In view of the reported association between exposure in utero to diethylstilbestrol (DES) and clear-cell adenocarcinoma of the vagina, data on the prenatal use of DES in some 51,000 pregnancies in 12 hospitals between the years, 1959 and 1965, were examined. Among these women, in whom prenatal drug exposure was carefully documented, there was considerable variation in DES usage, the frequency being highest in the Boston LyingIn Hospital (exposure in 1.5% of pregnancies) and the Children’s Hospital, Buffalo (exposure in 0.8% of pregnancies). Data from two marketing research sources were used to estimate DES usage in the United States. It is calculated that a maximum of 50,000 liveborn females per year, born between 1960 and 1970, were exposed to DES in utero, while the most likely estimate is in the range 10,000 to 16,000.
DIETHYLSTILBESTROL IN PREGNANCY, Frequency of Exposure and Usage Patterns, From The Boston Collaborative Drug surveillance Program, Boston University Medical Center, Manuscript Prepared by OLLI P. HEINONEN, MD, ER March 1973.
There is now substancial evidence that the administration of diethylstilbestrol (DES) during pregnancy may produce clearcell adenocarcinoma of the vagina in female offspring. More than 60 cases of this malignancy, which has hitherto been extremely rare in young females, have now been reported to the Registry of Clear-Cell Carcinoma of the Genital Tract in the United States. The size of the population exposed to DES during the past two to three decades is unknown. The present report is concerned with a description of the use of DES in some 51,000 pregnancies seen in 12 hospitals. Prescription data obtained from two marketing research groups concerning DES usage in the population of the United States at large are also reported.
The information from the hospitals was collected as part of the Collaborative Study on Cerebral Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of Infancy and Childhood of the National lnstitute of Neurological Diseases and Stroke (Collaborative Perinatal Study-CPS). It should be noted that this study had no influence in determining the medical care provided. The study design and methods of data collection employed by the CPS have been described in detail previous1y.l For the purposes of the present report, the following details are emphasized. On entry into the study, each woman was interviewed to obtain a medical, social, and medication history. Irrespective of the time of entry into the study, a detailed history of drug use was obtained for each woman including the one month prior to her last menstrual period. The systematic interview on medication intake was repeated at four weekly intervals. With few exceptions, each medication history was confirmed by the attending physician. To secure complete information on medications, hospital records and charts from private doctors were aIso reviewed. The data were abstracted, coded, placed on computer tape, and processed. In the present study, the original record of each woman identified from the computer tape as having received DES was reviewed by hand.
The original material consisted of 58,807 pregnancies from 12 participating hospitals. Cases were excluded for the following reasons: entry into the study during labor; abortion: stillbirth; multiple birth; race other than Caucasian, Negro, or Puerto Rican; and use of an unidentified drug during the first 4 lunar months of pregnancy. In the final analysis, 51,071 pregnancies were considered.
In nine hospitals, the sampling scheme was systematic; in one, it was random, and, in two, all patients presenting were entered into the study. About 20% of the participating women had more than one pregnancy while in the study.
Age, parity, socioeconomic status, and other characteristics of the study cohort have been described in detail elsewhere.
The 51,071 pregnancies included 23,096 Caucasians, 24,443 Negroes, and 3,532 Puerto Ricans. Their mean age was 24.1 years (whites including Puerto Ricans, 24.7 years; non-whites, 23.7 years). The proportion of nulliparous women was 28.1%, and the mean parity was 2.8 (whites, 2.8; non-whites, 2.9). The mean socioeconomic index was 6.8 (whites, 8.3; non-whites, 5.5). Most of the women (63.0%) entered the study during the first and second trimester, the mean time of entry being 21.6 weeks from the last menstrual period. Vaginal bleeding during the first trimester was recorded in 13.5% of the pregnancies.
DES was received by 217 pregnant women in this series (0.42%). The distributions of patients by hospital and ethnic group are given in Table 1 (below).
