Maternal Physiology

Heart

Some of the most profound physiologic changes of pregnancy take place in the cardiovascular system. These changes maximize oxygen delivery to both the mother and fetus. The combination of displacement of the diaphragm and the effect of pregnancy on the shape of the rib cage displaces the heart upward and to the left. The heart also rotates along its long axis, thereby resulting in an increased cardiac silhouette on imaging studies. No change is evident in the cardiothoracic ratio. Other radiographic findings include an apparent straightening of the left-sided heart border and increased prominence of the pulmonary conus. It is therefore important to confirm the diagnosis of cardiomegaly with an echocardiogram and not simply to rely on radiographic imaging.

Eccentric cardiac hypertrophy is commonly noted in pregnancy. It is thought to result from expanded blood volume in the first half of pregnancy and progressively increasing afterload in later gestation. These changes, similar to those found in response to exercise, enable the pregnant woman's heart to work more efficiently. Unlike the heart of an athlete, which regresses rapidly with inactivity, the pregnant woman's heart decreases in size less rapidly and takes up to 6 months to return to normal.

Cardiac Output

One of the most remarkable changes in pregnancy is the tremendous increase in cardiac output (CO). A review of 33 cross-sectional and 19 longitudinal studies revealed that CO increased significantly beginning in early pregnancy and peaked at an average of 30% to 50% above preconceptional values. In a longitudinal study using Doppler echocardiography, CO increased by 50% at 34 weeks from a prepregnancy value of 4.88 to 7.34 L/min ( Fig. 3.1 ). In twin gestations, CO incrementally increases an additional 20% above that of singleton pregnancies. 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, which accounts for about 75% of the total increase in CO during pregnancy. Although the literature is not clear regarding the exact point in gestation at which CO peaks, most studies point to a range between 25 and 30 weeks. 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. Thus little to no change is likely during this period. 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.

Most of the increase in CO is directed to the uterus, placenta, and breasts. In the first trimester, as in the nongravid state, the uterus receives 2% to 3% of CO and the breasts receive 1%. The percentage of CO that goes 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%. By term, the uterus receives 17% (450 to 650 mL/min) and the breasts receive 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.

CO is the product of stroke volume (SV) and heart rate (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 of gestation and reaches its maximum at about 20 weeks at 20% to 30% above nonpregnant values.

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 and lateral recumbent positions at 6.9 and 6.6 L/min, respectively. CO decreased by 22% to 5.4 L/min in the standing position ( Fig. 3.2 ). 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 (IVC), which reduces venous return; before 24 weeks, this effect is not observed. In late pregnancy, the IVC is completely occluded in the supine position, and venous return from the lower extremities occurs through the dilated paravertebral collateral circulation. It is worth noting that whereas the original studies of CO were done with invasive testing, the current accepted practice is to estimate CO in pregnancy using echocardiography.

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 compared with asymptomatic women. Interestingly, with engagement of the fetal head, less of an effect on CO is seen. 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 nonreassuring fetal HR tracing. The finding of a decreased CO in the standing position may give a physiologic basis for the finding of decreased birthweight in working women who stand for prolonged periods. In twin pregnancies, CO is notably 15% higher than in singleton pregnancies. This finding is corroborated with findings of increased left atrial diameter in twin pregnancies, indicating volume overload.

Arterial Blood Pressure and Systemic Vascular Resistance

BP is the product of CO and SVR (BP = CO × SVR). Despite the significant increase in CO, the maternal BP is decreased until later in pregnancy as a result of a decrease in SVR that reaches its nadir at midpregnancy and is followed by a gradual rise until term. Even at full term, SVR remains 21% to 26% lower than prepregnancy values in pregnancies not affected by gestational hypertension or preeclampsia. The most obvious cause for the decreased SVR is progesterone-mediated smooth muscle relaxation. However, the exact mechanism for the fall in SVR is poorly understood and likely involves vasorelaxation via the nitric oxide (NO) pathway and blunting of vascular responsiveness to vasoconstrictors such as angiotensin II and norepinephrine. As a result, despite the overall increase in the renin-angiotensin aldosterone system (RAAS), the normal gravida is refractory to the vasoconstrictive effects of angiotensin II. Gant and colleagues showed that nulliparous women who later develop preeclampsia retain their response to angiotensin II before the appearance of clinical signs of preeclampsia.

