Diethylstilbestrol syndrome (DES syndrome) refers to developmental or health problems caused by exposure to DES before birth (in utero), such as reproductive tract differences, infertility, and an increased risk for certain cancers. DES is a synthetic form of the female hormone estrogen that was prescribed to pregnant women between about 1940 and 1971 to prevent miscarriage and premature labor. DES also may have been prescribed to women to inhibit lactation, as hormone replacement therapy for menopause symptoms, and as a post-coital emergency contraceptive (“morning-after pill”). It was first thought to be safe and effective, but studies later found that DES was not effective in preventing pregnancy complications, and caused health problems in some children of mothers exposed during pregnancy, as well as some of the women exposed during pregnancy or for other reasons. It is important to note that not all people exposed to DES have health problems due to the exposure.

Females exposed to DES in utero may have reproductive tract differences affecting the uterus, fallopian tubes, cervix, and/or vagina. Examples include incomplete development of the uterus or cervix, a differently-shaped uterus or cervix, and a transverse vaginal septum. These differences may increase the risk of infertility. Females exposed to DES in utero also are more likely to experience various pregnancy complications including ectopic pregnancy, miscarriage, and preterm birth. However, most have healthy babies. Additionally, females exposed in utero are at increased risk to develop cancers such as vaginal or cervical clear cell adenocarcinoma, squamous cervical cancer, and breast cancer.

Males exposed to DES in utero have not been studied as extensively as females, but may be at increased risk for epididymal cysts, undescended testes, and inflammation or infection of the testicles. Males exposed to DES do not appear to have an increased risk of infertility.

Of note, women exposed to DES after birth (those exposed while they were pregnant or those exposed for other reasons) have an increased risk of developing breast cancer. The children of women exposed to DES in utero (grandchildren of mothers exposed during pregnancy) may also have an increased risk for cancer, as well as higher infertility rates.

Treatment for health problems associated with DES exposure depends on each person's signs and symptoms. Women who took DES during pregnancy or for other reasons are encouraged to inform their doctors and children of the exposure, and children exposed in utero should inform their doctors so they can be monitored for possible health problems that may arise.

Diethylstilbestrol (DES) is an estrogen that was first manufactured in a laboratory in 1938, so it is called a "synthetic estrogen." During 1938-1971, U.S. physicians prescribed DES to pregnant women to prevent miscarriages and avoid other pregnancy problems. As a result, an estimated 5-10 million pregnant women and the children born of these pregnancies were exposed to DES. Physicians prescribed DES to pregnant women on the theory that miscarriages and premature births occurred because some pregnant women did not produce enough estrogen naturally. At the time, physicians thought DES was safe and would prevent miscarriages and pre-term (early) births.

In 1953, published research showed that DES did not prevent miscarriages or premature births. However, DES continued to be prescribed until 1971. In that year, the Food and Drug Administration (FDA) issued a Drug Bulletin advising physicians to stop prescribing DES to pregnant women. The FDA warning was based on a study published in 1971 that identified DES as a cause of a rare vaginal cancer in girls and young women who had been exposed to DES before birth (in the womb).

The news that DES could be harmful led to a national effort to find women prescribed DES while pregnant and notify them of the potential DES-related health problems. Physicians reviewed patients' medical records and notified women who had been prescribed DES. As a result of this effort, many women were made aware of the DES health risk known at that time, known as clear cell adenocarcinoma (CCA), a rare vaginal cancer. Women were encouraged to have their DES-exposed daughters screened regularly by a gynecologist because CCA was found in girls as young as 8 years old.

Women contacted during the 1970s, along with their children, formed the core of large study groups that researchers call "cohorts." Researchers studied the health of these DES-exposed cohorts for more than 20 years. Much of what is known about DES-related health risks is the result of these long-term studies.

Despite earlier efforts to identify DES-exposed women and men, many persons exposed to DES were not located. These persons may not realize that they were exposed to DES. Unfortunately, no medical test (such as blood, urine, or skin analysis) can detect DES exposure.

All DES-exposed persons are at an increased risk for developing some health problems when compared with persons who were not exposed to DES. All of the health problems related to DES exposure also can occur in persons who were not exposed to DES.

Many companies manufactured DES and similar synthetic drugs. In 1976, the Journal of the American Medical Association (JAMA) published a list of the most commonly used names and spellings for DES and similar drugs.

What is DES?

Diethylstilbestrol (DES) is a synthetic form of the female hormone estrogen. It was prescribed to pregnant women between 1940 and 1971 to prevent miscarriage, premature labor, and related complications of pregnancy. The use of DES declined after studies in the 1950s showed that it was not effective in preventing these problems.

