The importance of controls in a clinical experiment

The importance of controls in a clinical experiment; stilbestrol therapy in pregnancy, Obstetrics & Gynecology, Volume 3 – Issue 4 – ppg 452-456 Citation/1954/04000, April 1954.

In 1954, HENRY FERGUSON, JAMES M.D. highlighted the need for adequate and rigorous research into the use of the DES drug in pregnancy – by using controls – to ensure that it actually had therapeutic value and was doing more good than harm.
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Effect of stilbestrol on pregnancy compared to the effect of a placebo

Compared to a placebo, there was no benefit with the use of stilbestrol in preventing miscarriages.

Abstract

Effect of stilbestrol on pregnancy compared to the effect of a placebo, American journal of obstetrics and gynecology, Volume 65, Issue 3, Pages 592–601 0002-9378(83)90615-4, March 1953.

One hundred ninety pregnant women received increasing doses of stilbestrol. Treatment was begun by at least the twentieth week of pregnancy and continued through the thirty-fifth week of pregnancy, unless the patient delivered or aborted while on the treatment. The dose of stilbestrol began with 6.3 mg. to 50 mg. a day and ended with 137.5 mg. a day.

Two hundred three similar women received an indistinguishable placebo and provided a fair comparison.

The stilbestrol had no effect on :

  • pre-eclampsia,
  • prematurity,
  • fetal weight and survival,
  • or the size of the placenta.

The importance of adequate controls is discussed.

Discussion

All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Antenatal oestrogen (stilbestrol) was not shown to be of benefit in preventing adverse fetal outcome. The miscarriage rate, preterm labour, birthweight, stillbirth or neonatal death were not positively influenced by the intervention as compared to the control group.

Another researcher presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts Smith’s 1948 theory. The DES tragedy buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

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Diethylstilbestrol in the prevention and treatment of complications of pregnancy

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.

Free full text available via sci-hub.

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.

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Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters

trying-to-rest
Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. trying to rest.

Abstract

Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters, American journal of obstetrics and gynecology, NCBI PubMed PMID: 7315913, 1981 Dec.

Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago.

  • A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less.
  • A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known.
  • Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001).
  • The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005).
  • An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges.
  • However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child.
  • More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group.
  • The spectrum of diseases at operation in both groups was similar.
  • Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar.
  • For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
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Pregnancy outcome in women exposed to DES in utero, their mothers, and unexposed siblings

Pregnancy Outcome in 98 Women Exposed to Diethylstilbestrol In Utero.

Abstract

Pregnancy Outcome in 98 Women Exposed to Diethylstilbestrol In Utero, Their Mothers, and Unexposed Siblings, Obstetrics and gynecology, Volume 59 – Issue 3, July 1981.

The reproductive capability and labor complications of 98 women exposed to diethylstilbestrol (DES) in utero were compared with those of three separate control groups. The controls consisted of:

  1. 167 age-matched, normal women,
  2. 20 siblings not exposed to DES who had achieved pregnancy,
  3. and their mothers.

Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls.

The controls also achieved a higher percentage of desired pregnancies overall; this was statistically significant (89.6 versus 75.0%, P less than .001).

When compared with their mothers, however, the DES-exposed population achieved a greater percentage of desired, viable pregnancies (75.6 versus 67.0%, P less than .001).

The unexposed siblings of the DES women achieved a higher percentage of desired, viable pregnancies than did their exposed sisters (86.9 versus 73.6%, P = .274), but less than the normal population (86.9 versus 89.6%).

Click to download the full study.

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Placental changes due to administration of Diethylstilbestrol DES

image of lab mice
This 1980 study was undertaken to characterize placental changes in mice given daily injections of DES after implantation.

Abstract

A number of pathologic changes in the placenta and decidua basalis after exposure to DES are presented and are related to concurrent embryotoxicity.

Pregnant mice were injected with 12.5 micrograms DES/kg body weight or 25 micrograms DES/kg body weight daily from gestation day 9 through day 12 or 16 and sacrificed on day 13 or 17.

Placentas of DES treated animals were smaller than controls, the effect being dose dependent. Histologic changes in 13 gestation day placentas regional thinning of the labyrinth associated with an apparent inhibition of trophoblast maturation and development of fetal blood vessels. Knots of mononuclear cells form in the labyrinthine region of 13 day placentas exposed to the higher dose of DES. By 17 days gestation, coagulative necrosis is common in the decidua basalis, being most severe in those animals receiving 25 micrograms DES/kg. In many placentas the labyrinthine region is absent. The only remaining elements are trophoblast cells, giant cells and glycogen-containing cells.

Fetal deaths associated with the lower dose of DES increased with time whereas 100% fetal mortality was associated with the higher dose.

