Mechanism of failed labor after fetal death and its treatment with prostaglandin E2 HAROLD LUIS
SCHULMAN, SALDANA,
CHIN-CHU GEORGIA
LIN,
M.D.,
F.A.C.0.G
M.D..
F.A.C.O.G.
M.D.,
F.A.C.O.G.
RANDOLPH.
B.S.
At-on.\, New York Pregnancy was terminated with prostaglandin E, in 65 women harboring a dead fetus for 3 days to 8 weeks. The study was designed to: (1) elucidate the mechanism of failed onset of labor in the presence of fetal death, (2) determine appropriate dose-response relationships, and (3) evaluate safety and efficacy of this new method of intervention. Results indicate that plasma progesterone levels from 12 to 40 weeks’ gestation are in the lower normal statistical range as compared to those seen in pregnancy with a living fetus. Uterine size as estimated from fetal birth weight is also in the low normal range compared to that seen in a viable pregnancy. Hence the uterine volume-progesterone ratio is equal to or greater than that in normal pregnancy and thereby partially explanatory for the failed initiation of labor. The dosage required to produce delivery &;?lined in each month’s grouping from a mean of 56 r 26 (SD) mg at 12 to 15 weeks to 22 2 8.4 mg at 38 to 40 weeks. Dose-delivery response did not correlate with age, parity, or progesterone levels but did correlate with oxytocin response. Three unusual and Serious complications occurred. (AM. J. OBSTET. GYNECOL. 133:742, 1979.)
of prostaglandin preparations has offered a new look at an old clinical problem, that of prolonged fetal death without the onset of labor.‘. ‘. 23 This report will summarize an experience in which some theoretical and practical questions were posed about the efficacy of prostaglandin E2 (PGE,) vaginal suppositories in initiating labor after fetal death. It will be shown that PGE2 is highly successful in initiating labor, but a number of drug-related and disease-related complications were encountered. The lack of spontaneous onset of labor in these women can be partially explained by the preservation of a uterine volume-progesterone ratio or relationship.” THE
AVAILABILITY
FI-om tkr Department of G,nmlo, and Ohtrtrzc.\..4lhurt Eiwteirc College qf Me&w, Yeshwa Clniwrsit~. Presented by invitation at the Eighty-ninth ilnntral Meeting of the American Association of Obrtetriciamr and Gynecologists, Hot Springs, Virginia, Scpternber 7-9. 1978. Reprint request, at a level approximately 80% of the mean (Fig. 2). Although we used the oxytocin test as a rough gauge of uterine responsiveness, we could not demonstrate a consistent relationship to progesterone levels, PGE Z dosage, or instillation-to-deliver!, time (IDT) within each group. It will be noted that the dosage requirements progressively decreased with each gestational week grouping (Fig. 3) and corresponded with a greater oxytocin sensitivity,. When patients were grouped into fetal death at > or 2 weeks previously. Uterine height was 25 cm. Bishop score was 0, and an extraovular balloon catheter could not be passed into the lower uterine segment. Good uterine activity was noted after one suppository. At 3% hr. a half suppository was inserted; blood pressure fell to SO/50 and pulse was 120 beatsimin. The uterus was firm. The woman was quite anxious and in pain. Hematocrit was unchanged, and extremities were warm, but the blood pressure did not respond to an infusion of >700 ml of 5% dextrose in Ringer’s lactate after 1 hr., nor was
Fetal weight (gm.) 125 400 600 872 1304 2081 2520
of placenta;
t r -t k t 2 2
Abortion
80 126 130 163 234 126
80, incomplete
92 90 95 96.4 96.4
score k5 -t t rt ‘_ 100 100
delivery
3.9 4.5 2.1 3.2
of
there any urine output. Examination in the delivery room revealed the external cervical OS to be 2 to 3 cm dilated, but a broad band of tissue extended across the internal OS. Gentle probing released the band and the fetal head descended to the external OS. Immediately the blood pressure returned to normal and urine flow was noted in the Foley catheter. Review of the patient’s history revealed that she had become pregnant immediately after a curettage and cone biopsy of the cervix. The clinical analysis suggested cervical synechia and excessive uterine activity resulting in neurogenic shock and oliguria. Comment The pathogenesis of failed labor in fetal death is not adequately understood. The onset of labor is dependent to some degree upon the cause of the fetal death. For example, if the etiology is of maternal origin, such as hypertension, the average onset of labor is approximately I week. If fetal death is secondary to an intrinsic intrauterine disorder such as Rh isoimmunization, the
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onset of labor may not occur for 2 weeks5 This study has demonstrated that plasma progesterone concentrations are in the low normal range of those of women carrying a living fetus. The fetal weights are also in the low normal statistical range; thus, an effective uterine volume-progesterone ratio is maintained. Since a sharp drop in estrogen secretion occurs after fetal death, the key ingredients are provided for the maintenance of uterine inhibition.” PGEp has a unique and predictable ability to initiate labor in prolonged fetal death. The dosage required progressively declines as pregnancy advances and is less than that needed for an induced abortion probably because of the lowered progesterone level in the former. Efforts to terminate these pregnancies prior to the use of prostaglandins met with mixed success.3’ ‘3 r1 If an oxytocin infusion was attempted, it failed approxiinstillation mately 50% of the time. ‘3 *, i* Intra-amniotic of hypertonic solutions were hypothetically contraindicated because of the predisposition of these patients to develop coagulation disorders. Surgical evacuation through the vagina is difficult and associated with an excessive amount of hemorrhage because the placenta is usually adherent to the uterine wa11.20 Reports on the usage of PGE2 suggest a high success rate in inducing labor,‘, 13, 15. 24 However, prostaglandins create side effects, which include nausea, vomiting, diarrhea, hyperthermia, and hypotension, in approximately 60% to 70% of patients. Since prostaglandins are powerful myometrial stimulants, uterine rupture is a predictable consequence of this therapy and three cases have been reported at this Writing, all in women para 3 or more.3, I432o Several large studies over the past 40 years have demonstrated that when fetal death occurs labor will begin in 2 to 3 weeks in 77% to 93% of women.‘, 7, g, lo, I39 25 When spontaneous labor takes place there are virtually no complications. There is an overwhelming and understandable desire of the woman with a fetal death to have the pregnancy terminated. However, this desire must be balanced against the natural history of the disorder. In most cases labor will occur in 2 to 3 weeks and there will be no physical consequences. When the fetus has been dead for more than 3 to 4 weeks there may be a progressive decline in serum fibrinogen and platelets, and the onset of labor becomes unpredictable.r2, ls This study has demonstrated that, although effective, PGEp has too many undesirable side effects to be used as an elective medication. Nausea, vomiting, and diarrhea, although tolerable, are unpleasant, particularly when iatrogenic. The alliance of hyperthermia
Failed labor after fetal death treated with PGE,
747
and hypotension may mislead one to combat aggressively a septic process. Hypotension can cause a misdiagnosis of uterine rupture. The latter is a genuine risk in parous women, and the combination of PGE2 and oxytocin should be avoided in fetal death, at least for an interval of 12 hours. An elective attempt at induction may turn into an iatrogenic nightmare as demonstrated by Case 2. Finally the current packaging of PGE2 represents too large a dose for most women, and a more disciplined initiation of labor should be carried out. Our experience has led to the following program of management for women with fetal death. Once the diagnosis is made, an explanation should be offered to the woman of the benefits of waiting at least 2 weeks before active intervention is considered. After this time has elapsed, consideration can be given to termination since the time of the probability of the onset of labor is now less clear. Baseline blood studies should be obtained for fibrinogen and platelet levels. The presence of hypofibrinogenemia or thrombocytopenia is not an indication for replacement therapy. However, fresh frozen plasma and packed red blood cells should be on hand in case uncontrollable bleeding develops. If the cervix demonstrates changes so that a Bishop score of 4 or more exists, an intravenous infusion of oxytocin should be successful.“j If the cervix has a Bishop score of 3 or less, there is a choice of continued observation or the initiation of labor with PGE, vaginal suppositories. In the last trimester we cut the suppository in half and repeat its usage approximately every 3 hours. Women receiving PGE, therapy for fetal death should have a constant intravenous infusion of dextrose in Ringer’s lactate as a means of dealing with possible complications. Within an hour of insertion of the suppository, 50% will experience episodes of nausea or vomiting or have loose stools. Also 10% to 15% will show temperature elevations to 38” C or more and have shaking chills. In association with this, the blood pressure may fall to ranges of 80/60. Usually the extremities are warm, and the pulse only mildly elevated; urine flow continues. A rapid infusion of 300 ml of 5% dextrose in Ringer’s lactate usually restores the pressure to within normal limits. Effective uterine contractile activity with PGEz usually occurs almost every minute so that when the uterus is palpated it has a feel similar to that of abruptio placentae. If this kind of activity is present at the end of 3 hours, we do not give further drug because of the desire to minimize side effects. We have used chlorpromazine and Lomotil to attempt to reduce the gastrointestinal side effects. These are administered before the suppository is given. If uterine activity is not
748
Schulman
satisfactory, this
will
uterine
a second, he repated activity
minimal
changes therefore,
not
a useful
every
index
of retained
problems
half
suppository
is only
in
the
cervix
the
placentas 10 to
until
It is not
cervical of
is inserted,
3 to 4 hours
is established.
