Impaired reproductive performance in DES-exposed women, Obstetrics and gynecology, NCBI PubMed PMID 7352058, 1980 Jan. Full text: Obstetrics & Gynecology, January 1980 – Volume 55 – Issue 1, 1980/01000.
The reproductive history of 69 women with demonstrated diethylstilbestrol (DES)-related cervical-vaginal abnormalities is reviewed.
All of the patients were sexually active non-contraceptive users who were studied over an 8-year period.
Forty-six patients conceived, for an uncorrected fertility rate of 66.7%. Fourteen patients elected therapeutic abortion.
The 32 remaining patients had 62 pregnancies which resulted in 26 living children, for a success rate of 41.9%. However, cervical cerclage was required for continuation of 8 of these successful pregnancies.
The 36 pregnancy failures consisted of 19 first- and 11 second-trimester spontaneous abortions, 3 third-trimester losses due to permaturity, and 3 tubal pregnancies.
Uterine abnormalities were found in all of the 25 patients who underwent hysterosalpingograms.
Although other reproductive diseases unrelated to DES exposure in utero were also present in this select group of patients, it is probable that the high rate of infertility and pregnancy wastage is related to the uterine structural abnormalities encountered.
Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol, The New England journal of medicine, NCBI PubMed PMID: 7351908, 1980 Mar 13.
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.
Infertility among women exposed prenatally to diethylstilbestrol, American journal of epidemiology, NCBI PubMed PMID: 11495854, 2001 Aug. Full study: Am. J. Epidemiol, doi: 10.1093/aje/154.4.316, January 17, 2001.
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.
Diethylstilbestrol (DES) exposure in utero in females is a cause of clear-cell adenocarcinoma of the cervix and of several anatomical and functional disorders of the genital tract. DES exposure must be evoked whenever counselling women for reproductive disorders.
In France around 80,000 women have had in utero DES exposure. The cases of four young women who consulted our Reproduction Center for reproductive disorders illustrate the usual difficulties faced by these patients.
In spite of their difficult past reproductive history (uterine malformations, repeated miscarriages, ectopic pregnancies) and low fertility rate, all four women conceived successfully, either after spontaneous or induced ovulation. We stress the need for adapted psychological and medical care which can lead to successful childbearing in the vast majority of these high-risk patients.
Infertility among daughters either exposed or not exposed to diethylstilbestrol, American journal of obstetrics and gynecology, NCBI PubMed PMID: 3348310, 1988 March.
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 married 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 less than 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 less than 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 less than 0.05).
Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, National Institutes of Health, NCBI PubMed PMCID: PMC3817964, 2013 June.
Although women were prescribed DES to improve the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous abortion, prematurity or postmaturity, and the study suggested that DES enhanced premature labor. However, it continued to be used for another nearly 20 years.
DES Pregnancy: DES Daughters
Hoover determined that DES daughters have an increased risk for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm delivery (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life. Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery have been reported in more than one study, and appear to be exacerbated effects for which DES was prescribed to prevent.
The effects of prenatal DES exposure on the ability to reproduce are substantial. The risk for infertility (defined as ? 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001), and full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80). The Dutch DES cohort reports that 33% of DES daughters are nulliparous at the age of ? 40 yr, compared with only 17% in the Dutch population. Kaufman and co-workers also reported that that once pregnant, 20% of DES daughters experience preterm delivery (versus 8% of unexposed population (RR=2.93; 95% CI, 2.23–3.86)), their risk of ectopic pregnancy was 3 to 5 times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, 1.54–2.60). These adverse pregnancy-related outcomes in DES daughters are also experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant. Also, there are strong data suggesting that the presence of vaginal epithelial changes at cohort entry examination adds to the cumulative risk for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.
Term delivery rate after hysteroscopic metroplasty in patients with recurrent spontaneous abortion and T-shaped, arcuate and septate uterus, Gynecologic and obstetric investigation, NCBI PubMed PMID: 21150155, 2011 Dec.
