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Arrest of premature labor by isoxsuprine
Arrest of premature labor by isoxsuprine A.
I.
CSAPO”
St. Loub, J.
Missouri
HERCZEG
Swged,
Hungary
Thirty-six patients with clinical symptoms of premature labor of unidentified obstetric cause were admitted to the study group at 31 .O weeks 2 0.5 of gestation. At admission the patients had greater than five uterine contractions per 10 minutes, a Bishop score of greater than 5, and distinct progesterone deficiency, as compared to 137 women with normal pregnancy. After the 36 patients were divided into two groups, 19 treated with isoxsuprine and 17 with placebo, the obstetric status and endocrine profile of the experimental and control patients remained similar. Intravenous dextrose (placebo) administered during 24 hours, followed by oral treatment, did not arrest the further evolution of the clinical symptoms and the regulatory imbalance of the 17 control patients. Thus, 71 per cent of the gravid women were delivered of premature newborn infants weighing 1,654.2 grams 2 201.2 at 32.9 weeks ? 1 .O of gestation. This confirmed, in retrospect, the assessment that the study patients as selected at admission were at high risk of premature labor. Three premature infants were delivered with respiratory distress syndrome and four died within 46 hours after delivery. In contrast, isoxsuprine treatment arrested the evolution of clinical symptoms and corrected the regulatory imbalance in all 19 study patients. However, three gravid women (16 per cent) had relapses and were delivered at 34.3 weeks 2 1.2 of pregnancy of newborn infants who weighed 2,140.6 grams i- 181.5 and who showed normal development at six-week follow-up examination. The remaining 16 newborn infants were delivered at 38.7 weeks 2 0.5 of gestation with a birth weight of 3,106.3 grams it 122.3. While the isoxsuprine regimen did provoke hypotension and maternal and fetal tachycardia, these side effects did not demand the discontinuation of the carefully monitored treatment. Since the clinical outcome of the study was significantly different in the experimental and cqntrol patients, further and more extensive trials of this therapeutic regimen in the prevention of premature labor seem desirable. (AM. J. OBSTET. GYNECOL. 129: 482, 1977.)
PREMATURITY obstetricse3
IS the At
a recent
greatest
single
symposium
problem on
in
labor,
premature
Coordinator
reason
for
Rckwd
publrcation
March
18, 1977.
dl/r~ 31, 19;;.
Accepted June
Zuspan progress
concisely
formulated
the
in resolution:
The real issue is to identify the problem, i.e. which regulatory system is disturbed. If this were known, and it usually isn’t, a more rational approach to therapy could be achieved.
From the Departments of Obstetrics and Gynecology. Washington University School of Medicine, St. Louis, and Szeged Uniwrsity Medican &h&l, Szeged. Recei7vd,for
slow
In designing
15, 1977.
the
Reprint requests: Dr. A. I. Csapo, Defiartnwnt of Obstetrics and Gynecology Wo.&ng& Unir&y School of Medicine, 4911 Barnes HosPit& Plaza, St. Loui.\. iLfiaouri 631 IO.
premature earlier terone
*Research Career j4umrder of the National Institute of Child Health and Human Deuelobment, No. 5K6-HD-20, 169, Supported by km&t No. AIDicsd 3160 from The Agency for International Development, Department qf State.
482
the present
question
of the labor
studies’l, (P)
we limited in order
of unidentified
group. metic
Crediting compound
may the
to
trials,
[CC focused
disturbance
’ suggested
deficiency
ingly, tients
clinical
regulatory
obstetric that,
play
present examine
cause,
in its etiology, a pivotal
on
underlying
role.
since proges-
Accord-
trials to P-deficient paa presumably high-risk
the assessments”-” isoxsuprine suppresses
that the uterine.
/3-miactiv-
Arrest
l
of premature
labor
by isoxsuprine
483
. Normal
Pregnant
4
lsoxsuprine
f
Placebo
Q
MeanfS.E.
Group
/
Group
l t
Mean2S.E.
*
1
I
24
26
26
30
WEEKS
OF
32
I
1
34
36
GESTATION
Fig. 1. The circulating plasma progesterone levels of 137 normal pregnant control patients and 36 patients in premature labor before treatment. Note that all 36 study patients had less than normal progesterone levels and that this average value is significantly different (P < 0.001) from the control values.
ity
and
is probably
mature
labor
pressure tic..”
effective
and
(IUP)
that
which
WC formulated
in
the
the
treatment
evolution
triggers
of
of
prc-
intrauterine
parturition
is autocataly-
hypothesis
and
a working
tested
its
validitv. have
cental
assumed
P genesis
that
(signaled
only
predisposes
to premature
tion
of
activity
further
uterine promotes
utrroplacental
reduction
by partial
P vvithdra\val[
labor
flow
and
thus
also
assumed
ir process may time if placenta1
(RIA), the clinical
which,
that,
we
once
partial
Pw of the the
of Pw. reflected and verified by is suppressed
promotion
intercepted,
the evolu-
increases
activity might
Pvv] )
examined
degree labor
autocatalytic
in pla-
suppression
in turn.
uterine
progress
this
the
Therefore,
radioimmunoassay isoxsuprine
by
through
autocatalytically.
IUP
because
provoked
Pw blood
a transient
possibility that if at a moderate by the symptoms of premature by
and
veloped progressive
fetus
ture
of Pw
be arrested. this
This
contention that
could
when
P levels
increase
and
to unsuccessful the evolution
the
undeof the prema-
in
be substantiated
the precocious
in premature
contrast promotes
protect
severe consequences IUP, culminating
progress
labor
pregnancy
evolution are
arrested,
is maintained,
treatment, of IUP.
in
when continued Pw which terminates
pregnancy. Of
course,
we
also
considered
the isoxsuprine effect complicated by maternal as well
and
side
We
treatment
autocatalyt-
P levels
the of
and
the
effects
of prematurity Nevertheless, placebo-treated
in fetal
position
that
heart in
can be controlled according far before
the
is transient hypotension
as by decrease
adopted
remain arrested for various lengths of P genesis recovers from transient sup-
increasing
from evolution
observation
of IUP the
the
delivery.
by the
We
IUP
pression
opinion’“,
rate.”
by adjusting
outweigh the randomizing we first
I4 that
negligible and and tachycardia,
a monitored
to patient’s
patients,
or
tolerance,
However, trial, the
we when level
of
t.he hazards
risks of side the isoxsuprineobtained
is
effects. and
reassurance
484
Csapo
Table
and Herczeg
I. Obstetric
history’:
No. ?f
.1g”
Cc7sP.S Iso~s~lpri,lc-trpntrci
G?-CLZdO no.
Thrapr u tic a hortior2
24.5 1.1
30.7 0.6
2.2 0.3
0.8 0.2
0.2 0.1
0.2 0. 1
24.9 1.2
31.1 0.8
2.1 0.3
0.4 0.2
0.2 0.1
0.4 0. I
groupt
Plarrbo-treated
17
values here and elsewhere are means 2 S.E. placebo-treated patient had a previous premature
Table
II.
Bishop
Dilatatzon
delivery.
born
score
Effacrmr?lt
Consictmcy
Position
scorl’
Station
infants
weighing
facilitate
distinction
normal”
P levels,
Iso.rslSrine-treated
group
1.1 0.1
1.0 0.2
Plarcbo-treated
0.6 0.2
1.4
1.4
5.4
0.2
0.2
0.5
1.3 0.1
1.3 0.2
1.1 0.2
0.7 0.2
1.6
0.1
5.9 0.6
and
analyzed
for
of these
normal
ified
that
the level
only
effective,
of isoxsuprine but
treatment
is subjectively
employed
and
good
is not
the
obtained
persistent
therapeutic
prevention pilot study had
do not,
problem
of prematurity. exposed significant
encouraging
porting
so far
by Table
resolve
placebo-treated
patients
clinical
of
the
outcome,
we
predictable
tories.
since this and since it
pregnancies, spontaneous
considered
re-
desirable.
The
similar
abortion, two
the
Bishop
placebo-treated A total hospital
of with
unidentified the
common
effacement
40
study
patients symptoms
obstetric
cause.”
clinical
symptoms
and
dilatation
were
admitted
of premature All
gravid
of
and
or
the of
women
precocious
three
to labor
had
the
contrac-
cervical
ceeding are
dilatation
70 per
considered
exceeding
cent,
or
3 cm.,
ruptured
contraindications
effacement
membranes, for
are
those
who
are P deficient.
Thus,
while
admitted
to the
study,
mission had less than levels (Fig. 1). However, women outcome,
we selected
those
from the study group since three of them
did not affect were delivered
values several
the clinical of nelv-
rests
premature
the
isoxsuprine labor
tients
became randomized The
trial.
study
was mandatory
isoxsuprine OUS~Y with
at
isoxsupriue-
and
greater
than contrat-
that
these
pregnant
in premature,
labor.
in rctrospcc
(7 1 per small
tent)
I and
II)
rcflec
of the
employed
the
errors
lvithin
feasibility
L 1,) ill
standard
parameters
and
\vcre that
t small the
study,
two e.g.,
effectively
is subjectively
and
ar-
medically
first 13 patients were treated with isoxplacebo. However. after the efficacy of
were
treatment. P
statistics
uterine
(Tables
the
17 his-
illustrates
was verified
regimen
regimen
tients
at ad-
plasma pregnant
to estimate
the
acceptable, the suprine without
defined initially
36 who
normal peripheral the exclusion of four
so
the regu-
latory syndrome of “P deficiency” has not been quantitatively as yet, ofthe 40 pregnant women
mean
and
three
were
The
ok pa-
obstetric
similar:
rate
in the of patients.
that
the
0.5
group.
In order
Ear-
of
indicating i
prematurity
of the
II
than
assessment
excessive
variations groups
ex-
lier studies4 suggested that, in a group of patients selected, those who have the greatest risk of prematurity
minutes),
diagnostic
(S.E.)
which
treatment.3
10
verbased
groups
delivery
Table was also
at 3 1 .O weeks
placebo-treated
tions in 10 minutes, at a gestational age ranging from 26 to 36 weeks. However, none of the study patients had
in
lvomen This
cervical
more
tions
\\as
frequency of prc-vious and curettage and
term
of greater
rcliabilit)
19 isoxsuprine-
score’l
the and
the t\\ cntyand shot\ rd
comparable
groups.
patients
.5 (at a frequency
clinical
different
I, the
and
the
admission
Patients and procedures
literaturc.“~‘”
age, gestational age, elective dilatation
in
The
published
had
from
gestation
as controls,
the
of course,
Nevertheless, basic issues
of
by RI,4.16
among
tients. As illustrated
able. results
agreement
accept-
than
betrteen
of plasma P between weeks of gestation
medically
TCJ
“less
was collected women
to be used
with
analysis thirty-sixth
grams.
and
week
P (in replicates) values.
