The widespread use of DES, specifically in the treatment of patients with threatening and habitual abortion, started in 1948 after O. Watkins Smith had published her article entitled Diethylstilbestrol in the Prevention and Treatment of Complications of Pregnancy
Background
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.
Laboratory evidence in the 1940s was proposed to support the concept that reduced placental hormone production was associated with a variety of adverse pregnancy outcomes such as miscarriage, preterm labour and hypertension in pregnancy. Animal models suggested that diethylstilbestrol, a synthetic oestrogen, was a suitable therapeutic agent. Diethylstilbestrol was thought to cause an increase in placental progesterone secretion because of its stimulatory effects on human chorionic gonadotrophin secretion without responding to negative inhibition by progesterone. On the basis of this, a rationale for providing hormone therapy to women in pregnancy, particularly those at risk of miscarriages, was advanced. Synthetic oestrogens were administered to women, often at an incremental dosage, throughout pregnancy.
The rationale for the use of DES was based on observations in animals and humans that stilbestrol might enhance the production of progesterone, thereby preventing early abortion and later pregnancy complications. As emphasized by Drs Olive and George Smith, prophylactic therapy was necessary.
1948 Study Abstract (Smith OW)
Diethylstilbestrol in the prevention and treatment of complications of pregnancy, American journal of obstetrics and gynecology, Volume 56, Issue 5, Pages 821–834, AJOG 0002-9378(48)90440-2, November 1948.
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” The basis for the use of stilbestrol in pregnancy is briefly reviewed, together with the indications and the dosage schedule recommended. Complete case reports on 632 pregnant women, to whom diethylstilbestrol was given largely for the indications and in the amounts recommended by us, have been analyzed. They have been divided according to the indications for therapy, i.e., threatened abortion (219 cases), abortion prophylaxis (272 cases) and prophylaxis against late pregnancy toxemia, intrauterine death, and premature delivery (98 cases). Although we have not recommended stilbestrol as a definitive measure in later pregnancy, 24 patients were so treated and are considered separetely. Nineteen cases that fell into none of these categories are omitted.
Seventy-eight per cent of the patients who were treated for bleeding between the sixth and twenty-first weeks carried to twenty-eight weeks, and 72 per cent had living and well babies. The highest spontaneous cure rate reported in the literature is 50 per cent. Eighty-three per cent of the patients who were given stilbestrol prophylactically against abortion carried to twenty-eight weeks, and 78 per cent had living and well babies. In the 127 cases who had two to five consecutive abortions prior to the one in which stilbestrol was given, the fetal salvage 77 per cent. In each group it was very significantly higher than the spontaneous cure rate as established by Malpas and Eastman. In the total 491 cases treated for abortion the incidence of abortion and of later pregnancy complications was higher when the dosage schedule was not followed than it was in the group as a whole.
In many of the patients treated prophylactically for late pregnancy complications it was impossible to evaluate the effect of stilbestrol therapy, and this part of our report must be considered preliminary. Twenty-two of them, however, had had three or more previous obstetric abnormalities, 27 had had two or more premature deliveries, 17 had known essential hypertension with bad obstetric histories, and nine had diabetes, six of these with bad obstetric histories. Considering the past obstetric histories of these patients, the course and outcome on stilbestrol gave good indication that the administration of this drug as a preventive measure may be expected to reduce the incidence of those complications of later pregnancy associated with a premature deficiency of the placental steroid hormones, estrogen and progesterone. There was even stronger evidence that the onset of thse complications would be postponed and the fetal mortality reduced. The results of the use of stilbestrol as a definitive measure in later pregnancy were not promising. “
Discussion
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.
The dictum ‘do no harm’ is relevant to the diethylstilboestrol saga of the 1950s. It was demonstrated physiologically that oestrogens and progesterone were necessary for pregnancy continuation. Thus, it was scientifically logical to postulate that diethylstilboestrol might prevent adverse pregnancy outcome. The sound physiological reasoning and impressive results from non-randomised studies resulted in enthusiastic uptake of the treatment before it was adequately tested in controlled clinical trials.
Dieckmann presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts the findings of Smith. During discussion time, Smith made a remark:
“Our experience with the use of stilbestrol continues to be satisfactory … we are convinced that it has reduced the complications of late pregnancy and saved many babies“.
He was at this time an authority in the field and the objective evidence provided by Dieckman was largely ignored. Doctors continued prescribing DES to several million women over the next 20 years. There were no known side effects, and despite lack of objective evidence of effectiveness, both doctors and women were happy with the therapy.
In view of the brilliant concept of the alleged value of DES in complications of pregnancy, i.e., threatening and habitual abortion, the seemingly good results, the low price of the drug, and the reputation of O. Watkins Smith of the famous husband-and-wife team, Smith and Smith, DES was used during the next twenty years by thousands of obstetricians in this country and abroad.
Biological inferences in clinical practice without properly designed clinical trials may lead to more harm than good. All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Had the principle of ‘best evidence’ been followed, the embarrassment of diethylstilboestrol as a medical intervention, and the effects on offspring who were exposed to it before birth, would have been avoided.
More DES DiEthylStilbestrol Resources
- Other studies on DES and pregnancy.
- Diethylstilbestrol DES studies by topics.