Decreases in maternal BP parallel the falling SVR, with initial decreased BP that manifests at 8 weeks’ gestation or earlier. 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 3 to 10 mm Hg ( Fig. 3.3 ). The diastolic BP and the MAP reach their nadir at midpregnancy and return to prepregnancy levels by term. In most studies, they rarely exceed prepregnancy or postpartum values; however, some investigators have reported that at term, the BP is greater than that in matched nonpregnant controls. They have also found that in the third trimester, the BP is higher than prepregnant values. As noted previously, pregnancy-induced BP changes happen very early, possibly even before the patient realizes that she is pregnant, and therefore even early pregnancy BP assessments may not be consistent with prepregnancy values.

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 that in the inferior arm. In the ambulatory setting, 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 a muffling of the sound is apparent. 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. 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 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 H ₂ O at 10 weeks’ gestation to 25 cm H ₂ O near term. From a clinical standpoint, this increase in pressure—in addition to the obstruction of the IVC by the expanding uterus—leads to the development of edema, varicose veins, and hemorrhoids, and increases the risk for deep venous thrombosis (DVT).

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 ). Newer, noninvasive methods of central hemodynamic monitoring are being developed and validated in the pregnant population. As described earlier, CO, HR, SVR, and pulmonary vascular resistance change significantly with pregnancy. In addition, clinically significant decreases occur in colloidal oncotic pressure (COP) and in the COP–pulmonary capillary wedge pressure (PCWP) difference, which explains 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, it can reach levels as low as 14 mm Hg. 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 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 significantly with advancing gestation. Second, physiologic dyspnea is usually mild, does not stop women from performing normal daily activities, and does not occur at rest. The mechanism for dyspnea of pregnancy is not well characterized but is thought to be secondary to the increased effort of inspiratory muscles. Other normal symptoms that can mimic cardiac disease include decreased exercise tolerance, fatigue, occasional orthopnea, syncope, and chest discomfort. Symptoms that should not be attributed to pregnancy and that need a more thorough investigation include hemoptysis, syncope or chest pain with exertion, progressive orthopnea, or paroxysmal nocturnal dyspnea. Normal physical findings that could be mistaken as evidence of cardiac disease include peripheral edema, mild tachycardia, jugular venous distension 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 exaggerated splitting is apparent. The second heart sound usually remains normal with only minimal changes. Up to 80% to 90% of gravidas demonstrate a third heart sound (S ₃ ) 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 ( Fig. 3.4 ).

Troponin 1 and creatinine kinase-MB levels are tests used to assess myocardial injury in acute myocardial infarction. Uterine contractions can lead to significant increases in the creatinine kinase-MB level, but troponin levels are not affected by pregnancy or labor.

Effect of Labor and the Immediate Puerperium

The profound anatomic and functional changes in 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 of 15 uncomplicated cases without epidural anesthesia, the CO between contractions increased 12% during the first stage of labor ( Fig. 3.5 ). This increase in CO is caused primarily by an increased SV, but HR may also rise. 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). 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. 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. 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) , with a further rise in CO of 10% to 20%, CO reaches its maximum. 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 auto-transfusion 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 the pre-labor 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 near-preconceptional levels.

Cardiac Rhythm

Pregnancy increases the maternal HR and also significantly increases the frequency of isolated atrial and ventricular contractions. In a Holter monitor study, 110 pregnant women referred for evaluation of symptoms of palpitations, dizziness, or syncope were compared with 52 healthy pregnant women. 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 (22% vs. 2%, P = .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 an HR of less than 60 beats/min in the immediate postpartum period. Other studies have shown that women with preexisting tachyarrhythmias have an increased incidence of these rate abnormalities during pregnancy. 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.

