Ann B. Barnes

Fertility and Outcome of Pregnancy in Women Exposed in Utero to Diethylstilbestrol

Fertility and outcome of pregnancy were examined in women participating in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. We compared 618 subjects who had prenatal exposure to DES with 618 control subjects. Fertility, measured in terms of pregnancies achieved, did not differ between the women exposed to DES and the controls. An increased risk of unfavorable outcome of pregnancy was associated with DES exposure (the relative risk of any unfavorable outcome of pregnancy was 1.69; P less than 0.001). Speculation on biologic mechanisms that might produce this difference is premature, since additional data about these subjects must be collected. Among DES-exposed women who became pregnant, 81 per cent had at least one full-term live birth.

Design and preliminary observations of National Cooperative Diethylstilbestrol Adenosis (DESAD) Project.

The National Cooperative Diethylstilbestrol Adenosis (DESAD) Project has completed the major portion of its enrollment phase with the examination of more than 3000 daughters of women taking synthetic nonsteroidal estrogens (denoted DES) during pregnancies occurring from the early 1940s to the mid-1960s. The aims of the Project are to fill urgent needs for information on the prevalence and incidence of structural and epithelial abnormalities or neoplastic changes and their complications in these young women. Participants are grouped by mode of entry as identified by prenatal record review (40.1%), documented as DES-exposed but walking in (25.1%), or referred (22.8%) to the DESAD Project for examination, and not documented as exposed but having gynecologic abnormalities typical of those associated with DES exposure (12.0%). This study cohort, in part having paired controls, will be examined annually for at least 5 years. Details of the design and selected preliminary findings are reported.

Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project.

Abstract This report presents the cytologic findings and the rates of dysplasia for 4,589 young women enrolled in the National Cooperative Diethylstilbestrol-Adenosis (DESAD) Project. Mucinous columnar cells and/or metaplastic squamous cells with or without mucinous droplets were encountered in 22% of vaginal scrape smears from all diethylstilbestrol (DES)-exposed participants identified by review of prenatal records and in 43% of women in whom vaginal epithelial changes (VEC) were observed by colposcopy or by iodine staining. The frequency of cellular findings in the vaginal scrape smears was closely related to the timing of the administration of the DES to the mother. With increasing age of the daughters, the overall frequencies of both the mucinous and metaplastic cells decreased; relative to each other, an increasing proportion was metaplastic squamous cells. These data suggest that, as the women grow older, vaginal adenosis regresses by the process of squamous metaplasia. Endometrial type cells were found in 2% of vaginal scrape smears. Their cyclical occurrence during the menstrual cycle and lack of correlation with the presence of VEC indicated an origin from the uterine corpus rather than the tuboendometrial type of adenosis. Squamous cell dysplasia of the vagina and cervix was detected by biopsy or scrape smear specimens in 1.8% of DES-exposed women in the record review group. The rate in unexposed women was twice as high. In general, the rates of dysplasia were higher in the cervix than vagina, and the more severe degrees of dysplasia were encountered only in those women who were referred to the DESAD Project or who themselves requested entry. Four patients who were referred or who themselves requested entry were found to have clear cell adenocarcinoma of the vagina. The vaginal smear provided the first clue to the presence of an abnormality in three of them.

Comparison of Histologic and Colposcopic Findings in Des-Exposed Females

A study was undertaken to evaluate the histologic alterations associated with two or the most abnormal colposcopic findings, mosaicism and punctation, that are commonly found in the vaginas and cervices of young women who have been exposed prenatally to diethylstilbestrol (DES). Four-fifths of 215 biopsy specimens from 171 exposed subjects with mosaicism or punctation disclosed metaplastic squamous epithelium, the presence of which is thought to reflect the repair of vaginal adenosis and cervical ectropion. Hyperkeratosis was observed in one-fifth of the specimens and was more frequent in lesions colposcopically graded I than II. Mild dysplasia was encountered in only one specimen. The findings indicate that the presence of squamous cell dysplasia cannot be predicted by the finding of Grade I or II mosaicism or punctation in the DES-exposed female despite the fact that these abnormal colposcopic patterns are associated with dysplasia in about 10% of cases when encountered in the cervix of the unexposed woman.

