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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Effects of Mullerian anomalies on in vitro fertilization outcome

image of IVF
Among women with Mullerian anomalies, those with DES exposure in utero demonstrated the poorest outcome.

Abstract

Effects of Mullerian anomalies on in vitro fertilization outcome, Journal of assisted reproduction and genetics, NCBI PubMed PMID: 11699126, 2001 Oct.
Full text: Journal of Assisted Reproduction and Genetics, Vol. 18, No. 10, 2001 PMC3455312, May 7, 2001.

PURPOSE
To assess the effect of Mullerian anomalies on pregnancy rates in women undergoing in vitro fertilization (IVF).

METHODS
The records of 37 patients with and 819 patients without Mullerian anomalies undergoing a first cycle of IVF between December 1995 and July 1998 were included in this retrospective study. Outcome variables included maximal estradiol level, number of days of stimulation, number of follicles, number of oocytes, fertilization rate, and ongoing/livebirth pregnancy rate.

RESULTS
Patients with Mullerian anomalies had a significantly lower ongoing pregnancy rate (8.3%) than did controls (24.8%). No patients with diethylstilbestrol (DES)-related anomalies had an ongoing pregnancy.

CONCLUSIONS
Among women with Mullerian anomalies, those with DES exposure in utero demonstrated the poorest outcome, with no ongoing pregnancies in 22 cycles. Physicians should use this information in counseling such patients about reproductive choices.

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Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring

pregnancy-outcomes-in-des-exposed chart
It is important for obstetrician-gynecologists to be aware of the consequences of DES exposure in utero on pregnancy outcome.

Abstract

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring, Obstetrics and gynecology, NCBI PubMed PMID: 11004345, 2000 Oct.
Full text: The American College of Obstetricians and Gynecologists, VOL. 96, NO. 4, OCTOBER 2000 pregnancyoutcomesdes2000, October 2000.

OBJECTIVE
To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women.

METHODS
This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstilbestrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women.

RESULTS
The response rate was 88% among exposed and unexposed women.

Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies.

  • Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64. 1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). (64.5 percent of women with in utero DES exposure had full-term infants, compared with 84.5 percent of matched women who had not been exposed to DES).
  • Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. The DES-exposed women had higher rates of ectopic pregnancy (4.2 percent versus 0.77 percent).
  • Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60).
  • According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). The DES-exposed women had higher rates of preterm delivery (19.4 percent versus 7.5 percent)
  • Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). The DES-exposed women had higher rates of second-trimester spontaneous abortion (6.3 percent versus 1.6 percent).
  • More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54).

CONCLUSION
This comprehensive review confirmed that pregnancy outcomes for DES-exposed women are significantly worse than those of unexposed women.

Among DES-exposed women identified by record review, 74.5% became pregnant (5.6% fewer than unexposed controls), and among those women 85% delivered at least one live full-term infant. Although pregnancy outcomes in DES-exposed women were significantly worse than those of unexposed women, many of the exposed women were able to conceive and deliver a live full-term infant.

Even if it is assumed that DES was no longer used in pregnancy after 1971 in the United States (which is not actually the case), there are still many DES-exposed women of reproductive age. Thus, it is important for obstetrician-gynecologists to be aware of the consequences of DES exposure in utero on pregnancy outcome. Consequently, high-risk obstetric care may be indicated for pregnant women who were exposed to DES in utero.

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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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Effect of diethylstilbestrol on reproductive function

image of DES-exposed-births
Rates of term delivery and live birth in DES-exposed patients versus controls.
An understanding of the reproductive performance of women who were exposed to DES in utero is useful for counseling these patients regarding their risks and treatment options.

Abstract

Effect of diethylstilbestrol on reproductive function, Fertility and sterility, NCBI PubMed PMID: 10428139, 1999 Jul.
Full text: FERTILITY AND STERILITY, Volume 72, Issue 1, Pages 1–7 S0015-0282(99)00153-3, July 1999.

OBJECTIVE
To review the effects of in utero exposure to diethylstilbestrol (DES) on müllerian development and subsequent reproductive function.

DESIGN
The literature on DES and reproductive function was reviewed and summary data are presented. The studies were identified through the computerized MEDLINE database and a manual search of relevant bibliographies.

RESULT(S)
In utero exposure to DES resulted in

  • reduced fertility
  • and increased rates of ectopic pregnancy,
  • spontaneous abortion,
  • and preterm delivery.

CONCLUSION(S)
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 during pregnancy. The anatomic changes associated with exposure to DES in utero are well known even though the pathogenic mechanisms are not.

