Diethylstilbestrol-exposed Women Research Articles

An Update on Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Intraepithelial Lesions of the Lower Genital Tract.

Women with prenatal diethylstilbestrol exposure are excluded from less frequent cervical cancer screening because of their increased neoplasia risk. We report the results of a prospective follow-up study of prenatal diethylstilbestrol exposure and lower genital tract high-grade (grade 2 or higher) squamous intraepithelial lesions (HSIL). The age-adjusted risk of HSIL among diethylstilbestrol-exposed women (n=4,062) was higher than among the diethylstilbestrol unexposed (n=1,837) through age 44 years (hazard ratio 2.03, 95% CI, 1.31-3.14) but not age 45 years or older. Elevated HSIL risk remained higher in diethylstilbestrol-exposed women, after accounting for frequency of cervical cancer screening. Compared with unexposed women, HSIL risk was higher among women with earlier gestational and high-dose diethylstilbestrol exposure. These data confirm the appropriateness of more frequent screening among diethylstilbestrol-exposed women through age 44 years. Whether those aged 45 years or older should continue to have increased screening will require careful weighing of possible risks and benefits.

Cervical Screening and General Physical Examination Behaviors of Women Exposed In Utero to Diethylstilbestrol

To estimate whether women exposed in utero to diethylstilbestrol (DES) report receiving more cervical and general physical examinations compared to unexposed women. 1994 Diethylstilbestrol Adenosis cohort data are used to assess the degree of recommended compliance of cervical screenings found in 3,140 DES-exposed and 826 unexposed women. Participants were enrolled at 4 sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data, which included reported frequency over the preceding 5 years (1990-1994) of Papanicolaou smears and general physical examinations. Diethylstilbestrol-exposed women exceeded the recommended frequency of Papanicolaou smear screenings [adjusted odds ratio (aOR) = 2.15, 95% CI (confidence interval) = 1.60-2.88] compared to the unexposed. This association held among those without a history of cervical intraepithelial neoplasia (aOR = 1.88, 95% CI = 1.35-2.62). Diethylstilbestrol-exposed women exceeded annual recommendations for physical examinations (aOR = 2.27, 95% CI = 1.16-4.43) among women without a history of chronic disease when compared to unexposed women. Most DES-exposed women are receiving cervical cancer screening at least at recommended intervals, but one third of the women are not receiving annual Papanicolaou smear examinations.

Infertility among women exposed prenatally to diethylstilbestrol.

Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy. In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility. A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5), and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1). Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively. The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.

Altered immune response in adult women exposed to diethylstilbestrol in utero

Objective: Between 1940 and 1970, 1.5 million female fetuses were exposed to diethylstilbestrol in utero. Numerous deleterious effects on reproductive anatomic and physiologic characteristics have been documented in these women. However, the effects of this exposure on nonreproductive systems, which may have lifelong consequences as this cohort of women progresses beyond the childbearing years, have received little attention. On the basis of an earlier preliminary observation of altered immune reponse, we hypothesized that diethylstilbestrol-exposed women may show abnormalities in T-cell–mediated immune response. Study Design: Thirteen women exposed to diethylstilbestrol in utero were compared with 13 age- and menstrual cycle phase–matched control subjects with respect to the in vitro T-cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin 2. Results: As compared with controls, tritiated thymidine incorporation by T cells harvested from diethylstilbestrol-exposed women was increased 3-fold over a range of concentrations in response to concanavalin A (P <.001), increased by 50% over a range of concentrations in response to phytohemagglutinin (P <.001), and increased 2-fold in response to the endogenous mitogen interleukin 2 (P <.05). Conclusions: In vitro evidence suggests that women exposed to diethylstilbestrol have alterations in T-cell–mediated immunity. These changes require further attention with regard to their characterization, their role in the pathogenesis of cancer and autoimmunity, and their presence in normal women exposed to diethylstilbestrol in utero. (Am J Obstet Gynecol 2001;185:78-81.)

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring

Objective: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. Methods: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. Results: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). Conclusion: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

The effect of intrauterine diethylstilbestrol exposure on ovarian reserve screening

