Gaps in knowledge in treating pregnant women

Abstract

Because studies are often undertaken without knowledge of the pharmacokinetics of a drug, efficacy is difficult to assess in pregnant women. To address this lack, basic and clinical research within the National Institute of Child Health and Human Development is focusing on expanding knowledge of pharmacology during pregnancy. Although medication use, including prescription, over-the-counter, and herbal products, is common during pregnancy, physicians may not be aware of the nonprescription products their patients are taking or the interactions these products may have with prescribed medications. A number of studies have found sex differences in oxidative metabolism and transport, as well as pharmacologic and toxicologic differences in hepatic metabolism, that are ultimately reflected in pharmacokinetics. Sex differences exist in distribution volumes, transport proteins, and drug clearance. Beyond these sex differences, pregnancy itself affects the absorption, distribution, metabolism, and elimination of a drug. Women experience more adverse drug reactions (ADRs) than do men, and these reactions tend to be more severe. QT prolongation (torsades de pointes) and hepatic toxicity are two of the most severe ADRs, frequently causing withdrawal of a drug from the market. Women may also metabolize drugs more quickly than do men, and drugs metabolized by cytochrome P3A4 are cleared more rapidly during pregnancy. A substantial increase in the clearance of drugs eliminated by renal mechanisms also has been noted. A significant number of women are clinically depressed during pregnancy and postpartum, and eliminating treatment for depression during pregnancy may have negative consequences for both mother and fetus. Among women with depression who are treated with selective serotonin reuptake inhibitors, the dose needed to maintain efficacy increases across the course of pregnancy. Drug disposition and response not only can differ between men and women, but also between pregnant and nonpregnant women. Research is needed to understand how pregnancy alters the pharmacokinetics and pharmacodynamics of drugs; then, efficacy trials can be initiated. Alternative strategies also need to be developed to characterize safety information.