Pharmacokinetic Changes in the Pregnant Woman

Many women use prescribed and over-the-counter drugs during pregnancy. Mitchell et al¹ examined drug use during pregnancy between 1976 and 2008. They found that in 2008, 94% of women took at least 1 prescribed drug during pregnancy; the average number of prescribed and over-the-counter drugs used increased during this time from 2.5 in 1976 (similar to other earlier studies^2–4) to 4.2 in 2008. Less than 1% of pregnant women took an antidepressant in 1988–1990 versus 7.5% in 2006–2008.¹

Drug handling changes during pregnancy. The woman's responses to drugs during pregnancy are influenced by maternal physiology and the placental-fetal unit.^5,6 “Variations in handling of specific drugs by the pregnant woman may occur due to effects of the normal physiologic changes of pregnancy on drug absorption, distribution, metabolism, and excretion.”^5(p196) Studies of individual drug pharmacokinetics during pregnancy are often lacking because pregnant women are frequently not included in drug trials. This column summarizes some of the physiologic adaptations that may alter pharmacokinetics in the pregnant woman.

Drug absorption via pulmonary, skin, and gastrointestinal routes may be altered. Pulmonary changes and the increased cardiac output can alter absorption of drugs from the lungs by increasing the rate of drug uptake across the alveoli.^7–9 “The increased extracellular water and blood flow to the skin may enhance absorption and alter distribution of topical agents.“^{5(p 197)} Increased peripheral perfusion may also increase absorption of intramuscular drugs.⁸ Oral absorption of drugs is influenced by gastric acidity, gastric motility, and intestinal transit time.^5,10 Changes in gastrointestinal physiology during pregnancy include decreased gastric acid secretion, delayed emptying time and decreased gastric and intestinal motility.⁵ These changes increase the oral bioavailability of slowly absorbed drugs, decrease peak plasma levels of rapidly absorbed drugs and may lead to unpredictable patterns of intestinal absorption.^5,10 Peak plasma levels may be delayed. However, the clinical effect for most drugs is generally not significant because of the relatively wide therapeutic windows for drugs administered orally.^5,8

Distribution of drugs in body depends on the amount of body water, which affects the volume of distribution, binding of drug to plasma proteins or body tissues, and the fetal-placental unit.⁵ Pregnancy is characterized by increased plasma and blood volume, cardiac output, and total body water and body mass.⁵ All these factors can increase the volume of distribution for some drugs, which may lead to reduced serum levels of drugs, and the need for larger loading doses.^10,11 For example, some women may notice that their prepregnancy dose of a drug taken on a long-term basis, such as digoxin or phenytoin, may not achieve the same therapeutic effect during pregnancy.^5,6,8 The fat accumulation during pregnancy may increase tissue binding of lipophilic drugs, leading to prolonged drug effects, as the drug is released slowly over time for these tissues.^5,6

Factors reducing maternal serum drug levels increase the risk of subtherapeutic drug levels in some women. Drugs in plasma are either unbound (free) or bound to plasma proteins. One of the main binding proteins is albumin, so the usual reduction in albumin during pregnancy may increase free drug levels in the plasma levels of drugs such as salicylates, anticonvulsants, nonsteroidal anti-inflammatory agents, warfarin, and diazepam.⁶ In some cases, this increase in free drug is balanced by more rapid hepatic biotransformation or renal elimination.^6,9,10 In other cases, doses of some drugs that are bound to albumin may need to be altered during pregnancy.^6,9,10 Another factor that may alter protein binding of drugs during pregnancy are substances such as free fatty acids and steroid hormones, both of which are increased during pregnancy, that compete for albumin binding sites.^5,10 Decreased protein binding can increase the availability of free drug to cross the placenta.

Hepatic drug metabolism and clearance may also be altered during pregnancy. Increases and decreases in clearance are seen, depending on the hepatic enzymatic processes involved and the drug. For example, hepatic elimination of many antibiotics, pancuronium, phenytoin, and acetaminophen is increased in the pregnant woman.^5,6 Other hepatic enzymatic processes may be slowed during pregnancy, delaying drug metabolism and degradation. Activity of CYP1A2, which is responsible for hepatic elimination of many drugs, is decreased.^12,13 Because this enzyme is also involved in clearance of caffeine, the decreased CYP1A2 activity may enhance caffeine effects during pregnancy.⁹

Some extrahepatic enzymes, such as cholinesterase, are also decreased, which may alter the woman's response to neuromuscular agents.¹⁰

In general, slowly metabolized drugs that are cleared primarily by the liver tend to be cleared more slowly in pregnancy due to decreased enzymatic activity and the net decrease in liver blood flow. This may also increase the length of time potentially teratogenic intermediary metabolites remain in circulation.⁵(p198)

Hepatic clearance and metabolism of drugs is also influenced by the elevated levels of steroid hormones in the pregnant women, which may stimulate hepatic microsomal enzyme activity.^6,10

The increased glomerular filtration rate during pregnancy alters renal excretion of drugs such as penicillin G, digoxin, aminoglycosides, cephalosporins, sulfonamides, and lithium.^{5,6,8–10,14} This leads to shorter half-life that often is not clinically significant.¹⁰ However, these changes may sometimes be significant enough to require alterations in drug dosage or intervals, such as with digoxin (for paroxysmal atrial tachycardia), nifedipine, labetalol, atenolol, peripheral myorelaxants, and lithium.^6,9,14

In the postpartum period, the altered pharmacokinetics last until the pregnancy-induced physiologic alterations of each system return to nonpregnant status.¹⁵ In summary, the normal physiologic changes during pregnancy may alter drug absorption, transport, metabolism, and excretion, although there are considerable variations in the direction of pharmacokinetic changes among different drugs and between individual women. In many cases, these changes do not seem to be clinically significant; however, more research is needed. The net result of changes in drug handling during pregnancy depends on the individual drug, with both increases in levels (with need for a lower dose or less frequent dosing) and decreases in levels (with a need for a higher dose or more frequent dosing) seen for some drugs. In general, both peak and steady-state serum concentrations are greater in pregnant women, although these changes may not be clinically significant.

—Susan Blackburn, PhD, RN, FAAN

Professor Emeritus

Department of Family and Child Nursing

University of Washington, Seattle