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Consequences of diethylstilbestrol (DES) exposure for grandchildren

The “DES granddaughters and grandsons”: third generation exposed to diethylstilbestrol

The "DES third generation", i.e. the children of children exposed in utero to the drug, meaning women and men whose grandmothers received diethylstilbestrol — known as "DES Grandchildren" — also suffer the consequences of diethylstilbestrol (DES) exposure.

In France, around 200,000 pregnant women have received diethylstilbestrol (Distilbène®, Stilbestrol-Borne® or Furostilboestrol® — a delayed release form) during pregnancy, and 160,000 children were born from these pregnancies, including 80,000 girls and 80,000 boys.

As there is no patient registry, we do not know how many people in this third generation are affected.

However, we can confirm that a large proportion of DES Grandchildren are now well into their child-bearing years.

This prenatal exposure to DES has led to the definition of a rare disease: diethylstilbestrol syndrome (or distilbene embryofoetopathy). As no PNDS exists, no patient can currently be diagnosed.

DES Children Diethylstilbestrol syndrome
 
Consequences of exposure to diethylstilbestrol (DES) on the health of DES granddaughters

Health consequences of diethylstilbestrol exposure for DES Granddaughters

Among “DES Granddaughters”, i.e. women whose one or both parents were exposed in utero to diethylstilbestrol, it has been found*,**:

  • Precocious puberty: breast development in girls less than 8 years, pubic or underarm hair, start of menstruation before age 10...1;
  • Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (MRKH), characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina2;
  • Endometriosis3, 4;
  • Irregular menstrual cycle, amenorrhea5 ;
  • Risk of ectopic pregnancy5 ;
  • Premature deliveries5 ;
  • Increased risk of delivering a low birth weight baby6 ;
  • Several cases of vaginal or cervical cancers7,8 (clear-cell adenocarcinoma or CCA) have been reported;
  • 3 cases of ovarian cancer have been reported by the NCI (National Cancer Institute) in: two women aged 20 and 22 years included in the cohort, and one girl too young to be included. These are really rare cancers in young women9.

* non-exhaustive list

*Note that the majority of scientific studies focus on women born from women exposed in utero to diethylstilbestrol.

Pathological pregnancies linked to diethylstilbestrol (DES)

In our opinion, the pregnancies of DES Granddaughters are, just like those of their mothers, “DES pregnancies” and as such, require rest to minimize the risks, which is why we have launched a petition so that they can “have their pregnancy(ies) covered from the 1st day they are off work, under the same compensation conditions as for statutory maternity leave” (See the petition).

Urbania - Le Distilbène | Entre moi et moi, Stephy, a DES Granddaughter, shares her story.

Recommendations for women whose grandmother received diethylstilbestrol (DES), or DES granddaughters

Health recommendations for DES Granddaughters

There are no official recommendations in France for women indirectly exposed to D.E.S..

Thus, the recommendations you will find below are taken from the guide "CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposedproduced by the American association DES Info and the Diethylstilbestrol (DES) International Information and Research Group, itself based on the recommendations of the National Cancer Institute (NCI).

Women whose mother and/or father were exposed in utero to diethylstilbestrol (DES) are invited to perform:

  • Monthly self-breast exams10. his examination consists of carefully palpating the breasts — including the nipples, clavicle and armpits — in search of any deep-seated or superficial abnormalities. 
    If you notice any abnormality, such as changes in the shape, size and color of your breasts, puckering or bulging of the skin, scaling or a rash on your nipples, redness, soreness, rash or swelling... make an appointment with your doctor.
  • Annual breast screenings (included in the annual gynecological exam).10.
  • The guide recommends yearly clinical breast exams10, which essentially consists of a mammogram. In France, screening mammography is usually offered every two years to women between 50 and 74 years old. We recommend that you ask your doctor for medical advice. He will be able to determine the necessity and frequency of this examination — which is not without health risks11 — and may prescribe others in addition (ultrasound, MRI scan, ...).
  • Healthcare professionals are advised to pay particular attention to breast health for DES Granddaughters who report changes.
  • Researchers are watching DES Granddaughters and recommend, as is the case for their mothers (DES Daughters), that annual gynecological examinations include a check for the presence of clear-cell adenocarcinoma (CCA) of the vagina and/or cervix.10
Download the complete guide
 