Although new cases of vaginal clear cell adenocarcinoma resulting from exposure to DES in utero are not expected at this point, an unknown number of exposed women are still facing several reproductive hazards in their quest for a viable live birth. These patients must be observed closely for ectopic pregnancy, spontaneous abortion, and PTD. In spite of their poor obstetric histories, they can be reassured that approximately 80% ultimately will 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 a consensus is lacking.

Click to download the full study.

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Outcome of IVF in DES-exposed daughters: experience in the 90s

image of ivf-treatment-post
Infertile patients with a history of in utero exposure to DES exhibit a significantly impaired implantation rate following Iin vitro fertilization, and the outcome of assisted reproductive technology remains poor.

Abstract

Outcome of IVF in DES-exposed daughters: experience in the 90s, Journal of assisted reproduction and genetics, NCBI PubMed PMID: 9401869, 1997 Oct.
Full text: Journal of Assisted Reproduction and Genetics, Vol. 14, No. 9, 1997, NCBI PubMed PMC3454843, 1997 Oct.

Purpose
The outcome of in vitro fertilization (IVF) in a group of infertile women with a history of in utero exposure to diethylstilbestrol (DES) was analyzed. Records from an academic IVF program were retrospectively reviewed.

Methods
Seventeen infertile women with a self-reported history of exposure to DES in utero, attending the IVF unit at Massachusetts General Hospital (MGH) for assisted reproductive technology (ART), underwent 27 IVF cycles. Analysis of the outcome of IVF including implantation and ongoing pregnancy rates was performed. The data were compared with results from a group of 20 infertile patients with idiopathic infertility undergoing 27 IVF cycles at MGH during the same period. The patients in the two groups were matched for age, basal day 3 levels of follicle stimulating hormone and serum estradiol, and the number and quality of embryos transferred.

Results
The response to controlled ovarian hyperstimulation was comparable in the two groups. Significantly lower implantation and ongoing pregnancy rates following IVF and embryo transfer were seen in the utero DES-exposed group compared to the control patients.

  • This study confirms a poor outcome of IVF in infertile women with a history of in utero exposure to DES. The significantly impaired implantation rate (2%) following IVF in this category of infertile women is striking and concordant with earlier reported data.
  • The risk of ectopic pregnancy is quoted to be eight times greater in women with a history of exposure to DES and appears to be the leading factor contributing to a poor reproductive performance in this group.
  • No prognostic implication could be attributed to the presence of a T-shaped uterine cavity in terms of ability to conceive and carry a pregnancy to term. Of the two successful IVF cycles in the DES-exposed group, one of the patients had a T-shaped uterine abnormality, while in the second patient the uterine cavity was hypoplastic.

Conclusions
This study determined impaired implantation to be a major factor contributing to infertility in women undergoing IVF with a history of in utero exposure to DES. The ovarian response to controlled hyperstimulation, the fertilization and cleavage rates, and the embryo quality remain unaffected in these patients. The mechanism for implantation failure remains obscure and the prognosis for ART is guarded for patients exposed to DES in utero.

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Beneficial effect of hysteroscopic metroplasty on the reproductive outcome in a T-shaped uterus

image of Hysterosonography-of-T-shape
Hysterosonography of T-shaped uterus. DES-exposed women with a T-shaped uterus who want to improve their reproductive function should be encouraged to undergo hysteroscopic metroplasty.

Abstract

Beneficial effect of hysteroscopic metroplasty on the reproductive outcome in a ‘T-shaped’ uterus, Gynecologic and obstetric investigation, NCBI PubMed PMID: 8821883, 1996.

Eight women (aged 27-43) with reproductive dysfunction who were diagnosed by hysterosalpingogram and hysteroscopy as having a ‘T-shaped‘ uterus were operated on using fiberoptic hysteroscopic guidance; the uterine side walls were incised until a normal uterine cavity was achieved.

The women’s gynecologic and obstetric records were compared before and after the operation.

  • In all the 8 women the operation was without complications and resulted in a satisfactory uterine cavity.
  • Before the operative procedure, the women had had 10 spontaneous abortions and 1 ectopic pregnancy.
  • The postoperative performance available for 7 of the 8 women showed 4 term pregnancies in 3 women, 1 ectopic pregnancy, and no abortions.

Our study suggests that hysteroscopic metroplasty in women with a T-shaped uterus improves the reproductive outcome, mainly in women with repeated abortions. We conclude that women with a T-shaped uterus who want to improve their reproductive function should be encouraged to undergo hysteroscopic metroplasty.

