Physiologic Changes During Pregnancy

Physiologic Changes During Pregnancy

Physiologic Changes During Pregnancy Luis D. Pacheco, Maged M. Costantine, Gary D.V. Hankins 2 2.1 Physiologic changes during pregnancy 5 2.2 ...

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Physiologic Changes During Pregnancy Luis D. Pacheco, Maged M. Costantine, Gary D.V. Hankins

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2.1

Physiologic changes during pregnancy

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2.2

Cardiovascular system

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2.3

Respiratory system

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2.4

Renal system

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2.5

Gastrointestinal system

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2.6

Hematologic and coagulation systems

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2.7

Endocrine system

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2.8

Summary

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2.1

Physiologic changes during pregnancy

Human pregnancy is characterized by profound anatomic and physiologic changes that affect virtually all systems and organs in the body. Many of these changes begin in early gestation. Understanding of pregnancy adaptations is vital to the clinician and the pharmacologist as many of these alterations will have a significant impact on pharmacokinetics and pharmacodynamics of different therapeutic agents. A typical example of the latter involves the increase in glomerular filtration rate leading to increased clearance of heparins requiring the use of higher doses during pregnancy. The present chapter discusses the most relevant physiologic changes that occur during human gestation.

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2.2  Cardiovascular system

2.2

Cardiovascular system

Profound changes in the cardiovascular system characterize human pregnancy and are likely to affect the pharmacokinetics of different pharmaceutical agents. Table 2.1 summarizes the main cardiovascular changes during pregnancy. Cardiac output (CO) increases by 30–50% during pregnancy secondary to an increase in both heart rate and stroke volume [1]. Most of the increase occurs early in pregnancy, such that by the end of the first trimester 75% of such increment has already occurred. CO plateaus at 28–32 weeks and afterwards remains relatively stable until the delivery period [2]. As CO increases, pregnant women experience a significant decrease in both systemic and pulmonary vascular resistances [1]. Systemic vascular resistance decreases in early pregnancy, reaching a nadir at 14–24 weeks. Subsequently, vascular resistance starts rising, progressively approaching the prepregnancy value at term [1]. Blood pressure tends to fall toward the end of the first trimester and then rises again in the third trimester to pre-pregnancy levels [3]. Physiologic hypotension may be present between weeks 14 and 24 and likely this is due to the decrease in the systemic vascular resistance described previously. Maternal blood volume increases in pregnancy by 40–50%, reaching maximum values at 32 weeks [4]. Despite the increase in blood volume, central filling pressures like the central venous Table 2.1  Summary of cardiovascular changes during pregnancy Variable

Change

Mean arterial pressure

No significant change

Central venous pressure

No change

Pulmonary arterial occlusion pressure

No change

Systemic vascular resistance

Decreased by 21% (nadir at 14–24 weeks)

Pulmonary vascular resistance

Decreased by 34%

Heart rate

Increased (approaches 90 beats/minute at rest during the third trimester)

Stroke volume

Increases to a maximum of 85 mL at 20 weeks of gestation

Colloid osmotic pressure

Decreased by 14% (associated with a decrease in serum osmolarity noticed as early as the first trimester of pregnancy)

Hemoglobin concentration

Decreased (maximum hemodilution is achieved at 30–32 weeks)

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and pulmonary occlusion pressures remain unchanged secondary to an increase in compliance of the right and left ventricles [5]. The precise etiology of the increase in blood volume is not clearly understood; however, increased mineralocorticoid activity with water and sodium retention does occur [6]. Production of arginine vasopressin (resulting in increased water absorption in the distal nephron) is also increased during pregnancy and thought to contribute to hypervolemia. Secondary hemodilutional anemia and a decrease in serum colloid osmotic pressure (due to a drop in albumin levels) ensue. The latter physiological changes could have theoretical implications on pharmacokinetics. The increase in blood volume, increased capillary hydrostatic pressure, and decrease in albumin concentrations would be expected to increase significantly the volume of distribution of hydrophilic substances. Highly protein bound compounds may display higher free levels due to decreased protein binding availability.

