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Hormone changes in relation to the time of fetal death after prostaglandin-induced abortion
PROSTAGLANDINS
HORMONE DEATH
I.S.
Fraser:
CHANGES AFTER
IN
RELATION
TO
THE TIME
PROSTAGLANDIN-INDUCED
Katherine
M.
Nicholson,
Gail
OF
FETAL
ABORTION
Graham and
H. Boyle
Department of Obstetrics and Gynaecolo ~,.Universi~y of Edinburgh and Simpson Memorial Maternity avrlron, Edmburgh. ABSTRACT The changes in unconjugated estradiol-178 and estriol, progesterone and chorionic somatomammotropin (HCS) in peripheral plasma have been studied in adminis18 women at 30minute intervals following intra-terine prostaglandin tration for therapeutic termination of second trimester pregnancy. The Eaormonal changes were related to the time of fetal death detected by the disappearance of was given by the intra-amniotic route with fetal heart pulsations. Prostaglandin urea (5 patients) or with intravenous o% ocin (5 patients), or by the extra-amniotic route with intravenous oxytocin (8 patients). Fetal death occurred rapidly with intra-amniotic PGE2, but usually at a late stage with extra-amniotic PG . Three fetuses in the extra-amniotic group died at or just before abortion. A vart‘a ty of fetal heart changes were noted and the time of fetal death did not appear to influence the time of abortion within each treatment subgroup. Estradiol and estriol showed a slight but persistent fall over 24 hours prior to induction of abortion. A more rapid fall usually occurred after induction, with a consistent fall around the time of fetal death. Progesterone and HCS usually fell much less before and immediately after fetal death. A marked rise in estradiol sometimes occurred before fetal death, particularly in the intraamniotic PGE and urea subgroup. Estriol levels declined more rapidly before than after fet 4 death, whereas fetal death had less consistent effects on the other hormones. All hormones had usually fallen considerably at the time of abortion, and in some individuals marked fluctuations in hormone levels were seen. ACKNOWLEDGEMENTS The authors are garteful to the consultant staff of the hospital for permission to study their patients, to Sister Revolta and her staff for dedicated nursina care of the wtients. to Dr. Rex Scaramuzzi and Dr. Georae Wilson for gifts 07 the antibodies used \n the radioimmunoassay, to the Upjohi Company for a grant, to Mrs. E.A. Michie for assistance with the endocrine aspects of the study and to Miss Rose Leask for expert technical assistance. Present address and address for correspondence Department of Obstetrics University of Sydney, Australia.
JUNE 1977 VOLi 13 NO. 6
:
and G naecology, New Youth Wales,
2006,
1161
PROSTAGLANDINS
IMRODUCT
ION
Numerous papers have reported changes in plasma hormone concentrations following prostaglandin (PG) therapy for induction of abortion (for example l-8) Most of these report that hormones of fetal and placental origin show a variable fall by the time of abortion but there is much disagreement about details. Differences in the reported results may be due to differences in dosage, types and route of administration of prostaglandins, the use of additional drugs including oxytocin and urea, and to the infrequency of sampling of maternal plasma in some of the studies. The hormone changes have not been closely correlated with the time of fetal death although it has been postulated that the efficacy of intraamniotic PGE when combined with urea is partly due to rapid fetal demise (9). in culture of fetal tissue obtained after On the other Kand, good cell viability suggests that fetal death occurred abortion induced with intro-amniotic PGF shortly before abortion (10). This suggest!%?I is supported by the occasional abortion of a fetus with a heartbeat after intro-uterine PG administration. In this investigation fetal heart rate changes and the time of fetal death have been related to alterations in the levels in maternal plasma of unconjugated estradiol-17R, unconjugated estriol,progesterone and chorionic somatomammotropin (HCS) for three different regimes of PGE2administration. CLINICAL
MATERIAL
AND
METHODS
In a small preliminary study 3 normal primigravid patients were followed and with 1 to 2 hour1 blood samples for 24 hours prior to induction of abortion, with hourly sampr es following induction of abortion with intro-amniotic PGE2. During this time the patients were mainly resting in bed or sitting in a comfortable chair. These samples were assayed for unconjugated estradiol-170 and estriol. In the main study eighteen patients (age 16 to 27) had their pregnancies Statutory approval for therapeutic abortion terminated using intro-uterine PGE . The under the 1967 United Kingdom Ab&tion Act had previously been given. following prostaglandin regimes were used : -
1)
Intro-amniotic PGE2(5 mg) and urea (40 g or 80 g) given single dose by transabdominal amnioover 5 minutes in a centesis.