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Hysteroscopic metroplasty in DES-exposed and hypoplastic uterus

image of Septate-uterus
Septate uterus: partial (1 and 2), complete (3), complete with septate cervix (4), and complete with cervical and vaginal septation (5). JMIG.

Abstract

Hysteroscopic metroplasty for uterine enlargement: a treatment for diethylbestrol-exposed and hypoplastic uteri, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PubMed PMID: 8901300, 1996. Full text: Hysteroscopic metroplasty in diethylbestrol-exposed and hypoplastic uterus: a report on 24 cases , Human reproduction (1998) 13 (10): 2751-2755, oxfordjournals, 1996.

OBJECTIVE
To determine the feasibility of correcting the uterine deformity in the diethylbestrol-exposed uterus and hypoplastic uterus.

DESIGN
Hysteroscopic metroplasty. Patients served as their own controls.

PATIENTS
Five patients referred for primary sterility (2 cases) or primo-secondary infertility with recurrent pregnancy loss or ectopic pregnancy (3 cases). Three of them had been exposed in utero to diethylbestrol. All of them have a hypoplastic uterus or uterine deformities as seen by hysterosalpingogram.

OUTCOME MEASURES
Postoperative hysterosalpingogram aspect. Ability to conceive and carry pregnancy to livebirth.

RESULTS
All the postoperative hysterosalpingograms appeared more normal than the preoperatively. Three patients have conceived since surgery.

CONCLUSION
Hysteroscopic metroplasty is feasible. It gives good anatomic results. This technique could be used in the patients with diethylbestrol-exposed or hypoplastic uteri, with severe infertility, recurrent pregnancy loss or implantations failures in a IVF program.

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Endometrial pattern in DES-exposed women undergoing IVF

undergoing-ivf
These 1996 study data suggested that endometrial pattern is one of the most significant variables for pregnancy outcome in DES-exposed women undergoing in-vitro fertilization.

Abstract

Endometrial pattern in diethylstilboestrol-exposed women undergoing in-vitro fertilization may be the most significant predictor of pregnancy outcome, Human reproduction (Oxford, England), NCBI PubMed PMID: 9021378, 1996 Dec. Full text: Human reproduction (1996) 11 (12): 2719-2723., oxfordjournals, 1996.

The objective of this study was to compare prospectively pregnancy outcome as it is related to ultrasonic endometrial echo pattern in women exposed to diethylstilboestrol (DES) in utero by their mother’s consumption with women not exposed to DES, all of whom were undergoing in-vitro fertilization (IVF).

Pregnancy outcome relative to endometrial thickness and pattern was evaluated in 540 cycles of IVF including DES (n = 50) and non-DES-exposed (n = 490) women. Endometrial patterns were designated as p1 = solid; p2 = ring; and p3 = intermediate.

  • DES patients exhibited p1 more often than the majority of the non-DES-exposed group.
  • There was no significant difference in endometrial thickness among the cycles where p1 was noted when comparing the DES (10.3 mm) with the non-DES-exposed (10.7 mm) groups.
  • Notably, within the group exhibiting p1, no pregnancies occurred in the 18 cycles of DES-exposed women compared with a 39.2% clinical pregnancy and 36.5% delivery rate in the non-DES-exposed controls (P < 0.0001 and P = 0.008 respectively).
  • Pregnancy rates were not significantly different in the cycles where the other endometrial patterns were found when comparing the two groups.

The impact of uterine shape on pregnancy outcome was also investigated.

  • A T-shaped uterine configuration was noted in 11 out of 18 (61.1%) cycles of DES-exposed women with pattern p1 compared with nine out of 23 (39.1%) with pattern p2.
  • Of cycles where a T-shaped uterus was demonstrated, none out of 11 (0%) with pattern p1 compared with four out of nine (44.4%) with pattern p2 resulted in pregnancy (P = 0.026).

These data suggest that endometrial pattern is one of the most significant variables for pregnancy outcome in DES-exposed women undergoing IVF.

It is our recommendation, based on the above results, that patients with a history of in-utero DES exposure who repeatedly demonstrate a solid endometrial pattern consider a gestational carrier as a possible means of achieving a biological offspring. Further investigation of both natural and hormone-replaced cycles in DES-exposed patients would address the potential for improvement of endometrial receptivity in these women. If improvement is possible, one could consider foregoing embryo replacement during the stimulated cycle with cryopreservation of the embryos for transfer at a later date. Perhaps midcycle endometnal sampling of DES-exposed women undergoing assisted reproductive technologies would help to define the endometrial variation.

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