In 1971, researchers linked prenatal (before birth) DES exposure to a type of cancer of the cervix and vagina called clear cell adenocarcinoma in a small group of women. Soon after, the Food and Drug Administration (FDA) notified physicians throughout the country that DES should not be prescribed to pregnant women. The drug continued to be prescribed to pregnant women in Europe until 1978.

DES is now known to be an endocrine-disrupting chemical, one of a number of substances that interfere with the endocrine system to cause cancer, birth defects, and other developmental abnormalities. The effects of endocrine-disrupting chemicals are most severe when exposure occurs during fetal development.

What is the cancer risk of women who were exposed to DES before birth?

The daughters of women who used DES while pregnant—commonly called DES daughters—have about 40 times the risk of developing clear cell adenocarcinoma of the lower genital tract than unexposed women. However, this type of cancer is still rare; approximately 1 in 1,000 DES daughters develops it.

The first DES daughters who were diagnosed with clear cell adenocarcinoma were very young at the time of their diagnoses. Subsequent research has shown that the risk of developing this disease remains elevated as women age into their 40s.

DES daughters have an increased risk of developing abnormal cells in the cervix and the vagina that are precursors of cancer (dysplasia, cervical intraepithelial neoplasia, and squamous intraepithelial lesions). These abnormal cells resemble cancer cells, but they do not invade nearby healthy tissue and are not cancer. They may develop into cancer, however, if left untreated. Scientists estimated that DES-exposed daughters were 2.2 times more likely to have these abnormal cell changes in the cervix than unexposed women. Approximately 4% of DES daughters developed these conditions because of their exposure. It has been recommended that DES daughters have a yearly Pap test and pelvic exam to check for abnormal cells.

DES daughters may also have a slightly increased risk of breast cancer after age 40. A 2006 study from the United States suggested that, overall, breast cancer risk is not increased in DES daughters, but that, after age 40, DES daughters have approximately twice the risk of breast cancer as unexposed women of the same age and with similar risk factors. However, a 2010 study from Europe found no difference in breast cancer risk between DES daughters and unexposed women and no difference in overall cancer risk. A 2011 study found that about 2% of a large cohort of DES daughters has developed breast cancer due to their exposure.

DES daughters should be aware of these health risks, share their medical history with their doctors, and get regular physical examinations.

Do DES daughters have problems with fertility and pregnancy?

Several studies have found increased risks of premature birth, miscarriage, and ectopic pregnancy associated with DES exposure. An analysis of updated data published in 2011 is outlined in the table below.

*The total risk (probability) that a certain problem will occur.

Some studies suggest that the increased risk of infertility is mainly due to uterine or fallopian tube problems.

What other health problems might DES daughters have?

Concerns have been raised that DES daughters may have problems with their immune system. However, research thus far suggests that DES daughters do not have an increased risk of autoimmune diseases. Researchers found no difference in the rates of lupus, rheumatoid arthritis, optic neuritis, and idiopathic thrombocytopenia purpura between DES-exposed and unexposed women.

Studies examining the risk of depression among DES daughters have had conflicting results. One study found a 40% increase in risk of depression, whereas another found no increased risk for these women. A study published in 2003 found little support for the possibility that prenatal exposure to DES influences certain psychological and sexual characteristics of adult men and women, such as the likelihood of ever having been married, age at first sexual intercourse, number of sexual partners, and having had a same-sex sexual partner in adulthood.

DES daughters have more than twice the risk of early menopause (menopause that begins before age 45) as unexposed women. Scientists estimate that 3% of DES-exposed women have experienced early menopause due to their exposure to DES.

What health problems might DES-exposed sons have?

Some studies have found that men whose mothers used DES during pregnancy have an increased risk of testicular abnormalities, including undescended testicles or development of cysts in the epididymis. There is also some evidence of increased risks of inflammation or infection of the testicles .

Whether DES-exposed sons have increased risks of testicular or prostate cancer is unclear; studies to date have produced mixed results. As the cohort of these men gets older, more data will be available to help answer this question.

Research has shown that men who were exposed to DES through their mothers do not have an increased risk of infertility, even when they have genital abnormalities.

What health problems might women who took DES during pregnancy have?

Women who used DES may have a slight increase in the risk of developing and dying from breast cancer compared with women who did not use DES. No evidence exists to suggest that women who took DES are at higher risk for any other type of cancer.

What health problems might DES-exposed grandchildren have?

