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Intra-amniotic administration of prostaglandin F2α to induce therapeutic abortion
Ma-amniotic
administration of prostaglandin
F,, to induce therapeutic abortion Efficacy and tolerance
of two dosage schedules
W.
M.D.
E.
BRENNER,
C.
H.
J.
T.
BRAAKSMA,
M.D.
J,
I.
FISHBURNE,
JR.,
F.
G.
KRONCKE,
L.
STAUROVSKY,
Chapel
HENDRICKS,
Hill,
North
M.D.
JR.,
M.D. M.D.
C.N.M. Carolina
Forty-one physically healthy gravid women between 13 and 20 weeks’ gestation were treated with intra-amniotic injections of prostaglandin in FI,(PGF+J by one of two dosage schedules to induce therapeutic abortion. The results were compared over a 48 hour period. In one group, 15 mg. of PGFs. was injected initially, and this dose was repeated after 24 hours in those patients who failed to abort. In the second group 25 mg. of PGF,. was administered by the same schedule. The results obtained by this latter method were superior to those achieved by either the 15 mg. schedule or by hypertonic saline instillation. Patients premeditated with prochlorperatine had less vomiting. Multiparous patients had higher rates of abortion and aborted in a significantly shorter period of time than nulliparous patients. Although the 25 mg. dosage schedule is more effective than hypertonic saline instillation, it is likely that still more effective intra-amniotic schedules will be developed.
B E c A u s E of the occasional serious complications and the prolonged time required to accomplish abortions with hypertonic From the Department Gynecology, University Carolina.
of Obstetrics of North
saline, the intra-amniotic administration of prostaglandin F,, (PGF,,) is being investigated. Other investigator@ have reported variable efficacy in a total of 49 patients over different periods of time with the use of different dosages. This is a report of a comparison of the efficacy and tolerance of intra-amniotic dosage schedules 2 PGF,a within a 48 hour period of observation.
and
This work was supported in part by grants from the National Institute of Child Health and Human Development (HD-04148-03), The General Research Centers, Program of the Division of Research Sources, National Institutes of Health (RR-46). and the International Fertility Research Program of the Carolina Population Center of the University of North Carolina (AID/csd 2979. The Upjohn Company supplied prostaglandin and financial assitance. Received for publication May 30,1972. Accepted
for
publication
June
Material
and methods Prostaglandin F,,, 5 mg. per milliliter diluent, was injected through a polyethylene catheter* which was inserted through an 18 gauge thin-wall needle into the clear amniotic cavity by either the transabdominal or transvaginal approach. One of two dos-
20, 1972.
Reprint requests: Dr. W. E. Brenner, Dept. of Ob./Gyn., The University of North Carolina, Chapel Hill, North Carolina 27514.
‘Becton VXOZO.
781
Dickinson
&
Co.,
Rutherford,
New
Jersey,
782
Brenner
November
et al.
Table I. Summary
Am.
of the 41 patients’
characteristics
in the various 25
Characteristics
15
mg.
Group
J. Obstet.
groups mg.
A
Group B
Total
20
10
11
21
Age (yr.) Mean Range
21.1 18-27
23.1 18-38
21.5 18-27
22.3 18-38
Race (No.) Negro Caucasian
6 14
5 5
5 6
10 11
Parity (No.) Nulliparas Multiparas
12 8
6 4
8 3
14 7
16.1 14-18
16.4 14-20
16.3 14-m
16 4
7 3
8 3
l:j 6
57.1 44-79
56.3 50-77
60.9 48-69
58.7 48-77
64.6 52-70
63.0 61-65
64.5 59-69
Patients
Gestation Mean Range
(No.)
(weeks) 16.8 14-20
Marital status Single Married Weight Mean Range Height
(No.)
(Kg.)
(inches)
Mean Range Twenty patients planned PGFa (25 mg. Group A); amniotic administration of
to be initially treated with 15 mg. of PGFza 11 patients were premed&ted with 10 mg. PGFza (25 mg. Group B).
age schedules was used if tolerated: (1) 5 mg. of PGF,, was injected at 10 minute intervals to a total dose of 15 mg. at the initiation of the study in 20 patients, with an identical dose 24 hours later if abortion had not occurred (15 mg. group) ; (2) 5 mg. was injected at 10 minute intervals to a total initial dose of 25 mg. in 21 subjects and repeated after 24 hours to those who had not yet aborted (25 mg. group). The first 10 patients of this group of 21 subjects were not premeditated (25 mg. Group A). However, because nausea and vomiting were frequent, the final 11 patients were premedicated with 10 mg. of prochlorperazine,* administered intramuscularly, 15 minutes prior to the initial injection and before the repeat injection at 24 hours (25 mg. Group *Compazinr, brand of prochlorperazine, 10 mg. per cubic wntimeter. Smith, Kline & Fwnch Labs., Philadelphia, Pennsyl~arria.
