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Effect of prostaglandin F2α and hypertonic saline on the placental function during midtrimester abortion
Effect of prostaglandin Fza:and hypertonic saline on the placental function during midtrimester abortion S. JAYARAMAN,
B.V.Sc.,
M.
K.
K.
S. RAGHAVAN,
SINHA,
M.Sc.
V. S. MATHUR,
PH.D. M.D.,
G.
K.
RASTOGI,
P.
K.
DEVI,
Chandigarh,
M.Sc.
D.PHIL.(OXON.)
M.B.B.S.,
F.R.C.P.E.,
M.R.C.P.(LOND.)
F.R.C.S.
India
Changes in placental function during the induction of midtrimester abortion by prostaglandin F,, and hypertonic saline were investigated. Serial estimations of human placental lactogen (HPL) and cystine aminopeptidase (CAP) were carried out in 17 subjects. There was a significant (P < 0.01) reduction in the plasma CAP and HPL levels 4 hours after PGFply administration. In the case of hypertonic saline abortions only HPL levels showed a reduction at 8 and 12 hours after induction.
1 N T R A - A M N I 0 T I C administration of PGF,, and hypertonic saline has been successfully used for the induction of midtrimester abortion.*? 2 Various hypotheses have been put forward to explain the abortifacient action of prostaglandins. Direct stimulatory effect on the myometrium has been reported to be responsible.3, 4 Luteolysis preceding abortion has been consistently observed in a variety of species. 5y 6 Cantor and associateq7 after estimating maternal plasma progesterone during PG infusions, have suggested the possibility of a prostaglandin-induced insult to the fetoplacental unit. On the contrary, Keller and associateq8 after repeated estimations of a number of placental hormones and enzymes including HPL, human chorionic gonadotropin (HCG) , progesterone, and heat-stable alka-
line phosphatase (HSAP) during prostaglandininduced labor in postmature women, have reported a lack of action of the compound on placental function. Intra-amniotic and extra-amniotic PGF,, has been widely used for its abortifacient actions during the second trimester. Since there are very few studies concerning the action of the compound on placental function, the present study was undertaken to examine the changes in the maternal plasma concentrations of two of the placental productsHPL and CAP-during prostaglandin-induced abortions. An estimation of these can be expected to indicate the prostaglandin-induced changes in placental activity during the abortion. For comparison, similar studies were carried out in women undergoing therapeutic abortion with intra-amniotic hypertonic saline.
From the Departments of Pharmacology, Endocrinology, and Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research. Received Revised AccePted
for July
publication
March
Materials and methods The study was carried out in 17 obstetrically healthy volunteers between 14 and 20 weeks of gestation who were admitted for therapeutic abortion to the Nehru Hospital of Postgraduate Medical Education and Research, Chandigarh. A control sample of 3 ml. of venous blood was collected in a heparinized vial from each subject 10 minutes prior
7, 1974.
29, 1974.
August
7, 1974.
Reprint requests: Dr. K. S. Raghavan, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh-160011, India.
528
Volume Number
121 4
to the administration of the agent. A polyethylene catheter (O.D., 0.965 mm.; I.D., 0.580 mm.) was inserted transabdominally into the amniotic sac through a 18 gauge thin-walled needle. In the first group, containing 12 subjects, two 25 mg. doses of PGFZa (5 mg. per milliliter) were injected through the catheter at 6 hour intervals after removal of 1.0 ml. of amniotic fluid. In the second group, therapeutic abortion was induced in five subjects with intra-amniotic administration of 150 to 200 ml. of 20 per cent sodium chloride solution. Then 3 ml. blood samples were collected in both groups at 4, 8, and 12 hours after the induction. Plasma was separated by spinning the blood in a centrifuge, The samples were analyzed immediately or quick frozen and stored at -20° C. until the tests were done. CAP was estimated by the method of Small and Watkins9 and HPL by a double-antibody radioimmunoassay technique.* A paired ‘Y test was done for comparison of the changes in the HPL and CAP values from the controls. Results The women in the PGF2, group had a mean induction-abortion interval of 22 hours with a range of 6 to 46 hours. The mean induction-abortion interval was 26 hours with a range of 18 to 30 hours in the hypertonic saline group. The changes in the plasma CAP and HPL concentrations in women undergoing abortion with PGF,, are given in Table I and Fig. 1. HPL concentrations showed a significant fall during the 12 hours of study (P < 0.01). There was a significant (P < 0.01, paired t test) reduction in the plasma CAP concentrations 4 hours after the induction, later (at 8 hours) the values tended to rise to reach the preinduction levels. The changes in the plasma concentrations of the enzyme and the hormone of the saline group are given in Fig. 2. There was no change in the plasma CAP concentrations of these women during the study. The HPL concentrations also did not show any change at 4 hours after the induction. An apparent reduction in the hormone levels in the plasma, which is not statistically significant, was observed in the 8 and 12 hour samples. *HPL standard, anti-HPL serum, and methodology kindly supplied by the Hormone Distribution Officer, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014.