2)
Intro-amniotic PGE mented by intraven &I Oxytocin was started to a maximum of 240
3)
Extra-amniotic
(10 mg) given in a single dose supples oxytocin starting at the same time. at 30 mu/minute and increased hourly mu/minute.
PGE2 given as described previously
(11)
in a &sage of 2OOpg hourly (total dose 0.4 to 2.5 mg). Simultaneous intravenous oxytocin was given as above.
1162
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
in Table
Parity, 11.
gestation and numbers of patients for each regime are shown
The fetal heart was recorded using a Sonicaid D 205 M ultrasonic fetal heart detector for 4 to 10 minutes every 15 minutes until fetal death. Maternal blood samples were collected in heparinised tubes from an indwelling catheter in the ante-cubital vein every 30 minutes until fetal death (or every 60 minutes if the fetus was still alive after 6 to 8 hours), and every 1 to 2 hours after fetal death until after the abortion of the fetus. In several patients some placental tissue remained in the uterus after abortion and was removed by curettage several hours later. Each blood sam le was centrifuged at 4’C shortly after collection and the plasma stored in - 159C. and estriol were PI asma unconjugated estradiol-178 measured in duplicate by radioimmunoassay using antibodies raised in sheep to estradiol-178-17-hemisuccinate-bovine serum albumen and to estriol 16, 17dihemisuccinate bovine serum albumen(12). Plasma pools run with each assay gave a within-assay variation of 7.9O% for estradiol and 8.4% for estriol, and an interassay variation of 8.5% for estradiol and 15.9% for estriol. Plasma progesterone raised in sheep was measured in duplicate by radioimmunoassay using an antibo to progesterone-l la-bovine serum albumen (13) and giving a wit“k in-assay variation of 8% and an inter-assay variation of 15.7%. Plasma HCS was measured in unextracted plasma in duplicate using a commercially available radioimmunoassay kit (The Radiochemical Centre, Amersham, Bucks, England) and giving a withinassay variation of 9.4% and an inter-assay variation of 14.1%. Samples from each individual patient were usually run in the same assay. RESULTS In the preliminary study plasma estradiol and estriol levels showed a to fall progressively during the 24 hours prior to induction of abortion r and Table 1). Estriol fell slightly in all three patients and estradiol fell ;(,FiKZt of 3 [mean = 27pg/mI/h our for estradiol ; 17 pg/mI/hour for e.strioIJ. Moderate fluctuations in the levels were seen in all three patients(with coefficients of variation of 10.9%, 14.9% and 15.9% for estradiol and 8.9%, 12.0% and 21.4% for estriol). Following induction of abortion both hormones fell markedly prior to abortion.
tendenc
The relationship of the times of fetal death and abortion to the mode of prostaglandin administration in the main study are shown in Table 11. There was no significant difference in the induction+bortion intervals between the three different regimes, and no difference in the time to fetal death for the two intraamniotic regimes. However, the induction to fetal death interval was significantl longer for the extra-amniotic regime than for the other two methods. The tota r cbse of PGE given by the extra-amniotic route was usually considerably less than for the i&ra-amniotic route (11). The fetal heart recordings showed a variet y of patterns which did not appear to be related to changes in plasma hormone eve s or to mode of PG administration :
64
Fairly steady prior to sudden terminal disappearance (9 cases)
JUNE 1977 VOL. 13 NO. 6
bradycardia and
1163
PROSTAGLANDINS
TABLE REGRESSION
EQUATIONS
I
FOR PLASMA
UNCONJUGATED
ESTRIOL FOR 24 HOURS BEFORE TREATMENT ABORTION
INTERVAL
AND
ESfRADlOL
DURING
IN 3 PATIENTS TREATED WITH
INTRA-AMNIOTIC
Estradiol Before Treatment
I
Regression Coefficient (r)
PGE2
Estriol
During InductionAbortion Interval
-0.066
AND
THE INDUCTION-
Before Treatment
During induction kzn
-0.272
I
7
4
\j
dml
(I
‘r
3
I I I I
2
a- ---------
--_____________ -------0
i
II II
I
P-L___
1.
I
0 --__
I 1 I 0
2
1
6
8
ICI
II
I8
22
II
---a1 ’
hf lb
2
4
6
8
10
nom
FIGURE
1
Changes in plasma unconjugated estradiol and estriol levels jn 3 patients admitted to hospital 24 hours before induction of abortion with intra-amniotic PGE (10 mg.). The figure shows the regression lines for one t 2 two hourly blood samples prior to initiation of therapy and during the induction-abortion period.