1; i!liL’ (;vncr-:~i
(15 mg. group); of intramuscular
10 patients were prochlorperazine
-
63.8 59-69 treated with 25 mg. prior to the intra-
R) . If abortion did not occur within 48 hours after the initial injection, the trial was declared a failure. In the Clinical Research Unit of North Carolina Memorial Hospital at the University of North Carolina, 41 physically healthy women between 13 and 20 weeks’ gestation had PGF,, administered to them bj one of these 2 dosage schedules to induce therapeutic abortion. There were no significant differences in the patients’ characteristics between the groups (Table I). For comparative purposes, the abortion times of 200 patients who had 200 ml. of 20 per cent hypertonic saline instilled intra-amniotically were determined. Patients were monitored for vital signs and a variety of hematologic and chemical parameters. As noted, the following parameters were monitored before initial injrction and at hourly intervals until 12 hours
Volume Number
114 6
Intra-amniotic
Table II. Abortifacient 15 mg. of PGF,,
results administered
of 20 patients planned intra-amniotically
Results Abortions (No.) Complete Incomplete Mean time (hr.) Range (hr.) Failure I No. I Tw,o
patients
were
treated
after
24
hours
A 10
Patients (No.) Abortions (No.) Complete Incomplete Mean time (hr.) Range (hr. ) Failure (No. ) zinc
Ten patients administered
treated
abortion
783
with Total < 48 hr.
2 2 19.0 15.6-21.5 16
7 3 31.6 25.8-46.4 4
9 5 28 15.6-46.4 4
by alternate
management
initially
< 24 hr. Group 1 B JA+B 11 21
5 3 2 1 15.3 13.5 6.6-20.0 4.8-16.8 3 7
therapeutic
14 Patients 24-48 hr.
results of 21 patients intra-amniotically
Results
to be initially
for
20 Patients < 24 hr.
Table III. Abortifacient administered
PGFza
8 3 14.6 4.8-20.0 10
were not premeditated (25 mg. Group intramuscularly (25 mg. Group B).
as described
treated
1 4 2 1 31.0 36.1 24.5-35.3 30.2-42.6 0 2
after abortion or to the end of the trial: blood pressure by stethoscope and sphygmomanometer, heart rate by palpation, and temperature by oral thermometer. Blood was obtained for tests of hematopoietic, liver, and renal toxicity before the initial injection, 6 hours after this injection, and at the time of abortion or at 48 hours if no abortion occurred. The Mann-Whitney test was used to determine significance. Results
Administration of 15 mg. of PGF,,. Within the initial 24 hour period, 4 of the women aborted, 2 completely (Table II). At the onset of the second 24 hour period, 2 of the remaining 16 patients received alternate management that was not according to the plan. One subject’s amniotic fluid was grossly bloody, and repeated injection was considered unsafe; therefore, the abortion was successfully completed by a 9.4 hour intravenous infusion of PGF,, at 50 ,ug per minute. In the other subject, it became advis-
with
25 mg. of PGF2,
24-48 hr. Group ( B IA+B 7 10
A 3
A),
in the text.
while
11 patients
5 3 34.2 24.5-42.6 2 were
< 48 hr. Groufi 1 B 1 A+B 11 21
A 10 6 4 20.0 6.6-35.3 0
premeditated
with
7 2 26.1 4.8-42.6 2
13 6 22.9 4.8-42.6 2
10 mg. of prochlorpera-
able, for nonmedical indications, to inject 250 ml. of 20 per cent saline solution intraamniotically at the end of 24 hours; this woman completely aborted 19.8 hours later. Of the 14 women who were reinjected with 10 aborted within the sec15 mg. of PGF,,, ond 24 hour period. Thus, of the 20 women in whom the original study design was initiated, 14 (70 per cent) aborted within the 48 hour observation period while being managed within the stipulated plan. Administration of 25 mg. of PGF,,. During the 24 hours following the initial injection, 11 patients aborted, 8 completely (Table III). Ten subjects were reinjecte.d at 24 hours, and 8 of these aborted within the second 24 hour period of observation. Thus, within the 48 hour observation period, 19 of 21 patients (90 per cent) aborted. Although both failures occurred in Group B and the mean abortion time was 6.1 hours longer, no statistically significant differences were noted in the number of patients aborting or between the mean abortion times of
784
Brenner
et al.
s o 90P a 80K z 0 i
7060-
g 507 a Y 405
30-
: I =
20io0
4
8
12
16
20 24 28 32 36 40 44 48 TIME (Hrs) Fig. 1. The cumulative abortion rates (per cent) resulting from intra-amniotically administered medication during the observation time in hours for: ( 1) 21 patients receiving an initial dosr of 25 mg. PGF2,, (2) 20 subjects planned to be injected with an initial dose of 15 mg. of PGFi,, and (3) 200 patients who received 200 ml. of 20 per cent saline solutions.