Researchers are also studying possible health effects among women and men who are the children of DES daughters. These groups are called DES granddaughters and DES grandsons, or the third generation. Researchers are studying these groups because studies in animal models suggest that DES may cause DNA changes (i.e., altered patterns of methylation) in mice exposed to the chemical during early development. These changes can be heritable and have the potential to affect subsequent generations.

A comparison of the results of DES granddaughters’ pelvic exams with those of their mothers’ first pelvic exams found none of the changes that had been associated with prenatal DES exposure in their mothers. However, another analysis showed that DES granddaughters began their menstrual periods later and were more likely to have menstrual irregularities than other women of the same age. The data also suggested that infertility was greater among DES granddaughters, and that they tended to have fewer live births. However, this association is based on small numbers of events and was not statistically significant. Researchers will continue to follow these women to study the risk of infertility.

Recent studies have found that DES granddaughters and DES grandsons may have a slightly higher risk of cancer and birth defects, including hypospadias in DES grandsons. However, because each of these associations is based on small numbers of events, researchers will continue to study these groups to clarify the findings.

How can people find out if they took DES during pregnancy or were exposed to DES in utero?

It is estimated that 5 to 10 million Americans—pregnant women and the children born to them—were exposed to DES between 1940 and 1971. DES was given widely to pregnant women between 1940 and 1971 to prevent complications during pregnancy. DES was provided under many different product names and also in various forms, such as pills, creams, and vaginal suppositories. The table below includes examples of products that contained DES.

Women who think they used DES during pregnancy, or people who think that their mother used DES during pregnancy, can try contacting the physician or institution where they received their care to request a review of their medical records. If any pills were taken during pregnancy, obstetrical records could be checked to determine the name of the drug.

However, finding medical records after a long period of time can be difficult. If the doctor has retired or died, another doctor may have taken over the practice as well as the records. The county medical society or health department may know where the records have been stored. Some pharmacies keep records for a long time and can be contacted regarding prescription dispensing information. Military medical records are kept for 25 years. In most cases, however, it may be impossible to determine whether DES was used.

What should DES-exposed daughters do?

• Women who know or believe they were exposed to DES before birth should be aware of the health effects of DES and inform their doctor about their possible exposure. It has been recommended that exposed women have an annual medical examination to check for the adverse health effects of DES (6). A thorough examination may include the following:
• Pelvic examination
• Pap test and colposcopy—A routine cervical Pap test is not adequate for DES daughters. The Pap test must gather cells from the cervix and the vagina. It is also good for a clinician to see the cervix and vaginal walls. They may use a colposcope to follow-up if there are any abnormal findings.
• Biopsy
• Breast examinations—It is recommended that DES daughters continue to rigorously follow the routine breast cancer screening recommendations for their age group. The NCI fact sheet Mammograms includes information about these guidelines.

What should DES-exposed mothers do?

A woman who took DES while pregnant or who suspects she may have taken it should inform her doctor. She should try to learn the dosage, when the medication was started, and how it was used. She also should inform her children who were exposed before birth so that this information can be included in their medical records.

It is recommended that DES-exposed mothers have regular breast cancer screenings and yearly medical checkups that include a pelvic examination and a Pap test.

What should DES-exposed sons do?

Men whose mothers took DES while pregnant should inform their physician of their exposure and be examined periodically. Although the risk of developing testicular cancer among DES-exposed sons is unclear, males with undescended or unusually small testicles have an increased risk of testicular cancer whether or not they were exposed to DES.

Is it safe for DES daughters to use hormone replacement therapy?

Each woman should discuss this question with her doctor. Studies have not shown that hormone replacement therapy is unsafe for DES daughters. However, some doctors believe that DES daughters should avoid these medications because they contain estrogen.

What is the focus of current research on DES exposure?

In 1992, NCI, together with collaborators at five research centers, began a long-term study of individuals exposed to DES, the DES Follow-up StudyExit Disclaimer. Participants were initially drawn from eight different medical centers and consisted of five individual cohorts of people. In order for the study findings to be valid, enrollment in the study is limited to participants who have been part of existing cohorts. It is not currently possible for the DES Follow-up Study to accept new participants.

Researchers continue to study DES daughters as they move into their menopausal years. The cancer risks for exposed sons are also being studied to determine whether they differ from those for unexposed men. In addition, researchers are studying possible health effects on the grandchildren of mothers who were exposed to DES during pregnancy (also called third-generation daughters or DES granddaughters).

The National Institute of Environmental Health Sciences (NIEHS) is leading laboratory studies to investigate DES exposure and its effects on health. NIEHS researchers developed a rodent model of prenatal DES exposure that has been useful in replicating and predicting adverse health effects in prenatally exposed men and women. This experimental model has been used worldwide to study mechanisms involved in DES-related toxicity and the adverse effects of less potent environmental estrogens.