Plasma Volume and Red Cell Mass

Maternal blood volume begins to increase at about 6 weeks’ gestation. Thereafter, it rises progressively until 30 to 34 weeks and then plateaus until delivery. The average expansion of blood volume is 40% to 50% (range, 20% to 100%). Women with multiple pregnancies have a larger increase in blood volume than those with singletons. 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 expand at about 10 weeks’ gestation. Although the initial slope of this increase is slower than that of the plasma volume, erythrocyte mass continues to grow 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%, and a corresponding improvement is seen in hemoglobin levels. Because plasma volume increases more than the RBC mass, maternal hematocrit falls. This so-called physiologic 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 ( Fig. 3.6 ). The mean and fifth-percentile hemoglobin concentrations for normal iron-supplemented pregnant women are outlined in Table 3.2 . A hemoglobin level that reaches its nadir at 9 to 11 g/dL has been associated with the lowest rate of perinatal mortality, whereas values below or above this range have been linked to an increased perinatal mortality.

In pregnancy, erythropoietin levels increase twofold to threefold, starting at 16 weeks, and they may be responsible for the moderate erythroid hyperplasia found in the bone marrow and for the 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 by the large, low-resistance vascular pool within the uteroplacental unit, thereby preventing hypotension.

Vaginal delivery of a singleton infant at term is associated with a mean blood loss of 500 mL; an uncomplicated cesarean delivery, about 1000 mL; and a cesarean hysterectomy, 1500 mL. 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. Gravid women respond to blood loss in a different fashion than in the nonpregnant state. In pregnancy, the blood volume drops after postpartum bleeding, but no reexpansion to the prelabor level occurs, and less of a change is seen in the hematocrit. 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 the blood loss was greater than appreciated or the hypervolemia of pregnancy was less than normal, as in preeclampsia.

Iron Metabolism

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, such as during pregnancy, 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 is incorporated into hemoglobin (75% of iron) and myoglobin or is 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 an iron deficiency.

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. 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 via transferrin receptors located on the apical surface of the placental syncytiotrophoblast. Holotransferrin is then endocytosed, and the iron is released and follows a similar pattern to reach the fetal circulation. In the setting of maternal iron deficiency, the number of placental transferrin receptors increases so that more iron is taken up by the placenta; however, the capacity of this compensatory mechanism can be inadequate and can result in fetal iron deficiency. Maternal iron deficiency anemia has also been associated with adverse pregnancy outcomes, such as low birthweight infants and preterm birth. However, excess iron supplementation and higher levels of hemoglobin are also associated with adverse maternal outcomes, so a balance is required. For a review on the use of supplemental iron in pregnancy, see Chapter 49 .

Platelets

Before the introduction of automated analyzers, studies of platelet counts during pregnancy reported conflicting results. Even with the availability of automated cell counters, the data on the change in platelet count during pregnancy are still somewhat unclear. Pitkin and colleagues measured platelet counts in 23 women every 4 weeks and found that the counts dropped from 322 ± 75 × 10 ³ /mm ³ in the first trimester to 278 ± 75 × 10 ³ /mm ³ in the third trimester. More recent studies confirm 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 demonstrated that in the third trimester, about 8% of gravidas develop gestational thrombocytopenia with platelet counts between 70,000 and 150,000/mm ³ . Gestational thrombocytopenia is not associated with an increase in pregnancy complications, and platelet counts return to normal by 1 to 2 weeks postpartum (see Chapter 49 ). Many features of gestational thrombocytopenia are similar to those of mild immune thrombocytopenia, so the etiology may be immunologic. Another hypothesis is that gestational thrombocytopenia is due to exaggerated platelet consumption, similar to that seen in normal pregnancy. Consistent with these findings, Boehlen and associates compared platelet counts during the third trimester of pregnancy with those in nonpregnant controls and showed a shift to a lower mean platelet count and an overall shift to the left of the “platelet curve” in the pregnant women ( Fig. 3.7 ). This study found that only 2.5% of nonpregnant women have platelet counts less than 150,000/mm ³ , the traditional value used outside of pregnancy as the cutoff for normal, versus 11.5% of gravid women. A platelet count of less than 116,000/mm ³ 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.