Table IV. Incidence and severity of the complications observed in 41 patients treated with the intra-amniotic administration of either 15 mg. or 25 mg. of PGF,, without (25 mg. Group A), and with (25 mg. Group B) premeditation with 10 mg. prochlorperazine 25
~Complications Pain (%) Mean No. Range Emesis (70) Mean No. Range
15mg.j
A
mg. /
B
doses
70 1.6 O-.5
60 1.2 o-3
36 0.9 o-4
episodes
40 0.6 o-4
50 1.9 O-8
27 0.8 o-7
10 o-3 10 35 :i 0
30 O-2 10 0 0 0
100 I-2 0 0 0 9
Antiemetic (70) Range Blood loss >500 (%) Fever > 100” F. ( %.) Bronchoconstriction (% 1 Diarrhea (%) ’ ’
patients not premeditated (25 mg. Group A) and those premeditated with prochlorperazine (25 mg. Group B) . The cumulative abortion rates are compared in Fig. 1. No difference was noted between the cumulative abortion rates duri,ng the initial 48 hours for patients receiving hypertonic saline and those receiving 15 mg.
of PGF,,. Within 72 hours, 97 per cent of the patients given hypertonic saline aborted. More than one half of the patients injected with 25 mg. of PGF,, had aborted by 24 hours, while it was only after 32 hours that this rate was achieved in subjects receiving hypertonic saline or 15 mg. of PGF,,. A comparison of the incidence of complications between the 2 schedules ( 15 mg. group and 25 mg. Groups A and B‘I is summarized in Table IV. Although the numbers are too small to be expressed statistically as percentages because the numbers of patients are different in each group; the incidences arc expressed in percentages so that they may be more easily compared. No differences were noted in the incidencrs or scverity of pain, vomiting, or blood loss between the 15 mg. group and the 25 mg. Group A. The only apparent differcbnce bctween these 2 groups was in the incidence of fever (temperature > ZOO’ F.) . Five subjects had fever and one had bronchospasm in the 15 rqg. group, while neither of these complications was observed in the 25 mg. groups. There was no definite evidence that the f’ever was associated with intrauterine infection. However, because most patients clevehped fevers late in the course of the abortion. this
Volume Number
114 6
Intro-amniotic
ioo-
I ,
PGFza
Multipora
/O
for
therapeutic
abortion
785
(25mg)
705 ~60CO2 w40 ?30s g 205 2 IO-
,’ sl : I : I’ I
0
4
I
8
I
I
16 20 24 28 TIME(Hrs) Pig. 2. The cumulative abortion rate (per cent) nulliparous and multiparous patients resulting from either 15 mg. or 25 mg. of PGF2, with an identical not occurred. possibility must be considered. Only one patient developed fever in the first 24 hour period, while four subjects became febrile subsequently. When patients were premeditated with prochlorperazine, the frequency and incidence of vomiting decreased by one half. Although one patient had 7 episodes of vomiting, no additional antiemetic was administered because the onset of nausea was rapid and no nausea was complained of after each episode of vomiting. One patient had an episode of diarrhea. Fewer patients received pain medication (meperidine) with fewer doses per abortion when they were premeditated with prochlorperazine. Effect of parity. Multiparous patients aborted more frequently and in a shorter period of time than did nulliparous patients managed on the same protocol plan. In the 15 mg. group, 6 of 7 multiparous patients aborted with a mean time of 22.1 hours compared with 8 of the 11 nulliparous patients who aborted with a mean time of 32.3 hours. Likewise, when 25 mg. was administered, all 7 multiparous patients aborted (mean = 14.9 hours) and only 12 of 14 nulliparous patients aborted (mean = 27.5 hours). Over all, 13 of 15 multiparous patients
1
I
32 36 40
I
,
44 48
during the observation time in hours for the initial intra-amniotic administration of dose repeated at 24 hours if abortion had
(mean = 18.3 hours) aborted, compared with only 20 of the 25 nulliparous patients (mean = 29.4 hours). The abortion times of the nulliparous patients compared to the multiparous patients are greater in both the 15 mg. and 25 mg. groups at p 5 0.05. When both groups are combined, this difference is significant at p 5 0.01. The cumulative abortion rates by parity (Fig. 2) also demonstrate these differences in effectiveness with each dosage schedule. Thus, multiparous patients are not only more likely to abort, but they do so on the average of 11.1 hours sooner than do nulliparous patients. Laboratory results. No indication of hematopoietic, hepatic, or renal toxicity was noted by either average change in blood parameters or review of these changes in individual patients. Clinically, significant changes did not occur in hematocrit, hemoglobin, creatinine, blood urea nitrogen, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, total or direct bilirubin, alkaline phosphatase, platelets, sodium, potassium, or chloride. The average white blood cell count and neutrophi1 count increased, while the number of mononuclear cells decreased significantly. Differences between the different dosage
786
Brenner
et al.