Z,.iOO
plasma pregnant
thirty-sixth
by comparison
on sequential fourth and
than “normal”
peripheral normal
tlventy-fourth
group
greater betlzeen
137 obstetrically
The
7-v, m drii7~r.r.~
Spontnnco,c~ abortion
group
19
*All t&e
Gestational agr (wk.)
(Jr.)
apparent,
the
before
remaining
isoxsuprine
of the placebo-treated since
the
efficacy
23 paor
placebo
control of the
pa-
present
regimen has not been documented preyireliable evidence. The nature of the clinical
of course,
was explained
to the
patients
and
their
Volume Number
129 5
consent
was obtained.
history
and
women and II),
were similar, the obstetric
Since
clinical
at admission
conditions
of the
the
obstetric
individual
in retrospective status of the two
(Tables remained
I
I
similar. Once
premature
labor
was diagnosed rest3
were
5 ml.
and
ruled
while
in the
dose
leas
m-emature
of 0.2
without
this
loading
of
infusion
rate
0.1 to 0.3 mg.
per
acute
clinical
symptoms
during
this
the
of
treatment
bias
also
two
to three
weeks,
unless
the
patient
Of
dextrose
During
the
initial
and each
before
P assays
in
collected
from
In
or
\ias
patients
at admission
and
137
137 normally
pregnant
plasma
this
392
control
women
she
P from Of
pregnant, for the
present
trial
at least
ng.
milliliter
per
mission
at
3 1.0
study
patients
P, in 121.8
comparison ng. rt 2.9
gravid normal ter spy
lower
than + 0.5
of
63.3
ng.
had
tveeks
determine before
and
initial
weeks only
per
the
with the milliliter
women w,ho were P levels, averaging
at 29.8 To
1) by having
i the during
P levels
control
values.
pregnancy, 2 4.9
per
10
ng.
treatment,
1.462.1
? 224.2
Dextrose
”
+ 9.1
12.1 +- 1.5
19.3 5 3.3 20.6 + 3.2
6.5 t 2.5* 7.3 +- 2.6*
25.6
8.3 + 3.07
were
+ 3.7
recorded
sequentially
was
Unfortunately, of IUP its magnitude
are
uterine
resolution,
well
be the most labor, the
external
technique
offers
rate
of rise.
since
and
and only
most
This
thus
deThis
rate by
of in-
descriptive
technical
pa-
limitation
advanced
informative
uterine
ac-
diagnostic
its accurate
intrauterine
re-
only
no quantitative
and
the
activity.
urgent
justify
and
patients, the
for the magnitude can be quantitated
monitoring,
might
for this
about
of may
used
by
rate was also a fetal heart
19 isoxsuprine-treated
frequency
trauterine
During hospitalization, placebo-treated patients privileges
within
insertion
sign
quantitation of a microsen-
both the isoxsuprinewere kept at bed rest;
the
acute
symptoms
three from
days without the hospital
hospital
subsided.
if
the
symptoms
recurred.
placebo
treatment,
whenever
spontaneously
therblood
or
were
If they
medication, with instructions
of
clinical
given
had they
diatrician
examined
at repeated
each intervals
*Model No. 111, Corometrics Haven, Connecticut.
or
inevitable
and the reconsulting pe-
infant hospitalization
Medical
for
ruptured
signaled
newborn during
the
isoxsuprine
membranes
progress
when
were discharged to call immediately
During the
and walking
no symptoms
premature labor, therapy was discontinued search team attended the delivery. The and
maternal
Dextrose
36
from the study had -+- 15.6 per millili-
the
? 203.8
ad-
milliliter
of isoxsuprine
Dextrose
1,188.Y
At
1.3 of pregnancy. acceptability
0.1
Dextrose
these
normal control value of (P < 0.001). Those four
excluded 125.8
0.2 2
sor.
study.
P assays.
rate
15 of the
of premature
38 were
these I37 patients, 132 were 26 to 36 weeks as were the 36 study patients who qualified (Fig.
Dextrose
80.2
+
is a serious limitation, rise of IUP, which
tivity
for
the
the
demands
hospital.
collected for
0.1
29.1
of IUP.
rameters
normal
from
w’ere
15.
samples had
Placebotreutrd group
+
instrument
information
sequential
samples,
excluded
485
0.6 2
272.9
heart
In
same
scribes
sample
the
who
samples
sam-
unless of
Isoxsuprinetreated group
clinical methods. The fetal heart externally with the use of
monitor.*
six-hour
12, and
plasma
patients
were
plasma
blood at
from
these
four
was
received
treatment,
392
and
routine monitored
symptoms
completion
discharged Of
those
addition,
the
pressure
delivered
cording
one
by isoxsuprine
*P < 0.01. tP < 0.001.
for
infusion
P assays
provided
replicate.
was
6, 9,
labor
to
lasted
of treatment,
during to
schedule
Loading, intravenous (mg/min.) Maintenance, intravenous (mgimin.) Total, intravenous infusion (mg.) Oral (mg.) ” Total, intravenous oral (mg.) Duration of trratmrnt Total i;travenous (hr.1 Total oral (days) Total, intravenous oral (days) Hospitalization (davs)
Oral
according
patients
provided
III. Treatment
Rose of compound
usually day.
clinical
at Days
prior
orally.
orally.
plasma
12 samples
40 study
levels
days
patient
collection
The
two
the
subsided
and
control and
for
study
delivered
blood
the
Since
per
intravenous
subsequently
and
was
course,
collected
intervals
If the
recurred.
intravenously
w.ere
Thus
therapy.
labor
of
treatment.
adjusted effects
reinitiated.
ples
times
side
despite
the the
level
labor
was given
individually
in
After
intravenous
four
the
progress
24 hours.
and
of premature
intrave-
maintenance
about
mg.
P
10 minutes,
premature of
rest, for
minute;
effects.
symptoms
prematurely
only
20
given
arrest
side
isoxsuprine
level
clinical
for of
ar-
vein
per
during
to the
period
at a dose the
serious dose
minute
initial
subsequently
was
to 1.0 mg.
was reduced
attempted
cubital
to
cause
was at bed
the
individually
labor
delivery
patient
from
isoxsuprine
range
adjusted
1
for
each
was collected
assay. Ifi Subsequently, nously
obstetric
contraindications
out,
of blood
of unidentified
of premature
gravid
analysis groups ”
Table
Arrest
Systems,
immediately and Inc ., North
at
486
Csapo
and Herczeg
2. The effect of isoxsuprine on intrauterine pressure. Original tracitlg illustrating that isoxsuprine reduces the frequency of’intranterine pressure. A rcdttction in the amplitude of‘ pressur-e is also indicated but not documented bv this tracing. since rhc iucr;intrrine pressure was monitowd by the external method. Fig.
Table
IV.
Effect
Table
of treatment
D&q Gestational age (wk.) Days to confinement Delayed by (days)
Imsuprinf~hated group
Plnwbo/watrd gro /I/J
38.7 -12.7 46.3
-50.9 13.6
32.9
k 0.5 + 3.9 + 6.6
+ 1.0* " 7.8* 5 5.6*
*P < 0.001. six
weeks
(before, post
post
partum)
and were
significant the
partum.
during,
All
and
relevant
treatment,
recorded
differences
isoxsuprine-
data
after
to the
trials
at delivery,
and
to determine
statistically
the
course
between placebo-treated
clinical
of
patients.
Results Table tories
I illustrates of
the
patients were ences between tional
age,
at admission
19 isoxsuprine-
and
similar. There the two groups frequency
taneous abortion, only one, in the premature Table
that
of
and term placebo-treated
delivery. II illustrates
that
the
obstetric
his-
17 placebo-treated
were no significant differof patients in age, gesta-
gravidity,
elective
or
spon-
delivery. Of the 36 patients group, had a previous at admission,
and
thus
at the
V. (Xnical
outs omc
.-I1 r/hwr nntl p\/ parrrr,,r
2.953.7
Fetal weight (Gtn.) Apgar score ( 1 min.) C~neucntful postnatal period (‘;i) Normal six-week f’ollc~w-np resulrs (%)
2 134.1
start
cervical
and
parable,
as reflected
and
the by
the
admission the obstetric status tients was similar, statistically their clinical ences in the ted
course efficacy
Fig. I illustrates between the
syndrome
conditions patients
components
similarity of this of the two significant
could be explained of treatment, that all the twenty-sixth
& 238.2" + 0.w 65$ 769
distress
placebo-treated
in the individual
7.3
100
deaths.
of treatment,
2.117.1
9.4 t 0.2 IO0
:‘:P < 0.0 I. :I’ < 0.05. ~‘l’hree Mith respiratory postpartum fetal deaths. $Four- postpartum fetal
suprine-
P/m ,4o/watrd pup
I\irs\rr/Jlr,,,‘fwtrd g,onp
and
of were
the
isox-
also
com-
in Bishop score.
four
score Since
at
groups of padifferences in only
36 study patients to thirty-sixth
by differadmitweek of
Volume Number-
129 5
Arrest
0A
CLINICAL
0 6
CLINICAL
OUTCOME
Duration Treatment
PLACEBO
of
of premature
labor
by isoxsuprine
487
OUTCOME
Duration of Treatment
Fetal We1ght.g
ISOXSUPRINE
+
Fetal Weight.g
t 14140) m [isool m ;2220: RDS
m
~RDS
m
71230:
12pJo1
Died
llpool
-
&
m 12800]
m yg
m 131401
-laao:
-12840] T
m m
RDS
sD,ed
:2180:
PREMATURE
mD,ed
PREMATURE
&
EDled
&
26
2.9
30
32
WEEKS
34
36
birth: (A) the placebo-treated placebo-treated group only patients (84 per cent) were
VI. Changes
38
40
42
26
28
OF GESTATION
Fig. 3. The onset and duration
Table
IUGR
in maternal
blood
30 32 34 36 WEEKS OF GESTATION
40
42
of treatment, the gestational time of delivery, and the fetal weight at patients and (BJ the isoxsuprine-treated patients. Note that in the five of 17 patients (29 per cent) while in the osoxsuprine group 16 of 19 delivered of newborn infants weighing greater than 2,500 grams.
