MID-TRIMESTER ABORTION WITH INTRA-AMNIOTIC PROSTAGLANDIN F2 ALPHA AND INTRAVENOUS OXYTOCIN INFUSION M.
Salomy,
M.
D.
I. Halbrecht, M. D. R. London, M. D. Research Institute of Human Reproduction and Fetal Development, Department of Obstetrics and Gynecology, Hasharon Hospital, Petah Tikva, Tel Aviv University Medical School, Tel Aviv, Israel Department of Obstetrics and Gynecology, Sinai Hospital of Baltimore, Baltimore, Maryland ABSTRACT
Induction of abortion in mid-trimester pregnancies were performed on 26 patients. The first 12 patients were treated by intra-amniotic instillation of Prostaglandin F2 alpha, with a mean dosage of 40.2 mg. and mean abortion time of 24 hours and 41 minutes (ten patients). Fourteen additional mid-trimester abortions were performed using identical protocol plus the addition of oxytocin by intravenous infusion two hours after injection of the prostaglandin. All patients aborted, with mean dosage of PGF2 alpha of 28.2 mg. and mean abortion time of 15 hours and 37 minutes.
ACKNOWLEDGEMENTS PGF2 alpha was kindly supplied by The Upjohn Company, Kalamazoo, Michigan. This work was supported in part by the Jewish Federation of Worcester, Massachusetts. AcceptedJanuary16
PROSTAGLANDINS FEBRUARY
1975
VOL. 9 NO. 2
271
PROSTAGLANDINS
INTRODUCTION Due to increasing demand for termination of pregnancy in the second trimester, alternative methods are being sought to replace the use of intra-amniotic injection of hypertonic saline solution or surgical procedures. The use of intra-amniotic hypertonic saline solution for the induction of mid-trimester abortions may be associated with serious complications. Coagulation defects, cardiovascular side effects, and even maternal deaths have been reported (1,2,3). Risk of maternal mortality after second trimester abortion by surgical procedures has been noted (4). Prostaglandins have been utilized for termination of pregnancies at all stages of gestation, and appear to be particularly useful in the induction of second trimester abortions. The use of prostaglandins by different routes of administration to induce abortion has been demonstrated by several investigators (5,6). Side effects, which may be dose related, include vomiting and diarrhea. The present study was undertaken to determine if induction of second trimester abortions with intra-amniotic prostaglandin F2 alpha (PGFZ alpha) could be facilitated by the use of intravenous oxytocin. In addition, attempts were made to determine if side effects of the prostaglandin administration could be minimized by using lower doses of prostaglandin in conjunction with the oxytocin. MATERIALS AND METHODS Twenty-six patients were admitted to the hospital for elective mid-trimester abortions. No patient had a history of spontaneous abortion within the preceding nine months, threatened abortion, history of habitual abortions, prior gynecologic surgery, or active pelvic disease. Also excluded from the study were any patients with known cardiac, renal, hepatic, endocrine or systemic diseases. Patients admitted to the study were all healthy pregnant females aged 16-39 years, at 16-26 weeks' gestation. All patients were admitted to the hospital one day prior to the procedure for clinical and laboratory examination.