delivery; dence
April I, 1979 Am. .J. Obstet. Gynerol.
et al
1 to
progress
ress
satisfactory
unusual
prior
or effacement of
in PGE,treated
labor.
to
to have
2 hours
dilatation
Oxytocin
and
The fetal
quelae
is
the
allowed
XII heforc
he used
combination
tltetine
of clinical uterus.
not
‘The
excessive
to inci-
should
of labor.
activity
and,
coagulation interval osytocin
to accelerate of these disorders
of
at least
usage
drugs
therefore,
the
prog-
can the
lead sc-
and
rupture
of’
12 hours
should
he
is considered.
death
15%.
REFERENCES I.
2. 3.
4.
5.
6.
7. 8.
9.
10.
11. 12.
13.
Bailey, C. D., Newman, C., Ellinas. S. P., and Anderson, G. G.: Use of prostaglandin E2 vaginal suppositories in intrauterine fetal death and missed abortion, Obstet. Gynecol. 45: 110, 1975. Banner. E. A., and Bentler. H. K.: Intrauterine deaths, Obstet. Gynecol. 12: 661, 1958. Borten, M.. and Friedman, E. .4.: Uterine rupture: A complication of midtrimester abortion, Prostaglandins 15: 187. 1978. Csapo. A. I., jaffin, H., Kerenyi, T., deMattos, C. E. R., and deSousa Filho, M. B.: Fetal death in utero. AM. J. OBSTF.T.GYNECOL. 87:892. 1963. Csapo, A. I.: The “see-saw” theory of parturition, in The Fetus and Birth, Ciba Foundation Symposium 47, 1977, Excerpta Medica Amsterdam, Foundation, p. 159. Cordon, H., and Pipe, N. G. J.: Induction of labor after intrauterine fetal death: a comparison between prostaglandin E.’ and oxytocin, Obstet. Gynecol. 45: 44, 1975. Dippel. A. L.: Death of a fetus in utero, Johns Hopkins Med. J. 54: 24, 1934. El-Demarawy, H., El-Sahivi, S., and Toppozada, M.: Management of missed abortion and fetal death in utero, Prostaglandins 14: 583, 1977. Goldstein, D. P., Johnson, J. P., and Reid. D. E.: Management of intrauterine fetal death, Obstet. Gynecol. 21: 523, 1963. Grandin. D. J., and Hall, R. E.: Fetal death before the onset of labor. An analysis of 407 cases, AM. J. OBSTET. GYNECOL. 79: 237, 1960. Gustavii, B.: Missed abortion and uterine contractility, AM. J. OBSTET.GYNECOL. 130: 18. 1978. Jiminez. J. M., and Pritchard, J. A.: Pathogenesis and treatment of coagulation defects resulting from fetal death, Obstet. Gynecol. 32: 449, 1968. Kent, D. R., and Goldstein, A. I.: Prostaglandin E, induction of labor for fetal demise, Obstet. Gynecol. 48: 475, 1976.
Discussion DR. KENNETH R. NISWANDER, Davis, California. Therapy for fetal death in utero continues to he unsatisfactory. We are, of course, able to offer patients a much wider range of choices for management of the problem today than we were a few years ago. Dr. Schulman has cautioned us not to leap to these new ideas too quickly, however, since iatrogenic disease may follow their use. He counsels the time-honored therapy of procrastination, at least for a week or two, as the safest management for the patient. Since not all patients will accept this advice, and since some patients will stubbornly “refuse” to go into spontaneous labor, it
14.
15.
16.
17.
18.
19. 20. 21.
22.
23. 24.
2.5.
Kirton, K. T., and Forbes, A. D.: Activity of 15(S)-methyl prostaglandin E2 and F, as stimulants of uterine co,)tractility, Prostaglandins 1: 3 19, 1972. Lippert, T. H., and Luthi, A.: Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death, Prostaglandins 15: 533, 1978. Loudon, J. D. 0.: The use of high concentration oxytocin IV drips in the management of missed abortion, Br. J. Obstet. Gynaecol. 66: 277, 1959. Mitchell, M. D., Patrick, J. E., Robinson, J. S.. ‘Thorburn. G. D., and Challis, J. R. G.: Prostaglandins in the plasma and amniotic fluid of rhesus monkeys during pregnant) and after intrauterine foetal death, J. Endocrinol. 71: 67, 1976. Peyser. M. R.. and Toaff, R.: Rupture of the uterus in the first trimester caused by high concentration oxytocin drip, Obstet. Gynecol. 40: 371. 1972. Pritchard, J. A.: Fetal death in utero. Obstet. G, necol. 14: 573, 1959. Ratten, G. J.: The management of missed abortion. Aust. N. Z. J. Obstet. Gynaecol. 10: 115. 1970. Saldana, L., Schulman, H., Yang, W.. Cunningham, M. A., and Randolph, G.: Midtrimester abortion by prostaglandin impact, Obstet. Gynecol. 44: 579, 1974. Schulman. H., Saldana. L., Tsai, T.. Leibman. T.. Cutlningham. M. A.. and Randolph, G.: Prostaglandin Ei induced abortion with vaginal suppositories in a rontraceptive diaphragm, Prostaglandins 7: 195, 1974. Smith, .4. M.: Rupture of uterus during prostaglandin induced abortion, Br. Med. J. 1: 205, 1975. Southern, E. M.. Gutknecht, G. D., Mohberg. N. R., and Edelman. D. A.: Vaginal prostaglandin in the management of fetal intrauterine death, Br. J. Obsret. Gvnaecol. 85: 437. 1978. Tricomi, V.. and Kohl, S. G.: Fetal death in utero. A.M. J, OBSTET. GYNECOL. 74: 1092, 1975.
