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.

Late cervical and vaginal clear cell adenocarcinoma in women exposed in utero to diethylstilbestrol: Evaluation and screening.

OBJECTIVES: We aimed to evaluate the risk of cervical and vaginal clear cell adenocarcinoma (CCA) in women, aged 50 years or more, exposed in utero to diethylstilbestrol (DES) and contribute to a reevaluation of the recommendations for cervical and vaginal cancer and pre-cancer screening for these women. METHODS: We carried out a retrospective review for patients received in a cancer institute. Two cohorts were consecutively studied, the first from 1970 to 2003 and the second from 2004 to 2021, and then linked. RESULTS: During the first period, we observed 61 CCA cases, with a mean age at diagnosis of 23 years (7-42), 36 (59%) following DES exposure in utero. During the second period, we found 27 cases, with one case of DES exposure (4%) for a women diagnosed at the age of 40 years. The mean age of the second cohort was 38 years (14-79). For the seven women aged 50 years or more at the time of CCA diagnosis, DES exposure was excluded for five and considered unlikely for the other two. CONCLUSION: In total, 88 cases of cervical or vaginal CCA were observed over a period of 51 years in a cancer center. The 37 cases associated with DES exposure represented approximatively one third of the CCA related to DES expected in France. DES exposure was improbable for the seven cases of CCA for women aged 50 years or more. These results do not support the hypothesis of late cervical or vaginal CCA in women exposed to DES in utero and indicate the need for larger multicentric studies. For the present, we propose specific screening for women exposed to DES in utero in terms of : 1) methods: association of cytology and hrHPV testing, with cervical and vaginal sampling, 2) timing : annual, or without exceeding a three-year interval, continuing after 65 years of age and after hysterectomy.

Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium.

A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.

Postmenopausal Vaginal and Cervical Cancer Risk Related to In Utero Diethylstilbestrol Exposure.

OBJECTIVES: Women exposed to diethylstilbestrol (DES) in utero have an increased risk of clear cell adenocarcinoma of the lower genital tract, requiring lifelong cervical and vaginal cancer screening. We examined the incidence of DES-related cancers in postmenopausal women 50 years and older. MATERIALS AND METHODS: We conducted a retrospective chart review of patients 50 years and older exposed to DES in utero who received care at our institution. Patients were identified using billing codes and/or searching through the electronic record for the word DES. With this 2-pronged approach, we reviewed a total of 503 charts with confirmed DES exposure to identify gynecologic cancer occurrence. RESULTS: Within the 503 selected charts, 28 cases of gynecologic cancer occurrence were identified. Ten patients had cervical cancer and one patient had vaginal cancer. Only 1 woman of 503 developed a DES-related cervical or vaginal malignancy after age 50 years. No patients were diagnosed with cervical or vaginal cancer after age 65 years. CONCLUSIONS: Diethylstilbestrol-related malignancies are rare in those older than 50 years. Current cervical cancer screening guidelines recommend cessation of screening in an average risk, adequately screened patient at age 65 years, but patients exposed to DES have historically received lifelong screening. However, we found no cases of cervical or vaginal cancer related to DES after age 65 years, suggesting that screening recommendations could be changed for these patients to align with current screening guidelines.

Risk of clear-cell adenocarcinoma of the vagina and cervix among US women with potential exposure to diethylstilbestrol in utero.

PURPOSE: Women exposed to diethylstilbestrol (DES) in utero were at elevated risk of clear-cell adenocarcinoma of the vagina and cervix (CCA) as young women. Previous research suggested that this elevated risk of CCA may persist into adulthood. We extended a published analysis to measure CCA risk as these women aged. METHODS: Standardized incidence ratios (SIR) compared CCA risk among women born from 1947 through 1971 (the DES-era) to CCA risk among the comparison group of women born prior to 1947, using registry data that covered the US population. RESULTS: Incidence rates of CCA among both cohorts increased with age. Among the DES-era birth cohort, higher rates of CCA were observed across all age groups except 55-59 years. SIR estimates had wide confidence intervals that often included the null value. CONCLUSIONS: Results are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. The examination of population-based cancer surveillance data may be a useful tool for monitoring trends in the incidence of other rare cancers over time among specific birth cohorts.