Respiratory system

The respiratory system undergoes both mechanical and functional changes during pregnancy. Table 2.2 summarizes these changes. The sharp increase in estrogen concentrations during pregnancy leads to hypervascularity and edema of the upper respiratory mucosa [7]. These changes result in an increased prevalence of rhinitis and epistaxis in pregnant individuals. Theoretically, inhaled medications such as steroids used in the treatment of asthma could be more readily absorbed in the pregnant patient. Despite this theoretical concern, there is no evidence of increased toxicity with the use of these agents during pregnancy. Mainly driven by progesterone, minute ventilation increases by 30–50% secondary to an increase in tidal volume. Respiratory rate remains unchanged during pregnancy [8]. The increase in ventilation results in an increase in the arterial partial pressure of oxygen (PaO2) to 101–105 mmHg and a diminished arterial partial pressure of carbon dioxide (PaCO2), with normal values of PaCO2 during pregnancy of 28–31 mmHg. This decrement allows for a gradient to exist between the PaCO2 of the fetus and the mother so that carbon dioxide can diffuse freely from the fetus into the mother through the placenta and then be eliminated through the maternal lungs. The normal maternal arterial blood pH in pregnancy is between 7.4 and 7.45, consistent with a mild respiratory alkalosis. The latter is partially corrected by an increased renal excretion of bicarbonate,

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2.3

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2.4  Renal system

Table 2.2  Summary of respiratory changes during pregnancy Variable

Change

Tidal volume

Increased by 30–50% (increase starts as early as the first trimester)

Respiratory rate

No change

Minute ventilation

Increased by 30–50% (increase starts as early as the first trimester)

Partial pressure of oxygen

Increased (increase starts as early as the first trimester)

Partial pressure of carbon dioxide

Decreased (decrease starts as early as the first trimester)

Arterial pH

Slightly increased (increase starts as early as the first trimester)

Vital capacity

No change

Functional residual   capacity

Decreased by 10–20% (predisposes pregnant patients to hypoxemia during induction of general anesthesia)

Total lung capacity

Decreased by 4–5% (maximum diaphragmatic elevation happens during the third trimester of pregnancy)

rendering the normal serum bicarbonate between 18 and 21 meq/L during gestation [9]. As pregnancy progresses, the increased intraabdominal pressure (likely secondary to uterine enlargement, ­bowel dilation, and third-spacing of fluids to the peritoneal cavity secondary to decreased colloid-osmotic pressure) displaces the diaphragm upward by 4–5 cm leading to alveolar collapse in the bases of the lungs. Bibasilar atelectasis results in a 10–20% decrease in the functional residual capacity and increased right to left vascular shunt [10, 11]. The decrease in expiratory reserve volume is coupled with an increase in inspiratory reserve volume; as a result no change is seen in the vital capacity [10]. Changes in respiratory physiology may impact pharmacokinetics of certain drugs. Topical drugs administered into the nasopharynx and upper airway could be more readily available to the circulation as local vascularity and permeability are increased. As discussed earlier, the latter assumption is theoretical and no evidence of increased toxicity from inhaled agents during pregnancy has been demonstrated.

2.4

Renal system

Numerous physiologic changes occur in the renal system during pregnancy. These changes are summarized in Table 2.3.