schedules were not statistically significant. The mean white blood cell count had increased by a maximum of 2,781 per cubic millimeter and 4,550 per cubic millimeter while the maximum mean neutrophil count increased by 16 and 12 per cent and the mean lymphocyte count decreased by 8 and 9 at 6 hours after the initial injection and at the time of abortion or end of the trial, respectively. These changes were noted in patients independent of the development of fever and/or clinical signs of infection. Comment Of the 2 dosage schedules studied, the most satisfactory results were obtained with the intra-amniotic administration of 25 mg. of PGF,, at the initiation of the study and repeated after 24 hours in those patients who did not abort. With this dosage, 50 per cent of the patients aborted within the initial 24 hour period and 90 per cent aborted within the 48 hour period of observation, with a mean abortion time of 22.9 hours. The incidence and severity of complications were no greater than with the less effective 15 mg. schedule. No physical signs or laboratory changes indicated any hepatic, renal, or hematopoietic toxicity. The leukocytosis and neutrophilia were noted with all dosage schedules and are consistent with those observed with intravenous administration of PGF,,.4 Intra-amniotic administration of 15 mg. of PGF,,, according to the protocol, resulted in only 20 per cent of the 20 patients aborting within the 24 hour period and 70 per cent aborting within the 48 hour period of observation. Their rates of abortion were not significantly different from those patients receiving hypertonic saline. More women developed fevers in this low-dosage group, while this complication was not observed with the more effective 25 mg. dose schedule. Although one patient in the 15 mg. group had clinically apparent bronchoconstriction, she would have developed this complication with either dosage schedule because this complication occurred with the initial 5 mg. PGF,, injection.
The observation that multiparous patients abort more frequently and in a shorter period of time than do nulliparous patients is noteworthy for 2 reasons: First, the maximally effective dose with the minimum COIIIplications may be different in nulliparous and multiparous patients. Second, when various dosage schedules are compared, patient groups must have comparable parity distribution or one must compare nulliparous patients separately from multiparous patients. Premeditating patients with prochlorper;lzinc resulted in fewer patients having episodes of nausea and vomiting. However, prochlorperazine may decrease the effectiveness of PGF,,. This statement is made because: ( 1) both trials that failed occurred in tkli: premeditated group (25 mg. Group Bj, and (2) the average abortion time of patients aborting was 6 hours longer than that of the nonpremedicated group (25 mg. Group B). To determine whether prochlorperazine decreases the effectiveness of PGF,, as an abortifacient will require the study of ;t larger group of patients. Although nausea and vomiting may not be a serious complicatioti, premeditation has made abortion with PGFza more acceptable to the patients and medical personnel. Only one advantage of inducing ther;tpeutic abortion with intra-amniotically administered PGF,, rather than hypertonic saline can be demonstrated to date. There is a shorter induction-to-abortion time. Premedicating the patient with prochlorperazinc alleviates the major disadvantages which are nausea and vomiting. Although the serious complications occasionally obselvcd with hypertonic saline inductions have not been observed with the use of PGF,,, larger series must be conducted to determine if there will be an occasional serious complication. Although the 25 mg. dosage schedule is more acceptable than either hypertonic saline or the 15 mg. dosage schedule, a mole effective dosage schedule may be devised if intra-amniotic administration is potentially as effective as constant intravenous infusion.
Volume
114
Number6
Because all patients aborted within 24 hours with minimal complications when a maximally effective dose of PGF,, was administered by constant intravenous infusion,6 it is suspected that a more effective rate of intra-amniotic administration is possible.
Intra-amniotic
PGFZ,
for
therapeutic
abortion
787
Whether the most effective intra-amniotic rate will be the same for patients of different parities and whether one will have to compromise for less than the maximal effect of PGF,, for clinical practicability remain to be demonstrated.
REFERENCES
1. 2. 3.
Karim, S. M. M., and Sharma, S. D.: Lancet 2: 47, 1971. Bygdeman, M., Toppozada, M., and Wiqvist, N.: Acta Physiol. Stand. 82: 415, 1971. Toppozada, M., Bygdeman, M., and Wiqvist, N.: Contraception 4: 293, 1971.
4.
Hendricks,
Brotanek, 5.
C. H.,
Brenner,
W.
E., Ekbladh,
L.,
V., and Fishburne, J. I., Jr.: AM. J. OBSTET.GYNECOL. 111:564, 1971. Brenner, W. E.: AM. J. OBSTET. GYNECOL. 113: 1037, 1972.
administration of prostaglandin
F,, to induce therapeutic abortion Efficacy and tolerance
of two dosage schedules
W.