I = induction of abortion
1164
A = abortion
JUNE 1977 VOL. 13 NO. 6
PGE2 + oxytocin
Extra-amniotic
PGE2 + oxytocin
Intra-amniotic
Intra-amniotic PGE2 + urea
Multiparas
4
2
3
4
1
4
(12-16)
14.1wks
(13-l 8)
15.8wks
Plwk (18-25)
Mean (Range)
GESTATION
(04°0-2550hrs) f 7hrs lmin
9hrs 34mins (08l 0-2550hrs) f 6hrs 1Smins
14hrs 42mins
2hrs 26mins
12hrs 05 mins
(G015-a430h~s) f lhr 39mins
(01 15-0330ht.s) f 55 mins
(0655-2230hrs) f 6hrs 4 mins
(0715-1620hrs) * 4hrs lmin
Phrs 23mins
5kTF
(00 -14 hrs) f 5hrs 44mins
(070°-1 230hrs) f Phrs 3Omins
9hrs 39mins
(0325-2000hrs) f 6hrs 19mins
1Ohrs 2Omins
f SD
f SD
f SD 12hrs 43mins
Mean (Range)
Mean (Ran*)
FETAL DEATH ABORT ION I NT ERVAL
Mean (Range)
INDUCTIONFETAL DEATH INTERVAL
ABORTION
ADMINISTRATION
INDUCTIONABORT ION INTERVAL
OF PROSTAGLANDIN
OF TIMES OF FETAL DEATH AND
-I-
Primi paras
NUMBERS
TO METHOD
RELATIONSHIP
TABLE II
PROSTAGLANDINS
(b)
Increasingly wide swings in rate sometimes progressing to deceleration with contractions (2 cases)
(c)
Increasing tachycardia (2 cases)
before sudden fall and disappearance
(d)
Increasing bradycardia
(2 cases)
(e)
Normal
heartbeat
until 30 minutes before abortion
(3 cases).
One fetus from the extra-amniotic group was born with a heartbeat and two others died within 30 minutes before abortion (Group (e)). All fetuses in the intra-amniotic groups died within 44 hours of PGE2 administration. The hormone than s in maternal plasma immediate1 after fetal death and after abortion are detar.Ye ed in Table III as oercentaaes o r the basal levels. The difference in basal levels is consistent with’the diffgrent gestations of the three treatment groups. The data have been analysed in more detail (Table IV) by calculating the regression equations for each hormone in each treatment group prior to fetal death, and after fetal death but prior to abortion (Figures 2a and 2b). The samples collected immediately after fetal death and immediately after abortion were not included in the pre-fetal death and pre-abortion equations respectively. In the extra-amniotic treatment group (Group III ) there was no overall change in hormone levels during the first few hours of treatment in those cases where fetal death occurred late, so the regression equation for the whole group has been calculated for a period of five hours prior to fetal death. The chcmges in plasma hormone levels in six individual patients are shown in Figures 3 to 5. These have been included in order to illustrate the individual variations in response. Figures detailing changes in plasma levels of all these hormones at such frequent intervals and in relation to fetal death have not been published previously. The main findings of this study were -
1166
(a)
a consistent fall in estradiol and estriol levels during the 30 minutes around fetal death (Figure 2), but little or no fall in progesterone or HCS levels over the same period (except for HCS in the extra-amniotic group) ;
(b)
all hormones had fallen considerably at the time of abortion and usually the major part of this fall had occurred well In some individuals very ra id falls in all before abortion. hormone levels were sometimes seen around t g e time of abortion (Figs. 3a and Sa).
(c)
Progesterone and HCS fell comparatively little prior to fetal death particularly when the fetal death occurred early, except in 3 individual cases (e.g. Fig. 4b). Persistently high levels of HCS and progesterone after abortion were usually related to retained placental tissue (Fig. 3b).