Objective: Our goal was to evaluate the effect of intrauterine diethylstilbestrol exposure on ovarian reserve. Study design: Four hundred two women underwent ovarian reserve screening. Twenty had intrauterine diethylstilbestrol exposure, and 382 women did not have exposure. The groups were compared regarding age, the incidence of diminished ovarian reserve, and cycle length. Nine women with and 204 women without diethylstilbestrol exposure underwent comparison of the total human menopausal gonadotropin dose, the day of human chorionic gonadotropin administration, the peak estradiol level, and the number of mature follicles. Results: The diethylstilbestrol-exposed women were similar in age (37 ± 3.4 years) to the non-diethylstilbestrol-exposed women (35 ± 4.4 years, p > 0.05). Three of 20 exposed women (15.8%) and 57 of 382 nonexposed women (15.3%) had diminished ovarian reserve ( p = 0.41). When the exposed women were compared with the nonexposed subjects, the amounts of human menopausal gonadotropin (30 ± 10 vs 33.7 ± 10.6 ampules) required to achieve peak estradiol levels (633 ± 323 vs 817 ± 518 pg/ml) with comparable numbers of follicles (5.7 ± 2.7 vs 5.4 ± 2.8) on the day of human chorionic gonadotropin administration were similar ( p > 0.05). Conclusions: The diethylstilbestrol-exposed and nonexposed women had a similar incidence of diminished ovarian reserve and a similar follicular response to gonadotropins.

Effects on the menstrual cycle of in utero exposure to diethylstilbestrol

OBJECTIVES: The purpose of this study was to determine the effects of in utero exposure to diethylstilbestrol on the menstrual cycle. STUDY DESIGN: This was a prospective cohort study of 198 diethylstilbestrol-exposed women and 162 unexposed controls, recruited from women whose mothers participated in a randomized trial of diethylstilbestrol in pregnancy at the Chicago Lying-In Hospital from 1950 to 1952. Women with severe menstrual abnormality were excluded from the study. RESULTS: Diethylstilbestrol exposure was associated with a statistically significantly decreased duration of menstrual bleeding of approximately one half day and a lower average daily bleeding score (self-reported). We found no evidence for effects of diethylstilbestrol exposure on cycle length or variability of cycle length. Exposure was not related to symptoms of dysmenorrhea. CONCLUSIONS: The decreased duration and amount of menstrual bleeding among diethylstilbestrol-exposed women could be due to direct effects on the uterus. The lack of an effect on cycle length and variability appears to indicate that endocrine function is not grossly disturbed in those women studied. (AM J OBSTET GYNECOL 1994;170:709-15.)

Conservative management and pregnancy outcome in diethylstilbestrol-exposed women with and without gross genital tract abnormalities

Our goal was to determine the effect of conservative management on pregnancy outcome in diethylstilbestrol-exposed women with and without gross structural lesions of the genital tract. The study included a case series of women prospectively enrolled over a 10-year period. Pregnancy outcome and both antepartum and intrapartum events occurring in a case series of 120 conservatively managed pregnancies in 50 diethylstilbestrol-exposed women were reviewed. Group A (n = 34, 89 pregnancies) consisted of women with gross upper or lower genital tract lesions associated with diethylstilbestrol exposure, whereas group B (n = 16, 31 pregnancies) consisted of women whose lesions were limited to colposcopic findings. Cerclage was limited to women with a history of cervical incompetence (n = 1, two pregnancies) or acute cervical change in the second trimester (one pregnancy). Women with cervical change occurring after 25 weeks' gestation were managed with bed rest. Group A experienced more spontaneous first-trimester losses than group B (25.8% vs 12.9%, p < 0.01), whereas group B had a greater gestational age at delivery (39.8 +/- 1.5 vs 37.3 +/- 3.8 weeks, p < 0.01) than group A. Overall, pregnancies surviving the first trimester (n = 94) resulted in delivery of a viable infant discharged home 92.2% of the time; 77.9% of pregnancies reached term. The perinatal loss rate was 1.3%. Preterm labor (6.5%) and preterm rupture of membranes (3.8%) resulted in an overall rate of preterm birth of 9.2%. There were no significant differences in length of any labor stage between groups, nor were there any differences in the use of oxytocin augmentation or cesarean section rates between groups. Postpartum hemorrhage and retained placenta were infrequent complications. The majority of pregnancy loss in diethylstilbestrol-exposed patients occurs in the first trimester. Cervical incompetence is an infrequent cause of pregnancy loss even in patients with gross structural abnormalities of the genital tract. Patients who had conservative management had good pregnancy outcomes. Prophylactic cerclage for all diethylstilbestrol-exposed patients should not be recommended.

Cervical stenosis in pregnancy: A complication of cryotherapyin diethylstilbestrol-exposed women

Cryotherapy causes a high incidence of cervical stenosis in diethylstilbestrol-exposed women because of an abnormal healing response. Consequently, the cervix may not dilate during labor, necessitating cesarean section. To prevent this, therapy should be localized to the abnormal tissue on the cervix instead of the entire transformation zone whenever possible.

Are implantation and pregnancy outcome impaired in diethylstilbestrol-exposed women after in vitro fertilization and embryo transfer?

