Physiologic changes during pregnancy

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 the various physiologic adaptations in pregnancy 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 involves the increase in glomerular filtration rate (GFR) during pregnancy leading to increased clearance of heparins, thus requiring the use of higher doses during pregnancy. This chapter discusses the most relevant physiologic changes that occur during human gestation.

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; the increase in CO in early pregnancy is thought to be mainly mediated by an increase in stroke volume, whereas later in gestation the increase is attributed to elevated heart rate [ ]. Most of the increase in CO occurs early in pregnancy such that by the end of the first trimester 75% of the increase has already occurred. In addition, CO is expected to be 15% more in a twin pregnancy compared to a singleton [ ]. CO plateau at 28–32 weeks and afterward remains relatively stable until delivery. At 32 weeks, CO increased to about 7.21 l/min vs 4.88 l/min prior to conception .

As CO increases, pregnant women experience a significant decrease in both systemic and pulmonary vascular resistances [ ]. Systemic vascular resistance decreases in early pregnancy, reaching a nadir (5–10 mm below baseline) at 14–24 weeks. Subsequently, vascular resistance starts rising, progressively approaching the prepregnancy value at term [ ]. Blood pressure tends to fall toward the end of the first trimester and then rises again in the third trimester to prepregnancy levels [ ]. Physiologic hypotension may be present between weeks 14 and 24, likely due to the decrease in the systemic vascular resistance observed during pregnancy.

Maternal blood volume increases in pregnancy by 40%–50%, reaching maximum values at 32 weeks [ ]. Despite the increase in blood volume, central filling pressures like the central venous and pulmonary occlusion pressures remain unchanged secondary to an increase in compliance of the right and left ventricles [ ]. The precise etiology of the increase in blood volume is not clearly understood. However, increased mineralocorticoid activity with water and sodium retention does occur [ ]. Production of arginine vasopressin (resulting in increased water absorption in the distal nephron) is also increased during pregnancy and thought to further contribute to hypervolemia. Secondary hemodilutional anemia and a decrease in serum colloid osmotic pressure (due to a drop in albumin levels) are observed.

Finally, left ventricular wall thickness and left ventricular mass increase by 28% and 52% above pregnancy values [ ]. Despite the multiple changes in cardiovascular parameters, left ventricular ejection fraction does not appear to change during pregnancy [ ].

The latter physiological changes could have theoretical implications on the pharmacokinetics of drugs in pregnancy. 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. In addition, highly protein-bound compounds may display higher free levels due to decreased protein binding availability.

2.3