pressure
and heart rate Before treattncnt
Plnwbwfreatcd group Systolic Diastolic Heart rate (brat.rlminute) lsoxsuprine-treated group Placebo-treated group
38
Dij’mnrl
/4ftpr twrrtmmi
120.9 2 1.7 79.1 2 1.8
112.8 72.6
+ 1.7 t 1.3
8.0 i 2.3* 6.5 t 2.1*
117.9 “_ 3.5 74.7 _’ 2.1
115.8 f 2.7 72.3 _t 1.6
2.1 t 2.0 2.3 t 1.I
93.0 2 2.1 88.7 5 2.1
10.9 t 2.9t 5.1 2 2.9
81.9 83.6
t 1.5 t 3.2
*P < 0.01. tP
pregnancy had lower than normal peripheral plasma P levels. At 31.0 ? 0.5 weeks of pregnancy, on the average, the 36 patients in premature labor had only 63.3 ng. -t 4.9 per milliliter of plasma P rather than the 121.8 ng. k 2.9 per milliliter measured in the normal control patients (P < 0.001). Table 111 illustrates the treatment schedule of the 19 isoxsuprine-treated patients and the 17 placebo-treated patients. During the initial period of 10 minutes, the isoxsuprine-treated patients received an average loading dose of 0.6 mg. + 0.1 per minute of this /3-mimetic drug. Subsequently, the infusion was re-
duced to the maintenance level of 0.2 mg. 2 0.1 per minute. The total dose received by infusion was 272.9 mg. 2 80.2 during 29.1 hours 2 9.1. This treatment schedule arrested premature labor in all the 19 Subsequently, isoxsuprine-treated gravid patients. these 19 patients received orally 1,188.g mg. 2 203.8 of drug (four x 20 mg. per day) during an average of 19.3
days
-C 3.3.
isoxsuprine days ? 3.2. isoxsuprine 12.1 hours
The
intravenous
and
oral
doses
of
totaled 1,462.l mg. ? 224.4 during 20.6 The placebo-treated patients received no but did receive dextrose intravenously for k 1.5 and orally for 6.5 days 2 2.5 during a
488
Csapo
Nwetnher
and Herczeg
grams
+- 122.3
contrast, Normal
i.
l
Controls,MeanfS.E.
lsoxsuprine
Treated
of
at
the
lcomen
were
greater
than
of
grams
the of‘
2,500
grams
grams
& 201.2
? 0.5
nelvborn
at 37.2
remaining
(the
average
at 32.9
weeks
it was 7 1 per
76
peI-
grams
cent
if
at birth
--+A@ (x932)
rity,
3 R.
in the
ficiency
@(31) t 7PD
Numbers over Symbols=Number of Plasmas Numbers( )=Geslational Age at Dellvery PO=Premature Delivery I I 1 I I , 1 4 6 6 10 12 14 16 16 20 DAYS AFTER TREATMENT
2
Assayes
low
IV
4. The effect of isoxsuprine on circulating plasma progesterone levels: In the placebo-treated group, the already 10~ progesterone levels decreased further before the patients were delivered prematurely. In contrast, in the isoxsuprinetreated group, the progesterone levels increased significantly (P < 0.001) during the initial two days of treatment and only those three pregnant women who were delivered prematurely, had a delayed reduction in progesterone levels. The level of progesterone at which premature delivery occurred increased with gestational age.
Fig.
that
thr
of
pregnancy the
labor
each
group
total treatment period of 7.3 days significant difference (P < 0.01) in the therapy labor
resulted in
the
from
the
placebo-treated
already
during
treatment.
The
external
recording
60
minutes
of
Fig. study.
per
of
in
(P < 0.001)
birth
weight
? 1.2
were
delivered 2.500
of
grams;
was 2,140.6
gestation. of
delivered less than The
newborn the
average
1.5
of
of the only
weight
of the
18 1.5 at 34.3
weighing
+ 6.6,
13.6
i- 5.6
The was bo
prematurely 2,500 grams; k
days
age
16 patients greater was 3,106.3
sign
with
specifies
the
which
in both
days
pregnancy
while days
the
? 3.9
the
grams
t
group The
group period
was uneventful the six-week
and follow-up
in the placebo-treated had respiratory distress
c~nlv
un-
datv
in dc1ayc.d
ihc, t)\
grcjup. that
134.1.
in
\\hile
of isox46.3
b) only
that
the
Apgar \vas
9.4
score
? 0.2, 7.3
avcrgrcjup plate-
the
2, I 17.1 grams
onl)
it was only the
of while
tcrtn.
in Tahlc V show the isoxsuprine-trcatcd
in the
in
surgi-
(P < 0.001).
one-minute
postnatal
oc-
36 pa-
patient
expcctcd
Apparentlv. labor M as
group
all
maintenance
before
the
average
was
isoxsuprine-treated
labor In
in the placebo-treated on
but.
maintained
before
(P < 0.001). group.
tht
IT O..i.
to be delivcrcd
was
2 7.8
reeks
in
but in ant’ had
promoted 12.7
\\cek
lab01
(P < 0.001).
fetus
isoxsuprine
days
thirty-fir\1
38.7
spontaneously,
It
of’ patients,
spontaneous
1.0
mature -
of therapy.
the
group, t
at the
growth
groups
spontaneous until
P derisk
to therapy.
effect
during
group weeks
that of high
intrauterine
further
the
salvage
gl.oup,
be related
started
in
low
isoxsuprinc-treated fetus
data presented fetal tveighr in
placebo-treated
deliv-
rate
This
indicates
cannot
until
2,9.53.7
cent.
group
In the
the
treated
salvage
is a diagnostic
started
(P < 0.01).
The
24 per
of one
placebo
til - 50.9
19
2).
remaining birth
initial
outcome patients,
grams
infants
instances the
\vith
the
(IUGR)
confinc.ment suprinr-treated
average rc2 0.5 to
(Fig.
3. A and B, illustrates the clinical Of the 19 isoxsuprine-treated
weeks than
during
revealed an 4.1 contractions
three gravid tvomen were newborn infants weighing average
in most
IUP
This of
of premature
infusion
patients from
10 minutes
incidence group,
intravenous
isoxsuprine-treated duction in frequency 1.0 It 0.2
high
2 2.6. duration
was only
prevented
Thus,
bron-
aftcl.
of. prcmatu-
treatment,
pregnancy
developed hours
prevention
at 32.9
tients
48
to 2.660
that
placebo-treated
curred
cally.
( the infant within
increases
weighing
in the
isoxsuprine-treated in
value
illustrates
average.
011
3).
effective
weight
Table sho\vs
(Fig.
be considered
labor.
birth
latter infant
placebo-treated
retardation
than l.6.54.2
cannot
at admission
premature
\\as
dextrose
patients
rate
\\crc’
group the prematuin the placebo-treated
This
died
intravenous
Fig.
control
t 6PD
0
Since
therapeutically
tJPD \4Continued Pregnancies
\
and
gesta-
less
i- 1 .O of gestation)
is included
was
of
l\omc’n
\\cight
a “borderline”
chopneumonia cry).
cent.
weighing
weighing
birth
five
\vcight
-t 1.2
gravid
infants
In
only
birth
weeks 12
newborn
gestation.
infants
average
Thus in the isoxsuprine-treated rity rate was 16 per cent, while group
of
patients,
(the
? 260.0
[Chile
delivered
weeks
delivered 2,500
3,228.0 grams tion),
38.7
17 placebo-treated
I, 1977 ~vnecol.
J. Ohstrr.
Am.
rvhilr
t 238.2 in
the in the
or 0.8 (P < 0.05).
isoxsuprine-treated
group
clinical status of the infants at study tvas normal. In contrast, group three syndrome,
newborn and four,
infants with an
Volume Number
129 9
average
Arrest
weight
of
after
birth.
48 hours Table
VI
ternal
blood pressure
(P > 0.05).
The
minute
group
heart
nute. werr
instance
reduced ing
isoxsuprine
of
6.0
z
per
0.8
beats
These actions heart rate were effects.
dose,
one
the
per
had
tetany,
infusion
a 10 minute
shortness
seventh
patient
had
transient
tion,
another shortness
day
of’oral
Two
had
patient
was
at
the
the relative (greater
to the
maintenance
episode
of
and
hyper-
facial
of oral
skin
medica-
dizziness,
on the episode
third
supervision,
mg.
per
minute
per
minute
of
minute)
days
after
membranes
when the
ruptured
70 per
cent
if the
Thus,
loading by
Thus,
oxytocin
treatment
was
discontinuation
of
uterine
infusion
was
These
of In
who
in
milliliter
escaped in P
probably from the
P levels
from
as early
as the
continued
before
milliliter
and
during
increments
(P < 0.001). treatment,
the
P levels labor
values.
In
who
were
sec-
statisti-
of the
week
those
closely
contrast,
16
approxP levels
delivered
treatment
the
were
By the second
the
premature
isoxsuprine
of
prematurely
decreased
during
the
of therapy to 86.0 ng. t 14.8 per milliliter to decrease to 74.5 ng. ? 0.5 per millilithe
at which
ically
evident
rapid
point
progress
of
in premature
interest
progress
is the
in premature
was higher
labor.
finding
that
labor
became
as gestation
An the
P
clin-
advanced.
under
dose
of 0.2
of 0.1
mg.
medica-
discontinued. treatment,
administered
value
(P < 0.01).
isoxsuprine-treated
increase
? 9.4 per
patients
level
activity
ng.
normal
three
effacement)
oral
This
escaped
the
those
additional
dose
followed
the
17 de-
reduction
increase
2 4.4 per
significant who
imated
was to be
ng.
isoxsuprine
IO minutes,
fetus
13 of
initial
no significant
of treatment.
despite
she received,
maintenance
but
113.2
highly
after
patient did not develop significant tachycarthe ninth day of isoxsuprine therapy (120
per
and
cally
premature
low
milliliter patients
contrast,
of treatment.
ter
of per
in
reached 96.6 ng. + 5.5 per milliliter during the day, 99.3 ng. 2 8.8 per milliliter during the first
symptoms
the minimum the
day
of Wolff-Parkinson-White
and
isoxsuprine,
first
and perdespite
Ivith
had
a pre-
by a further
already
a slight
2 4.8 to 73.7
week
gestation
the
+ 6.2 per
further
63.3
second week and continued
treatment
and
of
showed
ond
isoxsuprine-treated
contractions
prematurity.
