Can a Pregnancy Drug Trigger ADHD Generations Later ? You Bet !

Aattention-Deficit/Hyperactivity Disorder Much More Common in Grandchildren of Women Who Were Prescribed the DES Drug in Pregnancy

A cohort study – Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits – published May 21, 2018, shows that prenatal diethylstilbestrol exposure may lead to neurodevelopmental disorders across several generations : DES grandchildren are more likely to be diagnosed with ADHD (36% to 63%).

The audio summary above reviews the cohort study that uses Nurses’ Health Study data to investigate associations between diethylstilbestrol (DES) use in pregnancy and self-reported development of ADHD in grandchildren.

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Much Higher Risk of ADHD in DES GrandChildren

Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits

New research published today, May 21, 2018, shows that prenatal diethylstilbestrol exposure may lead to neurodevelopmental disorders across several generations : DES grandchildren are more likely to be diagnosed with ADHD (36% to 63%).

Key Points

Question
Is exposure to diethylstilbestrol during pregnancy associated with adverse multigenerational neurodevelopmental outcomes?

Findings
A cohort study of 47 450 women in the Nurses’ Health Study II found significantly elevated odds for attention-deficit/hyperactivity disorder in the grandchildren (third generation) of users of diethylstilbestrol, a potent endocrine disruptor.

Meaning
Exposure to endocrine disruptors during pregnancy may be associated with multigenerational neurodevelopmental deficits.

Abstract

Importance
Animal evidence suggests that endocrine disruptors affect germline cells and neurodevelopment. However, to date, the third-generation neurodevelopmental outcomes in humans have not been examined.

Objective
To explore the potential consequences of exposure to diethylstilbestrol or DES across generations—specifically, third-generation neurodevelopment.

Design, Setting, and Participants
This cohort study uses self-reported health information, such as exposure to diethylstilbestrol during pregnancy and attention-deficit/hyperactivity disorder (ADHD) diagnosis, from 47 540 participants enrolled in the ongoing Nurses’ Health Study II. The 3 generations analyzed in this study were the participants (F1 generation), their mothers (F0 generation), and their live-born children (F2 generation).

Main Outcomes and Measures
Participant- and mother-reported exposure to diethylstilbestrol during pregnancy and physician-diagnosed child ADHD.

Results
The total number of women included in this study was 47 540. Of the 47 540 F0 mothers, 861 (1.8%) used diethylstilbestrol and 46 679 (98.2%) did not while pregnant with the F1 participants. Use of diethylstylbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted odds ratio (OR), 1.36 (95% CI, 1.10-1.67) and an OR of 1.63 (95% CI, 1.18-2.25) if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children’s sex.

Conclusions and Relevance
This study provides evidence that diethylstilbestrol exposure is associated with multigenerational neurodevelopmental deficits. The doses and potency level of environmental endocrine disruptors to which humans are exposed are lower than those of diethylstilbestrol, but the prevalence of such exposure and the possibility of cumulative action are potentially high and thus warrant consideration.

DES DiEthylStilbestrol Resources

Fetal Origin of Adult Disease

Abstract from “Environmental Exposures and Adverse Pregnancy Outcomes: A Review of the Science”

During the last two decades, chronic disease has replaced infectious disease as the major focus of public health concern. The top 4 leading causes of death in the United States are chronic diseases. There remains much unknown about the etiology of many chronic conditions, which in most cases is probably multifactorial. Studies from the 1990s found that effects on the fetal environment, such as through poor or inadequate nutrition, can result in an increased risk of adult onset of chronic conditions, such as coronary heart disease. This has been called the fetal origins hypothesis (also known as the Barker theory), which proposes that external influences on the fetal environment can increase the risk of later disease in adulthood.

Diethylstilbestrol (DES)—a synthetic estrogen given to US women between 1938 and 1971 to prevent pregnancy complications illustrates the fetal origins of later in life disease. In utero DES exposure left mature female offspring at increased risk of clear cell adenocarcinoma of the vagina and cervix, breast cancer, structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes, while male offspring have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. These observed human effects have been confirmed in numerous animal models, which have also predicted changes later found in DES-exposed humans, such as increased incidence of uterine fibroids, oviductal malformations, and second generational effects such as increased menstrual irregularities and possibly ovarian cancer in DES granddaughters and increased hypospadias in DES grandsons.

Diethylstilbestrol shows the adverse effects of fetal exposures to synthetic chemicals may not be apparent at birth or even for many years afterward, and that continued monitoring of this cohort of exposed children and grandchildren is necessary to inform potential effects of prenatal exposures to other contaminants.

Reference. Image credit Hush Naidoo.

DES DiEthylStilbestrol Resources

Follow-up of Patients with Clear-Cell Adenocarcinoma of the Vagina and Cervix

New England Journal of Medicine, May 3, 2018 – Supported by the National Cancer Institute, National Institutes of Health, through a cooperative agreement

A new report on the risks of exposure during pregnancy to a supplement, diethylstilbestrol (DES), that is linked to a rare cancer. The study found that DES-exposed patients with clear-cell adenocarcinoma had ‘increased mortality across their life span.’ For women aged 10 to 34 with DES-related clear-cell adenocarcinoma, the risk of death was 27 times higher than for other US women in that age group.

