Missed abortion following treatment of threatened abortion with progestational agents

38 Pages·2014·1.67 MB·English

by  Marlene E. Lengner

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MD Theses Special Collections
5-1-1964
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Marlene E. Lengner
University of Nebraska Medical Center
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IJIISSED .A]3OP..T I ON' , FOLLO'~JING TREATMEIfT OF TEREATE1\i]JJ)
ABORTION WITH PROGESTATIONAL
AG~TTS
14arlene Lengner
Submitted in Partial Fulfillment for the Degree of
Doctor of f.'Iedicine
College of Medicine, University of Nebraska
December, 1963
Omaha, NebrasJr-..a
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C..v fa::;":>
TABLE OF C01TTENTS
I. Missed Abortions
(a) Definition
(b) Possible Etiology
(c) Hormone Production Related to Missed
Abortion
(d) Hypofibrinogenemia
II. Progesterone and Progestational Agents
(a) General Properties
1. Effects of Agents on Endometrium
2. Action of Progesterone in
Pregnancy
(b) Use of Agents to Treat Threatened
Abortion
III. Review of Cases of Missed Abortion
Following Treatment of Threatened
Abortion with Progestational Agents
(a) List of Cases with Pertinent Data
(b) Discussion of Data
IV. Summary
V. General Conclusion
VI. Bibliography
In 1921 Litzenbergl~pplied the term missed abortion to all
cases of death of the fetus in utero before viability with no
effort at expulsion within the usual time of an ordinary abortion,
the expulsion considered occurring up to 8 weeks after death.
Eastman, 1961, defines a missed abortion as the retention,
two months or more after its death, of an early intra-uterine
pregnancy.
Litzenberg states that in his cases hemorrhage 'V,as a prom
inent finding, giving the ovum a hemorrhagic a:fJpearance; but
hemorrhage may be entirely absent. He noted that in the placenta
infarcts were numerous, sometimes occupying neal°ly the whole
organ, suggesting the probable cause of fetal death. One of the
great dangers of missed abortion, he thought, was due to degen
eration of the blood vessel walls which could be so completely
destroyed that uncontrollable hemorrhage could occur. Disap
pearance or marked diminution of the amniotic fluid without
rupture of the membrane was the rule.
He noticed the frequency of discrepancy between the size
of the placenta the fetus, the former being often as large
~~d
as the placenta of a fetus a month or more older than the one
found. This was considered to be due to connective tissue
increase, hemorr1">..age into the placenta and a curious true growth
of the placenta after the death of the fetus. He felt that when
1
the fetus died, especiallY in the early weeks, the chorion and
decidua may go on growing because they are nourished by the
maternal blood circulating in the intervillous spaces which may
continue for a long time. LaVerge observed karyokinesis indi
cating cell multiplication rather than hypertrophy. He noticed
that the inner layer of the villous epithelium, which is not in
direct contact with maternal blood, is an early victim to coag
ulation necrosis; but the outer syncytial layer, bathed in mater
nal blood, is preserved much longer until thrombosis takes place
shutting off the blood supply to the intervillous spaces. In
the second half of pregnancy Von Franque asserted that this
interesting phenomenon of continued growth after the death of
the fetus did not occur. Microscopic studies showed all stages
of necrosis of tissue, placenta, decidua, amnion, blood vessels.
the fetus and even uterine walls. If the remained in the
o~~
uterus for a long time, drying out or mummification occurred.
By Litzenberg's definition, the symptoms of miSsed abortion
are lack of increase in size of the uterus, cessation of fetal
movements and other signs of pregnancy. Regression changes in
the breasts also take place. Hemorrhage is a very inconstant
accompaniment of missed abortion, but in some form or another it
usually complicates the condition, sometimes constituting a
great danger.
Eastmanlbviews the cases of missed abortion as follows.
He states that in the typical instance, the first few months of
2
pregnancy are completely normal: amenorrhea. nausea and vom-
iting. breast changes, and gro",th of uterus. All goes well
until the ovum dies, when there mayor may not be vaginal bleed-
ing or even sY".llptoms denoting a threatened abortion, which sub-
side. It is then noted that the uterus seems to remain sta-
tionary in size and the breasts regress. The patient is likely
to lose a fe"t pounds in \<leight. Careful palpation and. measure-
ment of the uterus reveal the fact that it has not only ceased
to enlarge but is growing smaller, from the absorption of
amniotic fluid and maceration of the fetus. Most patients are
symptomless during this period, except for the persistence of
amenorrhea. Some, ho,.,ever, complain of lassitude and depress ion.
If the missed abortion terminates spontaneously, as most do, the
process of expulsion is quite the same as in any ordinary abor-
tion. The product, if reta.ined several weeks after fetal death.
is a shrivelled sac containing a highly macerated embryo, and
if retained for months or years, it appep..I's to be a mass of old
tissue and blood with areas of dense calcification. He states
that the cause of missed abortion is not known •
N. E. Borglin.: L( Sweden) stated in 1957, that there is
nothing essential to distinguish abortion with a demon-
~issed
strable embryo from an abortion occurring after more than 8
weeks in which the embryo has been absorbed. The duration of
retention is often difficult to assess because it is not easy
and is often impossible to decide whether the embryo died.
t~s
The strikingly large number of ordinary abortions suggests
