Use of Diethylstilbestrol in the Treatment of Threatened Abortion

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, JANUARY 1951

FOR a long time, and even now, the problem of finding a drug which would estop or control the threat of abortion in a majority of the cases is largely unsolved. Bed-rest alone is regarded highly, by some, as efficacious, if not more so, as any remedy employed heretofore. Obviously rest in bed alone was not the answer; for many a woman, while confined to bed for other reasons, has aborted in spite of the bed-rest and sedation of a sort.

The fact that from time immemorial the aborting woman was adjudged unfit to have the child, delayed for a long time, all but sporadic and perfunctory efforts at seeking remedial agents. As a consequence, morphine and viburnum (prunifolium and opulus) constituted the chief drug armamentarium in the treatment of threatened abortion.

Hence, it was not until long after the discovery and study of the physiology of the ovarian and placental steroid hormones (estrogen and progesterone) that consideration, pioneered by Karnaky, was given to the use of the estrogenic substance diethylstilbestrol for the treatment of threatened abortion, threatened premature labor, abnormal aterine bleeding, etc.

Impressed favorably by his published results and not satisfied with those obtained, heretofore, by the current treatment methods, we undertook the study which culminated in this report.

It was discovered through observation and experimentation, that maintenance of uterine pregnancy depends on the production by the corpus folliculare graviditatis and the placenta of adequate amounts of progesterone (endogenous) and estrogen. So, if there were a threat to the orderly continuation of the pregnancy, early or late, the use of progesterone seemed the logical treatment, since it was known to sedate the uterus [by depressing its neuro-muscular apparatus.] But as endogenous progesterone was impracticable to obtain as a commercial product, resort was had to the use of exogenous or synthetic progesterone.

However, wide clinical experience has shown the use of synthetic progesterone to be not only disappointing in the treatment of threatened abortion, but in a not insignificant number of cases, has seemed to convert a threatened into an inevitable abortion, by stimulating the uterus to contraction.

Furthermore, it has been observed that prior to the expression of threatened abortion, an abnormally high titer of chorionic gonadatrophic hormone appears in the blood with a concomitant decrease in the ovarian and placental steroid hormones and, in the urine, in pregnanediol glucuronidate, the end product of progesterone metabolism.

Contrariwise, the administration of large and repeated doses of diethylstilbestrol, in the presence of an active corpus folliculare or placenta, was followed by a rapid decline in the excessive chorionic hormone or prolan with a simultaneous rise in titer of the above steroid hormones, in the blood, and pregnanediol, in the urine; while the administration of progesterone in threatened abortion inhibits the production of endogenous progesterone evidenced by diminishing urinary pregnanediol.

By induction, therefore, it seems that the diethylstilbestrol stimulates the utilization of the excessive chorionic hormone in the production, by the corpus folliculare and the placenta, of quantities of their steroid hormones sufficient to estop an abortion threat with continuation of the pregnancy.

We believe that the role of the above steroid hormones in the control of threatened abortion is twofold:

1. the uterine cramps and the threat of painful uterine contractions are obviated through desensitization of the uterus by the progesterone;
2. the slight uterine bleeding is controlled by the high titer of estrogen above the so-called “bleeding level” either by local arteriolar constriction or/and alteration of the clotting elements of the blood; whereby the anticoagulants are depressed or diminished and the coagulating elements concentrated or increased, or by both.

On these grounds, the use of diethylstilbestrol in large and repeated doses as a sound and desirable remedy in the treatment of threatened abortion is readily suggested.

It may well be that much of the failure in the treatment of supposed threatened abortion was due to the fact that the treatments were directed at unrecognized inevitable abortion or abortion in progress. Obviously, such misdirected treatments could not achieve the intended purpose.

In order, therefore, to reduce to a minimum a misdirection of such treatments in the future, it might not be amiss, here, to contrast the diagnostic criteria of threatened abortion and inevitable abortion.

For threatened abortion

1. the confirmatory signs of uterine pregnancy must be established; the same holds good in case of inevitable abortion,
2. slight cramps felt in the midpelvis
3. slight uterine bleeding, the lesion being located in the decidua capsularis or lateralis
4. there are no painful uterine contractions
5. the cervix uteri is not dilating
6. Tarnier’s sign is negative
7. the bag of waters is not ruptured with escape of amniotic fluid. The latter four are negative but highly significant features.

If, on the other hand, an abortion is inevitable, there are:

1. painful uterine contractions simulating labor pains;
2. moderate or profuse uterine bleeding, the lesion probably in the chorio-decidua;
3. the cervix is dilating;
4. a positive Tarnier’s sign;
5. and with rupture of the bag of waters and escape of the amniotic fluid, the condition is undoubtedly abortion in progress.