The normal decrease in platelet count is associated with procoagulant morphologic changes, procoagulant change in platelet-erythrocyte interactions, and an increase in platelet aggregability. Increased platelet aggregability is evidenced by decreased platelet-function analyzer (PFA-100) values, which signify a decreased time for a platelet plug to occlude an aperture in a collagen membrane and measures the ability of platelets to occlude a vascular breach. Thus while the number of platelets decreases, platelet function increases to maintain hemostasis.

Leukocytes

The peripheral white blood cell (WBC) count rises progressively during pregnancy. During the first trimester, the mean WBC count is 8000/mm ³ with a normal range of 5110 to 9900/mm ³ . During the second and third trimesters, the mean is 8500/mm ³ with a range of 5600 to 12,200/mm ³ . In labor, the count may rise to 20,000 to 30,000/mm ³ , and counts are highly correlated with labor progression as determined by cervical dilation. 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 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 50 ). 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 stasis in the lower extremities is due to compression of the IVC 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 peripartum 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. 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. 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 it has no effect on the levels of protein C and antithrombin III. The activated protein C (APC)/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 it is less than 2.6. In a study of 239 women, 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. 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 thrombophilia 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%, respectively.

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. The most likely cause for these findings involves localized physiologic changes needed for maintenance of the uterine-placental interface.

The complex array of procoagulative changes can be further illustrated via emerging point-of-care analyses, such as thromboelastography and rotational thromboelastography. Briefly, these assays provide a visual and numeric representation of the rate of clot formation and the stability of the clot, which allows a detailed analysis of the expected hypercoagulable state and, if indicated, targets for transfusion. Use of these tests in pregnancy requires caution, however, because physiologic values vary in pregnancy compared with a nonpregnant state; these changes reflect a procoagulative state. Reference ranges for pregnancy are shown in Table 3.3 .

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 and decreased nasal patency; 27% of women at 12 weeks’ gestation report nasal congestion and rhinitis, and this increases to 42% at 36 weeks’ gestation. This decreased patency can lead to anesthesia complications; in fact, the Mallampati score is demonstrably increased (see Chapter 16 ). Epistaxis is also common and may rarely require surgery. In addition, the placement of nasogastric tubes may cause excessive bleeding if adequate lubrication is not used. 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 the 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. This increased diaphragmatic excursion is the effect of progesterone, which acts at the level of the central chemoreceptors to increase diaphragmatic effort and results in greater negative inspiratory pressures. Respiratory muscle function is not affected by pregnancy, and maximal inspiratory and expiratory pressures are unchanged.

Lung Volume and Pulmonary Function

The described alterations in chest wall configuration and in 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 ( Fig. 3.8 , Table 3.4 ). The elevation of the diaphragm decreases the volume of the lungs in the resting state, thereby reducing total lung capacity (TLC) and the functional residual capacity (FRC). The FRC can be subdivided into expiratory reserve volume (ERV) and residual volume (RV), and both decrease.

Some spirometric measurements to assess bronchial flow are unchanged in pregnancy, whereas others are altered. Historically, it has been well accepted that the forced expiratory volume in 1 second (FEV ₁ ) does not change, which suggests that the airway function remains stable. However, FEV ₁ may indeed decrease across pregnancy under certain circumstances, such as high altitude. Different studies have observed varied effects on the peak expiratory flow (PEF). In a longitudinal study of the peak flow in 38 women from the first trimester until 6 weeks postpartum, peak flows had a statistically significant decrease as gestation progressed, but the amount of the decrease was of questionable clinical significance. Likewise, a small decline in the peak flow was found in the supine position versus the standing or sitting position. In a similar study of 80 women, PEF was found to increase progressively after 14 to 16 weeks. Notably, these values were also significantly higher at any time point during pregnancy in parous compared with nulliparous women, which may suggest that this change is permanent. An additional finding of this study was that no differences in forced vital capacity (FVC), FEV ₁ , or PEF were noted based on overweight status or excess GWG. In summary, both spirometry and peak flowmeters can be used to diagnose and manage respiratory illness, but the clinician should ensure that measurements are performed in the same maternal position .