In
patients
week,
description.
delivery
was preceded
placebo-treated
hospital.
of rest-
to isox-
brief
premature
delivery
P levels second
weakness,
patient,
week
three
immediate
constant
evolve.
admitted
dilatation,
from
TWO
the
unrelated
deserve
advanced
salvaged
tion. This dia until
pressure and by additional
that
of
grams.
levels during the period of observation and had an increase after they were discharged
patients
which
than
cervical
demanded
the
in the extremities, symptoms subsided
thirty-fourth
Her
2 tm.
premature
a transient
contraindication
syndrome. labor
placebo-
day
complications
treatment
group
in
she experi-
2,280
ng.
when patient
milliliter,
weighing
from
after and
later,
infant
in P levels those
per
re-
patient
pregnant
was delivered
2 4.9 to 33.4
contrast,
hours
36 weeks and
patients
was this
additional days. spontaneously
Twelve
this
thirtyopera-
treatment operation,
for seven ruptured of
the
to undergo
isoxsuprine
4 illustrates
increase
of treatment.
patients
suprine
beats
had
headache, tremor In all cases these
continuation
One
A third
medication.
lessness, spiration. the
of breath.
Fig.
of
isoxsuprineat
had
abdominal
labor
placebo-treated
average
of breath,
the
newborn
63.3
and
140 to ‘74 ng.
mature
crease dur-
minute.
of
During
is
substantiated change
and
* 0.5
rate
from
this
baby
another
appendicitis
gestation
P level
spontaneous
12 hours
preterm
of treatment,
pregnancy membranes
plasma
489
complication.
the
enced of
heart
maximum
hyperaetesia. and
fetal
was not
the
decreased
discontinuation
the
a normal
was discontinued.
hyin
after
of
operation,
maintained which the the
and
and
minute,
developed
Despite
mi-
changes
acceptable
minute
the
patient
ventilation,
maternal
per
day of
After
treatment
per
these
of isoxsuprine on blood occasionally accompanied
During
& 2.2
third
week
sumed.
by isoxsuprine
without
patient
tion.
Hg
beats
% 2.9
caused
was a slight
1.5
mm.
the
treated
labor
delivered
grams
fourth
placebo-treated
beats
therapy for
treatment
patients
the
” that
studies,
beats
treated
in 5.1
demand
contention
present
of 8 mu. was
On
de-
k 2.1 mm. patients,
10.9
However,
by isoxsuprine
by the
side
while
medically
they
The
level
2,840
average
isoxsuprine-treated by
only
and
did
treatment.
The
+ 1.4
the
tachycardia.
subjectively
no
in
‘isoxsuprine
and
the
on mapatients
treatment
was
Apparently,
potensicm
rate.
? 2.0/2.3
rate
during
increase
heart
2.1
(P < O.OOl),
the
within
of isoxsuprine
by 8.0 & 2.316.5 the placebo-treated
only
increased
died
isoxsuprine-treated
treatment while in by
-+ 513.2
effect and
of the
decreased
per
the
pressure
creased during Hg (P < 0.01).
group
grams
patient
describes
blood
it
1,122.j
of premature
the did
not at
Comment The validity
present of the
mature
labor
ficiency
plays
rected,
amplifies
clinical premises of
study that:
was designed to test the (1) in the etiology of pre-
unidentified
a pivotal the
role; risk
obstetric
of premature
partial evolution of- IUP generated Pw, which increases IUP autocatalytically; ture
labor
and
Pw are
cause,
(2) moderate
recognized
P de-
Pw, if uncorlabor,
further
at an early
since
the
promotes (3) if premastage,
they
490
Csapo
and Herczeg
can be corrected for
if this
evolution
presumably (4)
by intercepting
the
process
progresses
by suppressing
once
the
evolution recovers
from
facilitate
are
suppression
pregnancy
it promotes of
Pw
placenta]
and
the
flow;
and
by
the
preclinical tively
evolution
and
clinical
suppressed
and
who
clinical
criteria
normal
peripheral
pregnant ceived
were
isoxsuprine
and
II).
this of
could
also
the
treatment
similar,
the differences
in the
variable clinical
ly
in
IUP. IUP
order
to
After
the
was
given
treatment
thus,
only
16 per
cent
in of
infants,
weighing
1,462.
2.140
84 per
cent
the
and + 181 .j
rate
However,
the
observed
salient
point
observation that, while the mission in the placebo-treated cent
of the
treatment
patients rapidly
t 224.2
of the
cases;
infants
were
in
al]
the
prior
three
high
have salvage
with the 24 per placebo-treated
of the present already group
the
at birth,
This
centi is to be contrasted
rate (84 per cent salvage group.
study
is the
low P levels at adfurther decreased to premature
elevated
the
P levels
labor,
tannot
can
can
the be
for trial
tan
isoxsuprine safely
of
and this
shwvcd
drug
provide
use is safe.
reassul-ant
treated
neously
and
reported
efftzc.tively
in
em-
administered
labor cent
frequency
I .G placebo-
women.
at first orally,
In
this
was arrested
indicates
reliablr
which
increases
confidence
then
in 80 per group.
criteria in the
for
1.5 twsubc-uta-
compound cent
in contrast
As in our labor
<‘areIvith
expcrimcntal
p-mimetic
premature
group
and
the
intravenously,
with
in the control of
e,
prcscntl\-
conditions.
gravid
patients,
it
the judicious
regimen
and
hospital
, did
arrrstcd.
isoxsuprinc
trials
label
predictably
monitored future
results
to 20 per
out
problem
While this study was being evaluated, another fully conducted clinical trial has been pub]ished.2Y similar
of
of only 36 g-t-avid in addition to the
premature
be
compound
that routine
action
be rlllcd
therapeutic
a rationale
a carefully
under
that
inc rwscd
in patient
therapeutic
studv. the
the
control sclcc lion, success
of treatment. The authors are grateful to Professor M. Sas of the Department of Obstetrics and Gynecology, University of Szeged Medical School, Hungary, for his continued interest and constructive comments during the conduct of this study at his clinic. Our thanks are also due to Drs. 1. Morvay and B. Resch of this clinic and Dr. T. Erdos of Centre Nationale Kecherche Scientifique, France, for repeated consultations and radioimmunoassays and to R. M. and E. I?. Csapo for the processing and analysis of the data and illustrations. The supply of isoxsuprine hydrochloride (Vasodilan) and placebo provided by the Mead Johnson Research C:enter, Evansville, Indiana, is appreciated.
and
REFERENCES I.
labor
extensive
ployed
high
three premature newseven days after ab-
course.
in
of’
outstanding
p-mimetic
premature the
successfully
newborn
grams
postnatal
I mg.
? 2.3,
(appendectomy).
an uneventful
stopped, Isoxsuprine,
days
However, of these one 1~~s delivered
operation
isoxsuprine
of
20.6
labor
advanced
was
treatment.
dose
for
dominal
in 76 per
precociously
oral
average
admission. intravenous-
labor
by
premature
premature. born infants,
the
symptoms
the
butaline-treated
administered
premature
administered
stopped
had
suppress
suppressed
at a total
and
was
out-
by a direct
P grnesis
provided
however. I
leaving
known
come of the two groups of‘ patients. During the initial 24 hours following isoxsuprine
19 re(Tables
clinical
the
Only
it is conceivable
factor.
premature
that
36
regulatory
only
of
delayed
isoxsuprinc
mediated
while the present pilot study characterized by P deficiency
resolve
had
Since
although
flojv.
on placental
nevertheless
by less than
and
remained
not
by
placebo
clinical
as the
only
groups;
P levels blood
classical how
1). These
two
of IUP. \\.a~
Thus. women.
patients
not
(Fig.
17 received
division.
explain
but
into
of the patients
efficacy
which
II)
study
P levels
divided
and
After
characteristics the
I and
the
women labor.
in
in-
subjectively
of 36 study
for
plasma
was
gravid
the evolution
increase
isoxsuprine
effec-
the
the
as a contributing
in an earlier
of
to premature
did intercept
the for
compound
and
A total
qualified
(Tables
women
this
activity
acceptable.
selected
because
study”
uterine
medically
M’ere
of IUP,
cent
prior
uteroplacental
P levels
prohibiting
precocious activation of the myometrium. The p-mimetic drug istrxsuprine was selected tercepting
the
P synthesis
increasing
maintenance
16 per
relapses
Pw
blood
promotion
intercepted,
only
of IUP,
uteroplacenta]
autocatalytic
of IUP
evolution
Hellman, L. M., and Pritchard, J. A.: In Williams’ Obstetrics, edi. 14, New York, 1971. Appleton-Century-Crofts, p. 526. 2. Reid, D. E., Ryan. K. J., and Benirschke. K.: III Principles and Management of Human Reproduction. Philadelphia, 1972, W. B. Saunders Company, p. 867.
Zuspan, F. P.: J. Reprod. Med. 9: 93, 1972. 4. Csapo. A. I.. Pohanka, 0.. and Kaihola, H. L.: Lancet 2: 1097, 1973. 5. Bishop, E. H.. and Woutersz, 7‘. B.: J. A. M. A. 178: 812, 1961. 6. Hendricks, C. H., Cibils. L. A., Pose, S. V.. and Eskes. T. K. A. B.: AM. J. OBSTET. GYNECOL. 82: 1064. 1961. 3.
\‘olume Number
129 5
7. Kelly, J. V.: Obstet. Gynecol. 17: 579, 1961. 8. Bravo. A. A., Serene, I. A.. Hidalgo, T. J., Guerra, L. N., Srrrano, A. A., and Arenas, A. E.: Obstet. Ginecol. Lat. Am. 1: 111, 1962. 9. Stander, R. W., Barden, T. P., Thompson, J. F., Pugh, W. R., and Werts. C. E.: AM. J, OBSTET. GYNECOI.. 89: 792,
Arrest
16.
17. 18.