is well worth discussing Dr. Schulman’s experience with intravaginal PGE, and drawing on his expertise to speculate on certain aspects of this treatment. To set the stage for a few questions I would like to pose, let me summarize the see-saw theory of Csapo.’ at least as I understand it. In simplistic terms, C:sapo helieves that there are two major endogenous myometrial regulators which exert opposing effects on the uterine musculature. Progesterone quiets the uterus and prostaglandin causes it to contract. Fortunately for the preservation of the species, nature has made the progesterone effect the dominant one. Unless the progesterone protection is removed, the uterus will not empty
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itself. These two substances exert their effects by controlling activator calcium which in turn is the trigger that sets off the interaction between the contractile proteins of the uterus, actin and myocin, and adenosine triphosphate. Progesterone “binds” activator calcium, thus raising the threshhold of excitability of the myometrium. Prostaglandin has the opposite effect, but only if the progesterone concentration is low. According to this theory, prostaglandin can exert no prolonged myometrial effect without first causing the progesterone protection to be broken. Thus, the mechanism of action of exogenous prostaglandin is to cause an increase in uterine tone with a resultant decrease in uterine blood flow and damage to the placenta. This placental damage decreases the effective level of the progesterone block. Intrinsic prostaglandin can then cause uterine emptying. The contractile effect of exogenous prostaglandin on the myometrium does not in itself cause the abortion. The level of tissue progesterone must be lowered before prostaglandin will cause labor to ensue. Factors other than a prostaglandin-induced decrease in uterine blood flow, of course, will also lower the level of the progesterone block. Damage to the placenta by disease (e.g., abruptio placentae, toxemia) is one example of such a factor. Similarly, manipulation of the lower uterine segment (e.g., stripping of the membranes) also apparently affects placental function, thus allowing labor to begin. I would like to ask Dr. Schulman if he thinks the insertion of the extraovular balloon in his experiment may have been a factor in initiating labor in these patients. Might this factor explain the success of PGEz after PGFzu had failed? If not, what other explanation does he have for the success of PGEz when PGFza had failed in so many of his patients? The mean level of serum progesterone was low normal. I assume the reported serum progesterone level was a single determination at the time of the drug instillation. Are progesterone levels at any other time available that might explain the few abortion failures or the long IDTs? The discovery of the prostaglandins has added a new dimension both to the study of the physiology of the myometrium and to the clinical practice of obstetrics and gynecology. Dr. Schulman and his co-workers are to be congratulated on this contribution to the development of knowledge of these fascinating substances. REFERENCE
1. Csapo, A. I.: The see-saw theory of parturition, in The Fetus and Birth, Ciba Foundation Symposium 47, Amsterdam, 1977, Excerpta Medica Foundation, p. 159.
DR. THEODORE M. KING, Baltimore, Maryland. This study was undertaken to elucidate the mechanism of failed onset of labor in the presence of fetal death, to determine appropriate dose-response relationships,
Failed labor after fetal death treated with PGE,
749
and to evaluate safety and efficacy of a new method of intervention. These questions have been asked before and the answers that have existed appear to be substantiated by the findings of this report. Csapo,’ in a detailed review of his “see-saw” theory of parturition stated “that as a rule, fetal death predictably tertninates pregnancy and that the timing of delivery is determined by residual placental endocrine function at the time of fetal demise.” He supported this statement by utilizing data published by Grandin and Hall2 in 1960 from their analysis of 407 cases of fetal death that occurred before the onset of labor. As an example, a fetal death caused by premature placental separation usually results in onset of labor in less than 2 days, while fetal death caused by rhesus incompatibility may have a delayed onset of labor for 14 days or more. In the former instance, all placental endocrine functions is lost immediately while in the latter example endocrine function persists. This concept is also supported by documentation of the necessary decrease in progesterone required for the evolution of cyclic uterine contractions in midtrimester abortions induced by hypertonic saline.3 Indeed, Aleem and Schulman4 showed a striking decline of progesterone in placentas from such pregnancies. The documentation of maintenance of the uterine volume-progesterone ratio similar to that in a normal pregnancy in intrauterine fetal deaths is not surprising, although it has been suggested in the past that the extent of progesterone decline appears to be a function of the length of time after fetal death.5 In regard to the patients studied in this report, the inclusion of midtrimester failed abortion cases makes the reported population of patients different from the usual population with fetal death in utero or missed abortion. The failed abortions account for 23% of the population studied. In the presentation of data, this group is not reported separately. In the 12 to 24 week group, there are 19 cases. Fifteen of these should have been the failed induced abortions. The Bishop scores of these groups do appear to be different from those of the remainder of the study population, and larger quantities of prostaglandin are required for the 12 to 24 week groups than for the 29 to 41 week groups. It is of interest that this report substantiates the package insert for PGE2 released by The Upjohn Co. in September, 1977.6 The indication cited for PGEB is the termination of pregnancy or evacuation of uterine contents in the presence of missed abortion or intrauterine fetal death up to the twenty-eighth week of gestation. The three serious complications in Dr. Schulman’s series occurred in patients with gestations of 30, 32, and 38 weeks, with an incidence of 9% for the total group of 34 patients who were in the third trimester of pregnancy. In review with The Upjohn Co. in late July of 1978, they are aware of six ruptured uteri subsequent to the
750
Schulman et al.
filing of their New Drug Agency data on PGE2.7 One of these cases sounds exceedingly similar to the case reported in this paper. Of these cases, four of six women received more than one kind of oxytocic agent, while the remaining patient was subjected to a vaginal manipulative procedure in the presence of an abnormal presentation. Two were multiparous patients and three patients were of unknown parity. Thus, it would appear that PGEt is not strikingly different from other oxytocic agents in that use in combination with other ecbolic agents is fraught with danger, particularly in multiparous patients who are in the third trimester of’ pregnancy. The author makes a point that the current packaging of PGE, represents too large a dose for most women and a more disciplined initiation of labor should be carried out. This is certainly true if it is to be used in a trimester of pregnancy not included in the package insert. It should also be noted that the current study deviates from recommended usage of PGEz by utilizing a vaginal diaphragm to contain the intravaginal suppository and by administering the drug more frequently than every 3 to 5 hours. In previous work by Dr. Schulman in which a diaphragm was utilized as a holder for PGEP vaginal suppositories, the results suggested that a reduced quantity of prostaglandin is absorbed with uterine activity and side effects less than those seen with free vaginal suppositories.* In that study it was suggested that PGEz might have a direct effect on the uterine cervix. Thus, one would anticipate a protection against uterine lacerations, except possibly when a second oxytocic agent is added or when the patient is multiparous with a malpresentation. The incidence of failure and the occurrence of’ the non-life-threatening untoward effects that include nausea, vomiting, diarrhea, hyperthermia, and hypotension associated with PGEz use occurred somewhat less than in past reports.“. ‘” The suggested management of patients with fetal death is appropriate for midtrimester cases. However, for patients in the third trimester of pregnancy who demonstrate a decline in fibrinogen to the 150 mg/ 100 ml range, I’ I would utilize laminaria to effect cervical ripening followed by intravenous oxytocin, an oxytocic agent and route that will allow some degree of control. In regard to the management of failed midtrimester abortion, vaginal evacuation has been demonstrated to be effective and safe.12 Case 1 is an example of a patient who received oxytocin at the rate of 15 to 20 mU/min. What determined the cessation of PGEy and the initiation of oxytocin in the first 10 cases of this series? Was the oxytocin administered via an electronic pump? Were the IDTs for these 10 cases analyzed separately from those of the remaining cases? How many of the midtrimester abortion failures were included in the first 10 cases?
April I, 1979 Am. J. Obstet. Cynecol.
