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.

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.

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.

Birth defects in children of men exposed in utero to diethylstilbestrol (DES).

OBJECTIVE: Prenatal exposure to diethylstilbestrol (DES) is associated with adverse effects, including genital anomalies and cancers in men and women. Animal studies showed birth defects and tumors in the offspring of mice prenatally exposed to DES. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to assess the birth defects in children of prenatally exposed men. METHODS: In a retrospective study conceived by a patients' association (Réseau DES France), the reports of men prenatally exposed to DES on adverse health effects in their children were compared with those of unexposed controls and general population. RESULTS: An increased incidence of two genital anomalies, cryptorchidism (OR=5.72; 95% CI 1.51-21.71), and hypoplasia of the penis (OR=22.92; 95% CI 3.81-137.90), was observed in the 209 sons of prenatally exposed men compared with controls, but hypospadias incidence was not increased in comparison with either the controls or the general population. No increase of genital anomalies was observed in daughters. CONCLUSION: With caution due to the methods and to the small numbers of defects observed, this work suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This transgenerational effect, already observed in animals and in the offspring of women prenatally exposed to DES, could be the result of epigenetic changes transmitted to the subsequent generation through men.

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls.

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure. Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey. Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer. Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women. Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES).

OBJECTIVE: Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women. METHODS: In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires. RESULTS: There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary. CONCLUSION: Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.

Cancer Risk in Women Exposed to Diethylstilbestrol in Utero.

OBJECTIVE: To evaluate the overall cancer risk, primarily breast cancer, for women exposed to diethylstilbestrol (DES) in utero in France. METHODS: A cohort of 3 436 prenatally DES exposed women and a comparable cohort of 3256 unexposed women were recruited retrospectively from voluntary responses to questionnaires, and cases were ascertained by medical history at the time of recruitment. RESULTS: One hundred ninety-five cancers were observed in exposed women (136 breast cancers, and 59 in other sites) and 141 cancers in unexposed women (90 breast cancers, and 51 others). A significant increase of breast cancers was found in exposed women, with a multivariate incidence rate ratio of 2.10 (95% CI 1.60-2.76) when compared with unexposed women. When exposed women were compared with the general population in France, the standardized incidence ratio was 2.33 (95% CI 1.93-2.72). CONCLUSION: Our results suggest a significant increase of breast cancer in prenatally DES exposed women when compared with unexposed women and with the general population. For other cancers, except clear cell carcinoma of the cervix or vagina, there was a global non-significant increase.

[Diethylstilbestrol story]. / Histoire du diéthylstilbestrol.

This story, that has been going on for 75 years begins with an infatuation for a "miraculous" drug supposed to, according to a theory and without scientific proof of effectiveness, reduce the pregnancy complications, especially the number of miscarriages. The next steps are painful with the discovery during the seventies, for the in utero exposed daughters, of particular cancers (clear cells adenocarcinoma) of the uterus cervix or the vagina, then during the eighties infertility and pregnancy accidents. This story is exemplary because it involves the different society actors whose roles will be analysed: health professionals, health authorities, patients associations, media and pharmaceutical companies. We will propose lessons for the future.

[Pregnancy complications according to maternal age]. / Risques pour la mère et l'enfant. Complications gravidiques en fonction de l'age.

The number of late pregnancies, at 40 years or more has dramatically increased recently, multiplying by more than three, in France, since 1980 (30000 versus 8500). Medical particularities are dominated by higher risks of first trimester miscarriages and Down syndromes. Screening and diagnostic conditions have changed recently in France with a reduiced number of invasive procedures (amniocentesis or chorionic villus sampling) but also a lower expected diagnostic ratio. Thanks to the present medical surveillance these pregnancies are not considered at high risk for the child. On the other hand, these pregnancies are at higher risk for the mothers, associated with the increased numbers, for the deliveries, of caesarean sections, hemorrhages, and thromboembolic accidents.

Complementary and alternative approaches to pain relief during labor.

This review evaluated the effect of complementary and alternative medicine on pain during labor with conventional scientific methods using electronic data bases through 2006 were used. Only randomized controlled trials with outcome measures for labor pain were kept for the conclusions. Many studies did not meet the scientific inclusion criteria. According to the randomized control trials, we conclude that for the decrease of labor pain and/or reduction of the need for conventional analgesic methods: (i) There is an efficacy found for acupressure and sterile water blocks. (ii) Most results favored some efficacy for acupuncture and hydrotherapy. (iii) Studies for other complementary or alternative therapies for labor pain control have not shown their effectiveness.

Preservation of pregnancy in a patient with a stage IIIB ovarian epithelial carcinoma diagnosed at 22 weeks of gestation and treated with initial chemotherapy: case report and literature review.

BACKGROUND: To report a case of successful management of a FIGO stage III endometrioid carcinoma of the ovary diagnosed during pregnancy at 22 weeks of gestation and treated with initial chemotherapy while preserving the pregnancy. CASE: The patient underwent a planned cesarean section at 34 weeks after two courses of carboplatin. She delivered a healthy baby. At the same time, a radical hysterectomy, omentectomy, pelvic and paraaortic lymphadenectomies and peritonectomies were carried out. The surgical resection was complete (no macroscopic residual disease). During histologic examination, traces of persistent disease were found. The patient underwent seven postoperative courses of chemotherapy (carboplatin + paclitaxel regimen) after radical surgery. After 18 months of follow-up posttreatment, the patient remains in complete remission and the child's development is normal. CONCLUSION: Chemotherapy during pregnancy with preservation of the fetus could be considered and should be discussed in case of epithelial ovarian cancer (EOC) diagnosed during the second trimester of the pregnancy.

Tocolytic effects of intravenous nitroglycerin.

Currently available tocolytic agents have shown partial or transient efficacy on uterine contractions delaying delivery for 24 or 48 h without reduction in perinatal morbidity and mortality. These facts led us to study a new tocolytic compound. A double-blind dose finding study of the nitroglycerin tocolytic effect during preterm labor was conducted using a continual reassessment method among six different doses (0.2-1.2 mg/h for 2 h) in pregnant women who were unresponsive, intolerant to salbutamol, or with a contraindication to this therapy. Twenty-five pregnant women were included. The probability of success in stopping uterine contractions reached, for the maximal dose (1.2 mg/h), only a 54% rate (95% CI: 29-79%). Twelve patients complained of headaches and 16 experienced a decrease in arterial blood pressure suggesting that it would not be safe to increase the dose in order to obtain a higher success rate. The present study suggests that nitroglycerin is not as effective as expected in controlling uterine contractions during severe preterm labor in patients where beta2 agonists cannot be used.