Vaginal epithelial changes in young women enrolled in the national cooperative diethylstilbestrol adenosis (Desad) project

Initial clinical findings arc reported for the 3339 young women enrolled in the Diethylstilbestrol Adenosis (DESAD) project. Changes in the vaginal nuicosa (VEC— vaginal epithelial changes), which were detected by colposcopy or iodine staining, occurred in 34% of 1275 participants identified by review of prenatal records, 59% of participants who themselves requested entry into the project, and 65% of participants referred by a physician. Analysis of data on the 298 women who were identified by record review and whose prenatal records contained complete information about drug exposure indicated that VEC is most closely associated with the timing of the onset of inlrauterine exposure to diethylstilbestrol (DES), total dose, and length of exposure. Frequency of VEC was also found to decrease with age. No instances of severe dysplasia, carcinoma in situ, invasive squamous cell adenocarcinoma, or clear cell carcinoma were observed among the women identified by record review.

Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project.

Among women exposed in utero to diethylstilbestrol (DES) and enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, structural anomalies of the cervix or vagina were found in 25% of the 1,655 subjects identified by review of prenatal records, 43% of the 800 who themselves requested entry into the project, and 49% of the 1,089 referred by physicians but in only 2% of the 963 control subjects. Among the 367 cases found by record review to have complete information on the DES exposure, multivariate analysis indicated close association of the anomalies with the gestational week of first exposure and the total dose. Also, the prevalence rate of the anomalies was lower among subjects who had been pregnant and higher among those with later age at menarche.

Ectopic pregnancy: incidence and review of determinant factors.

The incidence of ectopic pregnancies has been expressed in various ways that are not comparable and provide widely differing estimates due to individual definitions of the denominator. Population-based data are presented based on a count of all ectopic pregnancies reported in short stay hospitals in Maine, Rhode Island, and Vermont in 1974-1976. The incidence is 40 per 10(5) female population age 14-44 and is more consistent across 80 hospital service areas than other gynecological diagnoses. The data do not reveal an increasing incidence over these 3 years in contrast to national surveys based on a longer period of observation. A review of determinant factors for ectopic pregnancy is presented, and current theories concerning the etiology, changes in contraceptive practices, innovations in sterilization procedures, or advances in diagnosis do not appear individually or collectively to explain the increasing incidences reported by others. Further basic biologic and epidemiologic research is needed to determine causes and trends in this principal cause of first trimester mortality among pregnant women.

Squamous cell dysplasia and carcinoma in situ of the cervix and vagina after prenatal exposure to diethylstilbestrol.

Squamous cell abnormalities of the vagina and cervix were evaluated in 1424 women exposed to diethylstilbestrol (DES) in utero. The prevalence of dysplasia was 2.1% and the incidence 0.85/100 person-years of followup. The dysplastic epithelial changes were almost always mild in women with no prior history of dysplasia and was slightly more frequent in the cervix than the vagina. Severe dysplasia and carcinoma in situ (CIS) were encountered only in those subjects specifically referred because of those abnormalities. The most common problem in the diagnosis of these squamous cell changes was the misinterpretation of mature and immature metaplastic cells for dysplastic squamous cells. Discordance between biopsy and cytology was common-place in the detection and followup of dysplasia, especially when it was mild. There were no instances in the study where cytology and biopsy samples from the vagina were both abnormal concurrently. Colposcopically directed biopsies did not increase the frequency of confirmation of cytologic findings. These data suggest that both cytology and biopsy of abnormal segments of the vagina and cervix remain an integral part of the examination of the DES-exposed female during long-term follow-up studies.

Menstrual history of young women exposed in utero to diethylstilbestrol.

The menstrual histories of 218 patients exposed in utero to diethylstilbestrol (DES) were compared with those of 158 control subjects. No significant differences were revealed in the complaint of menstrual irregularities at either the initial or follow-up examination. Age at menarche was the same in both groups, and was the same as found in the United States as a whole. These findings differ from the report of a controlled trial in Chicago which suggests that there is a specific pattern of oligomenorrhea associated with DES exposure.

Maturation of vaginal and cervical epithelium in women exposed in utero to diethylstilbestrol (DESAD Project)

A total of 452 women with documented exposure in utero to diethylstilbestrol (DES) with epithelial findings present at the time of their initial examination have been evaluated prospectively to determine whether these findings changed over a period of 3 years. The examinations were all performed according to a strict protocol. Findings present at the time of the third annual examination were verified at a fourth examination. A verified decrease in the extent of epithelial findings occurred in 29.2% of these women and a verified increase in 6.6%; 53.1% had no change in the extent of epithelial findings, and 11.1% had a change that could not be verified at the time of the fourth visit. Analysis of many variables failed to identify a strong association between any variable and a decrease in the extent of the findings. It appears that the most important factor in the occurrence of changes in DES-associated findings is the passage of time.