Dr. Schulman stated that the current dosage of PGE2 is too high. What data did he use to support this statement? REFERENCES
Csapo, A. I.: The “see-saw” theory of parturition, it) The Fetus and Birth, Ciba Foundation Symposium 47, Amsterdam, 1977. Excerpta Medica Foundation, p. 159. 2. Grandin, D. J., and Hall, R. E.: Fetal death before the onset of labor. An analysis of 407 cases, AM. J. OBSTET. GYNECOL. 79: 237. 1960. 3. Csapo, A. I.: The four direct regulator) factors of myometrial function in progesterone: Its regulatory effect on the myometrium, Ciba Foundation Study Group 34, London, 1969, J. & A. Churchill, Ltd., p. 13. 4. Aleem, F. A., and Schulman, H.: Mid-trimester pregnancy interruption and the placental progesterone levels, Prostaglandin 9: 495, 1975. 5. Wiest, W. G.: Estimation of progesterone in biological tissue and Huids from pregnant women by double isotope derivative assay. Steroids 10: 279. 1967. 6. Vaginal suppokitory prostin E, (hinoprostone), package insert, September, 1977, The Upjohn Co., Kalamazoo, Michigan. 7. Hendrix, J. S.: Personal communication. 8. Schulman. H., Saldana, L., Tsai, T., Leibman, T.. Cunningham, M., and Randolph, G.: Prostagkmdin E:, induced abortion with vaginai suppositories i‘;l a contraceptive diaphragm. Prostaelandin 7: 195. 1974. 9. Lauersgn, NYH., and W?lson, K. H.: Induction of labor in patients with missed abortion and fetal death in utero with prostaglandin E2 suppositories, AH. J. OBSTET. GyNECOL. 127: 609. 1977. 10. Southern. E. ‘Lt., and Gutknecht, G. D.: Management of intrauterine fetal disease and missed abortion using prostaglandin E, vaginal suppositories, Obstet. Gynecol. 47: 602, 1976. 11 Pritchard, J. .A.: Fetal death in utero, Obstet. Gynecol. 14: 573, 1’358. 12 Burkman. R. .T.. Atienza, M. F., King, r. M., and BurI.
nett, L. S.: The management
of mid-trimester
abortion
failures IY77.
Obstet.
49: 233,
by vaginal
evacuation,
Gynecol.
PROFESSOR JOHN M. BEAZLEY (by invitation), Liverpool, England. If used intravenously, the dose rate of PGE 0052 required to promote labor in missed abortion or fetal death in utero. rarely exceeds 5 pgimin. This amounts to a total infusion of 900 pg in 3 hours or 2.7 mg in 9 hours. Dr. Schulman and his colleagues, using the vaginal route, had to employ doses which were 20 to 25 times greater. The reason for this enormous difference is not fully understood. The vaginal absorption rare of tritiated prostaglandins of the E group is probably of the order of only 10% to 20%‘. The rate of absorption is not known, nor is it clear whether the absorbed prostaglandins act locally upon the uterus or only systemically after venous passage through the liver and lungs, both of which reduce prostaglandin activity by at least 80%. It is our experience that when used intravenously, as much as 128 mU/min. of oxytocin may be combined with 4 pgimin. of PGE:! to stimulate a satisfactory and
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controllable degree of potentiation. However because the utilization of PGE2 inserted vaginally is so illunderstood, I believe the initial dose rate of 15 to 20 mU/min. of oxytocin, administered by Dr. Schulman, is probably too great. Quite a different result might have been obtained if only one tenth of this dose rate had been used. When labor does not ensue spontaneously within 2 to 3 weeks of fetal death in utero, it must be assumed that the mechanism usually initiating labor has not yet come into operation. Whatever the reason for this, simply to increase uterine force without first diminishing cervical resistance, for example, by the judicious use of estrogens, imposes an unnecessarily heavy demand upon the myometrium. Moreover, instead of expending its effort most efficiently, that is, in expelling the uterine contents, the force of the myometrium is usurped mainly in creating a uterine exit, hopefully via the cervix, but if this will not yield, more dramatically through the uterine wall. Gross uterine rupture, of the kind described by Dr. Schulman, is, of course, rare in a small uterus. Perhaps this relates to the law of Laplace, whereby, when the radius of curvature diminishes, tension in the wall also diminishes if the intracavitary pressure remains constant. Nevertheless, to apply the same uterine forces generated in labor at term to a cervix which has been singularly ill-prepared by pregnancy is always dangerous. There are, for example, at least 13 accounts of uterine dehiscence between the uterus and the cervix following the intra-amniotic instillation of prostaglandin Fza for midtrimester abortion. In conclusion, despite its clinical convenience, it is my view that the vaginal use of PGE2 is less dependable clinically than its intravenous use in conjunction with oxytocin. In combination, the intravenous route is capable of great precision and rapid control. Also, because PGE, is required in much smaller doses, mild vomiting occurs in only 25% of patients. DR. R. CLAY BURCHELL, Hartford, Connecticut. Intrauterine fetal death is a problem for the obstetrician and for the patient. Today we have better methods of diagnosis of fetal death and a greater choice of methods of beginning labor. One important factor, not often considered, is the emotional anguish of the patient in carrying a dead fetus. Better diagnosis has only intensified this problem. Often, in our efforts to be safe, this factor is not considered. I believe it should be incorporated into all decision making, and there will be times when it will be better from an emotional point of view to incur some risk than to wait for spontaneous onset of labor. This is a tangential point to the discussion, but I rise because one of the conclusions of the essayist was to support the concept of waiting. DR. SCHULMAN (Closing). I had expected something
Failed
labor
after
fetal
death
treated
with
PGE,
751
a little different from what the discussants stated and had prepared what I thought would be an appropriate anecdote. It is about a demented man, to whom, as he was lumbering along, someone said, “You are paranoic, my dear fellow,” and he answered, “Perhaps, but that doesn’t prevent people from plotting against me.” First, in answer to Dr. Niswander: Could the insertion of the balloon itself play a role in the initiation of labor? I doubt it. There has been extensive experience with this balloon. It is very tiny, of 0.8 ml capacity, and has been used for a number of studies of induction of labor in which placebo or drug was used. The question, “Why did PGE, succeed when PGF, succeed when PGFzu failed?” is not framed exactly right. PGE* was selected as a possible easier method than a second injection of PGF,,. We know that a second PGFza injection also would have worked. Progesterone levels were obtained when the women were admitted to the hospital. Therefore, these data fall short of the optimum study which would be to follow a group of women through pregnancy, at the onset of fetal death, and for the next few weeks. Dr. King’s comments were perceptive and our disagreements are not too serious. I think some of the problems we saw were related to excessive dosage, and one of the purposes of the study was to determine proper dosage. I do not quite know how to respond to the issue of the recom:liendations on the package insert. We were one of the groups of investigators for The Upjohn Co. and it is not clear how these guidelines were formulated. We think the drug can be used successfully after 28 weeks, and it is dependable. Whether the combination of laminaria and oxytocin represents a better method than prostaglandins needs to be determined by a comparative study. We know that studies to date have reflected a 50% failure rate with oxytocin alone. We used oxytocin in the first 10 cases because that had been our protocol in a study using PGE, suppositories for induced second-trimester abortion. A review of the literature had revealed only one documented case of uterine rupture in the presence of fetal death. We posed the theoretical question that after fetal death the uterus might be less susceptible to rupture because of the lessened volume, possible thickening of the wall, and diminution of uterine blood flow. This clinical study suggests that after fetal death the uterus does not have greater resistance to rupture. In the initial 10 cases we did not use oxytocin by infusion pump. We do use it when we have a viable fetus. Our conclusion about appropriate dosage is based upon the study design and data in the manuscript. There are a number of methods of deciding upon optimal dosage in a clinical study. One is to use several protocols and give the drug at varying time periods in varying dosages. The criteria used seem simple: What
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et al.
Am. J. Obstet.
is the maximum amount of drug which can be used to produce abortion or delivery without making the woman too ill.? Our approach utilized dose and response as determined by uterine activity. Redosage can be determined clinically by palpable uterine contractile activity, softening and dilatation of the cervix, or ballooning out of the lower segment. If these changes are present, we probably would not give additional drug, or no more than half of a suppository. In response to Professor Beazley, in regard to intravenous versus vaginal use, in fetal death, I cannot comment directly since we have no experience with an intravenous preparation. However, there is a large col-
Information
1979 Gynecol.
lection of animal and human data on usage of prostaglandins for induced abortion. These data suggest that the farther away from the uterus the drug is used, the less predictable is the drug’s action, e.g., intrauterine and intravaginal administration is significantly more effective than oral, intravenous, or intramuscular routes. In addition, parenteral injections of PGE have produced severe hyperthermia. I fully agree with Dr. Burchell’s admonition. The emotional aspects are very important, but the woman should be advised that when one matches an emotional issue against a life-threatening or physical issue, there may be some benefit in waiting a few weeks.
for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1. 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: “The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors.” Authors will be consulted, when possible, regarding republication of their material.