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 ventilation, 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 (PaO ₂ ) and decreased arterial carbon dioxide (PaCO ₂ ) from normal levels ( Table 3.5 ). The drop in the PaCO ₂ is especially critical because it drives a more favorable CO ₂ gradient between the fetus and mother, which facilitates CO ₂ transfer. The low maternal PaCO ₂ 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 (PaO ₂ ) increases (106 to 108 mm Hg) as the PaCO ₂ decreases, but by the third trimester, a slight decrease in the PaO ₂ (101 to 104 mm Hg) occurs as a result of the enlarging uterus. This decrease in the PaO ₂ late in pregnancy is even more pronounced in the supine position; one study found a further drop of 5 to 10 mm Hg and an increase in the alveolar-to-arterial gradient to 26 mm Hg. Up to 25% of women may exhibit a PaO ₂ of less than 90 mm Hg. The mean PaO ₂ is lower in the supine position than in the sitting position.

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 and 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. During a contraction, oxygen consumption can triple. As a result of the increased oxygen consumption, and because the FRC is decreased, a lowering of the maternal oxygen reserve occurs. Therefore the pregnant patient is more susceptible to the effects of apnea, such as during intubation, when a more rapid onset of hypoxia, hypercapnia, and respiratory acidosis is seen. Indeed, the desaturation time after thorough preoxygenation is shortened from 9 minutes in the nonpregnant state to 3 minutes in pregnancy.

Sleep

Pregnancy causes both an increase in sleep disorders and significant changes in sleep profile and pattern that persist into the postpartum period. Pregnancy causes such significant changes that the American Academy of Sleep Medicine has described a specific pregnancy-associated sleep disorder: diagnostic criteria include a complaint of either insomnia or excessive sleepiness with onset during pregnancy . Sleep disturbances are associated with poor health outcomes in the general population, and emerging evidence suggests that abnormal sleep patterns in pregnancy may contribute to certain complications, such as hypertensive disorders and fetal growth restriction (FGR). It is well known that hormones and physical discomfort affect sleep ( Table 3.6 ). 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 pregnant women (66% to 94%) report alterations in sleep that lead to the subjective perception of poor sleep quality. Sleep disturbances begin as early as the first trimester and worsen as the pregnancy progresses. During the third trimester, multiple discomforts occur that can impair sleep: urinary frequency, backache, general abdominal discomfort and contractions, leg cramps, restless legs syndrome (RLS), 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 stage 3 and 4 non-REM sleep. REM sleep is important for cognitive thinking, and stage 3 and 4 non-REM sleep is the so-called deep sleep that is important for rest. In addition, with advancing gestational age, a decrease in sleep efficiency and continuity and an increase in awake time and daytime somnolence is observed. By 3 months postpartum, the amount of non-REM and REM sleep recovers, but a persistent decrease in sleeping efficiency and nocturnal awakenings occurs, presumably because of the newborn. Although pregnancy causes changes in sleep, it is important for the clinician to consider other primary sleep disorders that may be unrelated to pregnancy, such as sleep apnea. The physiologic changes of pregnancy also increase the incidence of sleep-disordered breathing, which includes snoring (in up to 35% of women), upper airway obstruction, and potentially obstructive sleep apnea (OSA). The prevalence of sleep apnea in pregnancy is unknown and has been difficult to determine; the screening questionnaires appear to perform poorly in pregnancy, likely due to the frequency of daytime sleepiness and snoring in pregnancy in the absence of OSA. When it is diagnosed or highly suspected based upon symptoms, OSA appears to increase the risk for intrauterine growth restriction and gestational hypertension via endothelial dysfunction. Women with excessive daytime sleepiness, loud excessive snoring, and witnessed apneas should be evaluated for OSA with overnight polysomnography. In addition, individuals with known sleep apnea may need repeat sleep studies to determine whether changes in treatment are necessary to prevent intermittent 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 the use of sleep medications such as diphenhydramine (Benadryl) and zolpidem (Ambien).