Forty-six infertile women with a history of diethylstilbestrol (DES) exposure in utero underwent 149 stimulation attempts for in vitro fertilization (IVF). The mean (+/- SE) number of preovulatory oocytes harvested at retrieval and transferred was 3.9 +/- 3.3 (536/138) and 2.6 +/- 1.4 (328/124). When compared with patients with tubal factor infertility and less than or equal to 4 pre-embryos transferred, the clinical pregnancy rate (15.3% versus 22%) was not statistically different. However, the term/ongoing pregnancy rate was significantly lower in the study group (8% versus 16%). Comparison of the IVF outcome with different uterine anomalies as detected by hysterosalpingogram (n = 29) showed a trend for a worse prognosis in women with constrictions and a combination of T-shape and constrictions. It is concluded that implantation and pregnancy outcome are impaired in DES-exposed women after IVF.

Abortion and Pregnancy Loss Among Diethylstilbestrol-Exposed Women

Abortion and Pregnancy Loss Among Diethylstilbestrol-Exposed Women

Infertility among daughters either exposed or not exposed to diethylstilbestrol

Infertility was examined among 343 diethylstilbestrol-exposed and 303 unexposed daughters whose mothers participated in an evaluation of diethylstilbestrol use during pregnancy 35 years ago. Of the inarried individuals who were not using contraception and who were actively trying to conceive, a greater proportion of diethylstilbestrol-exposed women than unexposed subjects experienced primary infertility (33% versus 14%, p < 0.001). Among those with primary infertility, abnormal hysterosalpingograms were observed in 46% of the diethylstilbestrol-exposed group and in none of the unexposed group (p < 0.02), while tubal abnormalities were found in 42% of the exposed and in none of the unexposed (p = 0.02). First pregnancies were achieved by 40 (58%) women exposed to diethylstilbestrol and 18 (64%) unexposed subjects. Twenty-four (60%) of the exposed women and 15 (83%) of the unexposed individuals who conceived had a live-born infant who survived. The estimated cumulative rate of first pregnancy was 16% for the exposed group and 36% for the unexposed group at 12 months after the diagnosis of primary infertility (p < 0.05).

Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update

Abstract We reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago through June 30, 1985. In 60 percent of all cases the patient's mother had received diethylstilbestrol during pregnancy. An additional 12 percent of all mothers had been treated with another hormone or with an unidentified medication. Ninety-one percent of the cases in diethylstilbestrol-exposed women were diagnosed when the patient was between the ages of 15 and 27. The median age at diagnosis was 19.0 years. The risk that clear-cell adenocarcinoma will develop in an exposed female from birth through age 34 is 1 case per 1000 women. The temporal pattern of occurrence of clear-cell adenocarcinoma corresponds closely with that of the use of diethylstilbestrol for pregnancy support in the United States. The rarity of this tumor among exposed women suggests that diethylstilbestrol is not a complete carcinogen and th...

Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update.

We reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago through June 30, 1985. In 60 percent of all cases the patient's mother had received diethylstilbestrol during pregnancy. An additional 12 percent of all mothers had been treated with another hormone or with an unidentified medication. Ninety-one percent of the cases in diethylstilbestrol-exposed women were diagnosed when the patient was between the ages of 15 and 27. The median age at diagnosis was 19.0 years. The risk that clear-cell adenocarcinoma will develop in an exposed female from birth through age 34 is 1 case per 1000 women. The temporal pattern of occurrence of clear-cell adenocarcinoma corresponds closely with that of the use of diethylstilbestrol for pregnancy support in the United States. The rarity of this tumor among exposed women suggests that diethylstilbestrol is not a complete carcinogen and that some other factor is also involved in the pathogenesis of clear-cell adenocarcinoma of the vagina and cervix.

Risk factors for the development of diethylstilbestrol-associated clear cell adenocarcinoma: A case-control study

Factors related to the risk of developing clear cell adenocarcinoma in diethylstilbestrol-exposed women were investigated in 156 patients in the United States with clear cell adenocarcinoma and documented diethylstilbestrol exposure (Registry cases) and 1848 diethylstilbestrol-exposed women of similar age without cancer (National Cooperative Diethylstilbestrol Adenosis Project). Diethylstilbestrol dosage patterns, the use of other hormones, mother's age and pregnancy history, and daughter's birth month, birth weight, and age at menarche were compared. The relative risk was higher for those whose mothers began diethylstilbestrol before the twelfth week of pregnancy and for those who were born in the fall (winter conception). Maternal history of at least one prior spontaneous abortion elevated the risk. Supportive evidence for the difference in birth month distribution was also found by a comparison with United States vital statistics. Each factor was confirmed to be significant in a multivariate logistic model that examined all of them with region and year of birth adjusted.