Virchows Archiv. B, Cell pathology including molecular pathology, NCBI PubMed PMID: 6108645, 1980.

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Diethylstilbestrol Contraindicated in Pregnancy

image of the FDA-building
Considering the risks and the numerous studies showing DiEthylStilbestrol inefficiency and harm, it is unbelievable that the FDA never banned the use of DES during pregnancy.

Abstract

Diethylstilbestrol Contraindicated in Pregnancy: Drug’s Use Linked to Adenocarcinoma in the Offspring

Selected Item from the FDA Drug Bulletin, November 1971, National Institutes of Health, PMCID: PMC1518220.

” WE WISH TO BRING to the attention of all physicians, hospitals, and medical personnel an important possible toxic effect of diethylstilbestrol (DES) reported for the first time in April 1971 by Herbst et al. From their studies the authors concluded that maternal ingestion of diethylstilbestrol during pregnancy appears to increase the risk of vaginal adenocarcinoma developing years later in the offspring exposed. The authors studied eight cases of adenocarcinoma of the vagina in patients born between 1946 and 1951. The malignancies were identified and treated between 1966 and 1969. In seven of the eight cases, there was a history -of maternal use of diethylstilbestrol. Because this type of malignancy in young girls had rarely been reported previously, the authors conducted a retrospective investigation in an attempt to find factors that may be associated with such malignancy in this age group. Four matched controls were established for each patient and the data obtained were subjected to statistical analysis. A statistically significant relationship was observed for three variables: diethylstilbestrol given during pregnancy (p=.00001), bleeding in that pregnancy (p=less than .05) and prior pregnancy loss (p=less than .01). It is obvious that the most significant of the variables is the administration of diethylstilbestrol during pregnancy. Since publication of this study, five additional cases of this malignancy associated with the maternal use of diethylstilbestrol have been reported by Greenwald et al. Dr. Herbst, in a recent communication to FDA, has reported an additional 15 cases associated with use of this drug, bringing the total number of known cases to 27. It must be emphasized that this type of epidemiologic study defines only an association and not necessarily a cause-and-effect relationship. Further studies are underway to clarify the significance of these findings.

In the meantime, the FDA is initiating the following precautionary actions:

  1. All manufacturers of DES or closely related congeners (dienestrol, hexestrol, benzestrol, promethestrol) are being notified that appropriate changes will be required in the labeling for such drugs. This change will consist in the listing of pregnancy as a contraindication to the use of diethylstilbestrol and the other above-mentioned compounds.
  2. All other estrogens will be required to have the following WARNING in their labeling: “A statistically significant association has been reported between maternal ingestion during pregnancy of diethylstilbestrol and the occurrence of vaginal carcinoma developing years later in the offspring. Whether such an association is applicable to all estrogens is not known at this time. In any event, estrogens are not indicated for use during pregnancy.
  3. Epidemiological studies are being initiated to determine the true incidence of this disease in young women, the number at risk, the characteristics of patient populations with this malignancy, and the probability of a cause-and-effect relationship.

Both FDA and the medical profession face a responsibility to help determine whether this reported association constitutes a cause-and-effect relationship. We ask that all physicians consider appropriate steps to assist FDA casefinding and to protect any patients who might be at risk.

It may be possible to trace the offspring of those mothers who received DES during pregnancy. All physicians should be especially’ alert for young women whose mothers may have received hormonal therapy during pregnancy, particularly those young women who may be experiencing irregular vaginal bleeding. The association should be a routine consideration for physicians whose practice includes young women.

This is a previously unsuspected health problem. Further information is essential to the FDA and to the medical profession. We ask your help in reporting any cases you encounter for entry in a case registry.

FDA will take every possible step to insure that you are kept abreast of new information as soon as it can be gathered and analyzed.

For your convenience, an adverse reaction reporting form is printed below. FDA will forward a supply of forms to each practicing physician as soon as they are printed. Facsimile forms are acceptable. ”

Remarks

Many articles about DiEthylStilbestrol (DES) mention that the Food and Drug Administration (FDA) banned DES for pregnant women in 1971.
The FDA did NOT ban DES, but issued a warning and urged doctors to stop prescribing it for their pregnant patients. Most doctors did, but not all, and the information regarding the contraindication took many years to reach France and other European countries where the drug continued to be prescribed to pregnant women. Since 1971,  many studies have shown a variety of health effects associated with DES exposure, adenocarcinoma but also breast cancer and infertility to name just a few.  In 2011, 40 years after the DES cancer link was made, the FDA acknowledged the DES tragedy but refused to apologize to the many victims of this drug scandal. To this day, not one drug company has ever apologized or accepted responsibility for the DES tragedy.

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