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Variable

Change

Renal blood flow

Increased by 50%. Increase noticed as early as 14 weeks of gestation

Glomerular filtration rate

Increased by 50%. Increase noticed as early as 14 weeks of gestation

Serum creatinine

Decreased (normal value is 0.5–0.8 mg/dL during pregnancy)

Renin–angiotensin– aldosterone system

Increased function leading to sodium and water retention noticed from early in the first trimester of pregnancy

Total body water

Increased by up to 8 liters. Six liters gained in the extracellular space and 2 liters in the intracellular space

Ureter–bladder   muscle tone

Decreased secondary to increases in progesterone. Smooth muscle relaxation leads to urine stasis with increased risk for urinary tract infections

Urinary protein excretion

Increased secondary to elevated filtration rate. Values up to 260 mg of protein in 24 hours are considered normal in pregnancy

Serum bicarbonate

Decreased by 4–5 meq/L. Normal value in pregnancy is 18–22 meq/L (24 meq/L in non-pregnant individuals)

The relaxing effect of progesterone on smooth muscle leads to dilation of the urinary tract with consequent urinary stasis, predisposing pregnant women to infectious complications. The 50% increase in renal blood flow during early pregnancy leads to a parallel increase in the glomerular filtration rate (GFR) of approximately 50%. This massive elevation in GFR is present as early as 14 weeks of pregnancy [12]. As a direct consequence, serum values of creatinine and blood urea nitrogen will decrease. A serum creatinine above 0.8 mg/dL may be indicative of underlying renal dysfunction during pregnancy. Besides detoxification, one of the most important functions of the kidney is to regulate sodium and water metabolism. Progesterone favors natriuresis while estrogen favors sodium retention [13]. The increase in GFR leads to more sodium wasting; however, the latter is counterbalanced by an elevated level of aldosterone which reabsorbs sodium in the distal nephron [13]. The net balance during pregnancy is one of avid water and sodium retention leading to a significant increase in total body water with up to 6 liters of fluid gained in the extracellular space and 2 liters in the intracellular space. This “dilutional effect” leads to a mild decrease in both serum sodium (concentration of 135–138 meq/L) and serum osmolarity (normal value in pregnancy ~280 mOsm/L) [14]. In the non-pregnant state, normal serum osmolarity is 286–289 mOsm/L with a concomitant normal serum sodium concentration of

2  Physiologic Changes During Pregnancy

Table 2.3  Summary of renal changes during pregnancy

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2.5  Gastrointestinal system

135–145 meq/L. Changes in renal physiology have profound repercussions on drug pharmacokinetics. Agents cleared renally are expected to have shorter half-lives and fluid retention is expected to increase the volume of distribution of hydrophilic agents. A typical example involves lithium. Lithium is mainly cleared by the kidney and during the third trimester of pregnancy clearance is doubled compared to the non-pregnant state [15]. Not all renally cleared medications undergo such dramatic increases in excretion rates (digoxin clearance is only increased by 30% during the third trimester of pregnancy).

2.5

Gastrointestinal system

The gastrointestinal tract is significantly affected during pregnancy secondary to progesterone-mediated inhibition of smooth muscle motility [16]. Table 2.4 summarizes these changes. Gastric emptying and small bowel transit time are considerably prolonged. The increase in intra-gastric pressure (secondary to delayed emptying and external compression from the gravid uterus) together with a decrease in resting muscle tone of the lower esophageal sphincter favors gastroesophageal regurgitation. Of note, recent studies have shown that gastric acid secretion is not affected during pregnancy [17].

Table 2.4  Summary of gastrointestinal changes during pregnancy Variable

Change

Gastric emptying time

Prolonged, increasing the risk of aspiration in pregnant women. Intra-gastric pressure is also increased

Gastric acid secretion

Unchanged

Liver blood flow

Unchanged in the hepatic artery; however, more venous return in the portal vein has been documented with ultrasound Doppler studies

Liver function tests

No change during pregnancy except for alkaline phosphatase (increases in pregnancy secondary to placental contribution)

Bowel/gallbladder motility

Decreased, likely secondary to smooth muscle relaxation induced by progesterone

Pancreatic function enzymes (amylase, lipase)

