Infertility among women exposed prenatally to diethylstilbestrol

This 2001 study, which is larger and includes a considerably longer follow-up period than any previous study, indicates that women exposed to diethylstilbestrol in utero have an increased risk of infertility, both primary and secondary, and that the increase is primarily due to tubal and uterine factors. I is for Infertility.

Abstract

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.

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Female fertility prognosis and diethylstilbestrol. Personal data and review of the literature

In spite of their difficult past reproductive history 4 young DES-women conceived successfully with adapted psychological and medical care in 1998 in France. Las manos del destino.

Abstract

Female fertility prognosis and diethylstilbestrol, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PubMed PMID: 9648005, 1998 Apr.
Full study: em-consulte, Doi : JG-05-1998-27-3-0368-2315-101019-ART95, 1998.

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.

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Fertility in men exposed prenatally to diethylstilbestrol

In this 1995 survey of nearly 500 exposed and unexposed men, researchers say they found no evidence that diethylstilbestrol impairs male fertility.

Abstract

Fertility in men exposed prenatally to diethylstilbestrol, The New England journal of medicine, NCBI PubMed PMID: 7723797, 1995 May 25.
Full study: The NEJM, DOI: 10.1056/NEJM199505253322104, 1995 May 25.

BACKGROUND
Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol.

METHODS
In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility.

RESULTS
Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed).

  • Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group.
  • Within the exposed group, malformations were reported twice as often among those exposed to diethylstilbestrol before the 11th week of gestation as among those exposed later (P = 0.05).
  • Men with genital malformations were nonetheless as fertile as other men.
  • The diethylstilbestrol-exposed men (with or without genital malformations) had no impairment of fertility by any measure, including whether they had ever impregnated a women, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception in the most recent pregnancy of the female partner.
  • Finally, diethylstilbestrol-exposed men had no impairment of sexual function, as indicated, for example, by the frequency of intercourse or reported episodes of decreased libido.

CONCLUSIONS
High doses of diethylstilbestrol did not lead to impairment of fertility or sexual function in adult men who had been exposed to the drug in utero.

NB: this data focused exclusively on fertility outcomes, it does not address any of DES side-effects and/or health effects of diethylstilbestrol that might emerge at older ages.

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Infertility among daughters either exposed or not exposed to diethylstilbestrol

infertility
The estimated cumulative rate of first pregnancy was 16% for the DES-exposed.

Abstract

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).

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Pregnancy: DES Effects in DES Mothers and in DES Daughters

image of a pregnant-woman
Diethylstilbestrol causes a variety of birth-related adverse outcomes in DES daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death.

DES Pregnancy: DES Mothers

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.

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Hysteroscopic metroplasty: term delivery rate after T-shaped uterus surgery

Term delivery rate after hysteroscopic metroplasty in patients with recurrent spontaneous abortion and T-shaped.

Abstract

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.

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Surgical correction of a T-shaped uterus and DES Daughters pregnancy outcome

image of 3D-T-shaped-uterus
Reconstruction in 3D-US of T-shaped uterus. 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.

Abstract

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.

Discussion

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.

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Pregnancy outcomes in women exposed in utero to diethylstilbestrol

DES-pregnancy-risks chart
In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes.

Abstract

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.

Discussion

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.

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Preeclampsia risk in women exposed in utero to diethylstilbestrol

Preeclampsia-risk image
This 2007 study showed that In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk, a common pregnancy complication.

Abstract

Preeclampsia risk in women exposed in utero to diethylstilbestrol, NCBI PubMed PMID: 17601905, 2007 Jul.
Full text: Obstetrics & Gynecology, Volume 110 – Issue 1 – pp 113-120 doi: 10.1097/01.AOG.0000268796.75591.02, July 2007.

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.

RESULTS

  • 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.

DES Follow-up Study Summary

DES Follow-up Study Published Papers, National Cancer Institute, 1998-2015.

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.

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Early prophylactic cervical cerclage for hypoplastic cervix following exposure to DES in utero

image of cervical-cerclage
Mean position of the tape in the cervix. Sagittal view.

Abstract

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.

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