272
FEBRUARY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
After voiding, the abdomen was cleansed with antiseptic solution, draped, and the proposed amniocentesis site was injected with local anesthesia. An 18 gauge needle was inserted into the amniotic cavity and a polyethylene catheter (PE 50 Clay Adams) was inserted into the amniotic cavity through the needle. The catheter was connected to a Statham Strain Gauge pressure transducer which was connected to a Grass Model 7 Polygraph. Baseline intrauterine pressure changes were recorded for 15-30 minutes, after which 25 mg. of PGF2 alpha was injected slowly into the amniotic cavity. The following clinical parameters were monitored prior to injection and hourly during treatment: body temperature, heart rate, respiratory rate, and blood pressure. Blood was obtained for complete blood count (hemoglobin, hematocrit, white blood count with differential, and platelets), liver and kidney function (bilirubin, alkaline phosphatase, glucose, urea, serum creatinine, oxitocinase, electrolytes) prior to the initial injection of PGF2 alpha, 8 hours after induction and 12-24 hours after abortion. Urinalysis was also checked at these intervals. Patients were divided into two groups. In the first 12 patients, 25 mg. of PGF2 alpha was injected intraamniotically, and additional doses of 5-25 mg. of PGF2 alpha were injected at intervals of 8-10 hours depending on the uterine response as monitored on the polygraph. In the second group, two hours after the intra-amniotic injection of 25 mg. of PGF2 alpha an intravenous infusion of oxytocin was started (0.02 units per ml. of saline solution, 0.020.04 units per minute). Additional dosages of 5-25 mg. of PGF2 alpha were given intra-amniotically each hour if the uterine contractions were noted to decrease as monitored by the polygraph. In both patient groups Meperidine 75 mg. and Promethazine hydrochloride 25 mg. was used for analgesia. Some patients also received paracervical block for anesthesia. RESULTS In Group I, 9 patients out of 12 aborted within 36 hours (Table 1). In three of them, it was necessary to complete the abortion by ovum forcepts, but dilation was unnecessary. The tenth patient aborted 53 hours following the administration of PGF2 alpha. Patients 11 and 12, the first in this study, developed strong uterine contractions but did not abort within 72 hours of administration. One of them aborted following administration of 200 ml. of 20% NaCl solution intra-amniotically, and the other aborted following oxytocin infusion intravenously.
FEBRUARY
1975
VOL. 9 NO. 2
273
PROSTAGLANDINS
I”
f min
Figure
1:
90
Photograph of original recordings of intra-amniotic pressure changes in response to intra-amniotic instillation of 25 mcf. of PGF2 alpha: A - The first-45 minutes B - 60 minutes after instillation of 25 mg. of PGF2 alpha x NU‘LIPARA 0 MULTIPARA
7
i’
__-(r---
__-- --ff" C PGFI
p_--
rL ,
:
Time
Figure
274
2:
(hours)
of
Abortjon
number of patients during Cumulative abortion rate: the observed time in Group 1 (O------O) and Group II (Owing to small number of patients, the (0______O). figure is presented by number of patients and not by percentage.)
FEBRUAKY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
In Group II (Table 2), all 14 patients aborted within 20 hours, with 11 aborting within 18 hours and 30 minutes. Thirteen patients aborted completely, and one patient underwent gentle currettage with ovum forcepts. Analysis of data using the student t test demonstrate no significance at Pz.05 between the two groups for injection to abortion time. It should be noted that two patients in Group I (oxytocin) could not be included in this analysis because they did not abort. All patients developed detectable contractions on the polygraph within ten minutes of injection of the prostaglandin. Within 30 minutes, uterine tonus was about 50 mm Hg (Figure lA), and contractions as intense as 80-120 mm Hg. Initially, 5-12 contractions per 10 minutes were noted (Figure 1B). As time progressed, duration of the contractions increased while frequency decreased. In Group I, four patients received one dose of PGF2 alpha. Patient number 1 received only 5 mg., after which she developed severe pain, vomiting and intense uterine contractions. She subsequently aborted after 8 hours and 15 minutes. Eight patients in this group received additional smaller doses of PGF2 alpha after the initial 25 mg. dose. This was required to maintain good uterine contractions, with a maximum total dose of 50 mg. For analgesia, patients received 75 mg. Meperidine and 25 mg. Promethazine hydrochloride two hours after administration of the prostaglandin. The dose was repeated if needed eight hours later. Twelve of the 26 patients demonstrated decreased uterine tone and contractility following sedation. The decrease started within ten minutes of injection, and lasted 30-60 minutes before defervescing. Nine patients also received paracervical block (1% solution of procaine HCl, 10 cc. to each side). Pain relief was afforded with no change in uterine tone or contractility. Seven patients in Group I developed nausea with vomiting, and two developed diarrhea. In Group II, two patients vomited. Estimated blood loss during the abortion was 100-300 cc. NO significant changes in blood pressure, heart rate, respiration, or metabolic parameters were noted. A slight neutrophillia was noted during the test period, which returned to pre-injection levels after 12-24 hours.