M.D.
E.
BRENNER,
C.
H.
J.
T.
BRAAKSMA,
M.D.
J,
I.
FISHBURNE,
JR.,
F.
G.
KRONCKE,
L.
STAUROVSKY,
Chapel
HENDRICKS,
Hill,
North
M.D.
JR.,
M.D. M.D.
C.N.M. Carolina
Forty-one physically healthy gravid women between 13 and 20 weeks’ gestation were treated with intra-amniotic injections of prostaglandin in FI,(PGF+J by one of two dosage schedules to induce therapeutic abortion. The results were compared over a 48 hour period. In one group, 15 mg. of PGFs. was injected initially, and this dose was repeated after 24 hours in those patients who failed to abort. In the second group 25 mg. of PGF,. was administered by the same schedule. The results obtained by this latter method were superior to those achieved by either the 15 mg. schedule or by hypertonic saline instillation. Patients premeditated with prochlorperatine had less vomiting. Multiparous patients had higher rates of abortion and aborted in a significantly shorter period of time than nulliparous patients. Although the 25 mg. dosage schedule is more effective than hypertonic saline instillation, it is likely that still more effective intra-amniotic schedules will be developed.
B E c A u s E of the occasional serious complications and the prolonged time required to accomplish abortions with hypertonic From the Department Gynecology, University Carolina.
of Obstetrics of North
saline, the intra-amniotic administration of prostaglandin F,, (PGF,,) is being investigated. Other investigator@ have reported variable efficacy in a total of 49 patients over different periods of time with the use of different dosages. This is a report of a comparison of the efficacy and tolerance of intra-amniotic dosage schedules 2 PGF,a within a 48 hour period of observation.
and
This work was supported in part by grants from the National Institute of Child Health and Human Development (HD-04148-03), The General Research Centers, Program of the Division of Research Sources, National Institutes of Health (RR-46). and the International Fertility Research Program of the Carolina Population Center of the University of North Carolina (AID/csd 2979. The Upjohn Company supplied prostaglandin and financial assitance. Received for publication May 30,1972. Accepted
for
publication
June
Material
and methods Prostaglandin F,,, 5 mg. per milliliter diluent, was injected through a polyethylene catheter* which was inserted through an 18 gauge thin-wall needle into the clear amniotic cavity by either the transabdominal or transvaginal approach. One of two dos-
20, 1972.
Reprint requests: Dr. W. E. Brenner, Dept. of Ob./Gyn., The University of North Carolina, Chapel Hill, North Carolina 27514.
‘Becton VXOZO.
781
Dickinson
&
Co.,
Rutherford,
New
Jersey,
782
Brenner
November
et al.
Table I. Summary
Am.
of the 41 patients’
characteristics
in the various 25
Characteristics
15
mg.
Group
J. Obstet.
groups mg.
A
Group B
Total
20
10
11
21
Age (yr.) Mean Range
21.1 18-27
23.1 18-38
21.5 18-27
22.3 18-38
Race (No.) Negro Caucasian
6 14
5 5
5 6
10 11
Parity (No.) Nulliparas Multiparas
12 8
6 4
8 3
14 7
16.1 14-18
16.4 14-20
16.3 14-m
16 4
7 3
8 3
l:j 6
57.1 44-79
56.3 50-77
60.9 48-69
58.7 48-77
64.6 52-70
63.0 61-65
64.5 59-69
Patients
Gestation Mean Range
(No.)
(weeks) 16.8 14-20
Marital status Single Married Weight Mean Range Height
(No.)
(Kg.)
(inches)
Mean Range Twenty patients planned PGFa (25 mg. Group A); amniotic administration of
to be initially treated with 15 mg. of PGFza 11 patients were premed&ted with 10 mg. PGFza (25 mg. Group B).
age schedules was used if tolerated: (1) 5 mg. of PGF,, was injected at 10 minute intervals to a total dose of 15 mg. at the initiation of the study in 20 patients, with an identical dose 24 hours later if abortion had not occurred (15 mg. group) ; (2) 5 mg. was injected at 10 minute intervals to a total initial dose of 25 mg. in 21 subjects and repeated after 24 hours to those who had not yet aborted (25 mg. group). The first 10 patients of this group of 21 subjects were not premeditated (25 mg. Group A). However, because nausea and vomiting were frequent, the final 11 patients were premedicated with 10 mg. of prochlorperazine,* administered intramuscularly, 15 minutes prior to the initial injection and before the repeat injection at 24 hours (25 mg. Group *Compazinr, brand of prochlorperazine, 10 mg. per cubic wntimeter. Smith, Kline & Fwnch Labs., Philadelphia, Pennsyl~arria.