Another potential cause of sleep disturbances in pregnancy is the development of RLS and periodic leg movements during sleep. RLS 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 34% of gravidas reported symptoms of RLS, although the true prevalence of this disorder during pregnancy is unknown. If treatment is needed, options include improving sleep habits, use of an electric vibrator to the calves, and use of a dopaminergic agent such as levodopa or carbidopa.

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.

The well-known dilation of the ureters and renal pelvis 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 a renal transplant and pelvic kidney. By 6 weeks postpartum, ureteral dilation resolves. A clinical consequence of ureterocalyceal dilation, increased plasma volume, and increased bladder volume is an increased incidence of pyelonephritis among gravidas with asymptomatic bacteriuria. In addition, the ureterocalyceal dilation makes interpretation of urinary radiographs more difficult when evaluating possible 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 uterus, a decrease in bladder capacity develops as pregnancy progresses, accompanied by an increase in urinary frequency, urgency, and incontinence.

Renal Hemodynamics

Renal plasma flow (RPF) increases markedly from early in gestation and may begin to increase during the luteal phase before implantation. Dunlop showed convincingly that the effective RPF rises 75% over nonpregnant levels by 16 weeks’ gestation ( Table 3.7 ). The increase is maintained until 34 weeks’ gestation, when a decline in RPF of about 25% occurs. The fall in RPF has been demonstrated in subjects studied serially in sitting and 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. 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 used in patients with renal disease that estimate the GFR using serum collections and clinical parameters (which avoid a 24-hour urine collection) are inaccurate in pregnancy and underestimate the GFR.

The increase in the RPF and GFR precedes 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 the kidney with long-term consequences. Recently, the mechanisms that underlie the marked increase in RPF and GFR have 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. 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 is associated with adverse outcomes such as preeclampsia and FGR.

The clinical consequence of glomerular hyperfiltration is 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 to 0.5 mg/dL by term. Likewise, BUN falls from nonpregnant levels of 13 to 9 mg/dL by term. Serum uric acid declines in early pregnancy because of the rise in GFR and reaches a nadir by 24 weeks with levels of 2 to 3 mg/dL. 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 preeclampsia have elevated uric acid level concentrations; however, because uric acid levels normally rise during the third trimester, overreliance on this test should be avoided in the diagnosis and management of preeclampsia.

During pregnancy, urine volume is increased, and nocturia is more common. In the standing position, sodium and water are retained; 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, which results in nocturia. Later in gestation, renal function is affected by position, and the GFR and renal hemodynamics are decreased with changes from lateral recumbency to supine or standing positions.

Renal Tubular Function and Excretion of Nutrients

Despite high levels of aldosterone, which would be expected to result in enhanced urinary excretion of potassium, gravid women retain about 300 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 ability of the kidney to conserve potassium has been attributed to increased progesterone levels. For information on the changes in sodium, see the next section, “Body Water Metabolism.”

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 of glucose per day. 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. A change may occur 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. The exact mechanisms that underlie the altered handling of glucose by the proximal tubules appears to be a reduced threshold for glucose resorption via reduced renal glucose transporter expression combined with increased renal blood flow. Aberrations in this mechanism may play a pathophysiologic role in the development of gestational diabetes mellitus, and higher thresholds for glucose resorption have been associated with gestational diabetes mellitus. Even though glycosuria is common, gravidas with repetitive glycosuria should be screened for diabetes mellitus if they have not already been tested.

Urinary protein and albumin excretion increase during pregnancy, with an upper limit of 300 mg of proteinuria and 30 mg of albuminuria in a 24-hour period. Higby and associates found that the amount of proteinuria and albuminuria increases both when compared with nonpregnant levels and as the pregnancy advances. They collected 24-hour urine samples from 270 women over the course of pregnancy and determined the amount of proteinuria and albuminuria; they 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 ( Tables 3.8 and 3.9 ). Similarly, the protein/creatinine ratio increases across pregnancy. In women who did not have preeclampsia, underlying renal disease, or urinary tract infections, the mean 24-hour urine protein across pregnancy was 116.9 mg, with a 95% upper confidence limit of 260 mg. These researchers also noted that patients do not normally have microalbuminuria. In women with preexisting proteinuria, the amount of proteinuria 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 1.74g ± 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. 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.