FEBRUARY
1975
VOL. 9 NO. 2
275
31
12
Group I treated
20
11
Table 1:
29
10
,20
6
25
33
5
9
38
25
29
3
4
33
39
2
7
26
1
8
AGE (YEARS)
PATIENT NO
2 0 4
3 1 5
by intra-amniotically
1
2
1
2 1
6
11
2
9
3
2
4 13
2
1. 2
2 5
PARITY
GRAVIDITY
instillation
16
16
17
21
16
17
16
16
22
18
22
26
15
FAILURE
00
00
00
30
10
25
50
25
:
:
:
:
:
:
:
:
15
15
FAILURE
53
32.5
: :
25
36
20
40
30
19
37.5
25
18
26
12
35 37.5
50
8
25
8
5
ABORTION TIME (HOURS - MINUTES: FROM STARTING
25
DOSE (mg)
TOTAL
of PGF2 alpha alone.
GESTATION No OF WEEKS
II:
34
22
19
17
16
26
23
26
27
7
8
9
10
11
12
13
14
2
3
2
4
1
1
1
2
10
5
3
2
2
3
GRAVIDITY
Group II treated by instillation oxytocin infusion I.V.
27
5
6
Table
26
23
3
2
4
23
20
1
AGE (YEARS)
ATIENT NO
of
1
0
1
3
0
0
0
1
5
3
2
1
1
2
PARITY
PGF2
alpha
TOTAL.
50
25
25
35
35
25
25
25
25
25
25
25
25
25
DOSE hg)
intra-amniotically
18
22
19
16
20
22
16
26
16
18
18
19
20
24
GESTATION No OF WEEKS
combined
28
22
20
18
16
16
14
13
13
11
11
11
10
30
30
: : : :
00 00
20
55
15
30
:
:
:
40 45
55
:
15
05
05
: :
:
: : :
with
9
ABORTION TIME (HOURS - MINUTES) FROM STARTING
PROSTAGLANDINS
DISCUSSION Induction of mid-trimester abortions by intraamniotic hypertonic saline has been used for several years. However, this procedure may be accompanied by serious complications. As an alternative nonsurgical method of second trimester abortion the use of intra-amniotic administration of PGF2 alpha has been under investigatio'nin several centers. At the present time, research'is being conducted to find safe dosage schedules that will shorten the time between PG's administration and the time of abortion without increasing the side effects, This series has indicated a decrease in the mean injection to abortion time by using intravenous oxytocin in conjunction with intraamniotic PGF2 alpha with no increase in undesirable side effects. No cases of cervical rupture were noted, and estimated blood loss was not increased. The results obtained here are similar to those shown by Alderman and Thelwall-Jones (7) who utilized PGE2 extra-amniotic with oxytocin intravenous infusion. It seems that under carefully controlled conditions, the injection to abortion time can be shortened by the administration of intravenous infusion of oxytocin following intra-amniotic instillation of PGF2 alpha.
278
FEBRUARY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
REFERENCES 1.
Wagatsuma, T. Intra-amniotic injection of saline for therapeutic abortion, Am. J. Obst. & Gynec. 93:743, 1965.
2.
Brown, F. D., E. C. Davidson, F. and L. L. Phillips. Coagulation changes after hypertonic saline infusion for late abortions, Obst. & Gynec. 39:538, 1972.
3.
Termination of Second Trimester Pregnancy Using Prostaglandin F2 alpha, ACOG Technical Bulletin. April 27, 1974.
4.
Berger, G., Tietze, C., Pahter, J., and Katz, S. Maternal Mortality Associated with Legal Abortion in New York State: July 1, 1970-June 30, 1972. J of Obst. & Gynec. 43:3, P. 315-326, March, 1974.
5.
Toppazada, M., M. Bygdeman and N. Wiquist. Induction of abortion by Intra-amniotic administration of prostaglandin F2 alpha, Contraception 4:293, 1971.
6.
Anderson, G. G., J. C. Hobbins, V. Rajkovic, L. Speroff and B. V. Caldwell. Mid-trimester abortion using intraamniotic prostaglandin F2 alpha, Advance Abstracts p. 88, Supplement to Advances in the Biosciences 9, International Conference on Prostaglandins, Vienna, September 1972, Pergamon Press/Viewg.
7.
Alderman, B. and H. Thelwall-Jones. Application of the potentiating effect of prostaglandin E2 and oxytocin to induced second trimester abortion, The J. of Obst. & Gynec. of the British Commonwealth 80:1021, 1973.