PGFza
and
hypertonic
saline
on
placental
function
529
H I PI I.
rncI1 iill.
fi9
6.0
-
HPL CAP
/n\I. !
0.6
5.0
4.0
3.0
2.0
I.0
0
4
7 PGF2L
PC F2d 25
mg
8
12
25 m g AFTER INDUCTION
TIME
Fig. 1. Changes in the plasma HPL in women undergoing intra-amniotic PGR,.
(HRS.)
concentration therapeutic
of CAP and abortion with
CAP my/ml
HPL r”y/p
6.0 *--*.-
e---a c......
. . . ..__ “.“..,
06
CAP HPL
I.
5.0
.05
‘...
1
....
I
0.4
4.0. -.+
o-3
3.0-
4 HYPE:TONlC SALINE
TIME
8 AFTER
INDUCTION
Fig. 2. Changes in the plasma concentrations HPL in women undergoing therapeutic intra-amniotic hypertonic saline.
12 (HRS.)
of CAP and abortion with
Comment In this study evidence is presented to show that PGF,, has a definite action on the placental function. There was a reduction in the CAP and HPL levels within 4 hours following intra-amniotic administration of PGF,,, indicating a certain amount of placental damage. Evidence of placental insult was mainly deduced from the measurements of placental hormones and histologic examination of the placenta following prostaglandin administration.?, lo The failure of Keller and co-worker+ to
530
Jayaraman
February
et al.
Table I. Changes
Am. J. Obstet.
in CAP
and HPL
during
therapeutic
15. 1975 Gynecol.
abortions -_
Duration Drug
used
PGFz,
!
(wk.1
14 14 14 14 15 18 16 14 16 14 14 17
3 4 5 6 7 8 9 10 11 12 Mean Hypertonic
saline
14 18 16 15 15
Mean
*CAP in mI.U./ml.;
4 hours
0 hour
pregnancy
Pt. No. 1 2
of
1
CAP*
/ HPL”
0.55 0.66 0.66 0.52 0.66 0.54 0.44 0.30
CAP
12 hours
8 hours
1 HPL
CAP
/
HPL
CAP
/
HPL
0.15 0.56 0.52 0.50 0.64 0.36 0.31 0.20 0.37 0.26 0.32 0.42
1.83 1.50 3.38 3.18 2.48 4.00 2.30 4.20 4.64 4.10 3.05 3.50
0.12 0.14 0.12 0.12 0.14 0.46 0.34 0.20 0.32 0.28 0.34 0.34
3.80 1.76 3.92 4.18 2.62 4.12 2.16 4.20 4.46 4.20 2.20 3.70
0.10 0.10 0.10 0.10 0.10 0.25 0.25 0.12 0.15 0.15 0.20 0.34
4.50 2.80 3.88 4.28 3.73 4.67 4.60 4.48 5.18 4.65 4.61 3.90
ii; 0.46 0.48
1.30 1.68 3.57 4.28 2.67 4.12 2.23 4.20 4.56 4.20 3.51 3.50
4.27
0.495
3.31
0.384
3.18
0.243
3.44
0.163
2.30 4.90 3.38 3.25 3.46
0.44 0.72 0.62 0.40 0.61
2.30 4.40 2.84 3.25 3.20
0.37 0.72 0.62 0.36 0.62
4.70 4.40 2.84 2.70 3.66
0.10 0.36 0.10 0.36 0.66
3.90 4.10 2.40 1.40 2.95
0.10 0.10 0.10 0.42 0.66
3.46
0.558
3.298
0.538
3.660
0.316
2.950
0.276
HPL in ag/ml.
observe any change in placental function may be due to the fact that the study was undertaken in postmature women when one could not expect placental function to be at its best, as well as due to the low dose by intravenous infusion of the compound given. On the other hand, at midtrimester, when the placenta is rapidly developing, any damage to its integrity would lead to measurable changes in the plasma concentration of its products.