SCHULMAN, SALDANA,
CHIN-CHU GEORGIA
LIN,
M.D.,
F.A.C.0.G
M.D..
F.A.C.O.G.
M.D.,
F.A.C.O.G.
RANDOLPH.
B.S.
At-on.\, New York Pregnancy was terminated with prostaglandin E, in 65 women harboring a dead fetus for 3 days to 8 weeks. The study was designed to: (1) elucidate the mechanism of failed onset of labor in the presence of fetal death, (2) determine appropriate dose-response relationships, and (3) evaluate safety and efficacy of this new method of intervention. Results indicate that plasma progesterone levels from 12 to 40 weeks’ gestation are in the lower normal statistical range as compared to those seen in pregnancy with a living fetus. Uterine size as estimated from fetal birth weight is also in the low normal range compared to that seen in a viable pregnancy. Hence the uterine volume-progesterone ratio is equal to or greater than that in normal pregnancy and thereby partially explanatory for the failed initiation of labor. The dosage required to produce delivery &;?lined in each month’s grouping from a mean of 56 r 26 (SD) mg at 12 to 15 weeks to 22 2 8.4 mg at 38 to 40 weeks. Dose-delivery response did not correlate with age, parity, or progesterone levels but did correlate with oxytocin response. Three unusual and Serious complications occurred. (AM. J. OBSTET. GYNECOL. 133:742, 1979.)
of prostaglandin preparations has offered a new look at an old clinical problem, that of prolonged fetal death without the onset of labor.‘. ‘. 23 This report will summarize an experience in which some theoretical and practical questions were posed about the efficacy of prostaglandin E2 (PGE,) vaginal suppositories in initiating labor after fetal death. It will be shown that PGE2 is highly successful in initiating labor, but a number of drug-related and disease-related complications were encountered. The lack of spontaneous onset of labor in these women can be partially explained by the preservation of a uterine volume-progesterone ratio or relationship.” THE
AVAILABILITY
FI-om tkr Department of G,nmlo, and Ohtrtrzc.\..4lhurt Eiwteirc College qf Me&w, Yeshwa Clniwrsit~. Presented by invitation at the Eighty-ninth ilnntral Meeting of the American Association of Obrtetriciamr and Gynecologists, Hot Springs, Virginia, Scpternber 7-9. 1978. Reprint request, at a level approximately 80% of the mean (Fig. 2). Although we used the oxytocin test as a rough gauge of uterine responsiveness, we could not demonstrate a consistent relationship to progesterone levels, PGE Z dosage, or instillation-to-deliver!, time (IDT) within each group. It will be noted that the dosage requirements progressively decreased with each gestational week grouping (Fig. 3) and corresponded with a greater oxytocin sensitivity,. When patients were grouped into fetal death at > or 2 weeks previously. Uterine height was 25 cm. Bishop score was 0, and an extraovular balloon catheter could not be passed into the lower uterine segment. Good uterine activity was noted after one suppository. At 3% hr. a half suppository was inserted; blood pressure fell to SO/50 and pulse was 120 beatsimin. The uterus was firm. The woman was quite anxious and in pain. Hematocrit was unchanged, and extremities were warm, but the blood pressure did not respond to an infusion of >700 ml of 5% dextrose in Ringer’s lactate after 1 hr., nor was
Fetal weight (gm.) 125 400 600 872 1304 2081 2520
of placenta;
t r -t k t 2 2
Abortion
80 126 130 163 234 126
80, incomplete
92 90 95 96.4 96.4
score k5 -t t rt ‘_ 100 100
delivery
3.9 4.5 2.1 3.2
of
there any urine output. Examination in the delivery room revealed the external cervical OS to be 2 to 3 cm dilated, but a broad band of tissue extended across the internal OS. Gentle probing released the band and the fetal head descended to the external OS. Immediately the blood pressure returned to normal and urine flow was noted in the Foley catheter. Review of the patient’s history revealed that she had become pregnant immediately after a curettage and cone biopsy of the cervix. The clinical analysis suggested cervical synechia and excessive uterine activity resulting in neurogenic shock and oliguria. Comment The pathogenesis of failed labor in fetal death is not adequately understood. The onset of labor is dependent to some degree upon the cause of the fetal death. For example, if the etiology is of maternal origin, such as hypertension, the average onset of labor is approximately I week. If fetal death is secondary to an intrinsic intrauterine disorder such as Rh isoimmunization, the
Volume Number
133 7
onset of labor may not occur for 2 weeks5 This study has demonstrated that plasma progesterone concentrations are in the low normal range of those of women carrying a living fetus. The fetal weights are also in the low normal statistical range; thus, an effective uterine volume-progesterone ratio is maintained. Since a sharp drop in estrogen secretion occurs after fetal death, the key ingredients are provided for the maintenance of uterine inhibition.” PGEp has a unique and predictable ability to initiate labor in prolonged fetal death. The dosage required progressively declines as pregnancy advances and is less than that needed for an induced abortion probably because of the lowered progesterone level in the former. Efforts to terminate these pregnancies prior to the use of prostaglandins met with mixed success.3’ ‘3 r1 If an oxytocin infusion was attempted, it failed approxiinstillation mately 50% of the time. ‘3 *, i* Intra-amniotic of hypertonic solutions were hypothetically contraindicated because of the predisposition of these patients to develop coagulation disorders. Surgical evacuation through the vagina is difficult and associated with an excessive amount of hemorrhage because the placenta is usually adherent to the uterine wa11.20 Reports on the usage of PGE2 suggest a high success rate in inducing labor,‘, 13, 15. 24 However, prostaglandins create side effects, which include nausea, vomiting, diarrhea, hyperthermia, and hypotension, in approximately 60% to 70% of patients. Since prostaglandins are powerful myometrial stimulants, uterine rupture is a predictable consequence of this therapy and three cases have been reported at this Writing, all in women para 3 or more.3, I432o Several large studies over the past 40 years have demonstrated that when fetal death occurs labor will begin in 2 to 3 weeks in 77% to 93% of women.‘, 7, g, lo, I39 25 When spontaneous labor takes place there are virtually no complications. There is an overwhelming and understandable desire of the woman with a fetal death to have the pregnancy terminated. However, this desire must be balanced against the natural history of the disorder. In most cases labor will occur in 2 to 3 weeks and there will be no physical consequences. When the fetus has been dead for more than 3 to 4 weeks there may be a progressive decline in serum fibrinogen and platelets, and the onset of labor becomes unpredictable.r2, ls This study has demonstrated that, although effective, PGEp has too many undesirable side effects to be used as an elective medication. Nausea, vomiting, and diarrhea, although tolerable, are unpleasant, particularly when iatrogenic. The alliance of hyperthermia
Failed labor after fetal death treated with PGE,
747
and hypotension may mislead one to combat aggressively a septic process. Hypotension can cause a misdiagnosis of uterine rupture. The latter is a genuine risk in parous women, and the combination of PGE2 and oxytocin should be avoided in fetal death, at least for an interval of 12 hours. An elective attempt at induction may turn into an iatrogenic nightmare as demonstrated by Case 2. Finally the current packaging of PGE2 represents too large a dose for most women, and a more disciplined initiation of labor should be carried out. Our experience has led to the following program of management for women with fetal death. Once the diagnosis is made, an explanation should be offered to the woman of the benefits of waiting at least 2 weeks before active intervention is considered. After this time has elapsed, consideration can be given to termination since the time of the probability of the onset of labor is now less clear. Baseline blood studies should be obtained for fibrinogen and platelet levels. The presence of hypofibrinogenemia or thrombocytopenia is not an indication for replacement therapy. However, fresh frozen plasma and packed red blood cells should be on hand in case uncontrollable bleeding develops. If the cervix demonstrates changes so that a Bishop score of 4 or more exists, an intravenous infusion of oxytocin should be successful.“j If the cervix has a Bishop score of 3 or less, there is a choice of continued observation or the initiation of labor with PGE, vaginal suppositories. In the last trimester we cut the suppository in half and repeat its usage approximately every 3 hours. Women receiving PGE, therapy for fetal death should have a constant intravenous infusion of dextrose in Ringer’s lactate as a means of dealing with possible complications. Within an hour of insertion of the suppository, 50% will experience episodes of nausea or vomiting or have loose stools. Also 10% to 15% will show temperature elevations to 38” C or more and have shaking chills. In association with this, the blood pressure may fall to ranges of 80/60. Usually the extremities are warm, and the pulse only mildly elevated; urine flow continues. A rapid infusion of 300 ml of 5% dextrose in Ringer’s lactate usually restores the pressure to within normal limits. Effective uterine contractile activity with PGEz usually occurs almost every minute so that when the uterus is palpated it has a feel similar to that of abruptio placentae. If this kind of activity is present at the end of 3 hours, we do not give further drug because of the desire to minimize side effects. We have used chlorpromazine and Lomotil to attempt to reduce the gastrointestinal side effects. These are administered before the suppository is given. If uterine activity is not
748
Schulman
satisfactory, this
will
uterine
a second, he repated activity
minimal
changes therefore,
not
a useful
every
index
of retained
problems
half
suppository
is only
in
the
cervix
the
placentas 10 to
until
It is not
cervical of
is inserted,
3 to 4 hours
is established.