FEBRUARY
1975
VOL. 9 NO. 2
279
Salomy,
M.
D.
I. Halbrecht, M. D. R. London, M. D. Research Institute of Human Reproduction and Fetal Development, Department of Obstetrics and Gynecology, Hasharon Hospital, Petah Tikva, Tel Aviv University Medical School, Tel Aviv, Israel Department of Obstetrics and Gynecology, Sinai Hospital of Baltimore, Baltimore, Maryland ABSTRACT
Induction of abortion in mid-trimester pregnancies were performed on 26 patients. The first 12 patients were treated by intra-amniotic instillation of Prostaglandin F2 alpha, with a mean dosage of 40.2 mg. and mean abortion time of 24 hours and 41 minutes (ten patients). Fourteen additional mid-trimester abortions were performed using identical protocol plus the addition of oxytocin by intravenous infusion two hours after injection of the prostaglandin. All patients aborted, with mean dosage of PGF2 alpha of 28.2 mg. and mean abortion time of 15 hours and 37 minutes.
ACKNOWLEDGEMENTS PGF2 alpha was kindly supplied by The Upjohn Company, Kalamazoo, Michigan. This work was supported in part by the Jewish Federation of Worcester, Massachusetts. AcceptedJanuary16
PROSTAGLANDINS FEBRUARY
1975
VOL. 9 NO. 2
271
PROSTAGLANDINS
INTRODUCTION Due to increasing demand for termination of pregnancy in the second trimester, alternative methods are being sought to replace the use of intra-amniotic injection of hypertonic saline solution or surgical procedures. The use of intra-amniotic hypertonic saline solution for the induction of mid-trimester abortions may be associated with serious complications. Coagulation defects, cardiovascular side effects, and even maternal deaths have been reported (1,2,3). Risk of maternal mortality after second trimester abortion by surgical procedures has been noted (4). Prostaglandins have been utilized for termination of pregnancies at all stages of gestation, and appear to be particularly useful in the induction of second trimester abortions. The use of prostaglandins by different routes of administration to induce abortion has been demonstrated by several investigators (5,6). Side effects, which may be dose related, include vomiting and diarrhea. The present study was undertaken to determine if induction of second trimester abortions with intra-amniotic prostaglandin F2 alpha (PGFZ alpha) could be facilitated by the use of intravenous oxytocin. In addition, attempts were made to determine if side effects of the prostaglandin administration could be minimized by using lower doses of prostaglandin in conjunction with the oxytocin. MATERIALS AND METHODS Twenty-six patients were admitted to the hospital for elective mid-trimester abortions. No patient had a history of spontaneous abortion within the preceding nine months, threatened abortion, history of habitual abortions, prior gynecologic surgery, or active pelvic disease. Also excluded from the study were any patients with known cardiac, renal, hepatic, endocrine or systemic diseases. Patients admitted to the study were all healthy pregnant females aged 16-39 years, at 16-26 weeks' gestation. All patients were admitted to the hospital one day prior to the procedure for clinical and laboratory examination.
272
FEBRUARY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
After voiding, the abdomen was cleansed with antiseptic solution, draped, and the proposed amniocentesis site was injected with local anesthesia. An 18 gauge needle was inserted into the amniotic cavity and a polyethylene catheter (PE 50 Clay Adams) was inserted into the amniotic cavity through the needle. The catheter was connected to a Statham Strain Gauge pressure transducer which was connected to a Grass Model 7 Polygraph. Baseline intrauterine pressure changes were recorded for 15-30 minutes, after which 25 mg. of PGF2 alpha was injected slowly into the amniotic cavity. The following clinical parameters were monitored prior to injection and hourly during treatment: body temperature, heart rate, respiratory rate, and blood pressure. Blood was obtained for complete blood count (hemoglobin, hematocrit, white blood count with differential, and platelets), liver and kidney function (bilirubin, alkaline phosphatase, glucose, urea, serum creatinine, oxitocinase, electrolytes) prior to the initial injection of PGF2 alpha, 8 hours after induction and 12-24 hours after abortion. Urinalysis was also checked at these intervals. Patients were divided into two groups. In the first 12 patients, 25 mg. of PGF2 alpha was injected intraamniotically, and additional doses of 5-25 mg. of PGF2 alpha were injected at intervals of 8-10 hours depending on the uterine response as monitored on the polygraph. In the second group, two hours after the intra-amniotic injection of 25 mg. of PGF2 alpha an intravenous infusion of oxytocin was started (0.02 units per ml. of saline solution, 0.020.04 units per minute). Additional dosages of 5-25 mg. of PGF2 alpha were given intra-amniotically each hour if the uterine contractions were noted to decrease as monitored by the polygraph. In both patient groups Meperidine 75 mg. and Promethazine hydrochloride 25 mg. was used for analgesia. Some patients also received paracervical block for anesthesia. RESULTS In Group I, 9 patients out of 12 aborted within 36 hours (Table 1). In three of them, it was necessary to complete the abortion by ovum forcepts, but dilation was unnecessary. The tenth patient aborted 53 hours following the administration of PGF2 alpha. Patients 11 and 12, the first in this study, developed strong uterine contractions but did not abort within 72 hours of administration. One of them aborted following administration of 200 ml. of 20% NaCl solution intra-amniotically, and the other aborted following oxytocin infusion intravenously.