The mean age of the DES recipients was 27.6 years, and 10.6% were nulliparous. As expected, the frequency of vaginal bleeding during the first trimester was higher in women who received DES (36.3%). DES usage had no effect on the sex ratio observed in the liveborn.
Variation of DES usage frequency, by hospital
The frequency of DES usage was relatively high in 2 of the 12 hospitals. The drug was administered in 174 pregnancies at the Boston Lying-In Hospital (1.5%), and in 19 pregnancies at the Children’s Hospital in Buffalo (0.8%).
In the remaining 10 hospitals, the drug was given in only 24 out of 37,821 pregnancies (0.0670), and in two of these hospitals-the Johns Hopkins Hospital, Baltimore, and the Columbia-Presbyterian Hospital, New Yorknone of the women received the drug.
Dosage and duration
The total doses of DES received by women in the 12 hospitals are summarized in Table 2 (below).
At the Boston Lying-In Hospital, 146 out of 174 pregnancies were treated with the following schedule: the drug was started at a relatively low dose (0.0025 – 0.05 g/day) as early as feasible in the pregnancy. The dose was then increased every 2 weeks until a daily dose of 0.15 g/day was reached. The total dose received with this regimen varied from a low of 0.175 g to a high of 46.6 g, and the duration of treatment varied from 10 days to 9 lunar months. In the remaining 28 pregnancies, constant doses were generally used for short periods of time; in only two did the total DES dose reach high levels (16.5 g and 19.0 9). The total dose was less than 1 g in 19 pregnancies, and, in 10, DES was administered for less than 1 week.
At the Children’s Hospital, Buffalo, dosage was generally constant (0.1 to 5.0 mg per day). In 5 of 19 pregnancies in which DES was used, the total dose was 0.1 to 1.3 g, while, in 14, the total doses were all less than 0.1 g. In the remaining 10 hospitals, 22 out of 24 DES recipients received total doses of less than 1 g. One woman received 1.6 g, and one received 16.5 g.
Table 3 (below) shows the total dose of DES, across hospitals, divided according to whether constant or increasing daily dosage schedules were recieved.
The table 3 (above) shows that, as expected, high total doses were closely related to increasing daily dosage schedules.
Table 4 (above) summarizes the total dose, duration of administration, and time during pregnancy when exposure to DES commenced. The data on the 217 pregnancies exposed to DES are shown as percentile distributions. The table shows that more than 10 g were administered during half of the pregnancies.
In all hospitals in the study, the frequency of exposure to DES remained reasonably stable between the years, 1959 and 1965.
The reported association between maternal diethylstilbestrol usage and the subsequent development of adenocarcinoma of the vagina in female offspring has been given considerable publicity. Furthermore, it has been suggested that females known to have been exposed in utero to DES should undergo regular and frequent gynecological examinations. Any public health action, however, would depend upon the size of the population exposed, and the risk of developing vaginal adenocarcinoma in an exposed individual. While the present CPS data do not provide any direct information concerning the magnitude of the risk which is to date unknown, they do provide information on the population at risk after exposure to DES in 12 hospitals in the United States between the years, 1959 and 1965.
The data reveal that use of the drug varied considerably between hospitals located in different areas of the United States. Its use was uncommon in 10 of the 12 hospitals and, when used in these hospitals, the total dose was generally low. In only two hospitals was the usage relatively high in terms of either frequency or dosage.
For certain types of cancer, there is considerable evidence that the dose, duration, and time of exposure to carcinogens are all important determinants of risk. In the investigation of the relationship between intrauterine exposure to DES and the development of vaginal clear-cell adenocarcinoma, the relative importance of these factors remains to be established.
The present data suggest that increasing dose regimens generally result in high total doses while constant dosage regimens do so infrequently. Knowledge of the regimen employed might provide a reasonable index for investigators obtaining DES medication histories in pregnancies which occurred some 15 or more years previously. On the other hand, the CPS data suggest that knowledge of the duration of exposure alone will not provide a completely satisfactory index of the total dose administered.