It is to be emphasized that, if there is any uncertainty or question as to the correct diagnosis, treatment for threatened abortion should be instituted promptly as the preferable procedure for twenty-four to thirty-six hours or until it becomes apparent that that the treatment is of no avail, when treatment for inevitable abortion is indicated. Our concept, therefore, of threatened abortion is a uterine pregnancy in which there is a threat, before viability, to its continuation.

This threat may be arrested if treated promptly, properly and adequately. If left alone or improperly treated, the case will progress generally into inevitable abortion.

This report covers a twenty-four month period extending from July 1, 1948 through June 30, 1950. During the first twelve months, thirty-two consecutive cases of threatened abortion were treated with the use of diethylstilbestrol (25 mgmn in 1 cc. of oil dosage) injected, once daily, into the anterior lip of the cervix uteri until the symtoms abated. Not more than three such injections were required. This was followed by 5 mgm tablets per os, one q.i.d. through a ten-day treatment period.

Twenty-four of these cases (75 per cent) were controlled; there were eight failures.

During the second twelve months, thirty-six cases were treated successfully with the same drug by the use of a different technique to be described hereinafter and which we recommend.

That a not insignificant number of threatened abortions is not arrested by any of the currently known medicinal agents must be admitted; however, we did not encounter one failure in thirtysix cases during the second twelve months.

Although we appreciate that sixty-eight cases are too small a number from which to draw generalized or incontrovertible conclusions, such use of diethylstilbestrol, in our considered opinion based on the latter results, is sounder, safer and more satisfactory than any remedial agent employed by us, heretofore.

TECHNIQUE OF TREATMENT DURING THE SECOND TWELVE MONTHS

The patient was put to bed immediately with the foot elevated. One 25 mgm tablet of “des,” diethylstilbestrol,* was given the patient, per os, every fifteen minutes for six doses or until the symptoms abated, then one “des” tablet every hour for six doses, followed by one-half tablet every hour for six doses. If the symptoms did not recur within a twenty-four hour period, the patient was placed on a daily maintenance dosage of one to four “des” tablets, if necessary, through the thirty-fifth week of pregnancy.

Judging from the successful results following the treatment during this latter period in which there was no failure, the eight failures in the first series, could well be attributed to too little diethylstilbestrol administered during the first nine to twelve hours of treatment.

During the treatments no worthwhile side effects or discomfort to the patient occurred necessitating discontinuance of or decrease in the amount or frequency of dosage. It is noteworthy how pregnant women, especially, can take such large and repeated doses of diethylstilbestrol without gastric upset or other disturbance.

Interestingly and encouragingly enough fortysix of the treated cases, so far, have had term live-births. Neither premature labor, late pregnancy toxemia nor post-maturity was encountered. Also, whether or not the lack of development of toxemia of late pregnancy, in any of these cases, was coincidental or consequent to the diethylstilbestrol is worthy of further consideration and investigation.

This report is presented with the hope that a widespread use of diethylstilbestrol by the profession, as described and recommended herein for the treatment of threatened abortion, will prove as effective in their hands as in ours.

SUMMARY

1. The use of diethylstilbestrol in large and repeated doses in the successful treatment of sixtyeight cases of threatened abortion is presented.
2. The latter thirty-six of these cases were treated, without one failure, with “des,” diethylstilbestrol, together with the recommended technique of its administration.
3. The mechanism of stoppage of the abortion threat by use of diethylstilbestrol was discussed.
4. The prompt administration of large and repeated doses of diethylstilbestrol as the best means, to date, of insuring the production of adequate amounts of endogenous progesterone and estrogen, by the corpus folliculare and the placenta, to arrest an abortion threat with continuation of the pregnancy has been discussed.
5. Large and adequate amounts of endogenous and not synthetic progesterone are requisite for effective uterine sedation in threatened abortion has been emphasized.
6. The need of concomitantly high blood-levels of estrogen as an indispensible contributory factor in the arrest of threatened abortion has been pointed out.
7. The question, of whether or not the administration of large and increasing dosages of diethylstilbestrol, prenatally, would prevent the development of toxemia of late pregnancy, opens up a vista of possibility for a valuable obstetric contribution.
8. It is our hope and belief that the use of “des,” diethylstilbestrol, as recommended, will merit its widespread recognition as the method of choice in the treatment of threatened abortion.

Sources

• The Use of Diethylstilbestrol in Threatened Abortion, JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, NCBI PubMed PMC2616732, JANUARY, 1951.
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DES DIETHYLSTILBESTROL RESOURCES

• Source DES and pregnancy studies.
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