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Archived - Advisory on Diethylstilbestrol (DES) and the Risk of Genital and Obstetrical Complications - Health Professional Advisory

Starting date:
March 18, 2003
Posting date:
March 18, 2003
Type of communication:
Dear Healthcare Professional Letter
Subcategory:
Drugs
Source of recall:
Health Canada
Audience:
Healthcare Professionals
Identification number:
RA-17000470

Notice about Health Canada advisories

This is a letter issued by the Marketed Health Products Directorate and the Therapeutic Products Directorate

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Important Drug Safety Information

March 18, 2003

The Marketed Health Products and Therapeutic Products Directorates wish to draw your attention on a letter to prescribing physicians updated on January 2003 by the Agence française de sécurité sanitaire des produits de santé (Afssaps) regarding information on diethylstilbestrol (DES) and the risk of genital and obstetrical complications.

The original Afssaps posting is available at: http://ansm.sante.fr - available in French only

Letters to prescribing physicians

Advisory on diethylstilbestrol (DES) (Distilbène®, Stilboestrol-Borne®) and the risk of genital and obstetrical complications 
Update: January 2003

Diethylstilbestrol (DES), a non-steroidal synthetic estrogen, was used in France from 1948 to 1977 in pregnant women, to prevent miscarriage and pregnancy-related bleeding. It was marketed in France as of 1948 under the brand names Distilbène®, and Stilboestrol-Borne®.

It was in the United States in 1971 that the first cases of vaginal cancer in young women who has been exposed in utero to DES first drew attention. One of the first cases of vaginal adenocarcinoma in a young woman was published in 1975. In France, the indication "repeated miscarriage" was eliminated in 1976 and a contra-indication regarding use in pregnant women was added in 1977.

Since then, other genital and obstetrical complications of in utero DES exposure have been observed and reported on numerous occasions, particularly through information brochures for health professionals and the public.

The problem persists and is likely to do so for many years to come. Between 1948 and 1976, approximately 200,000 pregnant women were treated with DES in France. Taking into account miscarriages and fetal or neonatal deaths, the number of children born of these pregnancies is estimated to be 160,000 (80,000 girls and 80,000 boys exposed in utero). Prescriptions for DES reached a peak in the late 1960s and early 1970s. Patients exposed in utero are now between the ages of 25 and 52. Second generation effects in the form of obstetrical problems are therefore expected to occur until around 2015.

Even today, it would appear that not all physicians are aware of the consequences of in utero DES exposure. For this reason, the Agence Française de Sécurité Sanitaires des Produits de Santé has decided to inform health professionals of the procedure for screening and managing these patients. This notice has been prepared in cooperation with the Association Réseau D.E.S. France.

Diethylstilbestrol continues to be marketed today under the brand name Distilbène® and is indicated for certain prostatic conditions only.

What are the risks of in utero exposure to DES?

The risk of genital pathology as a result of in utero exposure is dependent upon the period of exposure far more than the duration of exposure or the dose prescribed. The risk period is situated between the 6th and 17th weeks of amenorrhea.

What are the risk for men who were exposed in utero?

Pathologies affecting the urogenital system, including epididymal cysts, testicular abnormalities such as testicular hypertrophy, cryptorchidism and capsular induration, as well as abnormalities relating to the position of the urinary meatus (hypospadias, epispadias) are more frequent in men exposed to DES in utero than in the general population.

What are the risks for women who were exposed in utero?

The primary complications are:

  • clear cell adenocarcinoma of the vagina or cervix occurring in approximately 1 out of every thousand patients exposed in utero. Given the average age of occurrence (age 22) and the current age of patients who were exposed in utero, this complication is now uncommon.
  • structural, morphological and functional abnormalities involving the vagina, cervix, uterus, and fallopian tubes, in order of frequency:
    • adenosis (ectopias of the columnar epithelium involving the cervix and vagina): presence beyond its normal location of the columnar epithelium of the cervix. Observed in approximately 30% of DES-exposed young women who are asymptomatic and in 60% of exposed young women who have clinical signs. Generally resolves itself spontaneously. Adenosis lesions often bleed or become infected and are aggravated by trauma to the cervix (coagulation, cryotherapy and laser).
    • other cervical or vaginal abnormalities (20-60% of young women exposed to DES): structural abnormalities of the cervix and vagina can be observed. The most common are cervical hypoplasia (absent or foreshortened cervix, presence of a cervical "hood").
    • abnormalities of the uterus: frequently associated with the preceding abnormalities. In decreasing order of frequency: "T" shaped uterus and small-size cavity, uterine hypoplasia (uterus which is small in its totality), narrowing of the cavity, strictions, uterine diverticula.

Some gynecologists are recommending hysteroscopic metroplasty--a surgical procedure to enlarge the uterus--to patients with uterine malformations. This surgical procedure is currently being evaluated by the Agence Nationale d'Accréditation et d'Evaluation en Santé (ANAES).