Women who had prenatal exposure to diethylstilbestrol (DES) are at increased risk for clear-cell adenocarcinoma of the vagina and cervix early in life. Previous studies have investigated the clinical features of this disease and survival among these patients, but data on their long-term survival are lacking. Women with DES-related clear-cell adenocarcinoma are aging into their 50s and 60s, but the effect of this condition during their overall life span has not been well established.

A total of 695 patients with clear-cell adenocarcinoma in the Registry for Research on Hormonal Transplacental Carcinogenesis were followed through 2014 (see the Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org). The mean year of birth was 1955. The mean age at diagnosis of clear-cell adenocarcinoma was 22 years, and 80% of the patients received the diagnosis between the ages of 15 and 30 years. In 415 patients, evidence of prenatal DES exposure was documented.

During a median follow-up of 22.7 years, 219 patients died, yielding a probability of 20-year survival of 69%. The 5-year probability of survival differed between the patients with prenatal DES exposure (86.1%) and patients without documentation of DES exposure (81.2%), but the 20-year probability of survival was similar between the two groups. After adjustment for tumor stage, histologic type, and age, the difference in probability of survival between patients with DES exposure and those without DES exposure was significant only in the first 5 years (P=0.025).

Since the epidemiologic curve was similar between the two groups, some of the patients with clear-cell adenocarcinoma for whom there was no documentation of DES exposure may have actually been exposed to DES in utero, and thus the true survival difference between women with DES exposure and those with idiopathic clear-cell adenocarcinoma would be larger without potential misclassification. This differential effect of DES according to time suggests that clear-cell adenocarcinoma associated with DES exposure and idiopathic clear-cell adenocarcinoma may have different tumor biologic features. Idiopathic clear-cell adenocarcinoma may be more likely to progress quickly or recur earlier, whereas clear-cell adenocarcinoma associated with DES exposure may be more likely to recur later. This interesting phenomenon has also been observed in other estrogen-associated cancers, including breast and endometrial cancers. During the first 5 to 7 years after diagnosis, patients with estrogen receptor (ER)–negative breast cancer have a worse survival than patients with ER-positive breast cancer, but the survival rates between the two groups become similar thereafter. Data from molecular studies of germline genetic mutations, tumor genomic changes, and epigenetic alterations to elucidate the underlying mechanisms for this improved behavior of estrogen-associated cancers are lacking.

We found that patients with clear-cell adenocarcinoma had increased mortality across their life span. The risk of death among women with DES-related clear-cell adenocarcinoma was 27 times higher than that in the general U.S. population of women between 10 and 34 years of age, 5 times higher between 35 and 49 years of age, and 2 times higher between 50 and 65 years of age. The excess mortality risk between the ages of 35 and 49 years is mainly due to late recurrences, whereas the excess mortality risk after 50 years of age may be due to other life-threatening health conditions in the population of women who were exposed to DES. It is therefore important to continue the surveillance of this unique cohort of patients with DES-related clear-cell adenocarcinoma to examine their health conditions late in life.

Press Releases

  • ‘DES daughters’ with rare cancer continue to face higher death rates, reuters, MAY 2, 2018.
  • The DES saga: Death risk high for young women exposed in utero, sciencedaily, May 2, 2018.
  • The pill that gave a generation deadly rare cancers: Mothers-to-be took DES to avoid the pain of a miscarriage – now their daughters are paying the price, DailyMail, 3 May 2018.
  • Mortality Risk Persists for Cancer Tied to Prenatal DES Exposure, empr, May 04, 2018.
DES DiEthylStilbestrol Resources

Les nouvelles grossesses

Collection questions – Presses Universitaires de France

Pr Jean-Claude PONS, 1998

Sujets :
– Grossesse à haut risque
– Procréation médicalement assistée
– Grossesse
– Techniques reproduction
– Législation médicale — France
– Bioéthique — France
– bioéthique — désir d’enfant — foetus — grossesse
– Aspect physiologique
– Aspect psychologique
– Femme enceinte
– Hygiène
– Santé

Le Distilbène DES, en savoir plus

L’impossible enfant

Don d’ovocytes, l’envers du décor

Géraldine Jumel-Lhomme relate cinq années d’odyssée dans l’univers segmenté et méconnu de l’assistance médicale à la procréation où médecine et business s’entremêlent dans un brouillage croissant de repères, de valeurs. Elle présente de l’intérieur le vécu tourmenté de son couple diagnostiqué infertile, elle-même ayant été exposée in utero au Distilbène. La rigidité de la loi française de bioéthique les a conduits à franchir les frontières afin de se soumettre à des fiv avec don d’ovocytes dans des cliniques étrangères. L’auteur décrit ces pratiques souvent lourdes et maltraitantes, décrypte certains tabous et démonte les principaux avatars de cette situation. Elle propose des pistes de réflexion, des éclairages nouveaux sur des sujets qui interpellent notre société.

