Intractable primary infertility in DES-exposed women

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

Abstract

Intractable primary infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 3712361, 1986 April.

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls.

Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls.

When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls.

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

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Primary infertility in DES-exposed women

In this 1986 study, more than 50% of the DES-exposed females showed primary infertility. Quiet in the Park.

Abstract

Primary infertility in women exposed to diethylstilboestrol in utero, British journal of obstetrics and gynaecology, NCBI PubMed PMID 3707881, 1986 May.

In a selected group of 40 women who had been exposed to diethylstilboestrol in utero, 18 conceived without difficulty and 22 had primary infertility.

Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility.

Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs.

Spontaneous abortion and tubal pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups.

Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia–a hithero unreported finding for such women.

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Infertility and upper genital tract changes in DES-exposed women

infertility-woman
In this 1986 study, more than 70% of the DES-exposed females showed abnormal hysterosalpingograms.

Abstract

Upper genital tract changes and infertility in diethylstilbestrol-exposed women, American journal of obstetrics and gynecology, NCBI PubMed PMID 3717241, 1986 Jun.

A possible relationship of upper genital tract abnormalities in the diethylstilbestrol-exposed woman and infertility was studied.

Six hundred thirty-two women had roentgenography performed. Three hundred sixty-seven of these women were not using contraception and were actively trying to become pregnant.

  • One hundred thirty-four (36%) of these women reported difficulties conceiving for a period of 1 or more years.
  • Seventy-three percent of these women had abnormal hysterosalpingograms.
  • The frequency of abnormal x-ray films in the women who did conceive within 1 year was essentially the same (74%). Furthermore, a similar number of women with normal x-ray films (37%) had difficulty conceiving as did women with abnormal x-ray films (36%).
  • When specific hysterosalpingographic abnormalities were related to the presence or absence of infertility, it was observed that the presence of a constriction of the upper uterine cavity resulted in a 2.26-times greater likelihood that a woman would not be able to conceive.
  • If a T-shaped uterus was found in association with constriction of the upper uterine cavity, the odds ratio for inability to conceive was found to be 2.63.
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Infertility in women exposed to DES in utero

fertility-test
Infertility among women exposed prenatally to DES. Image © Woman holding pregnancy test

Abstract

Infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 6663585, 1983 Dec.

To evaluate the reproductive consequences of prenatal diethylstilbestrol (DES) exposure, 33 infertile couples were studied in whom the female had been exposed to DES in utero.

Infertility was attributed to

  • uterotubal junction obstruction in 3 couples,
  • anovulation in 7,
  • endometriosis in 11,
  • cervical obstruction in 2,
  • adnexal adhesions in 2,
  • oligospermia in 1
  • and luteal insufficiency in 3;
  • in 4 couples no cause of infertility could be identified.

No unique intraabdominal abnormalities attributable to DES exposure were observed. Four tubal pregnancies occurred in women with grossly normal oviducts. Nine of 11 women who had previously undergone surgical manipulation of the cervix (cryosurgery, cautery or conization) developed cervical stenosis, and 8 of them were found to have endometriosis.

Despite our not having an appropriate referral infertility population for comparison, these findings are consistent with the following hypotheses regarding women prenatally exposed to DES:

  1. surgical manipulation of the cervix more frequently leads to cervical stenosis and ultimately pelvic endometriosis,
  2. tubal pregnancies may occur by a mechanism unrelated to salpingitis,
  3. the spectrum of problems causing infertility is similar to that in the non-DES-exposed population.
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Impaired reproductive performance in Diethylstilbestrol-exposed women

image of infertility
It is probable that the high rate of infertility and pregnancy wastage in the DES-exposed is related to the uterine structural abnormalities encountered. Image © Infertility. Sticky paralyzing discovery.

Abstract

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.

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Fertility and outcome of pregnancy in women exposed in utero to DES

fertility
An increased risk of unfavorable outcome of pregnancy is associated with DES exposure.

Abstract

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.

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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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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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