delivery; dence
April I, 1979 Am. .J. Obstet. Gynerol.
et al
1 to
progress
ress
satisfactory
unusual
prior
or effacement of
in PGE,treated
labor.
to
to have
2 hours
dilatation
Oxytocin
and
The fetal
quelae
is
the
allowed
XII heforc
he used
combination
tltetine
of clinical uterus.
not
‘The
excessive
to inci-
should
of labor.
activity
and,
coagulation interval osytocin
to accelerate of these disorders
of
at least
usage
drugs
therefore,
the
prog-
can the
lead sc-
and
rupture
of’
12 hours
should
he
is considered.
death
15%.
REFERENCES I.
2. 3.
4.
5.
6.
7. 8.
9.
10.
11. 12.
13.
Bailey, C. D., Newman, C., Ellinas. S. P., and Anderson, G. G.: Use of prostaglandin E2 vaginal suppositories in intrauterine fetal death and missed abortion, Obstet. Gynecol. 45: 110, 1975. Banner. E. A., and Bentler. H. K.: Intrauterine deaths, Obstet. Gynecol. 12: 661, 1958. Borten, M.. and Friedman, E. .4.: Uterine rupture: A complication of midtrimester abortion, Prostaglandins 15: 187. 1978. Csapo. A. I., jaffin, H., Kerenyi, T., deMattos, C. E. R., and deSousa Filho, M. B.: Fetal death in utero. AM. J. OBSTF.T.GYNECOL. 87:892. 1963. Csapo, A. I.: The “see-saw” theory of parturition, in The Fetus and Birth, Ciba Foundation Symposium 47, 1977, Excerpta Medica Amsterdam, Foundation, p. 159. Cordon, H., and Pipe, N. G. J.: Induction of labor after intrauterine fetal death: a comparison between prostaglandin E.’ and oxytocin, Obstet. Gynecol. 45: 44, 1975. Dippel. A. L.: Death of a fetus in utero, Johns Hopkins Med. J. 54: 24, 1934. El-Demarawy, H., El-Sahivi, S., and Toppozada, M.: Management of missed abortion and fetal death in utero, Prostaglandins 14: 583, 1977. Goldstein, D. P., Johnson, J. P., and Reid. D. E.: Management of intrauterine fetal death, Obstet. Gynecol. 21: 523, 1963. Grandin. D. J., and Hall, R. E.: Fetal death before the onset of labor. An analysis of 407 cases, AM. J. OBSTET. GYNECOL. 79: 237, 1960. Gustavii, B.: Missed abortion and uterine contractility, AM. J. OBSTET.GYNECOL. 130: 18. 1978. Jiminez. J. M., and Pritchard, J. A.: Pathogenesis and treatment of coagulation defects resulting from fetal death, Obstet. Gynecol. 32: 449, 1968. Kent, D. R., and Goldstein, A. I.: Prostaglandin E, induction of labor for fetal demise, Obstet. Gynecol. 48: 475, 1976.
Discussion DR. KENNETH R. NISWANDER, Davis, California. Therapy for fetal death in utero continues to he unsatisfactory. We are, of course, able to offer patients a much wider range of choices for management of the problem today than we were a few years ago. Dr. Schulman has cautioned us not to leap to these new ideas too quickly, however, since iatrogenic disease may follow their use. He counsels the time-honored therapy of procrastination, at least for a week or two, as the safest management for the patient. Since not all patients will accept this advice, and since some patients will stubbornly “refuse” to go into spontaneous labor, it
14.
15.
16.
17.
18.
19. 20. 21.
22.
23. 24.
2.5.
Kirton, K. T., and Forbes, A. D.: Activity of 15(S)-methyl prostaglandin E2 and F, as stimulants of uterine co,)tractility, Prostaglandins 1: 3 19, 1972. Lippert, T. H., and Luthi, A.: Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death, Prostaglandins 15: 533, 1978. Loudon, J. D. 0.: The use of high concentration oxytocin IV drips in the management of missed abortion, Br. J. Obstet. Gynaecol. 66: 277, 1959. Mitchell, M. D., Patrick, J. E., Robinson, J. S.. ‘Thorburn. G. D., and Challis, J. R. G.: Prostaglandins in the plasma and amniotic fluid of rhesus monkeys during pregnant) and after intrauterine foetal death, J. Endocrinol. 71: 67, 1976. Peyser. M. R.. and Toaff, R.: Rupture of the uterus in the first trimester caused by high concentration oxytocin drip, Obstet. Gynecol. 40: 371. 1972. Pritchard, J. A.: Fetal death in utero. Obstet. G, necol. 14: 573, 1959. Ratten, G. J.: The management of missed abortion. Aust. N. Z. J. Obstet. Gynaecol. 10: 115. 1970. Saldana, L., Schulman, H., Yang, W.. Cunningham, M. A., and Randolph, G.: Midtrimester abortion by prostaglandin impact, Obstet. Gynecol. 44: 579, 1974. Schulman. H., Saldana. L., Tsai, T.. Leibman. T.. Cutlningham. M. A.. and Randolph, G.: Prostaglandin Ei induced abortion with vaginal suppositories in a rontraceptive diaphragm, Prostaglandins 7: 195, 1974. Smith, .4. M.: Rupture of uterus during prostaglandin induced abortion, Br. Med. J. 1: 205, 1975. Southern, E. M.. Gutknecht, G. D., Mohberg. N. R., and Edelman. D. A.: Vaginal prostaglandin in the management of fetal intrauterine death, Br. J. Obsret. Gvnaecol. 85: 437. 1978. Tricomi, V.. and Kohl, S. G.: Fetal death in utero. A.M. J, OBSTET. GYNECOL. 74: 1092, 1975.