Unchanged

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Conflicting data exist regarding liver blood flow during pregnancy. Recently, with the use of Doppler ultrasonography, investigators found that blood flow in the hepatic artery does not change during pregnancy but portal venous return to the liver was increased [18]. Most of the liver function tests are not altered. Specifically, serum transaminases, billirubin, lactate dehydrogenase, and gamma-glutamyl transferase are all unaffected by pregnancy. Serum alkaline phosphatase is elevated secondary to production from the placenta and levels two to four times higher than that of non-pregnant individuals may be seen [19]. Other liver products that are normally elevated include serum cholesterol, fibrinogen, and most of the clotting factors, ceruloplasmin, thyroid binding globulin, and cortisol binding globulin. The increase in all these proteins is likely estrogen mediated [19]. Also mediated by progesterone, gallbladder motility is decreased, rendering the pregnant woman at increased risk for cholelitiasis. The latter changes will clearly affect pharmacokinetics of orally administered agents, with delayed absorption and onset of action as a result. Antimalarial agents undergo significant changes at the gastrointestinal level during pregnancy that could decrease their therapeutic efficacy [20].

Hematologic and coagulation systems

Pregnancy is associated with increased white cell count and red cell mass. The rise in white cell count is thought to be related to increased bone marrow granulopoeisis and may make a diagnosis of infection difficult sometimes; however, it is usually not associated with significant elevations in immature forms like bands. On the other hand, the 30% increase in red cell mass is thought to be secondary to increase in renal erythropoietin production, and may be induced by placental hormones. This occurs simultaneously with a much higher (around 45%) increase in plasma ­volume leading to what is referred to as “physiologic anemia” of pregnancy which peaks early in the third trimester (30–32 weeks) [21, 22]. This hemodilution is thought to confer maternal and fetal survival advantage as the patient will lose a more dilute blood during delivery, and the decreased blood viscosity improves uterine perfusion, while the increase in red cell mass serves to optimize oxygen transport to the fetus. To that account, patients with preeclampsia, despite having fluid retention, suffer from reduced intravascular volume (secondary to diffuse endothelial injury with resultant third-spacing) which makes them less tolerant to ­peripartum blood loss [23, 24].

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2.6

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2.7  Endocrine system

Table 2.5  Hemoglobin values during pregnancy Gestational age

Mean hemoglobin value (g/dL)

12 weeks

12.2

28 weeks

11.8

40 weeks

12.9

Pregnancy is associated with changes in the coagulation and fibrinolytic pathways that favor a hypercoagulable state. Plasma levels of fibrinogen, clotting factors (VII, VIII, IX, X, XII), and von Willebrand factor increase during pregnancy leading to a hypercoagulable state. Factor XI decreases and levels of prothrombin and factor V remain the same. Protein C is usually unchanged but protein S is decreased in pregnancy. There is no change in the levels of anti-thrombin III. The fibrinolytic system is suppressed during pregnancy as a result of increased levels of plasminogen activator inhibitor (PAI-1) and reduced plasminogen activator levels. Platelet function remains normal in pregnancy. Routine coagulation screen panel will show values around normal. This hypercoagulable state predisposes the pregnant patient to higher risk of thromboembolism; however, it is also thought to offer survival advantage in minimizing blood loss after delivery [25]. Tables 2.5 and 2.6 summarize some of the most relevant changes discussed previously.

2.7

Endocrine system

Pregnancy is defined as a “diabetogenic” state. Increased insulin resistance is due to elevated levels of human placental lactogen, progesterone, estrogen, and cortisol. Carbohydrate intolerance that occurs only during pregnancy is known as gestational diabetes. Most gestational diabetes patients are managed solely with a modified diet. Approximately 10% of patients will require pharmacological treatment, mainly in the form of insulin, glyburide, or even metformin. Available literature suggests that glyburide and metformin may be as effective as insulin for the treatment of gestational diabetes. Pregnancy is associated with higher glucose levels following a carbohydrate load. By contrast, maternal fasting is characterized by accelerated starvation, increased lipolysis, and faster depletion of liver glycogen storage [26]. This is thought to be related to the

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Variable

Change

Fibrinogen level

Increased (elevation starts in the first trimester of pregnancy and peaks during the third trimester)

