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Nongenital malformations following exposure to progestational drugs: The last chapter of an erroneous allegation


  • Robert L. Brent

    Corresponding author
    1. Research Department, Alfred I. duPont Hospital for Children, Wilmington, Delaware
    • Research Department, Alfred I. duPont Hospital for Children, P.O. Box 269, Wilmington, DE 19899
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    • The author, besides testifying on this subject at FDA hearings and publishing articles concerning his opinion, has also been a defense expert in birth defects litigation involving progestational drugs.


In the late 1960s and 1970s, a number of epidemiological studies were published indicating that pregnant women who were exposed to an array of sex steroids delivered infants with an increased incidence of nongenital congenital malformations. Because of these publications, the Food and Drug Administration (FDA), in conjunction with various pharmaceutical companies, labeled the therapeutic exposure of progestational drugs and contraceptives in pregnant women as a risk factor for limb-reduction defects (LRDs) and congenital heart defects (CHDs). Subsequently there was a rapid decrease in the exposure of pregnant women to these drugs and the initiation of numerous lawsuits alleging that a particular progestational drug was responsible for a child's nongenital congenital malformation. Wilson and Brent (1981) published an article indicating that epidemiological and animal studies of these drugs, and basic science did not support the package insert's warnings. Many new and previous animal and epidemiological studies did not support the FDA box warning. In 1987 the FDA held a hearing in which the FDA, the Teratology Society, the Centers for Disease Control and Prevention, the American College of Obstetrics and Gynecology, and other organizations supported the position that progestational agents did not result in nongenital malformations. An editorial appeared in Teratology congratulating the FDA for removing the warning label on oral contraceptives regarding nongenital malformations. In 1999 the FDA published new wording for package inserts that removed warnings for nongenital malformations for all progestational agents. In spite of the recent changes in the package inserts, lawsuits have alleged that progestational drugs cause nongenital malformations. It took 22 years from the time a box warning was required by the FDA until the warnings were removed in 1999. The 1999 FDA publication, which is a scholarly and objective document, should put an end to 2 decades of concern and anxiety for pregnant women or women of reproductive age. Could scientists, the pharmaceutical companies, or the FDA have prevented the mislabeling of progestational drugs with regard to their teratogenic risks? Was the epidemiological or teratology community at fault because they did not critique and respond to the early publications? Did the FDA act too slowly? The epidemiologic analyses, animal studies, and basic science principles have been reviewed, and it is obvious that clinically utilized progestational drugs do not cause nongenital malformations (i.e., LRDs and CHDs). Birth Defects Research (Part A) 2005. © 2005 Wiley-Liss, Inc.