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.
Early prophylactic cervical cerclage for hypoplastic cervix following exposure to DES in utero, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PubMed PMID: 16208200, 2005 Oct. Full text: Service de Gynécologie-Obstétrique DOI: 10.1016/S0368-2315(05)82882-0, OCTOBER 2005.
AIM Presentation of a prophylactic cerclage technique, placed in the beginning of second trimester of the pregnancy, derived from McDonald cerclage and adapted to hypoplastic cervix following exposure to DES in utero.
MATERIALS AND METHODS Prospective study including 20 pregnant patients exposed to DES in utero and presenting a hypoplastic cervix. Study of the location of the cerclage tape in the cervix and of changes in cervical length (before and after cerclage) assessed by physical examination of the cervix and by transvaginal ultrasonography.
RESULTS The cervix was longer after cerclage as shown by physical examination and by ultrasound. The tape was localized near the internal cervical os, its posterior portion nearer the internal cervical os than its anterior portion.
CONCLUSION This easy-to-perform technique of cerclage of hypoplastic cervix allows the tape to be localized near the internal cervical os without colpotomy and without use of the transabdominal approach, while allowing vaginal delivery.
Effects of Mullerian anomalies on in vitro fertilization outcome, Journal of assisted reproduction and genetics, NCBI PubMed PMID: 11699126, 2001 Oct. Full text: Journal of Assisted Reproduction and Genetics, Vol. 18, No. 10, 2001 PMC3455312, May 7, 2001.
PURPOSE To assess the effect of Mullerian anomalies on pregnancy rates in women undergoing in vitro fertilization (IVF).
METHODS The records of 37 patients with and 819 patients without Mullerian anomalies undergoing a first cycle of IVF between December 1995 and July 1998 were included in this retrospective study. Outcome variables included maximal estradiol level, number of days of stimulation, number of follicles, number of oocytes, fertilization rate, and ongoing/livebirth pregnancy rate.
RESULTS Patients with Mullerian anomalies had a significantly lower ongoing pregnancy rate (8.3%) than did controls (24.8%). No patients with diethylstilbestrol (DES)-related anomalies had an ongoing pregnancy.
CONCLUSIONS Among women with Mullerian anomalies, those with DES exposure in utero demonstrated the poorest outcome, with no ongoing pregnancies in 22 cycles. Physicians should use this information in counseling such patients about reproductive choices.
Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring, Obstetrics and gynecology, NCBI PubMed PMID: 11004345, 2000 Oct. Full text: The American College of Obstetricians and Gynecologists, VOL. 96, NO. 4, OCTOBER 2000 pregnancyoutcomesdes2000, October 2000.
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 Diethylstilbestrol 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). (64.5 percent of women with in utero DES exposure had full-term infants, compared with 84.5 percent of matched women who had not been exposed to DES).
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. The DES-exposed women had higher rates of ectopic pregnancy (4.2 percent versus 0.77 percent).
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). The DES-exposed women had higher rates of preterm delivery (19.4 percent versus 7.5 percent)
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). The DES-exposed women had higher rates of second-trimester spontaneous abortion (6.3 percent versus 1.6 percent).
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 This comprehensive review confirmed that pregnancy outcomes for DES-exposed women are significantly worse than those of unexposed women.
Among DES-exposed women identified by record review, 74.5% became pregnant (5.6% fewer than unexposed controls), and among those women 85% delivered at least one live full-term infant. Although pregnancy outcomes in DES-exposed women were significantly worse than those of unexposed women, many of the exposed women were able to conceive and deliver a live full-term infant.
Even if it is assumed that DES was no longer used in pregnancy after 1971 in the United States (which is not actually the case), there are still many DES-exposed women of reproductive age. Thus, it is important for obstetrician-gynecologists to be aware of the consequences of DES exposure in utero on pregnancy outcome. Consequently, high-risk obstetric care may be indicated for pregnant women who were exposed to DES in utero.
Effect of diethylstilbestrol on reproductive function, Fertility and sterility, NCBI PubMed PMID: 10428139, 1999 Jul. Full text: FERTILITY AND STERILITY, Volume 72, Issue 1, Pages 1–7 S0015-0282(99)00153-3, July 1999.
OBJECTIVE To review the effects of in utero exposure to diethylstilbestrol (DES) on müllerian development and subsequent reproductive function.
DESIGN The literature on DES and reproductive function was reviewed and summary data are presented. The studies were identified through the computerized MEDLINE database and a manual search of relevant bibliographies.
RESULT(S) In utero exposure to DES resulted in
and increased rates of ectopic pregnancy,
and preterm delivery.
CONCLUSION(S) In the wake of the DES and thalidomide tragedies, the effect of new pharmaceuticals on pregnancy is now considered and medications are used more judiciously during pregnancy. The anatomic changes associated with exposure to DES in utero are well known even though the pathogenic mechanisms are not.
Although new cases of vaginal clear cell adenocarcinoma resulting from exposure to DES in utero are not expected at this point, an unknown number of exposed women are still facing several reproductive hazards in their quest for a viable live birth. These patients must be observed closely for ectopic pregnancy, spontaneous abortion, and PTD. In spite of their poor obstetric histories, they can be reassured that approximately 80% ultimately will be successful. Surgical correction of the structural abnormalities in an attempt to improve their reproductive performance is not advised. The use of prophylactic cervical cerclage may be beneficial, but a consensus is lacking.
Outcome of IVF in DES-exposed daughters: experience in the 90s, Journal of assisted reproduction and genetics, NCBI PubMed PMID: 9401869, 1997 Oct. Full text: Journal of Assisted Reproduction and Genetics, Vol. 14, No. 9, 1997, NCBI PubMed PMC3454843, 1997 Oct.
Purpose The outcome of in vitro fertilization (IVF) in a group of infertile women with a history of in utero exposure to diethylstilbestrol (DES) was analyzed. Records from an academic IVF program were retrospectively reviewed.
Methods Seventeen infertile women with a self-reported history of exposure to DES in utero, attending the IVF unit at Massachusetts General Hospital (MGH) for assisted reproductive technology (ART), underwent 27 IVF cycles. Analysis of the outcome of IVF including implantation and ongoing pregnancy rates was performed. The data were compared with results from a group of 20 infertile patients with idiopathic infertility undergoing 27 IVF cycles at MGH during the same period. The patients in the two groups were matched for age, basal day 3 levels of follicle stimulating hormone and serum estradiol, and the number and quality of embryos transferred.
Results The response to controlled ovarian hyperstimulation was comparable in the two groups. Significantly lower implantation and ongoing pregnancy rates following IVF and embryo transfer were seen in the utero DES-exposed group compared to the control patients.
This study confirms a poor outcome of IVF in infertile women with a history of in utero exposure to DES. The significantly impaired implantation rate (2%) following IVF in this category of infertile women is striking and concordant with earlier reported data.
The risk of ectopic pregnancy is quoted to be eight times greater in women with a history of exposure to DES and appears to be the leading factor contributing to a poor reproductive performance in this group.
No prognostic implication could be attributed to the presence of a T-shaped uterine cavity in terms of ability to conceive and carry a pregnancy to term. Of the two successful IVF cycles in the DES-exposed group, one of the patients had a T-shaped uterine abnormality, while in the second patient the uterine cavity was hypoplastic.
Conclusions This study determined impaired implantation to be a major factor contributing to infertility in women undergoing IVF with a history of in utero exposure to DES. The ovarian response to controlled hyperstimulation, the fertilization and cleavage rates, and the embryo quality remain unaffected in these patients. The mechanism for implantation failure remains obscure and the prognosis for ART is guarded for patients exposed to DES in utero.