Association of In Utero Exposures With Risk of Early Natural Menopause.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

Evidence of intergenerational transmission of diethylstilbestrol health effects: hindsight and insight.

This review summarizes key findings from the US National Cancer Institute (NCI) diethylstilbestrol (DES) Combined Cohort Study with a focus on the results of the NCI Third Generation Study, a cohort of DES-exposed and -unexposed granddaughters. Findings to date from the Third Generation Study are discussed in the context of other research efforts and case reports, suggesting an intergenerational heritability of DES-related effects. The DES story serves as a model for the influence of endocrine disrupting chemicals on human health. It also serves as a warning of the special hazards of pregnancy exposures, and more broadly, of the potential for invisible health consequences arising from new or changing exposures.

The heritable legacy of diethylstilbestrol: a bellwether for endocrine disruption in humans.

Millions of women and their fetuses were exposed to the toxic pregnancy drug diethylstilbestrol (DES) from the 1940s into the 1970s, a time when the medical profession had little knowledge about potential developmental consequences of fetal drug exposures. Pathological consequences of DES exposure to the pregnant mothers and their offspring are well documented, but now generational research is finding that the grandchildren of women given DES in pregnancy are also at risk. This commentary summarizes presentations on this subject from the Beyond Genes panel "Heritable Impacts of Diethylstilbestrol (DES)."

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

BACKGROUND: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease. CASE PRESENTATION: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery. CONCLUSIONS: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.

Prenatal Diethylstilbestrol Exposure and Cancer Risk in Males.

BACKGROUND: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers. METHODS: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age. RESULTS: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77-1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68-1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23-1.00). CONCLUSIONS: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men. IMPACT: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.

Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6-51 and HR = 7.0, 95% CI 1.5-33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88-1.5) or diabetes (HR = 1.1, 95% CI 0.9-1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84-20) or general population (SIR: 1.9, 95% CI 1.0-3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

Screening for cancers of the cervix and vagina for women exposed to diethylstilbestrol (DES) in utero.

OBJECTIVES: In total, 80,000 women were exposed to diethylstilbestrol (DES) in utero in France (DES daughters) between 1950 and 1977. After having been dominated by the management of infertility and pregnancy accidents, monitoring must adapt to the increased risk of cancer of the cervix and vagina: doubling of the frequency of severe dysplasia and a risk of late clear-cell adenocarcinoma (CCA). Two recent changes in cervical cancer screening in France, the introduction of HPV tests in first-line screening and organized screening, should consider the particular situation of DES daughters. We aimed to assess the compliance of DES daughters with previous recommendations and propose specific screening practices in the new context. METHOD: A non-profit organization carried out a questionnaire survey of its members who were exposed to DES in utero. RESULTS: Among the 570 participants, 64 % had annual PAP tests, 25 % within the last three years, and 11 % more than three years before or never. The reasons for "dropout" were: 1) ignorance of the recommendations by practitioners (38 %) or patients (30 %), 2) fatigue (32 %) or apprehension of the exams (14 %), and 3) difficult access to care: time to get an appointment (26 %), difficulty in finding a doctor (28 %), or cost (6 %). CONCLUSION: These results concern women who were sufficiently aware of the issue to be a member of an association. They are encouraging but show a need to improve the dissemination of information to all "DES daughters" and health professionals. Patient associations can play a growing role in this "rare disease" by addressing patients and healthcare professionals. We propose that screening for these women include an annual screen of not only the cervix, but also the vagina, and that it continues beyond 65 years of age and after hysterectomy, with cytological examination, because ACC is unrelated to HPV.

Diethylstilbestrol exposure during pregnancy with primary clear cell carcinoma of the cervix in an 8-year-old granddaughter: a multigenerational effect of endocrine disruptors?