Intra-amniotic hypertonic saline has been reported to produce decidual damage. It has also been shown that prostaglandins were released from the damaged decidual cells.ll These released prostaglandins in turn can act on the placenta, affecting its function. This would possibly explain the delay observed in the saline group, where HPL levels tend to fall only later than 4 hours after the induction.
REFERENCES
1.
2. 3. 4. 5. 6.
Toppozada, M., Bygdeman, M., and Wiqvist, N.: Contraception 4: 293, 1971. Alpern, W. M., Charles, A. G., and Frideman, E. A.: AM. J. OBSTET. GYNECOL. 100: 250, 1968. Karim, S. M. M., and Filshie, G. M.: Lancet 1: 157, 1970. Csapo, A. I., Sauvage, J. P., and Wiest, W. G.: Ax J. OBSTET. GYNECOL. 111: 1059, 1971. Gutknecht, G. D., Wyngarden, L. J., and Pharriss, B. B.: Proc. Sot. Exp. Biol. Med. 136: 1151, 1971. Kirton, K. T., Pharriss, B. B., and Forbes, A. D.: Proc. Sot. Exp. Biol. Med. 133: 314, 1970.
7. Canter, B., Jewelewiez, R., Warren, M., Dyrenfurth, I., Patner, A., and Vande Wiele, R. L.: Asr. J. OBSTET. GYNECOL. 113: 607, 1972. 8. Keller, P. J., Ruppen, M., Gerber, C., and Schmid, .JG~~J. Obstet. Gynaecol. Br. Commonw. 79: 804, 9. Small, C. W., and Watkins, W. B.: Enzymologia 41: 121, 1971. 10. Bullard, P. D., Herrick, C. W., Hindle, W. H., Hale, R. E., and Pion, R. J.: Contraception 7: 133, 1973. 11. Gustavi, B., and Green, K.: AM. J. OBSTET. GYNECOL. 114: 1099, 1972.
B.V.Sc.,
M.
K.
K.
S. RAGHAVAN,
SINHA,
M.Sc.
V. S. MATHUR,
PH.D. M.D.,
G.
K.
RASTOGI,
P.
K.
DEVI,
Chandigarh,
M.Sc.
D.PHIL.(OXON.)
M.B.B.S.,
F.R.C.P.E.,
M.R.C.P.(LOND.)
F.R.C.S.
India
Changes in placental function during the induction of midtrimester abortion by prostaglandin F,, and hypertonic saline were investigated. Serial estimations of human placental lactogen (HPL) and cystine aminopeptidase (CAP) were carried out in 17 subjects. There was a significant (P < 0.01) reduction in the plasma CAP and HPL levels 4 hours after PGFply administration. In the case of hypertonic saline abortions only HPL levels showed a reduction at 8 and 12 hours after induction.
1 N T R A - A M N I 0 T I C administration of PGF,, and hypertonic saline has been successfully used for the induction of midtrimester abortion.*? 2 Various hypotheses have been put forward to explain the abortifacient action of prostaglandins. Direct stimulatory effect on the myometrium has been reported to be responsible.3, 4 Luteolysis preceding abortion has been consistently observed in a variety of species. 5y 6 Cantor and associateq7 after estimating maternal plasma progesterone during PG infusions, have suggested the possibility of a prostaglandin-induced insult to the fetoplacental unit. On the contrary, Keller and associateq8 after repeated estimations of a number of placental hormones and enzymes including HPL, human chorionic gonadotropin (HCG) , progesterone, and heat-stable alka-
line phosphatase (HSAP) during prostaglandininduced labor in postmature women, have reported a lack of action of the compound on placental function. Intra-amniotic and extra-amniotic PGF,, has been widely used for its abortifacient actions during the second trimester. Since there are very few studies concerning the action of the compound on placental function, the present study was undertaken to examine the changes in the maternal plasma concentrations of two of the placental productsHPL and CAP-during prostaglandin-induced abortions. An estimation of these can be expected to indicate the prostaglandin-induced changes in placental activity during the abortion. For comparison, similar studies were carried out in women undergoing therapeutic abortion with intra-amniotic hypertonic saline.