is well worth discussing Dr. Schulman’s experience with intravaginal PGE, and drawing on his expertise to speculate on certain aspects of this treatment. To set the stage for a few questions I would like to pose, let me summarize the see-saw theory of Csapo.’ at least as I understand it. In simplistic terms, C:sapo helieves that there are two major endogenous myometrial regulators which exert opposing effects on the uterine musculature. Progesterone quiets the uterus and prostaglandin causes it to contract. Fortunately for the preservation of the species, nature has made the progesterone effect the dominant one. Unless the progesterone protection is removed, the uterus will not empty
Volume 133 Number
7
itself. These two substances exert their effects by controlling activator calcium which in turn is the trigger that sets off the interaction between the contractile proteins of the uterus, actin and myocin, and adenosine triphosphate. Progesterone “binds” activator calcium, thus raising the threshhold of excitability of the myometrium. Prostaglandin has the opposite effect, but only if the progesterone concentration is low. According to this theory, prostaglandin can exert no prolonged myometrial effect without first causing the progesterone protection to be broken. Thus, the mechanism of action of exogenous prostaglandin is to cause an increase in uterine tone with a resultant decrease in uterine blood flow and damage to the placenta. This placental damage decreases the effective level of the progesterone block. Intrinsic prostaglandin can then cause uterine emptying. The contractile effect of exogenous prostaglandin on the myometrium does not in itself cause the abortion. The level of tissue progesterone must be lowered before prostaglandin will cause labor to ensue. Factors other than a prostaglandin-induced decrease in uterine blood flow, of course, will also lower the level of the progesterone block. Damage to the placenta by disease (e.g., abruptio placentae, toxemia) is one example of such a factor. Similarly, manipulation of the lower uterine segment (e.g., stripping of the membranes) also apparently affects placental function, thus allowing labor to begin. I would like to ask Dr. Schulman if he thinks the insertion of the extraovular balloon in his experiment may have been a factor in initiating labor in these patients. Might this factor explain the success of PGEz after PGFzu had failed? If not, what other explanation does he have for the success of PGEz when PGFza had failed in so many of his patients? The mean level of serum progesterone was low normal. I assume the reported serum progesterone level was a single determination at the time of the drug instillation. Are progesterone levels at any other time available that might explain the few abortion failures or the long IDTs? The discovery of the prostaglandins has added a new dimension both to the study of the physiology of the myometrium and to the clinical practice of obstetrics and gynecology. Dr. Schulman and his co-workers are to be congratulated on this contribution to the development of knowledge of these fascinating substances. REFERENCE
1. Csapo, A. I.: The see-saw theory of parturition, in The Fetus and Birth, Ciba Foundation Symposium 47, Amsterdam, 1977, Excerpta Medica Foundation, p. 159.
DR. THEODORE M. KING, Baltimore, Maryland. This study was undertaken to elucidate the mechanism of failed onset of labor in the presence of fetal death, to determine appropriate dose-response relationships,
Failed labor after fetal death treated with PGE,
749
and to evaluate safety and efficacy of a new method of intervention. These questions have been asked before and the answers that have existed appear to be substantiated by the findings of this report. Csapo,’ in a detailed review of his “see-saw” theory of parturition stated “that as a rule, fetal death predictably tertninates pregnancy and that the timing of delivery is determined by residual placental endocrine function at the time of fetal demise.” He supported this statement by utilizing data published by Grandin and Hall2 in 1960 from their analysis of 407 cases of fetal death that occurred before the onset of labor. As an example, a fetal death caused by premature placental separation usually results in onset of labor in less than 2 days, while fetal death caused by rhesus incompatibility may have a delayed onset of labor for 14 days or more. In the former instance, all placental endocrine functions is lost immediately while in the latter example endocrine function persists. This concept is also supported by documentation of the necessary decrease in progesterone required for the evolution of cyclic uterine contractions in midtrimester abortions induced by hypertonic saline.3 Indeed, Aleem and Schulman4 showed a striking decline of progesterone in placentas from such pregnancies. The documentation of maintenance of the uterine volume-progesterone ratio similar to that in a normal pregnancy in intrauterine fetal deaths is not surprising, although it has been suggested in the past that the extent of progesterone decline appears to be a function of the length of time after fetal death.5 In regard to the patients studied in this report, the inclusion of midtrimester failed abortion cases makes the reported population of patients different from the usual population with fetal death in utero or missed abortion. The failed abortions account for 23% of the population studied. In the presentation of data, this group is not reported separately. In the 12 to 24 week group, there are 19 cases. Fifteen of these should have been the failed induced abortions. The Bishop scores of these groups do appear to be different from those of the remainder of the study population, and larger quantities of prostaglandin are required for the 12 to 24 week groups than for the 29 to 41 week groups. It is of interest that this report substantiates the package insert for PGE2 released by The Upjohn Co. in September, 1977.6 The indication cited for PGEB is the termination of pregnancy or evacuation of uterine contents in the presence of missed abortion or intrauterine fetal death up to the twenty-eighth week of gestation. The three serious complications in Dr. Schulman’s series occurred in patients with gestations of 30, 32, and 38 weeks, with an incidence of 9% for the total group of 34 patients who were in the third trimester of pregnancy. In review with The Upjohn Co. in late July of 1978, they are aware of six ruptured uteri subsequent to the
750
Schulman et al.
filing of their New Drug Agency data on PGE2.7 One of these cases sounds exceedingly similar to the case reported in this paper. Of these cases, four of six women received more than one kind of oxytocic agent, while the remaining patient was subjected to a vaginal manipulative procedure in the presence of an abnormal presentation. Two were multiparous patients and three patients were of unknown parity. Thus, it would appear that PGEt is not strikingly different from other oxytocic agents in that use in combination with other ecbolic agents is fraught with danger, particularly in multiparous patients who are in the third trimester of’ pregnancy. The author makes a point that the current packaging of PGE, represents too large a dose for most women and a more disciplined initiation of labor should be carried out. This is certainly true if it is to be used in a trimester of pregnancy not included in the package insert. It should also be noted that the current study deviates from recommended usage of PGEz by utilizing a vaginal diaphragm to contain the intravaginal suppository and by administering the drug more frequently than every 3 to 5 hours. In previous work by Dr. Schulman in which a diaphragm was utilized as a holder for PGEP vaginal suppositories, the results suggested that a reduced quantity of prostaglandin is absorbed with uterine activity and side effects less than those seen with free vaginal suppositories.* In that study it was suggested that PGEz might have a direct effect on the uterine cervix. Thus, one would anticipate a protection against uterine lacerations, except possibly when a second oxytocic agent is added or when the patient is multiparous with a malpresentation. The incidence of failure and the occurrence of’ the non-life-threatening untoward effects that include nausea, vomiting, diarrhea, hyperthermia, and hypotension associated with PGEz use occurred somewhat less than in past reports.“. ‘” The suggested management of patients with fetal death is appropriate for midtrimester cases. However, for patients in the third trimester of pregnancy who demonstrate a decline in fibrinogen to the 150 mg/ 100 ml range, I’ I would utilize laminaria to effect cervical ripening followed by intravenous oxytocin, an oxytocic agent and route that will allow some degree of control. In regard to the management of failed midtrimester abortion, vaginal evacuation has been demonstrated to be effective and safe.12 Case 1 is an example of a patient who received oxytocin at the rate of 15 to 20 mU/min. What determined the cessation of PGEy and the initiation of oxytocin in the first 10 cases of this series? Was the oxytocin administered via an electronic pump? Were the IDTs for these 10 cases analyzed separately from those of the remaining cases? How many of the midtrimester abortion failures were included in the first 10 cases?
April I, 1979 Am. J. Obstet. Cynecol.
