Clinical Opinion
Review of pregnancy labeling of prescription drugs: Is the current system adequate to inform of risks?

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Abstract

Evidence-based medicine that is designed to guide benefit/risk drug therapy decisions does not exist for pregnant women. The types of studies that do exist are usually conducted in animals, which may not reflect human benefits and risks. The types of studies that do exist in humans are typically limited and, at best, may show an “association” between a particular drug therapy and an undesirable effect. This review outlines the difficulties that are associated with the assessment of the benefits/risks of drug therapy during pregnancy, the history of the Food and Drug Administration regulations for labeling prescription drugs, and the strengths and weaknesses of the current Food and Drug Administration pregnancy labeling system. Proposed changes to the current system are reviewed. (Am J Obstet Gynecol 2002;187:333-9.)

Section snippets

The history of pregnancy labeling

Approval of a drug's labeling is an important part of the overall drug approval process. Labeling includes the label, the printed or graphic material on the immediate drug container or on the outside container, and the package insert, which accompanies the drug, and is designed to give physicians clear and concise information that is necessary for the safe and effective use of the drug.10 Until 1979, most drugs were accompanied by standard disclaimers, the most common of which stated: “safe use

Assessing risk

Many new drugs are approved and marketed every year. Because there are few data on drug effects on the human fetus at the time of marketing, data from preclinical animal studies are used to provide initial guidelines. Changes after 1962 to the regulatory requirements that were instituted with the Kefaufer-Harris amendments mandated improved animal testing, including testing in primates. Typically, reproductive toxicity studies compare pregnancy outcome in animals that receive a range of doses

The FDA pregnancy risk categories

Depending on how one chooses to look at it, the disclaimer “safe use in pregnancy has not been established” can imply that a medication may indeed be a teratogen. The major drawback with such disclaimers was that it provided little to no information on which to “weigh the possible hazards.” Because of the ineffectiveness of this type of labeling, there were many efforts to encourage the FDA to change the manner in which drugs are classified with regard to their reproductive risks.18, 19

Unless a

Criticism of the current status of pregnancy labeling

Although the intent of the new labeling requirement was to facilitate drug prescribing for pregnant patients, many feel it has not lived up to original expectation in this regard.27 Clinicians and others have expressed to the FDA concern that the information contained in the typical pregnancy labeling subsection and the manner in which such information is presented are not sufficient to make informed decisions adequately about drug therapy in pregnant women and women of childbearing potential

Confusing terminology

The current labeling terminology refers to teratologic risk as the major adverse outcome of pregnancy. Because the term teratogenesis refers to the condition of structural malformation, the labeling appears to be restrictive in its consideration of adverse outcomes of pregnancy. There are four adverse outcomes of pregnancy: (1) embryonal or fetal death, (2) structural malformations, (3) perturbations of fetal growth, and (4) functional deficits.28, 30 The term risk is used in a manner that

Suggestions for the improvement of pregnancy labeling

A public hearing was held by the FDA on the current category requirements for pregnancy labeling in September 1997. The agency sought comments on the practical usefulness, effects, and problems that are associated with the categories and ways to address these problems.28, 30 The following are the specific issues that were discussed:

  • The extent to which the category designations are relied on in making decisions about drug therapy in pregnant women and women of childbearing potential and

Comment

Current pregnancy labeling probably is an improvement over that which previously existed. The traditional disclaimer that “… safety in pregnancy has not been established, therefore risks should be weighed against benefits …” provides no direction at all. However, the notion that the A, B, C, D, and X system somehow provides a gradation of reproductive risk across categories is mistaken. Together with the poor quality of published data on drug embryotoxicity, the practitioner is forced to make

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    Reprint requests: Paul L. Doering, MS, SHANDS DIPRC, PO Box 100316, Gainesville, FL 32610-6295.

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