(d)
In the intra-amniotic
PGE2with
urea group (Group I)
JUNE
1977
VOL. 13 NO. 6
Z O
ug/ml
HCS
0.93 ±0.40
0.96 ±0.41
100.0 -+~18.5
77.8 ±48.5
36.1 ±8.7
43.2 4-10.2
122.1 ±63.0
0.80 ±0.46
4.38 ±1.75
J (3)
83.9 4-35.5
80.5 4-21.8
36.4 ±25.0
70. 0 :k37.9
30.2 ±!3.5
56.6 4-27.8
42.5 4-18.8
36.1 4-16.4
% OF CONTROL LEVELS Immediately after Fetal Death (1) (3)
56.2 :~)4.6
31.9 4-26.4
12.7 +-4.9
29.5 ±25.6
(1)
2.2 4-2.2
19.1 4-10.9
12.1 +-4.5
30.5 :1:49.9
5.5 ~:8.4
24.7 ±15.4
28.8 4-26.3
15.8 4-13.5
J
(3)
% OF CONTROL LEVELS Immediately after Abortion
(1) Intra--amniotic PGE2 + urea (5 patients) (2) Intra-amnlotlc PGE2 + oxytocin (5 patients) (3) Extra-amniotic PGE2 + oxytocln (8 patients)
±0.48
1.30
53.4 4-20.0
64.7 4-26.0
ng/'ml
Progesterone
1.32 ±1.20
2.45 4-1.12
ng,/ml
Estriol (unconjugated)
8.12 ±5.48
ng/ml
9.37 ±3.78
I (2)
Estradiol-17B (unconiugated)
J (I)
BASAL LEVELS
HORMONAL CHANGES IN MATERNAL PLASMA IMMEDIATELY FOLLOWING FETAL DEATH AND ABORTION IN 18 PATIENTS UNDERGOING THERAPEUTICABORTION BY THREE DIFFERENTMETHODS OF PROSTAGLANDIN ADMINISTRATION (Mean ± SD)
TABLE III.
c~
~a o
O~
Z O
t-
--.I
O~ OO
111
GROUP
11
GROUP
r
intercept ng/ml regression coefficient
slope n~ml//hr
r
regression coefficient
intercept ng/ml
slope ng/ml/hr
r
1.23 -0.581
-0.292
-0.143
-0.125
5.64
-0.146
3.49
-0.230
-0.020
6.89
-0.084
-0.138
0.78
-0.047
-0.127
0.91
-0.071
-0.444
0.23
-0.024
-0.293
0.44
-0.036
-0.225
30.8
-1.35
-0.205
46.9
-1.97
-0.485
24.5
-2.28
-0.092
35.9
-0.44
-0.385
840
-71
+0.128
850
+37
-0.339
262
-25
-0.347
780
-39
TABLE IV REGRESSION EQUATIONS FOR FOUR HORMONES BEFOREAND AFTER FERAL DEATH AFTERTREATMENTWITH PROSTAGLANDINS (GROUP 1 - INTRA-AMNIOTIC PGE? AND UREA ; GROUP 11 - INTRA-AMNIOTIC PGE2 WITH OXYTOCIN; GROUP 111 - EXTRA-AMNIOTIC PGE2 WITH OXYTOCIN). Estriol Estradiol Progesterone HCS Before After After i Before After Before After Fetal Fetal Feta I Fetal Fetal Fetal Fetal Fetal Death Death Death Death Death Death Death Death slo~ +2.230 -0.860 -0.330 -0.072 -2.67 -4.00 -+25 -74 ng~ml/hr GROUP intercept 8.02 10.94 2.49 0.87 59.1 57.9 1230 1290 n~/ml 1 regression coefficient +0.490 -0.459 -0.398 -0.564 -0.080 -0.392 +0.047 -0.417
==
PROSTAGLANDINS
(a)
Gmupl
14
i
I
12
I
10 n&d
8
I
q
6
I
4 2
-------s
0 I
* ‘0. --_____
1
J
4
- ________ 3
6
I
I
_ _____ 8
7
______ II 12
ItI
8 7 6 5 4 3 2 1
-_____q
0
*---
-__-__
-___-________~,a 7 ",&
d
4
9
Group Ill
ID
i
1'1 lr
13
b"
3
I I I
2 1 0
FIGURE 2(a)
L
5
*____-___-___aM 4
3
10
12
3 tiwn
4
5
Changes in plasma unconjugated estradiol and estriol levels related to fetal death and abortion following treatment with intraamniotic PGE and urea (Group l), intra+mniotic PGE and intraPGE a r-8 intravenaus oxyto a n(Group 11) and extradmniotic venous oxytocin (Group 111). The graphs are derr‘dd from the regression equations of the plasma hormone levels for all patients before fetal death and after in each separate treatrt;; gra x
F/D
JUNE 1977
2
= fetal death
VOL. 13 NO. 6
A = abortion
1169
PROSTAGLANDINS
40 Progesterone ng/ml
30 20
‘0
I
0
I
I
I
I
I
I 10
(123456789
II
12
13
HOUIX Group
P/D 50 40
N
n9hI
i
I
;
_..a.