1; i!liL’ (;vncr-:~i
(15 mg. group); of intramuscular
10 patients were prochlorperazine
-
63.8 59-69 treated with 25 mg. prior to the intra-
R) . If abortion did not occur within 48 hours after the initial injection, the trial was declared a failure. In the Clinical Research Unit of North Carolina Memorial Hospital at the University of North Carolina, 41 physically healthy women between 13 and 20 weeks’ gestation had PGF,, administered to them bj one of these 2 dosage schedules to induce therapeutic abortion. There were no significant differences in the patients’ characteristics between the groups (Table I). For comparative purposes, the abortion times of 200 patients who had 200 ml. of 20 per cent hypertonic saline instilled intra-amniotically were determined. Patients were monitored for vital signs and a variety of hematologic and chemical parameters. As noted, the following parameters were monitored before initial injrction and at hourly intervals until 12 hours
Volume Number
114 6
Intra-amniotic
Table II. Abortifacient 15 mg. of PGF,,
results administered
of 20 patients planned intra-amniotically
Results Abortions (No.) Complete Incomplete Mean time (hr.) Range (hr.) Failure I No. I Tw,o
patients
were
treated
after
24
hours
A 10
Patients (No.) Abortions (No.) Complete Incomplete Mean time (hr.) Range (hr. ) Failure (No. ) zinc
Ten patients administered
treated
abortion
783
with Total < 48 hr.
2 2 19.0 15.6-21.5 16
7 3 31.6 25.8-46.4 4
9 5 28 15.6-46.4 4
by alternate
management
initially
< 24 hr. Group 1 B JA+B 11 21
5 3 2 1 15.3 13.5 6.6-20.0 4.8-16.8 3 7
therapeutic
14 Patients 24-48 hr.
results of 21 patients intra-amniotically
Results
to be initially
for
20 Patients < 24 hr.
Table III. Abortifacient administered
PGFza
8 3 14.6 4.8-20.0 10
were not premeditated (25 mg. Group intramuscularly (25 mg. Group B).
as described
treated
1 4 2 1 31.0 36.1 24.5-35.3 30.2-42.6 0 2
after abortion or to the end of the trial: blood pressure by stethoscope and sphygmomanometer, heart rate by palpation, and temperature by oral thermometer. Blood was obtained for tests of hematopoietic, liver, and renal toxicity before the initial injection, 6 hours after this injection, and at the time of abortion or at 48 hours if no abortion occurred. The Mann-Whitney test was used to determine significance. Results
Administration of 15 mg. of PGF,,. Within the initial 24 hour period, 4 of the women aborted, 2 completely (Table II). At the onset of the second 24 hour period, 2 of the remaining 16 patients received alternate management that was not according to the plan. One subject’s amniotic fluid was grossly bloody, and repeated injection was considered unsafe; therefore, the abortion was successfully completed by a 9.4 hour intravenous infusion of PGF,, at 50 ,ug per minute. In the other subject, it became advis-
with
25 mg. of PGF2,
24-48 hr. Group ( B IA+B 7 10
A 3
A),
in the text.
while
11 patients
5 3 34.2 24.5-42.6 2 were
< 48 hr. Groufi 1 B 1 A+B 11 21
A 10 6 4 20.0 6.6-35.3 0
premeditated
with
7 2 26.1 4.8-42.6 2
13 6 22.9 4.8-42.6 2
10 mg. of prochlorpera-
able, for nonmedical indications, to inject 250 ml. of 20 per cent saline solution intraamniotically at the end of 24 hours; this woman completely aborted 19.8 hours later. Of the 14 women who were reinjected with 10 aborted within the sec15 mg. of PGF,,, ond 24 hour period. Thus, of the 20 women in whom the original study design was initiated, 14 (70 per cent) aborted within the 48 hour observation period while being managed within the stipulated plan. Administration of 25 mg. of PGF,,. During the 24 hours following the initial injection, 11 patients aborted, 8 completely (Table III). Ten subjects were reinjecte.d at 24 hours, and 8 of these aborted within the second 24 hour period of observation. Thus, within the 48 hour observation period, 19 of 21 patients (90 per cent) aborted. Although both failures occurred in Group B and the mean abortion time was 6.1 hours longer, no statistically significant differences were noted in the number of patients aborting or between the mean abortion times of
784
Brenner
et al.
s o 90P a 80K z 0 i
7060-
g 507 a Y 405
30-
: I =
20io0
4
8
12
16
20 24 28 32 36 40 44 48 TIME (Hrs) Fig. 1. The cumulative abortion rates (per cent) resulting from intra-amniotically administered medication during the observation time in hours for: ( 1) 21 patients receiving an initial dosr of 25 mg. PGF2,, (2) 20 subjects planned to be injected with an initial dose of 15 mg. of PGFi,, and (3) 200 patients who received 200 ml. of 20 per cent saline solutions.