Contrepoints par Marie Darrieusecq, Geneviève Delaisi de Parceval, Sylvie Epelboin, Marie-José Soubieux.

“Même ceux qui sont familiers des parcours d’enfant à tout prix seront surpris, émus par la lecture de ce livre. Encore davantage évidemment ceux qui ne connaissent de l’amp que ses succès largement déployés dans les médias.”
Geneviève Delaisi de Parseval

“Personne ne peut sortir indemne d’un parcours de maternité aussi terrifiant que celui emprunté par Géraldine Jumel-Lhomme. Personne ne peut sortir indemne de la lecture de son livre !”
Marie-José Soubieux

“Ce que raconte Géraldine Jumel-Lhomme est très personnel, mais aussi caractéristique. C’est d’ailleurs une des forces de son témoignage, que de nouer l’intime (le très intime, le fond du ventre) à l’exemplarité.”
Marie Darrieusecq

Le Distilbène DES, en savoir plus

Le bonheur d’être mère

Pr Michel Tournaire – 2005 – Editions Odile Jacob

Aujourd’hui, les femmes sont de plus en plus nombreuses à travailler et à décider de faire un enfant plus tard. Les grossesses après 35 ans sont-elles particulières ? Comment mettre toutes les chances de son côté pour vivre une grossesse réussie ? Comment éviter les risques ? Les progrès de la médecine permet-tent désormais à ces grossesses de se dérouler presque comme toutes les autres, à condition d’être bien suivie. Le professeur Michel Tournaire vous guide pas à pas, depuis votre désir de maternité jusqu’à la naissance, et vous conseille au quotidien pour une grossesse épanouie.

Sommaire

  • CE QU’IL FAUT SAVOIR AVANT VOTRE GROSSESSE
  • Une grossesse après 35 ans
  • Faites le point sur votre santé et votre mode de vie
  • Mettez toutes les chances de votre côté pour être enceinte
  • BIEN VIVRE VOTRE GROSSESSE
  • Les trois premiers mois
  • Du quatrième au sixième mois
  • Les trois derniers mois
  • La naissance et les premières semaines de votre bébé
  • QUELLES SONT LES DIFFICULTES POSSIBLES ?
  • Et si la grossesse ne vient pas ?
  • Quelles sont les complications possibles de la grossesse et de l’accouchement ?

Michel Tournaire, professeur de gynécologie et d’obstétrique, expert Distilbène DES, est chef de service de la maternité de l’hôpital Saint-Vincent-de-Paul à Paris.

Le Distilbène DES, en savoir plus

Traité de Gynécologie

Le chapitre 50 traite du DES et pathologie gynécologique

Le chapitre 50 traite du DES et pathologie gynécologique.

Pr Hervé FERNANDEZ – 2004 – Editions Flammarion – Collection “Médecines-Sciences”.

Ce traité, à la fois moderne et pratique, couvre en 60 chapitres toute la gynécologie. Après une première partie de rappels physiologiques, la seconde partie est consacrée aux explorations en gynécologie, depuis l’échographie pelvienne et l’examen des frottis, jusqu’aux dosages hormonaux, à l’hystéroscopie et à la mammographie. La troisième partie, très originale, aborde des problèmes de santé publique. Puis, l’ouvrage traite des principaux symptômes et syndromes observés en gynécologie : l’aménorrhée, les métrorragies, les dyspareunies, etc. Sont ensuite abordés les troubles de la fonction ovarienne et la stérilité conjugale. La quatrième partie du traité expose de façon détaillée toutes les autres pathologies organiques, depuis le fibrome utérin jusqu’à la pathologie vulvaire, en passant par les cancers de l’endomètre, les tumeurs ovariennes, les malformations de l’appareil génital, etc. Dans tous les cas, les auteurs traitent des symptômes, des données de l’examen clinique, des stratégies diagnostiques les mieux adaptées, des indications thérapeutiques et des orientations pronostiques. La contraception, l’IVG, les violences sexuelles, les dysfonctions sexuelles font l’objet de chapitres spécifiques. Enfin est abordée la pathologie mammaire sous tous ses aspects.

Le chapitre 50 traite du DES et pathologie gynécologique.

Le Distilbène DES, en savoir plus

 

Pour que l’enfant paraisse

Comprendre et combatre la stérilité

Dr Anne CABAU – 1991 – Editions Flammarion – Collection Santé Mode d’Emploi

Un chapitre consacré au Distilbène explique que les filles DES ont certes du mal à être enceintes et à mener des grossesses mais que ce n’est pas impossible.

“Pourtant au printemps 1992, une nouvelle grossesse se solda encore par une fausse couche. Dans ces cas-là, on n’a pas le chox : on encaisse ! “

Le Distilbène DES, en savoir plus

 

I only felt half a woman

Europe plays Russian roulette with hormones

I only felt half a woman

said Myriam, a DES Daughter – victim from the DES hormone disorder – for the standaard, October 2017.
Image credit © Steve Michiels.

DES DiEthylStilbestrol Resources