 

Known health effects for both DES Granddaughters and Grandsons

It has been observed in DES Grandchildren*:

  • An increased number of esophageal atresia, as well as an increase in the number of malformations of the oral cavity and abnormalities of the musculoskeletal system12. 
  • An increased rate of Cerebral Palsy (CP), related to premature, even very premature births13.
  • An increased risk of cardiovascular malformations (including the tetralogy of Fallot) has also been reported14.
  • A study found a significant increase in the number of Attention Deficit Disorders with or without Hyperactivity (ADHD15.
  • There appears to be an increased risk of developing Autism Spectrum Disorders (ASD)16, but no scientific study has yet shown this.

* non-exhaustive list

 
 
Health consequences of diethylstilbestrol exposure for DES Grandsons

Health consequences of diethylstilbestrol exposure for DES Grandsons

In “DES Grandsons”, i.e. men of whom at least one of the two parents was exposed in utero to diethylstilbestrol (DES), it was found*:

1. in men from women exposed in utero to diethylstilbestrol:

  • Disorders of sex development: an increased risk of hypospadias and cryptorchidia17, 18.
  • Risk of genital malformations 2 times higher19.

2. in men from men exposed in utero to diethylstilbestrol:

  • Genital abnormalities: cryptorchidism, penile hypoplasia (micropenis), but no hypospadias9.

* non-exhaustive list

L'hypospadias chez les « petits-garçons DES » issus de « grands-mères distilbène ».

Health recommendations for men whose grandmother received diethylstilbestrol, or DES Grandsons

Health recommendations for DES Grandsons

There are no official recommendations in France for men indirectly exposed to D.E.S..

Thus, the recommendations you will find below are taken from the guide "CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposedproduced by the American association DES Info and the Diethylstilbestrol (DES) International Information and Research Group, itself based on the recommendations of the National Cancer Institute (NCI).

  • Healthcare professionals are advised to pay particular attention to male genitals for DES Grandsons who report changes10.
Download the complete guide
 

Potential health effects of diethylstilbestrol in the fourth generation

For the moment, scientific data are not available for the Fourth Generation, but the possibility that they will also be affected by the adverse effects of DES (diethylstilbestrol) cannot be excluded — and we have already received testimonies to this effect.

Indeed, transmission to the Third Generation is notably due to a phenomenon of epigenetic alteration: DES induces changes in gene expression that are transmitted from one generation to the next.

 

"Obstetrician-gynecologist Dr. Anne Wautier explains very clearly (using examples helping to understand) complex notions such as: epigenetics, endocrine disruptors, transgenerational effects of DES (diethylstilbestrol)."