BACKGROUND To evaluate the improvement of the term delivery rate after hysteroscopic metroplasty surgery in various uterine malformations.
METHODS 170 patients were eligible for the present retrospective case series study. Data were weighted for the number of pregnancies observed (n = 218) after surgical intervention, stratified to the number of previous abortions (at least 2) and type of malformation.
RESULTS Before surgery, the overall term delivery rate was 5.5%. After surgery, the overall term delivery rate was 59% (absolute benefit increase, ABI, was 54.5) and correlated with the number of previous abortions (69.7% ABI = 64.2, 56.5% ABI = 51 and 26.3% ABI = 20.8 for 2, 3-4 and >4 abortions, respectively; p = 0.0008, log-rank test). Data stratified according to uterine malformations yielded the following term delivery rate: 66.7% for T-shaped uterus, 62.8% for septum/partial septum and 55.6% for arcuate uterus (NS, log-rank test). The number of previous abortions and maternal age also affected the term delivery rate. Their effect upon the term delivery rate, expressed as an odds ratio, was 1.73 (95% CI: 1.20-2.49) and 1.11 (95% CI: 1.05-1.18), respectively.
CONCLUSION The term delivery rate was about 10-fold higher after surgery. T-shaped uterus surgery yielded the best term delivery rate.
Surgical approach to and reproductive outcome after surgical correction of a T-shaped uterus, Human reproduction (Oxford, England), NCBI PubMed PMID: 21398337, 2011 Jul. Full text: Human Reproduction, Vol.0, No.0 pp. 1–5, 2011, doi: 10.1093/humrep/der056, March 11, 2011.
BACKGROUND The aim of this study was to describe the surgical approach to, and evaluate the reproductive outcome of, a T-shaped uterus.
METHODS The study included 97 women who were eligible for hysteroscopic surgery, by either monopolar or bipolar electrosurgical instruments. All had diagnostic hysteroscopy 2 months afterwards to assess the success of the procedure and determine whether any synechiae were present.
RESULTS Forty-eight women (49.5%) became pregnant after metroplasty. The overall live birth rate per pregnancy before surgery was 0%; for these patients, it increased to 73%, and their miscarriage rate fell from 78 to 27% (P < 0.05). For all 57 pregnancies in 48 women, the ectopic pregnancy rate was 9% (n = 5), the miscarriage rate 28% (n = 16), the preterm delivery rate 14% (n = 8), the term delivery rate 49% (n = 28) and the live birth rate was 63% (n = 36).
CONCLUSIONS Hysteroscopic metroplasty improves the live birth rate for women with a T-shaped uterus and a history of primary infertility, recurrent abortion or preterm delivery, although it is not a treatment of infertility.
A T-shaped uterus can be a primary or congenital malformation (related to DES exposure or other causes) or can be acquired due to marginal adhesions with a T-shaped appearance. The description of the surgical technique and the results of this series are important regardless of the cause of the anomaly.
Two-third of our cases had history of DES exposure, and the results of this series are encouraging for all malformations requiring modification of the cavity volume. The question of systematic cervical cerclage during pregnancy after metroplasty remains open.
Adverse health outcomes in women exposed in utero to diethylstilbestrol, The New England journal of medicine, NCBI PubMed PMID: 21991952, 2011 Oct. Full text: NEJM, DOI: 10.1056/NEJMoa1013961, October 6, 2011.
BACKGROUND Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood.
METHODS We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero.
RESULTS Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows:
for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75);
spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88);
preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86);
loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54);
ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38);
preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89);
stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54);
early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31);
grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27);
and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18).
For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes.
CONCLUSIONS In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes.
Our study linked 12 adverse health outcomes in women to their exposure to DES in utero, with most risks increased by a factor of more than two as compared with the risks among unexposed women, resulting in substantial percentages of the exposed women having outcomes attributable to their exposure.
For most outcomes, risks were higher among women with vaginal epithelial changes, a histologic marker of high-dose DES exposure, than for women without this condition.