that a missed abortion is only a variety of ordinary abortion.
It is suggested that the term missed abortion be reserved for
fetal death after the fourth month of pregnancy with retention
of the dead fetus for at least six weeks. prefer con
~~ny
servative treatment, in other words, waiting for a spontaneous
abortion, especially because of the risk of hemorrhage in surg
ical intervention, which is partly due to the frequently poor
contractile power of the uterus in this condition. This inad
equate power of contraction probably also causes retention
of the dead ovum. Spontaneous abortion usually occurs ,,!ith
only slight loss of blood. because at this stage the vessels
of the uterine endometrium have thrombosed and the uterus has
recovered its power of contraction. The severe loss of blood
on surgical evacuation of the uterine cavity and the copious
bleeding sometimes accompanying spontaneous abortion, can
occasionally be ascribed in part to hypofibrinogenemia.
The characteristic features of a missed abortion are
considered as low spontaneous myometrial activity, low oxy
tocin sensitivity and danger of bleeding after surgical inter
vention mainly due to atony, but sometimes to afibrinogenemia.
In view of the inactive state of the myometrium, which is often
thin and fragile, and of the successful estrogen treatment of
4
a big of missed abortions, it is felt that it is justi-
gr~~p
fied to conclude that lack of estrogen is an etiologic factor.
rt
Cassmer has that when the fetus dies and the placenta
sho~m
is undamaged, the conditions predispose to mis.sed abortion. On
the basis of these findings, it was hypothesized that human
spontaneous missed abortion is due to fetal death and the conse-
quent changes in the hormone production of the relatively undam-
aged placenta. ]'or a time after fetal death, the myometrium
remains progesterone dominated (Stage 1), and effective activity
cannot develop. Sooner or later, placental hormone production
ceases; and bein.g devoid of both hormones, the myometrium is
"castrated" (or at least "non-pregnant") a.'1d unable to work
(Stage 2). Estrogen domination will not occur until the myo-
metrium is again stimulated by estrogen, either produced by the
ovaries or given therapeutically. The etiology provides a clue
to its treatment. In Stage 1. treatment with estrogen and oxy-
tocin has no effect. Destruction of placental function alone
(e.g. by intrauterine injection of hypertonic solution) removes
the progesterone block. Estrogens may be useful, though they
may not be necessary. Stage 2. estrogen alone usually starts
the abortion a.'1d surgical intervention is rarely necessary.
The validity of this theory of the etiology and treatment
of missed abortion was tested by these workers in thirteen con-
secutive patients. To accelerate abortion in seven of the thir-
teen patients, oxytocin was given as an I.V. drop. The purpose
of estrogen treatment in Stage 2 was to build up a potent
myometrium from a, IIcastrated" state and this necessarily
takes several days. The estrogen, therefore, should be con
tinued for 6 - 10 days. If abortion has not occurred after
ten days, the hormonal state should be rechecked.
Their hypothesis of missed abortion was supported by
the fact that two stages. characterized by different hormonal
condition, could be distinguished and that selected treatment
Was successful on all yatients.
Roland\oticed that almost all patients who aborted had
falling or 10'" urinary hormone excretion before the onset of
bleeding or other disturbances. When the preconceptional
endometrium showed poor premenstrual secretory activity and
urinary hormone excretions were correspondingly low, substi
tutional endocrine therapy during pregnancy appeared to salvage
a sizable percentage of pregnancies. When the preconceptional
endometrium sho1rled poor secretory and normal levels
~tctivity
of urinary hormone excretion, endocrine treatment during preg
nancy had no effect. When urinary hormone excretion levels,
particularly those of estrogen and pregnanediol were normal at
onset of bleeding, percentage of pregnancies with a favourable
outcome was much greater. Workers who feel that a considerable
percentage of spontaneous abortion is due to maternal factors.
have found hormone determinations of substantial importance.
6
3
Cassmer reported in 1959 that in therapeutic abortions
in mid-pregnancy he ruptured the membranes and pulled down
the umbilical cord, which was ligated and cut. The foetus
and the placenta were left in the uterus for three days and
then they were removed tll.l"ough the cervix. In these cases
with "isolated placentae" the urinary excretion of estrogens
decreased rapidly. Three days after fetal death the urinary
estrogens had fallen to )0% of their previous value, and the
estrogens in the placenta had disappeared. Some workers be-
Heve that the fetus may be responsible for estrogen pro-
duction. On the other hand, pregnanediol fell much less and
after three days, the output 'vas still 87% of the previous
value. During these three days no uterine activity was ob-
served. This indicates that if the foetus dies before the
placenta, the production of estrogen ceases before that of
progesterone. Because Cassmer removed the whole conceptus
after three days, we do not from his studies how rapidly
kno~l
and to what levels the production of estrogen and progesterone
may fall later.
When the fetus and placenta die simultaneously, as in
saline-induced abortions, the placental production of estro-
gen and progesterone falls rapidly and simultaneously. The
withdrawal of progesterone which affects only the excitability
of the myometrium, acts more quickly than does the withdrawal
of estrogens, which has the slower task of building up the
7