1964. IO. 11. 12. 13. 14. 15.
Castren, O., Gummerus, M., and Saarikoski, S.: Acta Obsret. Gynecol. Stand. 54: 95, 1975. <:sapo, A. I., Herczeg. J., Pitkanen, Y.. and Pulkkinen, M. 0.: Obstet. Gynecol. 46: 58, 1975. Csapo. A. I.: In Laki. K., editor: Contractile Proteins and Muscles, New York, 1971. Marcel Dekker, Inc., p. 413. (Campbell, C.: AM. J. OBSTET. GYNECOL. 91: 580. 1965. Taubert. H. D.. and Haskins, A. L.: Md. State Med. J. 10: 346. 1961. Eastman, N. .J.. and Hellman. L. M.: In Williams’ Obstetrics, ed. 13. New York, 1966, Meredith Publishing Co.
19.
20. 21. 22.
of premature
labor
by isoxsuprine
491
Jaffe, B. M., and Behrman, H. R.: In Methods of Hormone Radioimmunoassay, New York, 1974. Academic Press, Inc., p. 19. Csapo, A. I.: Knobil. E., van der Molen, H. J., and Wiest, W. G.: AM. J. OBSTET. GYNECOL. 110: 630, 1971. Turnbull. A. C., Flint, A. P. F., Jeremy, J. Y., Patten, P. T., Keirse. M. J. N. C., and Anderson, A. B. M.: Lancet 1: 101, 1974. Batra, S.. Bengtsson, L. P., Grundsell, H.. and Sjoberg, N.-O.: J. Clin. Endocrinol. Metab. 42: 1041. 1976. Chew, P. C. T., and Ratnam, S. S.:.J. Endocrinol. 69: 163, 1976. Vakhariya, V. R., and Sherman, A. I.: AM. J. OBSTET. GYNECOL. 113: 212, 1972. Ingemarsson, I.: AM. J. OBSTET. GYNECOL. 125: 520,
1976.
I.
CSAPO”
St. Loub, J.
Missouri
HERCZEG
Swged,
Hungary
Thirty-six patients with clinical symptoms of premature labor of unidentified obstetric cause were admitted to the study group at 31 .O weeks 2 0.5 of gestation. At admission the patients had greater than five uterine contractions per 10 minutes, a Bishop score of greater than 5, and distinct progesterone deficiency, as compared to 137 women with normal pregnancy. After the 36 patients were divided into two groups, 19 treated with isoxsuprine and 17 with placebo, the obstetric status and endocrine profile of the experimental and control patients remained similar. Intravenous dextrose (placebo) administered during 24 hours, followed by oral treatment, did not arrest the further evolution of the clinical symptoms and the regulatory imbalance of the 17 control patients. Thus, 71 per cent of the gravid women were delivered of premature newborn infants weighing 1,654.2 grams 2 201.2 at 32.9 weeks ? 1 .O of gestation. This confirmed, in retrospect, the assessment that the study patients as selected at admission were at high risk of premature labor. Three premature infants were delivered with respiratory distress syndrome and four died within 46 hours after delivery. In contrast, isoxsuprine treatment arrested the evolution of clinical symptoms and corrected the regulatory imbalance in all 19 study patients. However, three gravid women (16 per cent) had relapses and were delivered at 34.3 weeks 2 1.2 of pregnancy of newborn infants who weighed 2,140.6 grams i- 181.5 and who showed normal development at six-week follow-up examination. The remaining 16 newborn infants were delivered at 38.7 weeks 2 0.5 of gestation with a birth weight of 3,106.3 grams it 122.3. While the isoxsuprine regimen did provoke hypotension and maternal and fetal tachycardia, these side effects did not demand the discontinuation of the carefully monitored treatment. Since the clinical outcome of the study was significantly different in the experimental and cqntrol patients, further and more extensive trials of this therapeutic regimen in the prevention of premature labor seem desirable. (AM. J. OBSTET. GYNECOL. 129: 482, 1977.)
PREMATURITY obstetricse3
IS the At
a recent
greatest
single
symposium
problem on
in
labor,
premature
Coordinator
reason
for
Rckwd
publrcation
March
18, 1977.
dl/r~ 31, 19;;.
Accepted June
Zuspan progress
concisely
formulated
the
in resolution:
The real issue is to identify the problem, i.e. which regulatory system is disturbed. If this were known, and it usually isn’t, a more rational approach to therapy could be achieved.
From the Departments of Obstetrics and Gynecology. Washington University School of Medicine, St. Louis, and Szeged Uniwrsity Medican &h&l, Szeged. Recei7vd,for
slow
In designing
15, 1977.
the
Reprint requests: Dr. A. I. Csapo, Defiartnwnt of Obstetrics and Gynecology Wo.&ng& Unir&y School of Medicine, 4911 Barnes HosPit& Plaza, St. Loui.\. iLfiaouri 631 IO.
premature earlier terone
*Research Career j4umrder of the National Institute of Child Health and Human Deuelobment, No. 5K6-HD-20, 169, Supported by km&t No. AIDicsd 3160 from The Agency for International Development, Department qf State.
482
the present
question
of the labor
studies’l, (P)
we limited in order
of unidentified
group. metic
Crediting compound
may the
to
trials,
[CC focused
disturbance
’ suggested
deficiency
ingly, tients
clinical
regulatory
obstetric that,
play
present examine
cause,
in its etiology, a pivotal
on
underlying
role.
since proges-
Accord-
trials to P-deficient paa presumably high-risk
the assessments”-” isoxsuprine suppresses
that the uterine.
/3-miactiv-
Arrest
l
of premature
labor
by isoxsuprine
483
. Normal
Pregnant
4
lsoxsuprine
f
Placebo
Q
MeanfS.E.
Group
/
Group
l t
Mean2S.E.
*
1
I
24
26
26
30
WEEKS
OF
32
I
1
34
36
GESTATION
Fig. 1. The circulating plasma progesterone levels of 137 normal pregnant control patients and 36 patients in premature labor before treatment. Note that all 36 study patients had less than normal progesterone levels and that this average value is significantly different (P < 0.001) from the control values.
ity
and
is probably
mature
labor
pressure tic..”
effective
and
(IUP)
that
which
WC formulated
in
the
the
treatment
evolution
triggers
of
of
prc-
intrauterine
parturition
is autocataly-
hypothesis
and
a working
tested
its
validitv. have
cental
assumed
P genesis
that
(signaled
only
predisposes
to premature
tion
of
activity
further
uterine promotes
utrroplacental
reduction
by partial
P vvithdra\val[
labor
flow
and
thus
also
assumed
ir process may time if placenta1
(RIA), the clinical
which,
that,
we
once
partial
Pw of the the
of Pw. reflected and verified by is suppressed
promotion
intercepted,
the evolu-
increases
activity might
Pvv] )
examined
degree labor
autocatalytic
in pla-
suppression
in turn.
uterine
progress
this
the
Therefore,
radioimmunoassay isoxsuprine
by
through
autocatalytically.
IUP
because
provoked
Pw blood
a transient
possibility that if at a moderate by the symptoms of premature by
and
veloped progressive
fetus
ture
of Pw
be arrested. this
This
contention that
could
when
P levels
increase
and
to unsuccessful the evolution
the
undeof the prema-
in
be substantiated
the precocious
in premature
contrast promotes
protect
severe consequences IUP, culminating
progress
labor
pregnancy
evolution are
arrested,
is maintained,
treatment, of IUP.
in
when continued Pw which terminates
pregnancy. Of
course,
we
also
considered
the isoxsuprine effect complicated by maternal as well
and
side
We
treatment
autocatalyt-
P levels
the of
and
the
effects
of prematurity Nevertheless, placebo-treated
in fetal
position
that
heart in
can be controlled according far before
the
is transient hypotension
as by decrease
adopted
remain arrested for various lengths of P genesis recovers from transient sup-
increasing
from evolution
observation
of IUP the
the
delivery.
by the
We
IUP
pression
opinion’“,
rate.”
by adjusting
outweigh the randomizing we first
I4 that
negligible and and tachycardia,
a monitored
to patient’s
patients,
or
tolerance,
However, trial, the
we when level
of
t.he hazards
risks of side the isoxsuprineobtained
is
effects. and
reassurance
484
Csapo
Table
and Herczeg
I. Obstetric
history’:
No. ?f
.1g”
Cc7sP.S Iso~s~lpri,lc-trpntrci
G?-CLZdO no.
Thrapr u tic a hortior2
24.5 1.1
30.7 0.6
2.2 0.3
0.8 0.2
0.2 0.1
0.2 0. 1
24.9 1.2
31.1 0.8
2.1 0.3
0.4 0.2
0.2 0.1
0.4 0. I
groupt
Plarrbo-treated
17
values here and elsewhere are means 2 S.E. placebo-treated patient had a previous premature
Table
II.
Bishop
Dilatatzon
delivery.
born
score
Effacrmr?lt
Consictmcy
Position
scorl’
Station
infants
weighing
facilitate
distinction
normal”
P levels,
Iso.rslSrine-treated
group
1.1 0.1
1.0 0.2
Plarcbo-treated
0.6 0.2
1.4
1.4
5.4
0.2
0.2
0.5
1.3 0.1
1.3 0.2
1.1 0.2
0.7 0.2
1.6
0.1
5.9 0.6
and
analyzed
for
of these
normal
ified
that
the level
only
effective,
of isoxsuprine but
treatment
is subjectively
employed
and
good
is not
the
obtained
persistent
therapeutic
prevention pilot study had
do not,
problem
of prematurity. exposed significant
encouraging
porting
so far
by Table
resolve
placebo-treated
patients
clinical
of
the
outcome,
we
predictable
tories.
since this and since it
pregnancies, spontaneous
considered
re-
desirable.
The
similar
abortion, two
the
Bishop
placebo-treated A total hospital
of with
unidentified the
common
effacement
40
study
patients symptoms
obstetric
cause.”
clinical
symptoms
and
dilatation
were
admitted
of premature All
gravid
of
and
or
the of
women
precocious
three
to labor
had
the
contrac-
cervical
ceeding are
dilatation
70 per
considered
exceeding
cent,
or
3 cm.,
ruptured
contraindications
effacement
membranes, for
are
those
who
are P deficient.