DES Daughters are defined as women born between 1938 and 1971 who were exposed to DES before birth (in the womb). Research has confirmed that DES Daughters are at an increased risk for:

• Clear cell adenocarcinoma (CCA), a rare kind of vaginal and cervical cancer
• Increased risk for clear cell cancer appears to be highest for DES Daughters in their teens and early 20s. However, cases have been reported for DES Daughters in their 30s and 40s (Hatch, 1998).
• Reproductive tract structural differences (for example, T-shaped uterus)
• Pregnancy complications, such as ectopic (tubal) pregnancy and pre-term delivery
• Infertility

General Questons About Health Risks

My mother was prescribed DES while pregnant with me. Am I at an increased risk for any health problems?

Recent research has confirmed that women exposed to DES before birth (in the womb), known as DES Daughters, are at an increased risk for the following health problems:

• Clear cell adenocarcinoma (CCA) - A rare type of Vaginal and Cervical cancer. Approximately one in 1,000 (0.1 %) DES Daughters will be diagnosed with CCA. The risk is virtually non-existent among premenopausal women not exposed to DES.
• Reproductive tract structural differences - Including T-shaped uterus, hooded cervix, cervical cockscomb, and pseudopolyp.
• Pregnancy complications - Ectopic (tubal) pregnancy and pre-term (early) delivery.
• Infertility - Difficulty becoming pregnant.

The amount of risk for each of these problems varies, and all of these health effects also can occur in women not exposed to DES. The following information provides more detail about each of these health problems.

Clear Cell Adenocarcinoma (CCA) of the Vagina and Cervix

CCA, a rare form of vaginal and cervical cancer, was the first health problem identified as being associated with DES exposure (Herbst, 1971; Noller, 1972). CCA of the vagina and cervix occurs more frequently in DES Daughters than in women not exposed to DES. DES Daughters are 40 times more likely to develop CCA of the vagina and cervix than women not exposed to DES. This means that approximately one of every 1,000 women exposed to DES before birth (in the womb) will be diagnosed with CCA of the vagina and/or the cervix.

Before the use of DES, CCA of the vagina and cervix only occurred in women past childbearing age. In contrast, DES Daughters have been diagnosed with CCA of the vagina and cervix at as early as age 8 and up to their late teens and early 20s. In addition, recent studies have indicated that some DES Daughters have been diagnosed with CCA of the vagina and cervix in their 30s and 40s (Hatch, 1998). Therefore, DES Daughters should have regular cancer screenings as they grow older.

Reproductive Tract Structural Differences

Some studies have shown that up to one third of DES Daughters have had some form of reproductive tract abnormality of the cervix, uterus, or fallopian tubes, including vaginal adenosis or cervical changes (such as collars, hoods, septae, and cockscombs) (Jeffries, 1984; Herbst, 1984). Many of these changes are harmless and had no effect on physical development, risk of disease, or ability to conceive a child. However, some DES Daughters experienced health problems as a result of reproductive tract abnormalities. DES Daughters should talk with their health care providers about the possibility of reproductive tract structural differences so they can work together to identify and treat any potential problems.

Pregnancy Complications and Infertility

Most DES Daughters will be able to conceive and carry a healthy baby to term. However, DES Daughters are at an increased risk of reproductive problems, including complications during pregnancy and infertility.

• Premature Delivery. Consistently, research shows that DES Daughters are at an increased risk for problems during pregnancy. These problems are primarily associated with an increased risk for premature (early) delivery. Of DES Daughters, 64% deliver a full-term baby in their first pregnancy, compared with 85% of unexposed women. Approximately 20% of DES Daughters experience pre-term labor, compared with 8% of unexposed women (Kaufman, 2000).
• Other Pregnancy Complications. DES Daughters are also at an increased risk for other complications during pregnancy, including ectopic (tubal) pregnancy, and miscarriage. Estimates of a DES Daughter's risk for an ectopic pregnancy range from 3-5 times higher than the risk for a woman not exposed to DES. DES Daughters are also more likely to experience miscarriage than are unexposed women. The most recent study found almost 20% of DES Daughters had a miscarriage during their first pregnancy. About 10% of unexposed women had a miscarriage during their first pregnancy. The risk of miscarriage during the second trimester is slightly higher than the risk of miscarriage during the first trimester. Overall, 82%-85% of DES Daughters were able to deliver at least one healthy baby, compared to 87% of unexposed women. DES Daughters were less likely than unexposed women to have more than one child (Kaufman, 2000).
• Infertility. The most recent and comprehensive infertility study reported that 24% of DES Daughters were unable to become pregnant, compared with 18% of women not exposed to DES. Additionally, 28% of DES Daughters have tried for 12 months to become pregnant without success, compared with 16% of women not exposed to DES. DES exposure was most strongly associated with infertility caused by uterine problems (such as the shape of the uterus) (Palmer, 2001).