To date, vaginal/cervical clear cell adenocarcinoma (CCAC) has not been reported in the granddaughters of women treated with diethylstilbestrol (DES) during pregnancy. We present an 8-year-old girl with a history of severe vaginal bleeding who was diagnosed with cervical CCAC. She underwent fertility-sparing surgery and radiotherapy. No sign of recurrence was detected throughout a 10-year follow-up. Her grandmother had received DES therapy during pregnancy with the patient's mother. Although no direct causal link is demonstrated, this case raises for the first time, the hypothesis of multigenerational effects of DES in girls and strongly suggests the need to follow the granddaughters of DES-treated women.

SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

Early life factors for endometriosis: a systematic review.

BACKGROUND: Despite its high prevalence and health burden, many aspects of endometriosis remain unclear, including risk factors and the underlying biological mechanisms. Exposures during early life, including in utero, are thought to play an important role in the subsequent onset of the condition. To date, however, much of the evidence from studies on early life exposures and diagnosed endometriosis appears mixed and difficult to assess. OBJECTIVE AND RATIONALE: This study aims to provide a systematic review of the epidemiologic evidence on early life factors associated with the subsequent diagnosis of endometriosis. In utero and early life exposures have previously been linked to a range of adult health outcomes, including infertility. SEARCH METHODS: A systematic review of case-control, cross-sectional and cohort studies was conducted using the search terms 'endometriosis'[MeSH] AND ('risk factors'[MeSH] OR 'protective factors'[MeSH]) AND ('in utero', 'fetal', 'neonatal, 'perinatal', 'developmental origins', 'early life', 'childhood' OR 'life course') in Embase, PubMed and Scopus databases. The review included articles published in English until 10 June 2018 with original data from studies with diagnosed endometriosis. The quality of primary studies was evaluated using the Newcastle-Ottawa Scale by both authors independently. Due to the degree of inconsistency in the measurements and study methods, a qualitative assessment of findings was undertaken rather than meta-analysis. OUTCOMES: The search retrieved 70 records without duplicates that contained 20 records on human case-control, cross-sectional or cohort studies, from which 11 papers/studies were selected based on their assessment score. The majority of studies found that women born with low birthweight (<2.5 kg or <5.5 lb) were more likely to be diagnosed with endometriosis. For other early life factors, the evidence is mixed or limited, with further research needed on the association of endometriosis with preterm birth, in utero exposure to diethylstilbestrol and to maternal smoking, passive smoking in early life, and infant formula feeding (compared with breastfeeding). WIDER IMPLICATIONS: While the weight of evidence points to low birthweight as a risk factor for diagnosis of endometriosis, future research is warranted on this and other key early life exposures where the findings are mixed to provide more robust evidence and for insights on potential causal pathways. Such research, however, needs to address current methodological issues, such as the use of prospective data from large population-based studies, better diagnostic methods to confirm disease free status, more consistent definitions of variables and consideration of potential biological mechanisms to guide the analyses. The improvements will advance the future synthesis of evidence to support clinically relevant risk assessment for a more timely diagnosis and treatment of endometriosis.

Oestrogenic Endocrine Disruptors in the Placenta and the Fetus.

Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the stability and regulation of the endocrine system of the body or its offspring. These substances are generally stable in chemical properties, not easy to be biodegraded, and can be enriched in organisms. In the past half century, EDCs have gradually entered the food chain, and these substances have been frequently found in maternal blood. Perinatal maternal hormone levels are unstable and vulnerable to EDCs. Some EDCs can affect embryonic development through the blood-fetal barrier and cause damage to the neuroendocrine system, liver function, and genital development. Some also effect cross-generational inheritance through epigenetic mechanisms. This article mainly elaborates the mechanism and detection methods of estrogenic endocrine disruptors, such as bisphenol A (BPA), organochlorine pesticides (OCPs), diethylstilbestrol (DES) and phthalates (PAEs), and their effects on placenta and fetal health in order to raise concerns about the proper use of products containing EDCs during pregnancy and provide a reference for human health.

Drug-Related Carcinogenesis: Risk Factors and Approaches for Its Prevention.