Thus,
while
admitted
to the
study,
mission had less than levels (Fig. 1). However, women outcome,
we selected
those
from the study group since three of them
did not affect were delivered
values several
the clinical of nelv-
rests
premature
the
isoxsuprine labor
tients
became randomized The
trial.
study
was mandatory
isoxsuprine OUS~Y with
at
isoxsupriue-
and
greater
than contrat-
that
these
pregnant
in premature,
labor.
in rctrospcc
(7 1 per small
tent)
I and
II)
rcflec
of the
employed
the
errors
lvithin
feasibility
L 1,) ill
standard
parameters
and
\vcre that
t small the
study,
two e.g.,
effectively
is subjectively
and
ar-
medically
first 13 patients were treated with isoxplacebo. However. after the efficacy of
were
treatment. P
statistics
uterine
(Tables
the
17 his-
illustrates
was verified
regimen
regimen
tients
at ad-
plasma pregnant
to estimate
the
acceptable, the suprine without
defined initially
36 who
normal peripheral the exclusion of four
so
the regu-
latory syndrome of “P deficiency” has not been quantitatively as yet, ofthe 40 pregnant women
mean
and
three
were
The
ok pa-
obstetric
similar:
rate
in the of patients.
that
the
0.5
group.
In order
Ear-
of
indicating i
prematurity
of the
II
than
assessment
excessive
variations groups
ex-
lier studies4 suggested that, in a group of patients selected, those who have the greatest risk of prematurity
minutes),
diagnostic
(S.E.)
which
treatment.3
10
verbased
groups
delivery
Table was also
at 3 1 .O weeks
placebo-treated
tions in 10 minutes, at a gestational age ranging from 26 to 36 weeks. However, none of the study patients had
in
lvomen This
cervical
more
tions
\\as
frequency of prc-vious and curettage and
term
of greater
rcliabilit)
19 isoxsuprine-
score’l
the and
the t\\ cntyand shot\ rd
comparable
groups.
patients
.5 (at a frequency
clinical
different
I, the
and
the
admission
Patients and procedures
literaturc.“~‘”
age, gestational age, elective dilatation
in
The
published
had
from
gestation
as controls,
the
of course,
Nevertheless, basic issues
of
by RI,4.16
among
tients. As illustrated
able. results
agreement
accept-
than
betrteen
of plasma P between weeks of gestation
medically
TCJ
“less
was collected women
to be used
with
analysis thirty-sixth
grams.
and
week
P (in replicates) values.
Z,.iOO
plasma pregnant
thirty-sixth
by comparison
on sequential fourth and
than “normal”
peripheral normal
tlventy-fourth
group
greater betlzeen
137 obstetrically
The
7-v, m drii7~r.r.~
Spontnnco,c~ abortion
group
19
*All t&e
Gestational agr (wk.)
(Jr.)
apparent,
the
before
remaining
isoxsuprine
of the placebo-treated since
the
efficacy
23 paor
placebo
control of the
pa-
present
regimen has not been documented preyireliable evidence. The nature of the clinical
of course,
was explained
to the
patients
and
their
Volume Number
129 5
consent
was obtained.
history
and
women and II),
were similar, the obstetric
Since
clinical
at admission
conditions
of the
the
obstetric
individual
in retrospective status of the two
(Tables remained
I
I
similar. Once
premature
labor
was diagnosed rest3
were
5 ml.
and
ruled
while
in the
dose
leas
m-emature
of 0.2
without
this
loading
of
infusion
rate
0.1 to 0.3 mg.
per
acute
clinical
symptoms
during
this
the
of
treatment
bias
also
two
to three
weeks,
unless
the
patient
Of
dextrose
During
the
initial
and each
before
P assays
in
collected
from
In
or
\ias
patients
at admission
and
137
137 normally
pregnant
plasma
this
392
control
women
she
P from Of
pregnant, for the
present
trial
at least
ng.
milliliter
per
mission
at
3 1.0
study
patients
P, in 121.8
comparison ng. rt 2.9
gravid normal ter spy
lower
than + 0.5
of
63.3
ng.
had
tveeks
determine before
and
initial
weeks only
per
the
with the milliliter
women w,ho were P levels, averaging
at 29.8 To
1) by having
i the during
P levels
control
values.
pregnancy, 2 4.9
per
10
ng.
treatment,
1.462.1
? 224.2
Dextrose
”
+ 9.1
12.1 +- 1.5
19.3 5 3.3 20.6 + 3.2
6.5 t 2.5* 7.3 +- 2.6*
25.6
8.3 + 3.07
were
+ 3.7
recorded
sequentially
was
Unfortunately, of IUP its magnitude
are
uterine
resolution,
well
be the most labor, the
external
technique
offers
rate
of rise.
since
and
and only
most
This
thus
deThis
rate by
of in-
descriptive
technical
pa-
limitation
advanced
informative
uterine
ac-
diagnostic
its accurate
intrauterine
re-
only
no quantitative
and
the
activity.
urgent
justify
and
patients, the
for the magnitude can be quantitated
monitoring,
might
for this
about
of may
used
by
rate was also a fetal heart
19 isoxsuprine-treated
frequency
trauterine
During hospitalization, placebo-treated patients privileges
within
insertion
sign
quantitation of a microsen-
both the isoxsuprinewere kept at bed rest;
the
acute
symptoms
three from
days without the hospital
hospital
subsided.
if
the
symptoms
recurred.
placebo
treatment,
whenever
spontaneously
therblood
or
were
If they
medication, with instructions
of
clinical
given
had they
diatrician
examined
at repeated
each intervals
*Model No. 111, Corometrics Haven, Connecticut.
or
inevitable
and the reconsulting pe-
infant hospitalization
Medical
for
ruptured
signaled
newborn during
the
isoxsuprine
membranes
progress
when
were discharged to call immediately
During the
and walking
no symptoms
premature labor, therapy was discontinued search team attended the delivery. The and
maternal
Dextrose
36
from the study had -+- 15.6 per millili-
the
? 203.8
ad-
milliliter
of isoxsuprine
Dextrose
1,188.Y
At
1.3 of pregnancy. acceptability
0.1
Dextrose
these
normal control value of (P < 0.001). Those four
excluded 125.8
0.2 2
sor.
study.
P assays.
rate
15 of the
of premature
38 were
these I37 patients, 132 were 26 to 36 weeks as were the 36 study patients who qualified (Fig.
Dextrose
80.2
+
is a serious limitation, rise of IUP, which
tivity
for
the
the
demands
hospital.
collected for
0.1
29.1
of IUP.
rameters
normal
from
w’ere
15.
samples had
Placebotreutrd group
+
instrument
information
sequential
samples,
excluded
485
0.6 2
272.9
heart
In
same
scribes
sample
the
who
samples
sam-
unless of
Isoxsuprinetreated group
clinical methods. The fetal heart externally with the use of
monitor.*
six-hour
12, and
plasma
patients
were
plasma
blood at
from
these
four
was
received
treatment,
392
and
routine monitored
symptoms
completion
discharged Of
those
addition,
the
pressure
delivered
cording
one
by isoxsuprine
*P < 0.01. tP < 0.001.
for
infusion
P assays
provided
replicate.
was
6, 9,
labor
to
lasted
of treatment,
during to
schedule
Loading, intravenous (mg/min.) Maintenance, intravenous (mgimin.) Total, intravenous infusion (mg.) Oral (mg.) ” Total, intravenous oral (mg.) Duration of trratmrnt Total i;travenous (hr.1 Total oral (days) Total, intravenous oral (days) Hospitalization (davs)
Oral
according
patients
provided
III. Treatment
Rose of compound
usually day.
clinical
at Days
prior
orally.
orally.
plasma
12 samples
40 study
levels
days
patient
collection
The
two
the
subsided
and
control and
for
study
delivered
blood
the
Since
per
intravenous
subsequently
and
was
course,
collected
intervals
If the
recurred.
intravenously
w.ere
Thus
therapy.
labor
of
treatment.
adjusted effects
reinitiated.
ples
times
side
despite
the the
level
labor
was given
individually
in
After
intravenous
four
the
progress
24 hours.
and
of premature
intrave-
maintenance
about
mg.
P
10 minutes,
premature of
rest, for
minute;
effects.
symptoms
prematurely
only
20
given
arrest
side
isoxsuprine
level
clinical
for of
ar-
vein
per
during
to the
period
at a dose the
serious dose
minute
initial
subsequently
was
to 1.0 mg.
was reduced
attempted
cubital
to
cause
was at bed
the
individually
labor
delivery
patient
from
isoxsuprine
range
adjusted
1
for
each
was collected
assay. Ifi Subsequently, nously
obstetric
contraindications
out,
of blood
of unidentified
of premature
gravid
analysis groups ”
Table
Arrest
Systems,
immediately and Inc ., North
at
486
Csapo
and Herczeg
2. The effect of isoxsuprine on intrauterine pressure. Original tracitlg illustrating that isoxsuprine reduces the frequency of’intranterine pressure. A rcdttction in the amplitude of‘ pressur-e is also indicated but not documented bv this tracing. since rhc iucr;intrrine pressure was monitowd by the external method. Fig.
Table
IV.
Effect
Table
of treatment
D&q Gestational age (wk.) Days to confinement Delayed by (days)
Imsuprinf~hated group
Plnwbo/watrd gro /I/J
38.7 -12.7 46.3
-50.9 13.6
32.9
k 0.5 + 3.9 + 6.6
+ 1.0* " 7.8* 5 5.6*
*P < 0.001. six
weeks
(before, post
post
partum)
and were
significant the
partum.
during,
All
and
relevant
treatment,
recorded
differences
isoxsuprine-
data
after
to the
trials
at delivery,
and
to determine
statistically
the
course
between placebo-treated
clinical
of
patients.
