Catherine S Stika And Marilynn C Frederiksen

Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois

The pregnant woman is perhaps the last true therapeutic orphan. Because of the ethical, medicole-gal, and fetal safety concerns regarding pregnant women, few pharmacokinetic, pharmacodynamic, or clinical trials are conducted during pregnancy. The majority of drugs that are marketed in the United States, therefore, carry the following statement (1) in their labeling:

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. [Zinacef (cefuroxime) labeling; PDR; 2005. p. 1678]

This places the burden squarely on the practitioner to assess the risks and benefits of a particular agent in a given clinical situation. The risk most often considered is the fetal risk of teratogenesis, or drug-induced malformation, irrespective of the gestational age during the pregnancy when therapy is initiated. Pregnant women are more often than not left untreated in an attempt to avoid any perceived fetal risk related to use of a pharmacologic agent, and the effect of untreated maternal disease on either the pregnancy outcome or the offspring is not always considered. Issues of appropriate dosage and frequency of administration are often not evaluated, so that the usual adult dose is prescribed without thought to any changes dictated by physiologic differences between nonpregnant and pregnant women.

There are two compelling reasons for studying drugs and drug therapy during pregnancy. The first relates to the changing age of reproduction. Pregnancy once was mainly undertaken by healthy, younger women, but the age of reproduction now includes women ranging in age from 10 to approximately 50 years, and with in vitro fertilization and egg donation, even older women undertake pregnancy. Moreover, the age of a woman's first pregnancy has been steadily rising in the United States, with an increasing number of first pregnancies occurring after age 30 (2). The expansion of the reproductive age range, coupled with the occurrence of pregnancy later in life, increases the number of women who may require drug therapy for diseases present prior to pregnancy and who may need to continue therapy during pregnancy. Knowledge of drug therapy during pregnancy is needed if these women with underlying diseases are to be optimally treated.

The second reason supporting the need to study drugs during pregnancy relates to the physiologic changes that occur with gestation. To accommodate fetal growth and development, and perhaps provide a measure of safety for the woman, pregnancy alters a woman's underlying physiology. This altered physiology can affect the pharmacokinetics of drugs. The changes may alter peak drug concentration and time to peak drug concentration by affecting drug absorption, may decrease drug binding to plasma proteins and increase drug distribution volume, and may cause variations in either renal and/or hepatic drug clearance. Extrapolation of pharmacokinetic data from drug studies largely conducted in nonpregnant


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