If you are a DES Daughter, it is critical that you tell your health care provider when you begin planning your pregnancy. Many of the risk factors associated with DES exposure during pregnancy are preventable or treatable if you take action. Any pregnancy in a DES Daughter should be treated as "high risk" by health care providers.

DES Sons are defined as men born between 1938 and 1971 who were exposed to DES before birth (in the womb). Research has confirmed that DES Sons are at an increased risk for:

• Non-cancerous epididymal cysts

My mother was prescribed DES while pregnant with me. Am I at an increased risk for any health problems?

Only a few studies have focused on health problems experienced by men exposed to DES before birth (in the womb), known as DES Sons. The research has focused on the following health concerns among DES Sons.

• Non-Cancerous Epididymal Cysts
  The most consistent research finding for DES Sons indicates that they have an increased risk for non-cancerous epididymal cysts, which are growths on the testicles (Bibbo, 1977; Gill, 1979; Conley, 1983; Niculescu, 1985; Wilcox, 1995). In one study, 21% of DES Sons had non-cancerous epididymal cysts compared with 5% of unexposed men (Gill, 1979).
  
• Other Genital Abnormalities
  Whether DES increases the risk for other genital abnormalities in men remains unclear. A few studies have reported that DES Sons experience a greater likelihood of being born with undescended testicles (cryptorchidism), a misplaced opening of the penis (hypospadias), or a smaller than normal penis (microphallus). These studies estimated that 15%-32% of DES Sons experience one or more of these structural differences compared with 5%-8% of unexposed men (Gill, 1979; Wilcox, 1995). Other studies, however, have not identified an increased risk of structural differences (Leary, 1984; Vessey, 1983). Because findings have been inconsistent, researchers cannot say with certainty that DES causes these types of genital abnormalities in DES-exposed men.
  
• Infertility
  DES Sons are not at an increased risk for infertility. Some DES Sons have been concerned that DES exposure might be linked to infertility. Although one study found a lower sperm count in men exposed to DES compared with unexposed men (Gill, 1979), a 40-year follow-up study of DES Sons found no increased risk of infertility among men exposed to DES before birth (Wilcox, 1995).

Are there any ongoing follow-up studies of DES Sons?

The National Cancer Institute's DES Combined Cohort Study began in 1992. This study follows men and women exposed to DES before birth (in the womb), known as DES Sons and Daughters, to monitor their health patterns compared with the general population. These cohort studies will continue to follow DES Sons regarding a range of health issues (such as cancer, heart disease, and autoimmune disease).

Cohort studies are designed to follow the same group of people over long periods of time. This means that new participants cannot be added to the study.

What steps should I take with my health care provider in terms of special screenings or tests based on my DES exposure?

Although no special screenings or tests are necessary for DES Sons, for more information tips are provided for working with your health care provider.

My younger brothers/sisters are worried that they were exposed to DES, even though my mom was only prescribed DES when she was pregnant with me. What can I tell them?

Only children who were in the womb at the time their mother was prescribed DES are considered to have been exposed to DES.

Do the children of DES Daughters and Sons have any health risks?

Third-generation children (the offspring of DES Daughters and Sons) are just beginning to reach the age when relevant health problems (such as reproductive tract problems), can be studied.

A study of the health risks for the granddaughters of women prescribed DES while pregnant, or third-generation daughters, was published in 2002. The researchers compared findings of pelvic examinations of 28 DES Granddaughters with findings noted in their mothers (DES Daughters). Even though abnormalities were present in more than 60% of DES Daughters, no abnormalities were found in the DES Granddaughters (Kaufman, 2002).

DES Grandsons are being studied at the Netherlands Cancer Institute. Early research reported that hypospadias, misplaced opening of the penis, occurred 20 times more frequently among sons of DES Daughters (Klip, 2002).

What is known about third-generation health risks from laboratory animal studies?

In laboratory animal studies of elderly third-generation DES-exposed, female mice, an increased risk of uterine cancers, benign ovarian tumors, and lymphomas was found. Elderly third-generation DES-exposed male mice were at an increased risk of certain reproductive tract tumors. Both the female and male mice studied were the offspring of female mice exposed to DES before birth (in the womb). While DES research about third-generation health risks continues, you should protect your health by staying informed and talking with a health care provider about your concerns.