Since the material from 12 hospitals studied in the CPS cannot be considered as representative of the country at large, and in view of the large differences in DES use between the participating institutions, it is clear that no approximation of the number of DES users for the United States can be made from these data alone. However, in view of the importance of providing some estimate of DES exposure, albeit provisional and approximate, we requested and obtained information from two further sources.
The first of these, Lea, Inc. (Ambler, Pa.), obtains information from 1,500 private physicians who report on all pharmaceutical products which they prescribe, together with the indication for each drug and some selected patient characteristics. This information is obtained four times a year and covers a 48-hour period of practice. The sample of physicians is continuously changed. It consists of slightly less than 1% of the prescribing physicians in the United States who are mainly in private practice. The sample is selected at random from 72 region and specialty strata, each subsample being of equal size. Data were collected uninterruptedly from 1960 to 1970, and the reporting periods were equally distributed over time. The response rate was approximately 70y0. In order to derive estimates for the entire United States, the projection factor for each stratum was calculated monthly.
The second source, R. A. Gosselin and Company, Inc. (Dedham, Mass.), is based on new and refill prescription data collected on a 2-week basis, from 1964 to 1970, from 400 randomly selected pharmacies throughout the United States. The methods of sampling and projection were similar to those described for the first source. An average of 100,000 prescriptions per month were collected.
For the years, 1964 to 1970, the data from these two sources are in substantial agreement concerning the average total number of prescriptions which have been written for DES in the United States. The first source estimates 2.51 million prescriptions per year, and the second, 2.49 million per year.
In addition to obtaining the total number of prescriptions for each drug, the first source determines the indication for drug therapy. The data show that during the period between 1960 and 1970, an average of 100,000 prescriptions for DES, per year, were written in the United States for women who were pregnant. It is interesting to note that there was regional variation. If nine United States’ census areas are combined into four geographical regions, the drug was more commonly used for prenatal care in the East and Midwest than in the South and West (3.67 and 2.93 vs. 1.94 and 1.68 DES prescriptions per 100 livebirths).
Of the 100,000 DES prescriptions written each year for pregnant women, approximately 50,000 might have affected female offspring. It can be assumed, however, that not all of these pregnancies would have resulted in liveborn infants particularly since threatened abortion is a common indication for this drug. Since there are no data concerning rates of DES use in pregnancies resulting in abortion or stillbirth on the one hand, compared with pregnancies resulting in a liveborn child on the other, we examined the CPS material. Somewhat less than 5% of DES use occurred in the stillbirth/abortion group, and this proportion was similar at the Boston Lying-In Hospital, the Children’s Hospital in Buffalo, and at the other participating hospitals. However, it should be borne in mind that abortions are likely to be underrepresented in the CPS data because of the study design.
Unfortunately, information concerning the number of DES prescriptions per pregnancy is not available from the marketing research data. However, if it is assumed that DES is usually prescribed every 4 weeks, then the number of prescriptions, for any individual pregnancy, could not exceed 10. If the average number is between three and five, then the number of liveborn female offspring exposed to DES in utero would be between 10,000 and 16,000 per annum in the United States during the period 1960 to 1970. In the CPS material, it is of interest that the average number of prescriptions for DES was 4.4 per pregnancy, assuming the prescription was given every 4 weeks.
Herbst et al reported that DES was used in 4.60%, of pregnancies at the Boston Lying-In Hospital between the years, 1946 and 1951. The authors point out that this estimate is derived from all pregnancies including those resulting in abortions and stillbirths. No data are available on exposure to DES during pregnancy in the 1950’s. The current CPS data do not show any major change in usage of DES between 1959 and 1965. Since 1967, however, data from Lea, Inc., suggest a declining use of DES in pregnancy.
Other nonsteroidal synthetic estrogens are also under suspicion. At least one case of vaginal adenocarcinoma following in utero exposure to dienestrol has been reported. Oral use of this drug appears to be rare in pregnancy: no case was observed in the CPS data, and in the prescription data provided by the R. A. Gosselin and Company, Inc., it was used about 100 times less frequently than DES.
OLLI P. HEINONEN, MD, received for publication August 26, 1972.
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