  • abnormalities of the fallopian tubes: laparoscopy shows thin tubes

Some of these pathologies can result in fertility problems (in approximately one woman out of three) as well as obstetrical complications:

  • ovulation disorders: as yet unconfirmed data suggest that there may be a risk of early ovarian disgenesis cervical problems
  • cervical mucus abnormalities which inhibit the penetration of spermatozoa
  • ectopic pregnancy, risk multiplied by a factor of 6 relative to the general population
  • early miscarriage: more frequent than in the general population
  • late miscarriage: at 17-22 weeks of amenorrhea, particularly characteristic of these patients
  • prematurity

Screening for DES exposure

In some cases exposure to DES is confirmed by the mother and/or daughter:

If a woman indicates that she was treated with DES in the course of one or more pregnancies between 1948 and 1977 she should be told of the potential consequences for her children and urged to have them see a specialist for regular monitoring, particularly if the children are female.

If a young woman who knows she was exposed to DES in utero consults for gynecological or obstetrical reasons, she should be informed of the risks and referred to a specialist for appropriate monitoring.

In other cases, patients do not know whether they were exposed to DES:

In utero exposure can be established with complete or reasonable certainty on the basis of the following elements:

History taking: any mention of a maternal history of miscarriage or obstetrical problems by any patient born between 1948 et 1977

  1. History taking: any mention of a maternal history of miscarriage or obstetrical problems by any patient born between 1948 et 1977
  2. Clinical examination: discovery of cervical or uterine abnormalities which are suggestive of exposure
  3. Hysterography: images which are suggestive of exposure

Furthermore, any woman born before 1977 should be systematically screened for DES exposure in the following clinical situations:

  • fertility testing
  • ectopic pregnancy
  • repeated first trimester and, particularly, second trimester miscarriages
  • premature delivery

If exposure to DES is suspected, the patient should be referred to a specialist.

Systematic monitoring of women exposed in utero to DES

Even in the absence of symptoms, a gynecologist should be consulted annually for:

  • a gynecological examination to check for vaginal and uterine abnormalities
  • vaginal and cervical smears
  • a colposcopy, depending on the results of the smears

In cases of unexplained bleeding between periods, a gynecological examination should be done immediately in order to rule out DES complications.

Procedure to follow with young women exposed in utero who are experiencing fertility problems

If there are fertility problems, the check-up should include a Huhner test to evaluate the quality of the cervical mucus, a hysterography to screen for abnormalities of the uterine cavity and fallopian tubes, an ultrasound and, if possible, a Doppler to evaluate the pulsatility indices of the uterine arteries and therefore the potential for embryonic implantation.

This check-up should always be part of the general fertility testing which couples undergo.

Monitoring of pregnant women who were exposed to DES in utero

Any pregnancy in a young woman who was exposed to DES in utero should automatically be considered a risk pregnancy. In the vast majority of cases, however, the outcome of these pregnancies is completely normal.

Women should be given information on the increased risk of ectopic pregnancy, early and late miscarriage, and premature delivery, often with no warning contractions.

It is therefore important to verify that the ovum is located inside the uterus and to perform twice monthly checks of the cervix.

The need for early prevention measures, such as rest, reduced activity, work leave, home monitoring by a midwife, or even hospitalization, should be assessed on the basis of the individual's obstetrical history, and any uterine or cervical abnormality which regular monitoring may uncover.

Generally speaking, rest during the early phase of pregnancy is recommended as the risk of prematurity is of the same order of magnitude as in the case of a twin pregnancy. Rest is an essential element in the prevention of miscarriage and prematurity. Cerclage of the cervix is indicated in some cases.

Key elements to bear in mind:

It is imperative that all women exposed to DES during their own pregnancies or in utero be informed of the potential risks.

The possibility of in utero exposure should be considered: (i) at the history taking stage, if a woman born before 1977 is experiencing fertility problems or has a history of repeated miscarriages or ectopic pregnancies, (ii) if the clinical examination reveals characteristic lesions affecting the vagina and/or the cervix, (ii) following a hysterography if the images are suggestive of a T-shaped uterus or hypoplasia.

Systematic screening for in utero DES exposure in any of the following clinical situations: fertility tests, ectopic pregnancy, repeated first and (particularly) second trimester miscarriages, premature delivery.

Refer patient to a specialist and implement appropriate monitoring measures if exposure is known or suspected.

Automatically view any pregnancy in a woman who was exposed in utero to DES as a risk pregnancy.

Useful addresses

Association Réseau DES France
Centre administratif
12, rue Martinon 40000
Mont-de-Marsan, France

Tel: 05.58.75.50.04
http://www.des-france.org

Centres Régionaux de Pharmacovigilance et Centre de Renseignement sur les Agents Tératogènes (contact information provided on the Afssaps website)

Any suspected adverse reactions can also be reported to:

Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
Health Canada
Address Locator: 0201C2
Ottawa, Ontario, K1A 1B9
Tel: (613) 957-0337 or
Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345,
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the TPD web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

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