Results Table tories
I illustrates of
the
patients were ences between tional
age,
at admission
19 isoxsuprine-
and
similar. There the two groups frequency
taneous abortion, only one, in the premature Table
that
of
and term placebo-treated
delivery. II illustrates
that
the
obstetric
his-
17 placebo-treated
were no significant differof patients in age, gesta-
gravidity,
elective
or
spon-
delivery. Of the 36 patients group, had a previous at admission,
and
thus
at the
V. (Xnical
outs omc
.-I1 r/hwr nntl p\/ parrrr,,r
2.953.7
Fetal weight (Gtn.) Apgar score ( 1 min.) C~neucntful postnatal period (‘;i) Normal six-week f’ollc~w-np resulrs (%)
2 134.1
start
cervical
and
parable,
as reflected
and
the by
the
admission the obstetric status tients was similar, statistically their clinical ences in the ted
course efficacy
Fig. I illustrates between the
syndrome
conditions patients
components
similarity of this of the two significant
could be explained of treatment, that all the twenty-sixth
& 238.2" + 0.w 65$ 769
distress
placebo-treated
in the individual
7.3
100
deaths.
of treatment,
2.117.1
9.4 t 0.2 IO0
:‘:P < 0.0 I. :I’ < 0.05. ~‘l’hree Mith respiratory postpartum fetal deaths. $Four- postpartum fetal
suprine-
P/m ,4o/watrd pup
I\irs\rr/Jlr,,,‘fwtrd g,onp
and
of were
the
isox-
also
com-
in Bishop score.
four
score Since
at
groups of padifferences in only
36 study patients to thirty-sixth
by differadmitweek of
Volume Number-
129 5
Arrest
0A
CLINICAL
0 6
CLINICAL
OUTCOME
Duration Treatment
PLACEBO
of
of premature
labor
by isoxsuprine
487
OUTCOME
Duration of Treatment
Fetal We1ght.g
ISOXSUPRINE
+
Fetal Weight.g
t 14140) m [isool m ;2220: RDS
m
~RDS
m
71230:
12pJo1
Died
llpool
-
&
m 12800]
m yg
m 131401
-laao:
-12840] T
m m
RDS
sD,ed
:2180:
PREMATURE
mD,ed
PREMATURE
&
EDled
&
26
2.9
30
32
WEEKS
34
36
birth: (A) the placebo-treated placebo-treated group only patients (84 per cent) were
VI. Changes
38
40
42
26
28
OF GESTATION
Fig. 3. The onset and duration
Table
IUGR
in maternal
blood
30 32 34 36 WEEKS OF GESTATION
40
42
of treatment, the gestational time of delivery, and the fetal weight at patients and (BJ the isoxsuprine-treated patients. Note that in the five of 17 patients (29 per cent) while in the osoxsuprine group 16 of 19 delivered of newborn infants weighing greater than 2,500 grams.
pressure
and heart rate Before treattncnt
Plnwbwfreatcd group Systolic Diastolic Heart rate (brat.rlminute) lsoxsuprine-treated group Placebo-treated group
38
Dij’mnrl
/4ftpr twrrtmmi
120.9 2 1.7 79.1 2 1.8
112.8 72.6
+ 1.7 t 1.3
8.0 i 2.3* 6.5 t 2.1*
117.9 “_ 3.5 74.7 _’ 2.1
115.8 f 2.7 72.3 _t 1.6
2.1 t 2.0 2.3 t 1.I
93.0 2 2.1 88.7 5 2.1
10.9 t 2.9t 5.1 2 2.9
81.9 83.6
t 1.5 t 3.2
*P < 0.01. tP
pregnancy had lower than normal peripheral plasma P levels. At 31.0 ? 0.5 weeks of pregnancy, on the average, the 36 patients in premature labor had only 63.3 ng. -t 4.9 per milliliter of plasma P rather than the 121.8 ng. k 2.9 per milliliter measured in the normal control patients (P < 0.001). Table 111 illustrates the treatment schedule of the 19 isoxsuprine-treated patients and the 17 placebo-treated patients. During the initial period of 10 minutes, the isoxsuprine-treated patients received an average loading dose of 0.6 mg. + 0.1 per minute of this /3-mimetic drug. Subsequently, the infusion was re-
duced to the maintenance level of 0.2 mg. 2 0.1 per minute. The total dose received by infusion was 272.9 mg. 2 80.2 during 29.1 hours 2 9.1. This treatment schedule arrested premature labor in all the 19 Subsequently, isoxsuprine-treated gravid patients. these 19 patients received orally 1,188.g mg. 2 203.8 of drug (four x 20 mg. per day) during an average of 19.3
days
-C 3.3.
isoxsuprine days ? 3.2. isoxsuprine 12.1 hours
The
intravenous
and
oral
doses
of
totaled 1,462.l mg. ? 224.4 during 20.6 The placebo-treated patients received no but did receive dextrose intravenously for k 1.5 and orally for 6.5 days 2 2.5 during a
488
Csapo
Nwetnher
and Herczeg
grams
+- 122.3
contrast, Normal
i.
l
Controls,MeanfS.E.
lsoxsuprine
Treated
of
at
the
lcomen
were
greater
than
of
grams
the of‘
2,500
grams
grams
& 201.2
? 0.5
nelvborn
at 37.2
remaining
(the
average
at 32.9
weeks
it was 7 1 per
76
peI-
grams
cent
if
at birth
--+A@ (x932)
rity,
3 R.
in the
ficiency
@(31) t 7PD
Numbers over Symbols=Number of Plasmas Numbers( )=Geslational Age at Dellvery PO=Premature Delivery I I 1 I I , 1 4 6 6 10 12 14 16 16 20 DAYS AFTER TREATMENT
2
Assayes
low
IV
4. The effect of isoxsuprine on circulating plasma progesterone levels: In the placebo-treated group, the already 10~ progesterone levels decreased further before the patients were delivered prematurely. In contrast, in the isoxsuprinetreated group, the progesterone levels increased significantly (P < 0.001) during the initial two days of treatment and only those three pregnant women who were delivered prematurely, had a delayed reduction in progesterone levels. The level of progesterone at which premature delivery occurred increased with gestational age.
Fig.
that
thr
of
pregnancy the
labor
each
group
total treatment period of 7.3 days significant difference (P < 0.01) in the therapy labor
resulted in
the
from
the
placebo-treated
already
during
treatment.
The
external
recording
60
minutes
of
Fig. study.
per
of
in
(P < 0.001)
birth
weight
? 1.2
were
delivered 2.500
of
grams;
was 2,140.6
gestation. of
delivered less than The
newborn the
average
1.5
of
of the only
weight
of the
18 1.5 at 34.3
weighing
+ 6.6,
13.6
i- 5.6
The was bo
prematurely 2,500 grams; k
days
age
16 patients greater was 3,106.3
sign
with
specifies
the
which
in both
days
pregnancy
while days
the
? 3.9
the
grams
t
group The
group period
was uneventful the six-week
and follow-up
in the placebo-treated had respiratory distress
c~nlv
un-
datv
in dc1ayc.d
ihc, t)\
grcjup. that
134.1.
in
\\hile
of isox46.3
b) only
that
the
Apgar \vas
9.4
score
? 0.2, 7.3
avcrgrcjup plate-
the
2, I 17.1 grams
onl)
it was only the
of while
tcrtn.
in Tahlc V show the isoxsuprine-trcatcd
in the
in
surgi-
(P < 0.001).
one-minute
postnatal
oc-
36 pa-
patient
expcctcd
Apparentlv. labor M as
group
all
maintenance
before
the
average
was
isoxsuprine-treated
labor In
in the placebo-treated on
but.
maintained
before
(P < 0.001). group.
tht
IT O..i.
to be delivcrcd
was
2 7.8
reeks
in
but in ant’ had
promoted 12.7
\\cek
lab01
(P < 0.001).
fetus
isoxsuprine
days
thirty-fir\1
38.7
spontaneously,
It
of’ patients,
spontaneous
1.0
mature -
of therapy.
the
group, t
at the
growth
groups
spontaneous until
P derisk
to therapy.
effect
during
group weeks
that of high
intrauterine
further
the
salvage
gl.oup,
be related
started
in
low
isoxsuprinc-treated fetus
data presented fetal tveighr in
placebo-treated
deliv-
rate
This
indicates
cannot
until
2,9.53.7
cent.
group
In the
the
treated
salvage
is a diagnostic
started
(P < 0.01).
The
24 per
of one
placebo
til - 50.9
19
2).
remaining birth
initial
outcome patients,
grams
infants
instances the
\vith
the
(IUGR)
confinc.ment suprinr-treated
average rc2 0.5 to
(Fig.
3. A and B, illustrates the clinical Of the 19 isoxsuprine-treated
weeks than
during
revealed an 4.1 contractions
three gravid tvomen were newborn infants weighing average
in most
IUP
This of
of premature
infusion
patients from
10 minutes
incidence group,
intravenous
isoxsuprine-treated duction in frequency 1.0 It 0.2
high
2 2.6. duration
was only
prevented
Thus,
bron-
aftcl.
of. prcmatu-
treatment,
pregnancy
developed hours
prevention
at 32.9
tients
48
to 2.660
that
placebo-treated
curred
cally.
( the infant within
increases
weighing
in the
isoxsuprine-treated in
value
illustrates
average.
011
3).
effective
weight
Table sho\vs
(Fig.
be considered
labor.
birth
latter infant
placebo-treated
retardation
than l.6.54.2
cannot
at admission
premature
\\as
dextrose
patients
rate
\\crc’
group the prematuin the placebo-treated
This
died
intravenous
Fig.
control
t 6PD
0
Since
therapeutically
tJPD \4Continued Pregnancies
\
and
gesta-
less
i- 1 .O of gestation)
is included
was
of
l\omc’n
\\cight
a “borderline”
chopneumonia cry).
cent.
weighing
weighing
birth
five
\vcight
-t 1.2
gravid
infants
In
only
birth
weeks 12
newborn
gestation.
infants
average
Thus in the isoxsuprine-treated rity rate was 16 per cent, while group
of
patients,
(the
? 260.0
[Chile
delivered
weeks
delivered 2,500
3,228.0 grams tion),
38.7
17 placebo-treated
I, 1977 ~vnecol.
J. Ohstrr.
Am.
rvhilr
t 238.2 in
the in the
or 0.8 (P < 0.05).
isoxsuprine-treated
group
clinical status of the infants at study tvas normal. In contrast, group three syndrome,
newborn and four,
infants with an
Volume Number
129 9
average
Arrest
weight
of
after
birth.
48 hours Table
VI
ternal
blood pressure
(P > 0.05).
The
minute
group
heart
nute. werr
instance
reduced ing
isoxsuprine
of
6.0
z
per
0.8
beats
These actions heart rate were effects.
dose,
one
the
per
had
tetany,
infusion
a 10 minute
shortness
seventh
patient
had
transient
tion,
another shortness
day
of’oral
Two
had
patient
was
at
the
the relative (greater
to the
maintenance
episode
of
and
hyper-
facial
of oral
skin
medica-
dizziness,
on the episode
third
supervision,
mg.
per
minute
per
minute
of
minute)
days
after
membranes
when the
ruptured
70 per
cent
if the
Thus,
loading by
Thus,
oxytocin
treatment
was
discontinuation
of
uterine
infusion
was
These
of In
who
in
milliliter
escaped in P
probably from the
P levels
from
as early
as the
continued
before
milliliter
and
during
increments
(P < 0.001). treatment,
the
P levels labor
values.