.---30 c
p---_____ I I
10
I I II
1
2
1.0
I
20
0
II.
4I
I 3
rdml
3’
--.__
---__
----___
----___al,
:I
0.5
:It
4
5
6
7
8
9
1’011
Group
Ill.
A
Ill 12I((
’
13
Hours
F/D 40 q/ml
P _
30;
__---..
I .o.
t
20
FIGURE 2(b) Changes in plasma levels of progesterone and HCS related to fetal death and abortion as detailed in the legend for figure 2(a).
1170
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
4
24
WEEKS
1.0 -
-
~9 /ml
nq /ml 60 0.5
c--o 5
n9M
3
I
24
WEEKS i
i” 2.0
1.5 -
C-l
I.0
nglml
P9lml o-5
.-.
o---o
nqlml
nqlml S 3
I
-&&_-o--v-__._~ 0
4
a
. I2
16
-e10
HOu?S
FIGURE 3
Plasma hormone changes after intraannioticPGE2 and urea in two patients.
1 = Induction of abortion; FD = Fetal Death; A = Abortion; *--a Progesterone; e HCS; Estradiol ; o - - -0 Estriol .
JUNE 1977 VOL. 13 NO. 6
1171
PROSTAGLANDINS
60
40
I.0
20
0.5
-
9-4
lr9lml
nglml
I
16
I
I
LA&
I2 8 4
0
2
b
4
8
16
12
20
HOURS
*--. nglml
------L I
Ii
.-
IZ-
/I
8
I
I.0 o---o nghl
n5hl -0.5
4.41 s\:.-* \b&+_-C_
____-____-__
I I 0
FIGURE 4
2
6
10
14
18
2:
Plasma hormone changes after intramniotic PGE2 with intravenous oxytocin therapy in two patients. Symbols as in Figure 3
1172
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
I.0
40.
hd
m---s nqlm1
P9/‘1 0.5 20.
FIGURE
5
Plasma hormone changes during extraamniotic PGEz and intravenous oxytocin therapy in two patients. Symbols
JUNE 1977 VOL. 13 NO. 6
as in Figure
3
1173
PROSTAGLANDINS
plasma estradiol showed a consistent rise up to and sometimes beyond the time of fetal death (Figure 3). (e)
In all groups following the start of treatment (except initially in Group 1) plasma estradiol and estriol fell more steeply than in the preliminary study group over the 24-hour control period before treatment.
(f)
Marked fluctuations (Figures 3 to 5).
(s)
The rates of decline of each hormone were not consistently altered b fetal death except for estriol which declined faster be rore fetal death than after.
in hormone levels in some individuals
DISCUSSION Knowledge of the approximate timing of fetal death and the chances of delivery of a living fetus after therapeutic abortion using prostaglandins are of relevance in obtaining fresh fetal tissue for tissue culture and histological work and to the current concern about delivery of a live fetus with potential for longterm survival in a damaged state. This study indicates that fetal demise occurs at an early stage following intra-amniotic PGE augmented by urea or oxytocin, whereas fetal death usually occurs at a late sta 8 e with extra-amniotic PGE even when it is augmented with oxytocin. In three out of eight in the extra-am r?rotic group the fetus survived until around delivery with a normal fetal heart pattern. The fetal heart patterns showed similar wide variations to those recorded prior to fetal death in labour at term (14). Two other studies using ultrasonic fetal heart detectors have recorded the mean time of fetal death following intra-amniotic PGF (40 mg) as 14 to 2 hours in and 10.4 hours (8 ; 15). One of these groups expert *Q%zed some difficulty being certain of-the disappearance of the fetal heart due to strong contractfons. This difficulty was not noted in the present study. It seems likely that the time of fetal death is related to the intra-terine pressure changes associated with Following intra-amniotic PGE2 administration prostaglandin administration. (10 ma) there is usuallv a marked increase to 60-90 mmHa in baseline intra;terinYe’pressure within’ 1 to 2 hours, and contractions are”superimposed on this(l6). This could be expected to cause considerable impairment of placental and fetal perfusion. Indeed it has been suggested that combined intra-crmniotic PG and urea exert their effect on steroid levels in maternal plasma b anoxic impa4 ment of the fetoplacental unit leading to early fetal death (6). &th extra-clmniotic PGE administration there is genemlly a much smaller rise in baseline tone which e likely to permit continued placental perfusion between contmctions. The is& h rtonic intra-amniotic urea may have an additional, more direct, deleterious e !pe feet on fetal survival as has been observed with hypertonic saline (17), although in this study fetal death did not occur any earlier in the intra+mniotic urea subIn this study there &es not appear to be any clear relationship between group. the time of fetal death and the time of abortion, which is in agreement with studies PGF2a (8) and hypertonic saline (18). using intra-amniotic