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 44 ). Also, the kidney responds to the respiratory alkalosis of pregnancy by enhanced excretion of bicarbonate; however, renal handling of acid excretion is unchanged.

Osmoregulation

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 that continues through 1 to 2 weeks postpartum ( Fig. 3.9 ). 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 that involve NO and the hormone relaxin. After 8 weeks of 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 secretion, but this occurs at a new, lower “osmostat.”

Plasma levels of AVP remain relatively unchanged despite heightened production, owing to a threefold to fourfold increase in metabolic clearance. Increased clearance results from a circulating vasopressinase synthesized 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, presumably because of an insufficient pituitary AVP reserve, and it 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 (see Chapter 48 ).

Salt Metabolism

Sodium metabolism is delicately balanced and facilitates a net accumulation of about 900 mEq. 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 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, which results 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. Hormonal control of sodium balance is under the opposing actions of the 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 MAP. In turn, decreased MAP activates adaptations to preserve intravascular volume through sodium retention. 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 doubling of aldosterone levels by the third trimester, which increases sodium reabsorption and prevents 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 (DOC) and estrogen.

Importantly, whereas pregnant women are responsive to the sodium-retaining effects of mineralocorticoids, they are fairly refractive to their kaliuretic properties. Erhlich and Lindheimer hypothesized that progesterone strongly contributed to potassium homeostasis in pregnancy, and they found that renal potassium excretion was not increased in pregnant women exposed to exogenous mineralocorticoid administration and attributed this to the effects of progesterone.

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; 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. Although ANP levels in pregnancy are variably reported, a meta-analysis showed that 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 significantly in the third trimester of pregnancy compared with first-trimester levels (21.5 ± 8 pg/mL vs. 15.2 ± 5 pg/mL) and are highest in pregnancies complicated by preeclampsia (37.1 ± 10 pg/mL). In pregnancies with preeclampsia, higher levels of BNP are associated with echocardiographic evidence of left ventricular enlargement. Whereas the BNP levels are increased during pregnancy, in preeclampsia, the mean values are still lower than the levels used to screen for cardiac dysfunction (>75 to 100 pg/mL) . Therefore BNP can be used to screen for congestive heart failure in pregnancy (see Chapter 42 ).

Clinical Implications of Pregnancy-Related Renal and Urologic Changes

The normal pregnancy-related changes in the kidneys and urinary tract can have profound clinical implications. From 2% to 8% of pregnancies are complicated by asymptomatic bacteriuria, and risk is increased among multiparous women; those of a low socioeconomic class; and women with diabetes, sickle cell disease, and history of previous urinary tract infections. Although this prevalence is approximately equivalent to that in the nonpregnant population, in pregnancy, 30% of these progress to pyelonephritis. This rate is three to four times higher in pregnancy compared with that of nonpregnant controls; overall, 1% to 2% of all pregnancies are complicated by urinary tract infections. For this reason, many providers screen pregnant women for bacteriuria at every clinical encounter. Asymptomatic bacteriuria and symptomatic urinary tract infections are treated to prevent subsequent progression to pyelonephritis and the accompanying maternal and fetal morbidity (see Chapter 58 ).

Many pregnant women report urinary frequency and nocturnal voiding that start as early as the first trimester, and 60% describe urinary urgency, 10% to 19% develop urge incontinence, and 30% to 60% develop stress incontinence. In a longitudinal cohort study of 241 women, the onset of stress urinary incontinence during the first pregnancy was found to carry an increased risk of long-term symptoms. The rate of urinary incontinence at the 12-year mark was ultimately lower in women who had resolution of their symptoms postpartum (57%) compared with those who did not (91%).