Notes & references

  1. ↑ Assemblée Nationale - Question N° : 109961 http://questions.assemblee-nationale.fr/q13/13-109961QE.htm
  2. ↑ Wautier A, Tournaire M, Devouche E, Epelboin S, Pouly JL, Levadou A. Genital tract and reproductive characteristics in daughters of women and men prenatally exposed to diethylstilbestrol (DES). Therapie. 2020 Sep-Oct;75(5):439-448. doi: 10.1016/j.therap.2019.10.004. Epub 2019 Nov 1. PMID: 31806244.8
  3. ↑ Gaspari, L., Soyer-Gobillard, MO., Paris, F. et al. Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?. Environ Health 20, 96 (2021). https://doi.org/10.1186/s12940-021-00780-5
  4. ↑ We invite you to read the book-testimony of Enora Malagré, DES granddaughter, dedicated to her fight against endometriosis. Malagré Enora. 2019. “Un cris du ventre”, Leduc S. [in French]
  5. ↑ a ↑ b ↑ c Titus L, Hatch EE, Drake KM, Parker SE, Hyer M, Palmer JR, Strohsnitter WC, Adam E, Herbst AL, Huo D, Hoover RN, Troisi R. Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. Reprod Toxicol. 2019 Mar;84:32-38. doi: 10.1016/j.reprotox.2018.12.008. Epub 2018 Dec 27. PMID: 30594671; PMCID: PMC6382553
  6. ↑ Yim G, Roberts A, Wypij D, Kioumourtzoglou M-A, Weisskopf MG. Grandmothers’ endocrine disruption during pregnancy, low birth weight, and preterm birth in third generation. Int J Epidemiol 2022 ;50:1886–96
  7. ↑ Laura Gaspari, Françoise Paris, Nathalie Cassel-Knipping, Julia Villeret, Arnauld Verschuur, Marie-Odile Soyer-Gobillard, Xavier Carcopino-Tusoli, Samir Hamamah, Nicolas Kalfa, Charles Sultan, Diethylstilbestrol exposure during pregnancy with primary clear cell carcinoma of the cervix in an 8-year-old
  8. ↑ DES Info reported two cases of Clear Cell Adenocarcinoma of the Vagina in DES granddaughters in 2018.
  9. ↑ a ↑ b Sylvie Epelboin, Michel Tournaire, Emmanuel Devouche. Exposition au Distilbène® in utero : effets transgénérationnels. Médecine de la Reproduction. 2022;24(1):37-48. doi:10.1684/mte.2022.0875
  10. ↑ a ↑ b ↑ c ↑ d ↑ e CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposed. DES Info Association & Diethylstilbestrol (DES) International Information and Research Group - JUNE 20, 2023
  11. ↑ Learn more on the breast cancer screening information website Cancer Rose: https://cancer-rose.fr/.
  12. ↑ Michel Tournaire , Sylvie Epelboin, Emmanuel Devouche, Géraldine Viot, Jérôme Le Bidoi, Anne Cabau, Annabel Dunbavand, Anne Levadou. Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES). 2016.
  13. ↑ Hatch EE, Troisi R, Wise LA, Titus-Ernstoff L, Hyer M, Palmer JR, Strohsnitter WC, Robboy SJ, Anderson D, Kaufman R, Adam E, Hoover RN. Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES). 2011
  14. ↑ Titus-Ernstoff L, Troisi R, Hatch EE, Palmer JR, Hyer M, Kaufman R, Adam E, Noller K, Hoover RN. Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES). 2010
  15. ↑ Kioumourtzoglou MA, Weisskopf MG. Grandmaternal Diethylstilbestrol and Attention-Deficit/Hyperactivity Disorder in Children-Reply. JAMA Pediatr. 2018 Dec 1;172(12):1204-1205. doi: 10.1001/jamapediatrics.2018.3743. PMID: 30383104.
  16. Rise in Autism Travels Through Generations, By Jane Kay, from Environmental Health News. 2014.
  17. ↑ Pons JC, Papiernik E, Billon A, Hessabi M, Duyme M. Hypospadias in sons of women exposed to diethylstilbestrol in utero. Prenat Diagn. 2005 May;25(5):418-9. doi: 10.1002/pd.1136. PMID: 15906411.
  18. ↑ Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N. Hypospadias: a transgenerational effect of diethylstilbestrol? Hum Reprod. 2006 Mar;21(3):666-9. doi: 10.1093/humrep/dei398. Epub 2005 Nov 17. PMID: 16293648.
  19. ↑ Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertil Steril. 2011 Jun 30;95(8):2574-7. doi: 10.1016/j.fertnstert.2011.02.047. Epub 2011 Apr 2. PMID: 21458804.
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