Although DES has not been prescribed for pregnant women in the United States for 40 years, adverse outcomes continue to occur in women exposed in utero, and continued monitoring, as is ongoing in this cohort, for established and unexpected adverse outcomes seems prudent.
OBJECTIVE To assess whether preeclampsia risk is elevated in pregnancies of diethylstilbestrol (DES)-exposed daughters.
METHODS This study used data from the National Cancer Institute DES Combined Cohorts Follow-up Study. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7,313 live births (4,759 DES exposed and 2,554 unexposed). Poisson regression analysis estimated relative risks and 95% confidence intervals (CI) for preeclampsia adjusted for age at the index pregnancy, parity, education, smoking, body mass index, year of diagnosis, and cohort.
In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk.
Adjustment for preeclampsia risk factors attenuated the relative risk slightly (1.42, 95% CI 1.04-1.94).
The excess risk with DES was concentrated among women who developed preeclampsia in their first pregnancies (relative risk 1.81, 95% CI 1.17-2.79), who were exposed before 15 weeks of gestation (relative risk 1.57, 95% CI 1.11-2.23), and who were treated with magnesium sulfate (relative risk 2.10, 95% CI 0.82-5.42).
Among DES-exposed women who had a prior hysterosalpingogram, preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%).
CONCLUSION These data suggest that in utero exposure to DES is associated with a slightly elevated risk of preeclampsia, and that one possible biological mechanism involves uterine abnormalities.
Women exposed to diethylstilbestrol (DES) in utero experience a greater risk of adverse reproductive events including infertility, ectopic pregnancies, spontaneous pregnancy losses and premature births. These complications may in part be due to prenatal effects of DES on the structure of the uterus or cervix. Preeclampsia, a common pregnancy complication characterized by maternal hypertension, and high levels of uric acid and protein, frequently involves the placenta not entirely attaching to the mother’s endometrium (implantation). DES-associated uterine abnormalities and possible alterations in immune function may adversely affect successful implantation.
The hypothesis that prenatal DES exposure is associated with preeclampsia risk was previously addressed in a small case-control study that reported a greater than two-fold risk in women who reported a history of DES exposure compared with those who did not. We used data from the National Cancer Institute DES Combined Cohorts Follow-up Study to readdress this issue. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7313 live births (4759 DES exposed and 2554 unexposed). Prenatal DES exposure was associated with nearly a 50% elevation in preeclampsia risk in the daughters’ pregnancies. Taking into account differences in DES exposed and unexposed women in preeclampsia risk factors including age at the pregnancy, number of pregnancies, education, smoking, a measure of body fatness, and year of preeclampsia diagnosis, the risk was slightly lower, about 40%. The increased risk of preeclampsia associated with prenatal DES exposure was concentrated among women who developed preeclampsia in their first pregnancy (80% higher risk), those who were exposed to DES before 15 weeks of pregnancy (57% higher risk) and those who were treated with magnesium sulfate (over two times the risk). Among DES-exposed women who had a prior hysterosalpingogram (a procedure that allows physicians to view the reproductive organs), preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%). Our data suggest that prenatal DES exposure is associated with a slightly elevated risk of preeclampsia that is possibly due to a higher prevalence of uterine abnormalities in DES daughters.
Women exposed to diethylstilbestrol (DES) in utero experience a greater risk of adverse reproductive events including infertility, ectopic gestations, spontaneous pregnancy losses and premature births. These complications may in part be mediated through teratogenic effects, namely the structural uterine and cervical abnormalities that have been associated with in utero DES exposure. Preeclampsia, a common pregnancy complication characterized by maternal hypertension, hyperuricemia, and proteinuria frequently involves shallow placentation. Placental establishment requires cytotrophoblast invasion of the underlying stroma and blood vessels of the maternal endometrium, a process involving immune and angiogenic mechanisms. DES-associated uterine abnormalities and possible alterations in immune function (4-7) may adversely affect successful implantation.
The hypothesis that prenatal DES exposure is associated with preeclampsia risk was previously addressed in a small case-control study that reported a greater than two-fold risk in women who reported a history of DES exposure compared with those who did not.