In
who
were
sec-
statisti-
of the
week
those
closely
contrast,
16
approxP levels
delivered
treatment
the
were
By the second
the
premature
isoxsuprine
of
prematurely
decreased
during
the
of therapy to 86.0 ng. t 14.8 per milliliter to decrease to 74.5 ng. ? 0.5 per millilithe
at which
ically
evident
rapid
point
progress
of
in premature
interest
progress
is the
in premature
was higher
labor.
finding
that
labor
became
as gestation
An the
P
clin-
advanced.
under
dose
of 0.2
of 0.1
mg.
medica-
discontinued. treatment,
administered
value
(P < 0.01).
isoxsuprine-treated
increase
? 9.4 per
patients
level
activity
ng.
normal
three
effacement)
oral
This
escaped
the
those
additional
dose
followed
the
17 de-
reduction
increase
2 4.4 per
significant who
imated
was to be
ng.
isoxsuprine
IO minutes,
fetus
13 of
initial
no significant
of treatment.
despite
she received,
maintenance
but
113.2
highly
after
patient did not develop significant tachycarthe ninth day of isoxsuprine therapy (120
per
and
cally
premature
low
milliliter patients
contrast,
of treatment.
ter
of per
in
reached 96.6 ng. + 5.5 per milliliter during the day, 99.3 ng. 2 8.8 per milliliter during the first
symptoms
the minimum the
day
of Wolff-Parkinson-White
and
isoxsuprine,
first
and perdespite
Ivith
had
a pre-
by a further
already
a slight
2 4.8 to 73.7
week
gestation
the
+ 6.2 per
further
63.3
second week and continued
treatment
and
of
showed
ond
isoxsuprine-treated
contractions
prematurity.
In
patients
week,
description.
delivery
was preceded
placebo-treated
hospital.
of rest-
to isox-
brief
premature
delivery
P levels second
weakness,
patient,
week
three
immediate
constant
evolve.
admitted
dilatation,
from
TWO
the
unrelated
deserve
advanced
salvaged
tion. This dia until
pressure and by additional
that
of
grams.
levels during the period of observation and had an increase after they were discharged
patients
which
than
cervical
demanded
the
in the extremities, symptoms subsided
thirty-fourth
Her
2 tm.
premature
a transient
contraindication
syndrome. labor
placebo-
day
complications
treatment
group
in
she experi-
2,280
ng.
when patient
milliliter,
weighing
from
after and
later,
infant
in P levels those
per
re-
patient
pregnant
was delivered
2 4.9 to 33.4
contrast,
hours
36 weeks and
patients
was this
additional days. spontaneously
Twelve
this
thirtyopera-
treatment operation,
for seven ruptured of
the
to undergo
isoxsuprine
4 illustrates
increase
of treatment.
patients
suprine
beats
had
headache, tremor In all cases these
continuation
One
A third
medication.
lessness, spiration. the
of breath.
Fig.
of
isoxsuprineat
had
abdominal
labor
placebo-treated
average
of breath,
the
newborn
63.3
and
140 to ‘74 ng.
mature
crease dur-
minute.
of
During
is
substantiated change
and
* 0.5
rate
from
this
baby
another
appendicitis
gestation
P level
spontaneous
12 hours
preterm
of treatment,
pregnancy membranes
plasma
489
complication.
the
enced of
heart
maximum
hyperaetesia. and
fetal
was not
the
decreased
discontinuation
the
a normal
was discontinued.
hyin
after
of
operation,
maintained which the the
and
and
minute,
developed
Despite
mi-
changes
acceptable
minute
the
patient
ventilation,
maternal
per
day of
After
treatment
per
these
of isoxsuprine on blood occasionally accompanied
During
& 2.2
third
week
sumed.
by isoxsuprine
without
patient
tion.
Hg
beats
% 2.9
caused
was a slight
1.5
mm.
the
treated
labor
delivered
grams
fourth
placebo-treated
beats
therapy for
treatment
patients
the
” that
studies,
beats
treated
in 5.1
demand
contention
present
of 8 mu. was
On
de-
k 2.1 mm. patients,
10.9
However,
by isoxsuprine
by the
side
while
medically
they
The
level
2,840
average
isoxsuprine-treated by
only
and
did
treatment.
The
+ 1.4
the
tachycardia.
subjectively
no
in
‘isoxsuprine
and
the
on mapatients
treatment
was
Apparently,
potensicm
rate.
? 2.0/2.3
rate
during
increase
heart
2.1
(P < O.OOl),
the
within
of isoxsuprine
by 8.0 & 2.316.5 the placebo-treated
only
increased
died
isoxsuprine-treated
treatment while in by
-+ 513.2
effect and
of the
decreased
per
the
pressure
creased during Hg (P < 0.01).
group
grams
patient
describes
blood
it
1,122.j
of premature
the did
not at
Comment The validity
present of the
mature
labor
ficiency
plays
rected,
amplifies
clinical premises of
study that:
was designed to test the (1) in the etiology of pre-
unidentified
a pivotal the
role; risk
obstetric
of premature
partial evolution of- IUP generated Pw, which increases IUP autocatalytically; ture
labor
and
Pw are
cause,
(2) moderate
recognized
P de-
Pw, if uncorlabor,
further
at an early
since
the
promotes (3) if premastage,
they
490
Csapo
and Herczeg
can be corrected for
if this
evolution
presumably (4)
by intercepting
the
process
progresses
by suppressing
once
the
evolution recovers
from
facilitate
are
suppression
pregnancy
it promotes of
Pw
placenta]
and
the
flow;
and
by
the
preclinical tively
evolution
and
clinical
suppressed
and
who
clinical
criteria
normal
peripheral
pregnant ceived
were
isoxsuprine
and
II).
this of
could
also
the
treatment
similar,
the differences
in the
variable clinical
ly
in
IUP. IUP
order
to
After
the
was
given
treatment
thus,
only
16 per
cent
in of
infants,
weighing
1,462.
2.140
84 per
cent
the
and + 181 .j
rate
However,
the
observed
salient
point
observation that, while the mission in the placebo-treated cent
of the
treatment
patients rapidly
t 224.2
of the
cases;
infants
were
in
al]
the
prior
three
high
have salvage
with the 24 per placebo-treated
of the present already group
the
at birth,
This
centi is to be contrasted
rate (84 per cent salvage group.
study
is the
low P levels at adfurther decreased to premature
elevated
the
P levels
labor,
tannot
can
can
the be
for trial
tan
isoxsuprine safely
of
and this
shwvcd
drug
provide
use is safe.
reassul-ant
treated
neously
and
reported
efftzc.tively
in
em-
administered
labor cent
frequency
I .G placebo-
women.
at first orally,
In
this
was arrested
indicates
reliablr
which
increases
confidence
then
in 80 per group.
criteria in the
for
1.5 twsubc-uta-
compound cent
in contrast
As in our labor
<‘areIvith
expcrimcntal
p-mimetic
premature
group
and
the
intravenously,
with
in the control of
e,
prcscntl\-
conditions.
gravid
patients,
it
the judicious
regimen
and
hospital
, did
arrrstcd.
isoxsuprinc
trials
label
predictably
monitored future
results
to 20 per
out
problem
While this study was being evaluated, another fully conducted clinical trial has been pub]ished.2Y similar
of
of only 36 g-t-avid in addition to the
premature
be
compound
that routine
action
be rlllcd
therapeutic
a rationale
a carefully
under
that
inc rwscd
in patient
therapeutic
studv. the
the
control sclcc lion, success
of treatment. The authors are grateful to Professor M. Sas of the Department of Obstetrics and Gynecology, University of Szeged Medical School, Hungary, for his continued interest and constructive comments during the conduct of this study at his clinic. Our thanks are also due to Drs. 1. Morvay and B. Resch of this clinic and Dr. T. Erdos of Centre Nationale Kecherche Scientifique, France, for repeated consultations and radioimmunoassays and to R. M. and E. I?. Csapo for the processing and analysis of the data and illustrations. The supply of isoxsuprine hydrochloride (Vasodilan) and placebo provided by the Mead Johnson Research C:enter, Evansville, Indiana, is appreciated.
and
REFERENCES I.
labor
extensive
ployed
high
three premature newseven days after ab-
course.
in
of’
outstanding
p-mimetic
premature the
successfully
newborn
grams
postnatal
I mg.
? 2.3,
(appendectomy).
an uneventful
stopped, Isoxsuprine,
days
However, of these one 1~~s delivered
operation
isoxsuprine
of
20.6
labor
advanced
was
treatment.
dose
for
dominal
in 76 per
precociously
oral
average
admission. intravenous-
labor
by
premature
premature. born infants,
the
symptoms
the
butaline-treated
administered
premature
administered
stopped
had
suppress
suppressed
at a total
and
was
out-
by a direct
P grnesis
provided
however. I
leaving
known
come of the two groups of‘ patients. During the initial 24 hours following isoxsuprine
19 re(Tables
clinical
the
Only
it is conceivable
factor.
premature
that
36
regulatory
only
of
delayed
isoxsuprinc
mediated
while the present pilot study characterized by P deficiency
resolve
had
Since
although
flojv.
on placental
nevertheless
by less than
and
remained
not
by
placebo
clinical
as the
only
groups;
P levels blood
classical how
1). These
two
of IUP. \\.a~
Thus. women.
patients
not
(Fig.
17 received
division.
explain
but
into
of the patients
efficacy
which
II)
study
P levels
divided
and
After
characteristics the
I and
the
women labor.
in
in-
subjectively
of 36 study
for
plasma
was
gravid
the evolution
increase
isoxsuprine
effec-
the
the
as a contributing
in an earlier
of
to premature
did intercept
the for
compound
and
A total
qualified
(Tables
women
this
activity
acceptable.
selected
because
study”
uterine
medically
M’ere
of IUP,
cent
prior
uteroplacental
P levels
prohibiting
precocious activation of the myometrium. The p-mimetic drug istrxsuprine was selected tercepting
the
P synthesis
increasing
maintenance
16 per
relapses
Pw
blood
promotion
intercepted,
only
of IUP,
uteroplacenta]
autocatalytic
of IUP
evolution
Hellman, L. M., and Pritchard, J. A.: In Williams’ Obstetrics, edi. 14, New York, 1971. Appleton-Century-Crofts, p. 526. 2. Reid, D. E., Ryan. K. J., and Benirschke. K.: III Principles and Management of Human Reproduction. Philadelphia, 1972, W. B. Saunders Company, p. 867.
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19.
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by isoxsuprine
491
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