly affected by pregnancy. Serum prolactin levels begin to rise at 5 to 8 weeks’ gestation and by term are 10 times higher.
Consistent with this, the number of lactotroph (prolactinproducing) cells increases dramatically within the anterior lobe of the pituitary from 20% of the cells in nongravid women to 60% in the third trimester. In the second and third trimesters, the decidua is a source of much of the increased prolactin production. Despite the increase, prolactin levels remain suppressible by bromocriptine therapy.97 The principal function of prolactin in pregnancy is to prepare the breast for lactation. In nonlactating women, the prolactin levels return to normal by 3 months postpartum. In lactating women, the return to baseline levels takes several months, with intermittent episodes of hyperprolactinemia in conjunction with nursing. Maternal follicle-stimulating hormone and luteinizing hormone are decreased to undetectable levels as a result of feedback inhi­ bition from the elevated levels of estrogen, progesterone, and inhibin.97 Maternal pituitary growth hormone production is also suppressed because of the action of placental growth hormone variant on the hypothalamus and pituitary; however, the serum levels of growth hormone increase as a result of the production of growth hormone from the placenta.97
The hormones produced by the posterior pituitary are also changed. The changes in AVP were discussed earlier in this chapter. Oxytocin levels increase from 10 pg/mL in the first trimester to 30 pg/mL in the third trimester. At term, an increase is noted to about 75 pg/mL, and during labor, these levels dramatically rise and peak in the second stage of labor.98

PANCREAS AND FUEL METABOLISM
Glucose

Pregnancy is associated with significant physiologic changes in carbohydrate metabolism. This allows for the continuous transport of energy, in the form of glucose, from the gravid woman to the developing fetus and placenta.

Amino acids are actively transported across the placenta for the fetus to use for protein synthesis and as an energy source. In late pregnancy, the fetoplacental unit contains about 500 mg of protein. During pregnancy, fat stores are preferentially used as a substrate for fuel metabolism, and thus, protein catabolism is decreased.
Plasma lipids and lipoproteins increase in pregnancy. A gradual twofold to threefold rise in triglyceride levels occurs by term, and levels of 200 to 300 mg/dL are normal.
Total cholesterol and low-density lipoprotein levels are also higher so that, by term, a 50% to 60% increase is observed. High-density lipoprotein levels initially rise in the first half of pregnancy and then fall in the second half. By term, high-density lipoprotein concentrations are
15% higher than nonpregnant levels. Triglyceride concentrations return to normal by 8 weeks postpartum even with lactation, but cholesterol and low-density lipoprotein levels remain elevated (Figure 3-12). The mechanisms for the pregnancy-induced changes in lipids are not completely understood but appear to be partly caused by the elevated levels of estrogen, progesterone, and human placenta lactogen. The rise in low-density lipo­ proteins appears to be necessary for placental steroido­ genesis. Despite the increase in cholesterol and lipids, no increase in the long-term risk for atherosclerosis has been found. However, women with preexisting hyperlipidemia can have a transient worsening of their lipid profiles that is accentuated by the necessity for discontinuing medications such as HMG-CoA reductase inhibitors
(statins).

EYE

Two consistent and significant ocular changes occur during pregnancy: increased thickness of the cornea and decreased intraocular pressure. Corneal thickening is apparent by
10 weeks’ gestation and may cause problems with contact lenses. Corneal changes persist for several weeks postpar­ tum, and patients should be advised to wait before obtain­ ing a new eyeglass or contact prescription. Pizzarello found that 14% of women complained of vision changes. All had changes in their visual acuity and refractive error as well as a myopic shift (became more far-sighted) from pregravid levels, with return to baseline vision postpartum.100 Because of these transient alterations in the eye, pregnancy is considered by most to be a contraindication to photore­ fractive keratectomy, and it has been recommended that pregnancy be avoided for 1 year after such surgery.

Chapter 3 Maternal Physiology 63
Triglycerides

300
250
mg/dL

200
150
100
50
0
300

Cholesterol

250
Plasma
200

mg/dL

150

LDL

100
HDL

50

VLDL

0

0
Before
conception

8

14

20

28

Pregnancy

36

8
Lactation

FIGURE 3-12. Triglycerides (upper panel) and cholesterol (lower panel) in plasma and in lipoprotein fractions before, during, and after pregnancy. HDL, High-density lipoprotein; LDL, low-density lipoprotein;
VLDL, very-low-density lipoprotein. (From Salameh W, Mastrogiannis
D: Maternal hyperlipidemia in pregnancy. Clin Obstet Gynecol 37:66,
1994.)

Intraocular pressure falls by about 10%, and individuals with preexisting glaucoma typically improve. Pregnancy either does not change or minimally decreases visual fields.
Any complaints of visual field changes are atypical and need evaluation.
KEY POINTS
◆ Plasma

osmolality decreases during pregnancy as a result of a reduction in the serum concentration of sodium and associated anions. The osmolality set point for AVP release and thirst is also decreased. ◆ CO increases 30% to 50% during pregnancy.
Supine positioning and standing are both associated with a fall in CO. CO is maximum during labor and the immediate postpartum period.
◆ As a result of the marked fall in systemic vascular resistance and pulmonary vascular resistance,
PCWP does not rise, despite an increase in blood volume. ◆ Maternal BP decreases early in pregnancy. The diastolic BP and the mean arterial pressure reach

a nadir at midpregnancy (16 to 20 weeks) and return to prepregnancy levels by term.
◆ PaO2 and PaCO2 fall during pregnancy because of increased minute ventilation. This facilitates transfer of CO2 from the fetus to the mother and results in a mild respiratory alkalosis.
◆ Maternal plasma volume increases 50% during pregnancy. RBC volume increases about 18% to
30%, and the hematocrit normally decreases during gestation, but not below 30%.
◆ Pregnancy is a hypercoagulable state, with increases in the levels of most of the procoagulant factors and decreases in the fibrinolytic system and in some of the natural inhibitors of coagulation. ◆ BUN and creatinine normally decrease during pregnancy as a result of the increased glomerular filtration rate.
◆ Despite alterations in thyroid morphology, histology, and laboratory indices, the normal pregnant woman is euthyroid, with levels of free T4 within nonpregnant norms.
◆ Pregnancy is associated with a peripheral resistance to insulin, primarily mediated by human placental lactogen. Insulin resistance increases as pregnancy advances; this results in hyperglycemia, hyperinsulinemia, and hyperlipidemia in response to feeding, especially in the third trimester

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