DES Exposure and Infertility

By: Jeffrey M. Goldberg, M.D.
Director In Vitro Fertilization Program

Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen first synthesized in 1938. A study in 1948 reported that DES treatment initiated in early pregnancy in patients with threatened miscarriage or poor reproductive history reduced early pregnancy loss, intrauterine fetal death, pregnancy induced hypertension and preterm delivery (PTD). It was believed that DES improved pregnancy outcome by increasing production of placental steroid hormones.

In 1953 a large placebo controlled study failed to confirm that DES was of any therapeutic value in reducing fetal wastage, PTD or pregnancy induced hypertension. In 1971 a physician advisory was issued following the finding of an association between vaginal clear cell adenocarcinoma, a very rare type of cancer, in the daughters of women who took DES during pregnancy. The number of pregnant women treated with DES is unknown but estimates range from 2 - 10 million. The youngest DES daughters are only 27 years old so physicians still need to be prepared to counsel these patients regarding their reproductive potential.

DES INDUCED MALFORMATIONS

Even with in utero DES exposure, vaginal clear cell adenocarcinoma is very rare. However, benign vaginal adenosis and structural cervical changes such as collars, hoods and septae occur in a high percentage of DES daughters. DES also induces uterine malformations including a small T-shaped cavity, constriction bands and irregular borders. About 70% of DES daughters had uterine abnormalities noted on hysterosalpingography (HSG), an x-ray dye test. HSG is the most sensitive test for for detecting DES associated uterine changes. The presence of cervical and/or vaginal changes was associated with a 5-fold increase in abnormal HSGs. Tubal pregnancy, miscarriage and PTD were increased, and the term delivery reduced, in DES patients with abnormal HSGs compared to DES patients with normal HSGs. The embryologic mechanism for the anatomic alterations with DES is unknown.

REPRODUCTIVE FUNCTION

There are conflicting studies regarding infertility and fetal wastage resulting from DES exposure. It is difficult to compare studies as they differ in patient selection, the degree to which other contributory conditions excluded and/or treated and follow-up intervals. The studies also vary in how they established that the patients were in fact exposed to DES in utero. Ultimately, an overall pregnancy rate of 72% was achieved by the DES-exposed daughters, which is similar to the 75% pregnancy rate in the control group. Women with in utero DES exposure appear to carry a greater risk for adverse pregnancy outcomes. Combining the tubal pregnancy rates from the published studies yields a nine fold increased risk in the DES group. Miscarriage and PTD risks are each doubled in DES progeny. As a result of this propensity toward poor pregnancy outcome in the DES group, the term delivery rate overall is about 1.5 times lower that the controls; DES 54%, control 84%. Similarly, the overall live birth rate was 1.3 times lower for the DES group. Overall, about 80% of pregnant DES patients ultimately achieved at least one successful delivery. No vaginal, cervical or uterine abnormality, individually or in combination, has been shown to preclude term live births.

TREATMENT

Assisted reproductive techniques may be offered to infertile DES patients. These patients had a similar number of eggs retrieved and fertilized, and embryos replaced, to patients with tubal factor infertility. Pregnancy rates were also not significantly different though the DES patients had a poorer pregnancy outcome as expected. Consideration must be given to reducing the number of embryos transferred to avoid the complication of multiple pregnancy in the already compromised uterus. Gamete intrafallopian transfer (GIFT) [placing the sperm and eggs into the fallopian tubes] has been reported to have resulted successful pregnancy in a DES patient. However, in vitro fertilization (IVF) should be the preferred procedure due to the higher risk of tubal pregnancy in DES women. DES patients that have achieved a term pregnancy can expect subsequent pregnancies to be normal. There have been only three studies which have reported performing surgery to repair the uterine defects in DES patients with fetal wastage though surgery to correct the anatomic abnormalities is not currently recommended. The association of DES and cervical incompetence (painless dilation of the cervix leading to PTD, usually in the second trimester) and the use of prophylactic cervical cerclage (placing a stitch around the cervix to prevent cervical incompetence) are still unresolved after long-standing debate. The definition of cervical incompetence is poorly established and the diagnosis commonly is uncertain and difficult to prove. There are no randomized studies comparing prophylactic cerclage with expectant management. While a few small uncontrolled series claimed that prophylactic cervical cerclage should be a universal practice, most authors advocate limiting cerclage to the standard clinical indications. DES patients with cervical changes may be particularly difficult to monitor for early signs of cervical incompetence and cerclage may be technically challenging.

SUMMARY

In the wake of the DES and thalidomide tragedies, the effect of new pharmaceuticals on pregnancy is now considered and medications are used more judiciously in pregnancy. The anatomic changes associated with in utero DES exposure are well known even though the pathogenic mechanisms are not. While new cases of vaginal clear cell adenocarcinoma resulting from in utero DES exposure are not expected at this point, an unknown number of exposed women will still face reproductive difficulties in their quest for a healthy baby. These patients must be followed very closely for tubal pregnancy, miscarriage and PTD. In spite of their poor obstetrical histories, they can be reassured that approximately 80% will ultimately be successful. Surgical correction of the structural abnormalities in an attempt to improve their reproductive performance is not advised. The use of prophylactic cervical cerclage may be beneficial but consensus is lacking.