there is little protection for readers of "clinical the authors conducted a retrospective investiga- experience" articles. Compare, for example, the tion in an attempt to find factors that may be requirement for "substantial evidence," "full dis- associated with such malignancy in this age closure," and "fair balance" in the labeling and group. Four matched controls were established advertising of drug manufacturers with the free for each patient and the data obtained were rein that exists for presenting unilateral observa- subjected to statistical analysis. A statistically tions in a "scientific" meeting. The advocacy of significant relationship was observed for three DES in pregnancy, blood changes due to use of variables: diethylstilbestrol given during preg- methotrexate in psoriasis, and visual damage nancy (p=.00001), bleeding in that pregnancy from chloroquin in arthritis suggest the increas- (p=less than .05) and prior pregnancy loss ing need for a specialist to read beyond his spe- (p=less than .01). It is obvious that the most cialty and to keep up with the best informed significant of the variables is the administration clinical pharmacology before prescribing any of diethylstilbestrol during pregnancy. drug. This becomes especially important when Since publication of this study, five additional the drug is offered for an unaccepted, although cases of this malignancy associated with the ma- not unacceptable, use or in a decidedly unusual ternal use of diethylstilbestrol have been report- dosage or duration of administration. ed by Greenwald et al.2 Dr. Herbst, in a recent Perhaps we need a mechanism to pool data communication to FDA, has reported an addi- concerning medical experience with unusual tional 15 cases associated with use of this drug, doses and utilization of existing drugs. bringing the total number of known cases to 27. It must be emphasized that this type of epidem- iologic study defines only an association and not necessarily a cause-and-effect relationship. Fur- ther studies are underway to clarify the signifi- cance of these findings. In the meantime, the FDA is initiating the Selected Item from the following precautionary actions: 1. All manufacturers of DES or closely related FDA Drug Bulletin congeners (dienestrol, hexestrol, benzestrol, promethestrol) are being notified that ap- November 1971 propriate changes will be required in the labeling for such drugs. This change will consist in the listing of pregnancy as a con- Diethylstilbestrol Contraindicated in traindication to the use of diethylstilbestrol Pregnancy: Drug's Use Linked to and the other above-mentioned compounds. Adenocarcinoma in the Offspring 2. All other estrogens will be required to have WE WISH TO BRING to the attention of all physi- the following WARNING in their labeling: cians, hospitals, and medical personnel an im- "A statistically significant association has portant possible toxic effect of diethylstilbestrol been reported between maternal ingestion (DES) reported for the first time in April 1971 by during pregnancy of diethylstilbestrol and Herbst et al.1 From their studies the authors the occurrence of vaginal carcinoma devel- concluded that maternal ingestion of diethylstil- oping years later in the offspring. Whether bestrol during pregnancy appears to increase the such an association is applicable to all es- risk of vaginal adenocarcinoma developing years trogens is not known at this time. In any later in the offspring exposed. The authors stud- event, estrogens are not indicated for use ied eight cases of adenocarcinoma of the vagina during pregnancy." in patients born between 1946 and 1951. The 3. Epidemiological studies are being initiated malignancies were identified and treated be- to determine the true incidence of this dis- tween 1966 and 1969. In seven of the eight cases, ease in young women, the number at risk, there was a history -of maternal use of diethyl- the characteristics of patient populations stilbestrol. Because this type of malignancy in with this malignancy, and the probability young girls had rarely been reported previously, of a cause-and-effect relationship.
CALIFORNIA MEDICINE 85 The Western Journal of Medicine Both FDA and the medical profession face a lem. Further information is essential to the FDA responsibility to help determine whether this and to the medical profession. We ask your help reported association constitutes a cause-and-ef- in reporting any cases you encounter for entry fect relationship. We ask that all physicians in a case registry. consider appropriate steps to assist FDA case- FDA will take every possible step to insure finding and to protect any patients who might that you are kept abreast of new information as be at risk. soon as it can be gathered and analyzed. It may be possible to trace the offspring of For your convenience, an adverse reaction re- those mothers who received DES during preg- porting form is printed below. FDA will for- nancy. All physicians should be especially' alert ward a supply of forms to each practicing physi- for young women whose mothers may have re- cian as soon as they are printed. Facsimile forms ceived hormonal therapy during pregnancy, are acceptable. particularly those young women who may be experiencing irregular vaginal bleeding. The REFERENCES association should be a routine consideration 1. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina: Association of-- maternal stilbestrol therapy with tumor ap- for physicians whose practice includes young pearance in young women. New Engl j Med 284:878-881, Apr 22, 1971 women. 2. Greenwald P, Barlow JJ, Nasca PC, et al: Vaginal cancer,after maternal treatment with synthetic estrogens. New Engl J Med 285: This is a previously unsuspected health prob- 390-392, Aug 12, 1971
DRUG EXPERIENCE REPORT orm proved (IN CONVFIDENCE) 0B o xxx
PATIENT INITIALS (Optional) DATE OF REACTION ONSET
SUSPECTED REACTION (S)
SUSPECTED DRUG(S); TRADE/GENERIC NAME (Manufacturer's name, if possible)
DISORDER OR REASON FOR USE OF DRUG(S) (Optional) ROUTE TOTAL DAILY DATES OF ADMINISTRATION DOSE
OTHER DRUGS TAKEN CONCOMITANTLY
COMMENTS (Optional)
PHYSICIAN'S NAME, ADDRESS, AND ZIP CODE
FD PROPOSED FORM
86 FEBRUARY 1972 * 116 * 2