Factors VII, VIII, IX, X

Increased

Von Willebrand factor

Increased

Factors II and V

No change

Clotting times (prothrombin and activated partial thromboplastin times)

No change

Protein C, anti-thrombin III

No change

Protein S

Decreased. Free antigen levels above 30% in the second trimester and 24% in the third trimester are considered normal during pregnancy

Plasminogen activator inhibitor

Levels increase 2–3 times leading to a decrease in fibrinolytic activity

White blood cell count

Elevated. This increase results in a “left shift” with granulocytosis. Increase peaks at 30 weeks of gestation. During labor may see values of 20,000–30,000/mm³

Platelet count

No change

increased insulin resistance state of pregnancy induced by placental hormones such as human placental lactogen. Pancreatic β-cells undergo hyperplasia during pregnancy resulting in increased insulin production leading to fasting hypoglycemia and postprandial hyperglycemia. All of these changes facilitate placental glucose transfer, as the fetus is primarily dependent on maternal glucose for its fuel requirements [27]. Leptin is a hormone primarily secreted by adipose tissues. Maternal serum levels of leptin increase during pregnancy and peak during the second trimester. Leptin in pregnancy is also produced by the placenta. On the other hand, the thyroid gland faces a particular challenge during pregnancy. Due to the hyperestrogenic milieu, thyroid binding globulin (the major thyroid hormone binding protein in serum) increases by almost 150% from a pre-pregnancy concentration of 15–16 mg/L to 30–40 mg/L in mid-gestation. This forces the thyroid gland to increase its production of thyroid hormones to keep their free fraction in the serum constant [28, 29]. The increase in thyroid hormones production occurs mostly in the first half of gestation and plateaus around 20 weeks until term. Other

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Table 2.6  Summary of hematological changes during pregnancy

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2.8  Summary

Table 2.7  Summary of endocrine changes during pregnancy Variable

Change

Free T4 and T3 levels

Unchanged

Total T4 and T3 levels Increased secondary to increased levels of thyroid binding globulin (TBG) induced by estrogen. This elevation begins as early as 6 weeks and plateaus at 18 weeks of pregnancy Thyroid stimulating hormone (TSH)

Decreases in the first half of pregnancy and returns to normal in the second half of gestation. During the first 20 weeks of pregnancy, a normal value is between 0.5 and 2.5 mIU/L

Total cortisol levels

Increased, mainly driven by increased liver synthesis of cortisol binding globulin (CBG)

Free serum cortisol

Increased by 30% in pregnancy

factors that influence thyroid hormones (TH) status in pregnancy include minor thyrotropic action of human chorionic gonadotropin hormone (hCG), higher maternal metabolic rate as pregnancy progresses, in addition to increase in transplacental transport of TH to the fetus early in pregnancy, inactivity of placental type III monodeionidase (which converts T4 to reverse T3), and in maternal renal iodine excretion. Although the free fraction of T4 and T3 concentrations declines somewhat during pregnancy (but remains within normal values), these patients remain clinically euthyroid [28, 29]. Thyroid stimulating hormone (TSH) decreases during the first half of pregnancy secondary to a negative feedback from peripheral thyroid hormones secondary to thyroid gland stimulation by hCG. During the first half of pregnancy, the upper limit of normal value of TSH is 2.5 mIU/L (as compared to 5 mIU/L in the non-pregnant state). Serum cortisol levels are increased during pregnancy. Most of this elevation is secondary to increased synthesis of cortisol binding globulin (CBG) by the liver. Free cortisol levels are also increased by 30% during gestation. The endocrine changes during pregnancy are summarized in Table 2.7.

2.8

Summary

Pregnancy is associated with profound changes in human physiology. Virtually every organ in the body is affected and the clinical consequences of these changes are significant. Unfortunately, our knowledge of how these changes affect the pharmacokinetics and

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pharmacodynamics of therapeutic agents is still very limited. Future research involving pharmacokinetics of specific agents during pregnancy is desperately needed.

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References

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