Dr. Schulman stated that the current dosage of PGE2 is too high. What data did he use to support this statement? REFERENCES
Csapo, A. I.: The “see-saw” theory of parturition, it) The Fetus and Birth, Ciba Foundation Symposium 47, Amsterdam, 1977. Excerpta Medica Foundation, p. 159. 2. Grandin, D. J., and Hall, R. E.: Fetal death before the onset of labor. An analysis of 407 cases, AM. J. OBSTET. GYNECOL. 79: 237. 1960. 3. Csapo, A. I.: The four direct regulator) factors of myometrial function in progesterone: Its regulatory effect on the myometrium, Ciba Foundation Study Group 34, London, 1969, J. & A. Churchill, Ltd., p. 13. 4. Aleem, F. A., and Schulman, H.: Mid-trimester pregnancy interruption and the placental progesterone levels, Prostaglandin 9: 495, 1975. 5. Wiest, W. G.: Estimation of progesterone in biological tissue and Huids from pregnant women by double isotope derivative assay. Steroids 10: 279. 1967. 6. Vaginal suppokitory prostin E, (hinoprostone), package insert, September, 1977, The Upjohn Co., Kalamazoo, Michigan. 7. Hendrix, J. S.: Personal communication. 8. Schulman. H., Saldana, L., Tsai, T., Leibman, T.. Cunningham, M., and Randolph, G.: Prostagkmdin E:, induced abortion with vaginai suppositories i‘;l a contraceptive diaphragm. Prostaelandin 7: 195. 1974. 9. Lauersgn, NYH., and W?lson, K. H.: Induction of labor in patients with missed abortion and fetal death in utero with prostaglandin E2 suppositories, AH. J. OBSTET. GyNECOL. 127: 609. 1977. 10. Southern. E. ‘Lt., and Gutknecht, G. D.: Management of intrauterine fetal disease and missed abortion using prostaglandin E, vaginal suppositories, Obstet. Gynecol. 47: 602, 1976. 11 Pritchard, J. .A.: Fetal death in utero, Obstet. Gynecol. 14: 573, 1’358. 12 Burkman. R. .T.. Atienza, M. F., King, r. M., and BurI.
nett, L. S.: The management
of mid-trimester
abortion
failures IY77.
Obstet.
49: 233,
by vaginal
evacuation,
Gynecol.
PROFESSOR JOHN M. BEAZLEY (by invitation), Liverpool, England. If used intravenously, the dose rate of PGE 0052 required to promote labor in missed abortion or fetal death in utero. rarely exceeds 5 pgimin. This amounts to a total infusion of 900 pg in 3 hours or 2.7 mg in 9 hours. Dr. Schulman and his colleagues, using the vaginal route, had to employ doses which were 20 to 25 times greater. The reason for this enormous difference is not fully understood. The vaginal absorption rare of tritiated prostaglandins of the E group is probably of the order of only 10% to 20%‘. The rate of absorption is not known, nor is it clear whether the absorbed prostaglandins act locally upon the uterus or only systemically after venous passage through the liver and lungs, both of which reduce prostaglandin activity by at least 80%. It is our experience that when used intravenously, as much as 128 mU/min. of oxytocin may be combined with 4 pgimin. of PGE:! to stimulate a satisfactory and
Volume 133 Number7
controllable degree of potentiation. However because the utilization of PGE2 inserted vaginally is so illunderstood, I believe the initial dose rate of 15 to 20 mU/min. of oxytocin, administered by Dr. Schulman, is probably too great. Quite a different result might have been obtained if only one tenth of this dose rate had been used. When labor does not ensue spontaneously within 2 to 3 weeks of fetal death in utero, it must be assumed that the mechanism usually initiating labor has not yet come into operation. Whatever the reason for this, simply to increase uterine force without first diminishing cervical resistance, for example, by the judicious use of estrogens, imposes an unnecessarily heavy demand upon the myometrium. Moreover, instead of expending its effort most efficiently, that is, in expelling the uterine contents, the force of the myometrium is usurped mainly in creating a uterine exit, hopefully via the cervix, but if this will not yield, more dramatically through the uterine wall. Gross uterine rupture, of the kind described by Dr. Schulman, is, of course, rare in a small uterus. Perhaps this relates to the law of Laplace, whereby, when the radius of curvature diminishes, tension in the wall also diminishes if the intracavitary pressure remains constant. Nevertheless, to apply the same uterine forces generated in labor at term to a cervix which has been singularly ill-prepared by pregnancy is always dangerous. There are, for example, at least 13 accounts of uterine dehiscence between the uterus and the cervix following the intra-amniotic instillation of prostaglandin Fza for midtrimester abortion. In conclusion, despite its clinical convenience, it is my view that the vaginal use of PGE2 is less dependable clinically than its intravenous use in conjunction with oxytocin. In combination, the intravenous route is capable of great precision and rapid control. Also, because PGE, is required in much smaller doses, mild vomiting occurs in only 25% of patients. DR. R. CLAY BURCHELL, Hartford, Connecticut. Intrauterine fetal death is a problem for the obstetrician and for the patient. Today we have better methods of diagnosis of fetal death and a greater choice of methods of beginning labor. One important factor, not often considered, is the emotional anguish of the patient in carrying a dead fetus. Better diagnosis has only intensified this problem. Often, in our efforts to be safe, this factor is not considered. I believe it should be incorporated into all decision making, and there will be times when it will be better from an emotional point of view to incur some risk than to wait for spontaneous onset of labor. This is a tangential point to the discussion, but I rise because one of the conclusions of the essayist was to support the concept of waiting. DR. SCHULMAN (Closing). I had expected something
Failed
labor
after
fetal
death
treated
with
PGE,
751
a little different from what the discussants stated and had prepared what I thought would be an appropriate anecdote. It is about a demented man, to whom, as he was lumbering along, someone said, “You are paranoic, my dear fellow,” and he answered, “Perhaps, but that doesn’t prevent people from plotting against me.” First, in answer to Dr. Niswander: Could the insertion of the balloon itself play a role in the initiation of labor? I doubt it. There has been extensive experience with this balloon. It is very tiny, of 0.8 ml capacity, and has been used for a number of studies of induction of labor in which placebo or drug was used. The question, “Why did PGE, succeed when PGF, succeed when PGFzu failed?” is not framed exactly right. PGE* was selected as a possible easier method than a second injection of PGF,,. We know that a second PGFza injection also would have worked. Progesterone levels were obtained when the women were admitted to the hospital. Therefore, these data fall short of the optimum study which would be to follow a group of women through pregnancy, at the onset of fetal death, and for the next few weeks. Dr. King’s comments were perceptive and our disagreements are not too serious. I think some of the problems we saw were related to excessive dosage, and one of the purposes of the study was to determine proper dosage. I do not quite know how to respond to the issue of the recom:liendations on the package insert. We were one of the groups of investigators for The Upjohn Co. and it is not clear how these guidelines were formulated. We think the drug can be used successfully after 28 weeks, and it is dependable. Whether the combination of laminaria and oxytocin represents a better method than prostaglandins needs to be determined by a comparative study. We know that studies to date have reflected a 50% failure rate with oxytocin alone. We used oxytocin in the first 10 cases because that had been our protocol in a study using PGE, suppositories for induced second-trimester abortion. A review of the literature had revealed only one documented case of uterine rupture in the presence of fetal death. We posed the theoretical question that after fetal death the uterus might be less susceptible to rupture because of the lessened volume, possible thickening of the wall, and diminution of uterine blood flow. This clinical study suggests that after fetal death the uterus does not have greater resistance to rupture. In the initial 10 cases we did not use oxytocin by infusion pump. We do use it when we have a viable fetus. Our conclusion about appropriate dosage is based upon the study design and data in the manuscript. There are a number of methods of deciding upon optimal dosage in a clinical study. One is to use several protocols and give the drug at varying time periods in varying dosages. The criteria used seem simple: What
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April I,
et al.
Am. J. Obstet.
is the maximum amount of drug which can be used to produce abortion or delivery without making the woman too ill.? Our approach utilized dose and response as determined by uterine activity. Redosage can be determined clinically by palpable uterine contractile activity, softening and dilatation of the cervix, or ballooning out of the lower segment. If these changes are present, we probably would not give additional drug, or no more than half of a suppository. In response to Professor Beazley, in regard to intravenous versus vaginal use, in fetal death, I cannot comment directly since we have no experience with an intravenous preparation. However, there is a large col-
Information
1979 Gynecol.
lection of animal and human data on usage of prostaglandins for induced abortion. These data suggest that the farther away from the uterus the drug is used, the less predictable is the drug’s action, e.g., intrauterine and intravaginal administration is significantly more effective than oral, intravenous, or intramuscular routes. In addition, parenteral injections of PGE have produced severe hyperthermia. I fully agree with Dr. Burchell’s admonition. The emotional aspects are very important, but the woman should be advised that when one matches an emotional issue against a life-threatening or physical issue, there may be some benefit in waiting a few weeks.
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