From the Departments of Pharmacology, Endocrinology, and Obstetrics and Gynaecology, Postgraduate Institute of Medical Education and Research. Received Revised AccePted
for July
publication
March
Materials and methods The study was carried out in 17 obstetrically healthy volunteers between 14 and 20 weeks of gestation who were admitted for therapeutic abortion to the Nehru Hospital of Postgraduate Medical Education and Research, Chandigarh. A control sample of 3 ml. of venous blood was collected in a heparinized vial from each subject 10 minutes prior
7, 1974.
29, 1974.
August
7, 1974.
Reprint requests: Dr. K. S. Raghavan, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh-160011, India.
528
Volume Number
121 4
to the administration of the agent. A polyethylene catheter (O.D., 0.965 mm.; I.D., 0.580 mm.) was inserted transabdominally into the amniotic sac through a 18 gauge thin-walled needle. In the first group, containing 12 subjects, two 25 mg. doses of PGFZa (5 mg. per milliliter) were injected through the catheter at 6 hour intervals after removal of 1.0 ml. of amniotic fluid. In the second group, therapeutic abortion was induced in five subjects with intra-amniotic administration of 150 to 200 ml. of 20 per cent sodium chloride solution. Then 3 ml. blood samples were collected in both groups at 4, 8, and 12 hours after the induction. Plasma was separated by spinning the blood in a centrifuge, The samples were analyzed immediately or quick frozen and stored at -20° C. until the tests were done. CAP was estimated by the method of Small and Watkins9 and HPL by a double-antibody radioimmunoassay technique.* A paired ‘Y test was done for comparison of the changes in the HPL and CAP values from the controls. Results The women in the PGF2, group had a mean induction-abortion interval of 22 hours with a range of 6 to 46 hours. The mean induction-abortion interval was 26 hours with a range of 18 to 30 hours in the hypertonic saline group. The changes in the plasma CAP and HPL concentrations in women undergoing abortion with PGF,, are given in Table I and Fig. 1. HPL concentrations showed a significant fall during the 12 hours of study (P < 0.01). There was a significant (P < 0.01, paired t test) reduction in the plasma CAP concentrations 4 hours after the induction, later (at 8 hours) the values tended to rise to reach the preinduction levels. The changes in the plasma concentrations of the enzyme and the hormone of the saline group are given in Fig. 2. There was no change in the plasma CAP concentrations of these women during the study. The HPL concentrations also did not show any change at 4 hours after the induction. An apparent reduction in the hormone levels in the plasma, which is not statistically significant, was observed in the 8 and 12 hour samples. *HPL standard, anti-HPL serum, and methodology kindly supplied by the Hormone Distribution Officer, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014.
PGFza
and
hypertonic
saline
on
placental
function
529
H I PI I.
rncI1 iill.
fi9
6.0
-
HPL CAP
/n\I. !
0.6
5.0
4.0
3.0
2.0
I.0
0
4
7 PGF2L
PC F2d 25
mg
8
12
25 m g AFTER INDUCTION
TIME
Fig. 1. Changes in the plasma HPL in women undergoing intra-amniotic PGR,.
(HRS.)
concentration therapeutic
of CAP and abortion with
CAP my/ml
HPL r”y/p
6.0 *--*.-
e---a c......
. . . ..__ “.“..,
06
CAP HPL
I.
5.0
.05
‘...
1
....
I
0.4
4.0. -.+
o-3
3.0-
4 HYPE:TONlC SALINE
TIME
8 AFTER
INDUCTION
Fig. 2. Changes in the plasma concentrations HPL in women undergoing therapeutic intra-amniotic hypertonic saline.
12 (HRS.)
of CAP and abortion with
Comment In this study evidence is presented to show that PGF,, has a definite action on the placental function. There was a reduction in the CAP and HPL levels within 4 hours following intra-amniotic administration of PGF,,, indicating a certain amount of placental damage. Evidence of placental insult was mainly deduced from the measurements of placental hormones and histologic examination of the placenta following prostaglandin administration.?, lo The failure of Keller and co-worker+ to
530
Jayaraman
February
et al.