FEBRUARY
1975
VOL. 9 NO. 2
273
PROSTAGLANDINS
I”
f min
Figure
1:
90
Photograph of original recordings of intra-amniotic pressure changes in response to intra-amniotic instillation of 25 mcf. of PGF2 alpha: A - The first-45 minutes B - 60 minutes after instillation of 25 mg. of PGF2 alpha x NU‘LIPARA 0 MULTIPARA
7
i’
__-(r---
__-- --ff" C PGFI
p_--
rL ,
:
Time
Figure
274
2:
(hours)
of
Abortjon
number of patients during Cumulative abortion rate: the observed time in Group 1 (O------O) and Group II (Owing to small number of patients, the (0______O). figure is presented by number of patients and not by percentage.)
FEBRUAKY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
In Group II (Table 2), all 14 patients aborted within 20 hours, with 11 aborting within 18 hours and 30 minutes. Thirteen patients aborted completely, and one patient underwent gentle currettage with ovum forcepts. Analysis of data using the student t test demonstrate no significance at Pz.05 between the two groups for injection to abortion time. It should be noted that two patients in Group I (oxytocin) could not be included in this analysis because they did not abort. All patients developed detectable contractions on the polygraph within ten minutes of injection of the prostaglandin. Within 30 minutes, uterine tonus was about 50 mm Hg (Figure lA), and contractions as intense as 80-120 mm Hg. Initially, 5-12 contractions per 10 minutes were noted (Figure 1B). As time progressed, duration of the contractions increased while frequency decreased. In Group I, four patients received one dose of PGF2 alpha. Patient number 1 received only 5 mg., after which she developed severe pain, vomiting and intense uterine contractions. She subsequently aborted after 8 hours and 15 minutes. Eight patients in this group received additional smaller doses of PGF2 alpha after the initial 25 mg. dose. This was required to maintain good uterine contractions, with a maximum total dose of 50 mg. For analgesia, patients received 75 mg. Meperidine and 25 mg. Promethazine hydrochloride two hours after administration of the prostaglandin. The dose was repeated if needed eight hours later. Twelve of the 26 patients demonstrated decreased uterine tone and contractility following sedation. The decrease started within ten minutes of injection, and lasted 30-60 minutes before defervescing. Nine patients also received paracervical block (1% solution of procaine HCl, 10 cc. to each side). Pain relief was afforded with no change in uterine tone or contractility. Seven patients in Group I developed nausea with vomiting, and two developed diarrhea. In Group II, two patients vomited. Estimated blood loss during the abortion was 100-300 cc. NO significant changes in blood pressure, heart rate, respiration, or metabolic parameters were noted. A slight neutrophillia was noted during the test period, which returned to pre-injection levels after 12-24 hours.