The review summarizes the data on the role of metabolic and repair systems in the mechanisms of therapy-related carcinogenesis and the effect of their polymorphism on the cancer development risk. The carcinogenic activity of different types of drugs, from the anticancer agents to analgesics, antipyretics, immunomodulators, hormones, natural remedies, and non-cancer drugs, is described. Possible approaches for the prevention of drug-related cancer induction at the initiation and promotion stages are discussed.

Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol.

We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who participated in a study of prenatal DES exposure. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models adjusted for birth year, study cohort, and education. Among women, the OR for DES in relation to reporting sexual orientation identity as nonheterosexual was 0.61 (95% CI 0.40-0.92) primarily due to a strong inverse association with a lesbian identity (OR 0.44, 95% CI 0.25-0.76). Among men, the OR for DES in relation to reporting a nonheterosexual sexual orientation identity was 1.4 (95% CI 0.82-2.4), and ORs were similar for having a gay identity (1.4, 95% CI 0.72-2.85) and bisexual identity (1.4, 95% CI 0.57-3.5). Only five individuals reported a gender identity not conforming to that assigned at birth, preventing meaningful analysis. Women who were prenatally exposed to DES were less likely to have a lesbian or bisexual orientation, while DES-exposed men were somewhat more likely to report being gay or bisexual, but estimates were imprecise.

SIDE EFFECTS OF DIETHYLSTILBESTROL (DES) FROM THE PERSPECTIVE OF TORT LAW.

OBJECTIVE: The aim of the article is to analyze the reasoning of the Supreme Court of California in Sindell v. Abbott Laboratories. PATIENTS AND METHODS: Materials and methods: Materials of the study encompass US case law as well as case law of other countries concerning compensation of damage caused by defective drugs and other cases of uncertain causation. The survey is conducted within the framework of comparative law studies. In addition, elements of law and economics approach are also employed in the paper. CONCLUSION: Conclusions: Case of Sindell v. Abbott Laboratories has launched a new direction in discourse on causation in tort law and product liability. The mathematical elegance of the Court's theory is that net burden of liability borne by a particular drug manufacturer is equal to the amount of damage actually caused by its drug.

Genital tract and reproductive characteristics in daughters of women and men prenatally exposed to diethylstilbestrol (DES).

OBJECTIVE: Prenatal exposure of women to diethylstilbestrol (DES) has been associated with reproductive tract anomalies, menstrual irregularity, infertility and pregnancy complications. In prenatally exposed men, adverse effects included genital anomalies and possible risk of infertility. In children of prenatally exposed women, i.e the third generation, an increased incidence of genital defects was observed in sons (hypospadias), but not in daughters. In daughters of prenatally exposed men, the incidence of genital anomalies was in the normal range. Experimental studies in mice evidenced an increased incidence of reproductive tract anomalies in the female descendants of females and males prenatally exposed to DES, indicative of transgenerational transmission of DES defects. The aim of this study is to assess genital tract defects, fertility and pregnancy outcome, in daughters of women and men prenatally exposed to DES. METHODS: In a retrospective observational analysis, 759 daughters of prenatally exposed women and men reported their genital and reproductive characteristics that were compared with those of: 1) general population in France; 2) two cohorts of daughters of exposed women reported in previous publications; 3) women prenatally exposed to DES. RESULTS: An increased incidence of uterine defects was observed, with both doubling of uterus and bicornuate and aplastic uterus which constitutes the Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). No specific anomalies described in prenatally exposed women such as T-shape or hypoplastic uterus were reported. Infertility appeared to be in the normal range. Pregnancy outcomes of our 121 pregnancies of women born to DES exposed mothers and two other published cohorts presented inconsistent results for ectopic pregnancy, miscarriage and preterm delivery. Early and late miscarriages were higher than expected in general population in our cohort but not in the two others. CONCLUSION: These results must be considered as preliminary, due to the small numbers of patients, limited follow-up duration after birth due to young age of the studied population, and observational methods. An important point is that the high risk of reproductive dysfunction of women prenatally exposed to DES was not observed in their daughters. There is a signal on the high incidence of uterine defects, especially aplastic uterus, and its possible link with DES exposure through epigenetic effects is discussed in our findings. Inconsistent findings regarding pregnancy outcomes in the third generation are worthy of further examination.