Table I. Changes
Am. J. Obstet.
in CAP
and HPL
during
therapeutic
15. 1975 Gynecol.
abortions -_
Duration Drug
used
PGFz,
!
(wk.1
14 14 14 14 15 18 16 14 16 14 14 17
3 4 5 6 7 8 9 10 11 12 Mean Hypertonic
saline
14 18 16 15 15
Mean
*CAP in mI.U./ml.;
4 hours
0 hour
pregnancy
Pt. No. 1 2
of
1
CAP*
/ HPL”
0.55 0.66 0.66 0.52 0.66 0.54 0.44 0.30
CAP
12 hours
8 hours
1 HPL
CAP
/
HPL
CAP
/
HPL
0.15 0.56 0.52 0.50 0.64 0.36 0.31 0.20 0.37 0.26 0.32 0.42
1.83 1.50 3.38 3.18 2.48 4.00 2.30 4.20 4.64 4.10 3.05 3.50
0.12 0.14 0.12 0.12 0.14 0.46 0.34 0.20 0.32 0.28 0.34 0.34
3.80 1.76 3.92 4.18 2.62 4.12 2.16 4.20 4.46 4.20 2.20 3.70
0.10 0.10 0.10 0.10 0.10 0.25 0.25 0.12 0.15 0.15 0.20 0.34
4.50 2.80 3.88 4.28 3.73 4.67 4.60 4.48 5.18 4.65 4.61 3.90
ii; 0.46 0.48
1.30 1.68 3.57 4.28 2.67 4.12 2.23 4.20 4.56 4.20 3.51 3.50
4.27
0.495
3.31
0.384
3.18
0.243
3.44
0.163
2.30 4.90 3.38 3.25 3.46
0.44 0.72 0.62 0.40 0.61
2.30 4.40 2.84 3.25 3.20
0.37 0.72 0.62 0.36 0.62
4.70 4.40 2.84 2.70 3.66
0.10 0.36 0.10 0.36 0.66
3.90 4.10 2.40 1.40 2.95
0.10 0.10 0.10 0.42 0.66
3.46
0.558
3.298
0.538
3.660
0.316
2.950
0.276
HPL in ag/ml.
observe any change in placental function may be due to the fact that the study was undertaken in postmature women when one could not expect placental function to be at its best, as well as due to the low dose by intravenous infusion of the compound given. On the other hand, at midtrimester, when the placenta is rapidly developing, any damage to its integrity would lead to measurable changes in the plasma concentration of its products.
Intra-amniotic hypertonic saline has been reported to produce decidual damage. It has also been shown that prostaglandins were released from the damaged decidual cells.ll These released prostaglandins in turn can act on the placenta, affecting its function. This would possibly explain the delay observed in the saline group, where HPL levels tend to fall only later than 4 hours after the induction.
REFERENCES
1.
2. 3. 4. 5. 6.
Toppozada, M., Bygdeman, M., and Wiqvist, N.: Contraception 4: 293, 1971. Alpern, W. M., Charles, A. G., and Frideman, E. A.: AM. J. OBSTET. GYNECOL. 100: 250, 1968. Karim, S. M. M., and Filshie, G. M.: Lancet 1: 157, 1970. Csapo, A. I., Sauvage, J. P., and Wiest, W. G.: Ax J. OBSTET. GYNECOL. 111: 1059, 1971. Gutknecht, G. D., Wyngarden, L. J., and Pharriss, B. B.: Proc. Sot. Exp. Biol. Med. 136: 1151, 1971. Kirton, K. T., Pharriss, B. B., and Forbes, A. D.: Proc. Sot. Exp. Biol. Med. 133: 314, 1970.
7. Canter, B., Jewelewiez, R., Warren, M., Dyrenfurth, I., Patner, A., and Vande Wiele, R. L.: Asr. J. OBSTET. GYNECOL. 113: 607, 1972. 8. Keller, P. J., Ruppen, M., Gerber, C., and Schmid, .JG~~J. Obstet. Gynaecol. Br. Commonw. 79: 804, 9. Small, C. W., and Watkins, W. B.: Enzymologia 41: 121, 1971. 10. Bullard, P. D., Herrick, C. W., Hindle, W. H., Hale, R. E., and Pion, R. J.: Contraception 7: 133, 1973. 11. Gustavi, B., and Green, K.: AM. J. OBSTET. GYNECOL. 114: 1099, 1972.