Table IV. Incidence and severity of the complications observed in 41 patients treated with the intra-amniotic administration of either 15 mg. or 25 mg. of PGF,, without (25 mg. Group A), and with (25 mg. Group B) premeditation with 10 mg. prochlorperazine 25
~Complications Pain (%) Mean No. Range Emesis (70) Mean No. Range
15mg.j
A
mg. /
B
doses
70 1.6 O-.5
60 1.2 o-3
36 0.9 o-4
episodes
40 0.6 o-4
50 1.9 O-8
27 0.8 o-7
10 o-3 10 35 :i 0
30 O-2 10 0 0 0
100 I-2 0 0 0 9
Antiemetic (70) Range Blood loss >500 (%) Fever > 100” F. ( %.) Bronchoconstriction (% 1 Diarrhea (%) ’ ’
patients not premeditated (25 mg. Group A) and those premeditated with prochlorperazine (25 mg. Group B) . The cumulative abortion rates are compared in Fig. 1. No difference was noted between the cumulative abortion rates duri,ng the initial 48 hours for patients receiving hypertonic saline and those receiving 15 mg.
of PGF,,. Within 72 hours, 97 per cent of the patients given hypertonic saline aborted. More than one half of the patients injected with 25 mg. of PGF,, had aborted by 24 hours, while it was only after 32 hours that this rate was achieved in subjects receiving hypertonic saline or 15 mg. of PGF,,. A comparison of the incidence of complications between the 2 schedules ( 15 mg. group and 25 mg. Groups A and B‘I is summarized in Table IV. Although the numbers are too small to be expressed statistically as percentages because the numbers of patients are different in each group; the incidences arc expressed in percentages so that they may be more easily compared. No differences were noted in the incidencrs or scverity of pain, vomiting, or blood loss between the 15 mg. group and the 25 mg. Group A. The only apparent differcbnce bctween these 2 groups was in the incidence of fever (temperature > ZOO’ F.) . Five subjects had fever and one had bronchospasm in the 15 rqg. group, while neither of these complications was observed in the 25 mg. groups. There was no definite evidence that the f’ever was associated with intrauterine infection. However, because most patients clevehped fevers late in the course of the abortion. this
Volume Number
114 6
Intro-amniotic
ioo-
I ,
PGFza
Multipora
/O
for
therapeutic
abortion
785
(25mg)
705 ~60CO2 w40 ?30s g 205 2 IO-
,’ sl : I : I’ I
0
4
I
8
I
I
16 20 24 28 TIME(Hrs) Pig. 2. The cumulative abortion rate (per cent) nulliparous and multiparous patients resulting from either 15 mg. or 25 mg. of PGF2, with an identical not occurred. possibility must be considered. Only one patient developed fever in the first 24 hour period, while four subjects became febrile subsequently. When patients were premeditated with prochlorperazine, the frequency and incidence of vomiting decreased by one half. Although one patient had 7 episodes of vomiting, no additional antiemetic was administered because the onset of nausea was rapid and no nausea was complained of after each episode of vomiting. One patient had an episode of diarrhea. Fewer patients received pain medication (meperidine) with fewer doses per abortion when they were premeditated with prochlorperazine. Effect of parity. Multiparous patients aborted more frequently and in a shorter period of time than did nulliparous patients managed on the same protocol plan. In the 15 mg. group, 6 of 7 multiparous patients aborted with a mean time of 22.1 hours compared with 8 of the 11 nulliparous patients who aborted with a mean time of 32.3 hours. Likewise, when 25 mg. was administered, all 7 multiparous patients aborted (mean = 14.9 hours) and only 12 of 14 nulliparous patients aborted (mean = 27.5 hours). Over all, 13 of 15 multiparous patients
1
I
32 36 40
I
,
44 48
during the observation time in hours for the initial intra-amniotic administration of dose repeated at 24 hours if abortion had
(mean = 18.3 hours) aborted, compared with only 20 of the 25 nulliparous patients (mean = 29.4 hours). The abortion times of the nulliparous patients compared to the multiparous patients are greater in both the 15 mg. and 25 mg. groups at p 5 0.05. When both groups are combined, this difference is significant at p 5 0.01. The cumulative abortion rates by parity (Fig. 2) also demonstrate these differences in effectiveness with each dosage schedule. Thus, multiparous patients are not only more likely to abort, but they do so on the average of 11.1 hours sooner than do nulliparous patients. Laboratory results. No indication of hematopoietic, hepatic, or renal toxicity was noted by either average change in blood parameters or review of these changes in individual patients. Clinically, significant changes did not occur in hematocrit, hemoglobin, creatinine, blood urea nitrogen, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, total or direct bilirubin, alkaline phosphatase, platelets, sodium, potassium, or chloride. The average white blood cell count and neutrophi1 count increased, while the number of mononuclear cells decreased significantly. Differences between the different dosage
786
Brenner
et al.