FEBRUARY
1975
VOL. 9 NO. 2
275
31
12
Group I treated
20
11
Table 1:
29
10
,20
6
25
33
5
9
38
25
29
3
4
33
39
2
7
26
1
8
AGE (YEARS)
PATIENT NO
2 0 4
3 1 5
by intra-amniotically
1
2
1
2 1
6
11
2
9
3
2
4 13
2
1. 2
2 5
PARITY
GRAVIDITY
instillation
16
16
17
21
16
17
16
16
22
18
22
26
15
FAILURE
00
00
00
30
10
25
50
25
:
:
:
:
:
:
:
:
15
15
FAILURE
53
32.5
: :
25
36
20
40
30
19
37.5
25
18
26
12
35 37.5
50
8
25
8
5
ABORTION TIME (HOURS - MINUTES: FROM STARTING
25
DOSE (mg)
TOTAL
of PGF2 alpha alone.
GESTATION No OF WEEKS
II:
34
22
19
17
16
26
23
26
27
7
8
9
10
11
12
13
14
2
3
2
4
1
1
1
2
10
5
3
2
2
3
GRAVIDITY
Group II treated by instillation oxytocin infusion I.V.
27
5
6
Table
26
23
3
2
4
23
20
1
AGE (YEARS)
ATIENT NO
of
1
0
1
3
0
0
0
1
5
3
2
1
1
2
PARITY
PGF2
alpha
TOTAL.
50
25
25
35
35
25
25
25
25
25
25
25
25
25
DOSE hg)
intra-amniotically
18
22
19
16
20
22
16
26
16
18
18
19
20
24
GESTATION No OF WEEKS
combined
28
22
20
18
16
16
14
13
13
11
11
11
10
30
30
: : : :
00 00
20
55
15
30
:
:
:
40 45
55
:
15
05
05
: :
:
: : :
with
9
ABORTION TIME (HOURS - MINUTES) FROM STARTING
PROSTAGLANDINS
DISCUSSION Induction of mid-trimester abortions by intraamniotic hypertonic saline has been used for several years. However, this procedure may be accompanied by serious complications. As an alternative nonsurgical method of second trimester abortion the use of intra-amniotic administration of PGF2 alpha has been under investigatio'nin several centers. At the present time, research'is being conducted to find safe dosage schedules that will shorten the time between PG's administration and the time of abortion without increasing the side effects, This series has indicated a decrease in the mean injection to abortion time by using intravenous oxytocin in conjunction with intraamniotic PGF2 alpha with no increase in undesirable side effects. No cases of cervical rupture were noted, and estimated blood loss was not increased. The results obtained here are similar to those shown by Alderman and Thelwall-Jones (7) who utilized PGE2 extra-amniotic with oxytocin intravenous infusion. It seems that under carefully controlled conditions, the injection to abortion time can be shortened by the administration of intravenous infusion of oxytocin following intra-amniotic instillation of PGF2 alpha.
278
FEBRUARY
1975
VOL. 9 NO. 2
PROSTAGLANDINS
REFERENCES 1.
Wagatsuma, T. Intra-amniotic injection of saline for therapeutic abortion, Am. J. Obst. & Gynec. 93:743, 1965.
2.
Brown, F. D., E. C. Davidson, F. and L. L. Phillips. Coagulation changes after hypertonic saline infusion for late abortions, Obst. & Gynec. 39:538, 1972.
3.
Termination of Second Trimester Pregnancy Using Prostaglandin F2 alpha, ACOG Technical Bulletin. April 27, 1974.
4.
Berger, G., Tietze, C., Pahter, J., and Katz, S. Maternal Mortality Associated with Legal Abortion in New York State: July 1, 1970-June 30, 1972. J of Obst. & Gynec. 43:3, P. 315-326, March, 1974.
5.
Toppazada, M., M. Bygdeman and N. Wiquist. Induction of abortion by Intra-amniotic administration of prostaglandin F2 alpha, Contraception 4:293, 1971.
6.
Anderson, G. G., J. C. Hobbins, V. Rajkovic, L. Speroff and B. V. Caldwell. Mid-trimester abortion using intraamniotic prostaglandin F2 alpha, Advance Abstracts p. 88, Supplement to Advances in the Biosciences 9, International Conference on Prostaglandins, Vienna, September 1972, Pergamon Press/Viewg.
7.
Alderman, B. and H. Thelwall-Jones. Application of the potentiating effect of prostaglandin E2 and oxytocin to induced second trimester abortion, The J. of Obst. & Gynec. of the British Commonwealth 80:1021, 1973.
FEBRUARY
1975
VOL. 9 NO. 2
279