schedules were not statistically significant. The mean white blood cell count had increased by a maximum of 2,781 per cubic millimeter and 4,550 per cubic millimeter while the maximum mean neutrophil count increased by 16 and 12 per cent and the mean lymphocyte count decreased by 8 and 9 at 6 hours after the initial injection and at the time of abortion or end of the trial, respectively. These changes were noted in patients independent of the development of fever and/or clinical signs of infection. Comment Of the 2 dosage schedules studied, the most satisfactory results were obtained with the intra-amniotic administration of 25 mg. of PGF,, at the initiation of the study and repeated after 24 hours in those patients who did not abort. With this dosage, 50 per cent of the patients aborted within the initial 24 hour period and 90 per cent aborted within the 48 hour period of observation, with a mean abortion time of 22.9 hours. The incidence and severity of complications were no greater than with the less effective 15 mg. schedule. No physical signs or laboratory changes indicated any hepatic, renal, or hematopoietic toxicity. The leukocytosis and neutrophilia were noted with all dosage schedules and are consistent with those observed with intravenous administration of PGF,,.4 Intra-amniotic administration of 15 mg. of PGF,,, according to the protocol, resulted in only 20 per cent of the 20 patients aborting within the 24 hour period and 70 per cent aborting within the 48 hour period of observation. Their rates of abortion were not significantly different from those patients receiving hypertonic saline. More women developed fevers in this low-dosage group, while this complication was not observed with the more effective 25 mg. dose schedule. Although one patient in the 15 mg. group had clinically apparent bronchoconstriction, she would have developed this complication with either dosage schedule because this complication occurred with the initial 5 mg. PGF,, injection.
The observation that multiparous patients abort more frequently and in a shorter period of time than do nulliparous patients is noteworthy for 2 reasons: First, the maximally effective dose with the minimum COIIIplications may be different in nulliparous and multiparous patients. Second, when various dosage schedules are compared, patient groups must have comparable parity distribution or one must compare nulliparous patients separately from multiparous patients. Premeditating patients with prochlorper;lzinc resulted in fewer patients having episodes of nausea and vomiting. However, prochlorperazine may decrease the effectiveness of PGF,,. This statement is made because: ( 1) both trials that failed occurred in tkli: premeditated group (25 mg. Group Bj, and (2) the average abortion time of patients aborting was 6 hours longer than that of the nonpremedicated group (25 mg. Group B). To determine whether prochlorperazine decreases the effectiveness of PGF,, as an abortifacient will require the study of ;t larger group of patients. Although nausea and vomiting may not be a serious complicatioti, premeditation has made abortion with PGFza more acceptable to the patients and medical personnel. Only one advantage of inducing ther;tpeutic abortion with intra-amniotically administered PGF,, rather than hypertonic saline can be demonstrated to date. There is a shorter induction-to-abortion time. Premedicating the patient with prochlorperazinc alleviates the major disadvantages which are nausea and vomiting. Although the serious complications occasionally obselvcd with hypertonic saline inductions have not been observed with the use of PGF,,, larger series must be conducted to determine if there will be an occasional serious complication. Although the 25 mg. dosage schedule is more acceptable than either hypertonic saline or the 15 mg. dosage schedule, a mole effective dosage schedule may be devised if intra-amniotic administration is potentially as effective as constant intravenous infusion.
Volume
114
Number6
Because all patients aborted within 24 hours with minimal complications when a maximally effective dose of PGF,, was administered by constant intravenous infusion,6 it is suspected that a more effective rate of intra-amniotic administration is possible.
Intra-amniotic
PGFZ,
for
therapeutic
abortion
787
Whether the most effective intra-amniotic rate will be the same for patients of different parities and whether one will have to compromise for less than the maximal effect of PGF,, for clinical practicability remain to be demonstrated.
REFERENCES
1. 2. 3.
Karim, S. M. M., and Sharma, S. D.: Lancet 2: 47, 1971. Bygdeman, M., Toppozada, M., and Wiqvist, N.: Acta Physiol. Stand. 82: 415, 1971. Toppozada, M., Bygdeman, M., and Wiqvist, N.: Contraception 4: 293, 1971.
4.
Hendricks,
Brotanek, 5.
C. H.,
Brenner,
W.
E., Ekbladh,
L.,
V., and Fishburne, J. I., Jr.: AM. J. OBSTET.GYNECOL. 111:564, 1971. Brenner, W. E.: AM. J. OBSTET. GYNECOL. 113: 1037, 1972.