1174
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
Hormonal changes measured in maternal plasma in this investigation are in general agreement with most other published studies, in spite of the infrequency hormones in of sampliny in many of these _studies. Almost all feto-placentat maternal p asma fa I by the trme of abortion except in rare cases where the fetus survives until abortion. Hormones solely of placental origin tend to fall less than those requiring a fetal contribution. Some fluctuation of the levels of all hormones was seen and may indicate episodic release. This fluctuation (outwith the intro-assay coefficient of variation) was also seen for estradiol and estriol prior to initiation of prostaglandin therapy. Fluctuations have been noted by others (1) but have not been studied by relatively frequent sampling. It is important to note that maternal estradiol and estriol levels may show a small but progressive fall over a 24-hour period before any treatment when the second trimester patient is first admitted to hospital. The large fall in estriol levels at the time of fetal death was not surprising for a hormone which requires continued fetal production of precursors for its synthesis by the placenta, and suggests that changes in fetal probction of precursors are fairly rapidly reflected by changes in circulating levels of maternal hormone. Progesterone is produced mainly, and HCS entirely, by the placenta, and the usual finding of only a small or negligible fall in maternal plasma levels prior to fetal death, and even abortion, indicates that placental synthesis of these hormones is largely unaffected by intro-uterine PGE administration and the presumed uterine hypertonicity associated with rapiBfetal death. This finding is at variance with published data (3) which indicates that there is a dmmatic fall in HCS levels following PGF . It is ssible that PGF and PGE may have differing actions on HCS s$‘thesis. It Pas been reporte d% at hyper 8. nrc urea does not have a specific effect on placental synthesis of these hormones (19), but this study has demonstrated an early sustained rise in estradiol in patients treated with intro-amniotic urea and This might have been due to a stimulatory action of the PGE on PGE plac 3’ntal estrogen synthesis (20) accentuated by urea or to a stress-In *?i uced increase in circulating maternaldehydm~piandmsterone sulphate precursor of adrenal origin(12). The moderate1 elevated levels of estmdiol continuing after fetal death are consistent wit 1: the observation that 50% of circulating estradiol comes from precursors of maternal origin (21). The use of intro-amniotic urea or intravenous oxytocin with intrauterine PGE shortens the induction-abortion interval corn ared with PGE2 alone (9, d, but it ap ears unlikely that they greatly of Pect the time of fetal death. It is more Y.rkelybat these substances potentiate the direct action of PGE on myometrial contractility, and it is only during the latter part of the a bL?r. tron process that declining levels of estradiol and progesterone in the uterus may also affect myometrial contractility.
JUNE 1977
VOL. 13 NO. 6
1175
PROSTAGLANDINS
REFERENCES
1.
Symonds, E.M., Fahmy, D., Morgan, C., Roberts, G., Gomersall, R. and Maternal plasma oestrogen and progesterone levels during Tumbull, A.C. therapeutic abortion induced by intra-amniotic injection of prostaglandin F2 a. J. Obstet. Gynaec. &it. C’wlth. 79 876-980 (1972).
2.
Speroff, L., Caldwell, B.V., Brock, W.A., J.C. Hormone levels during PGF2ainfusions 531-536 J. Clin. Endocrinol. Metab. 34 :
3.
Ylikorkala, 0. and Pennanen, S. Human placental lactogen levels in maternal serum during abortion induced by intra- and extra-amniotic injection of prostaglandin F2,. J. Obstet. Gynaec. Brit. C’wlth. 80 : 927-931 (1973).
4.
Shutt, D.A., Smith, I.D. and Shearman, R. P. Changes in oestrogen levels in maternal venous plasma after intra-crmniotic infusion of PGF2, for therapeutic abortion. Prostaglandins 4 : 291-299 (1973).
5.
Newton, J. and Collins, W. Plasma hormone changes during infusions of prostaglandins F2aand E2 for therapeutic abortion. Adv. Biosci. 9 : 689699 (1973).
6.
Craft, I. L., Fer usson, I.L.C., Smith, B. and Youssafnejdian, E. Sex steroid hormone aevels in plasma following intra-amniotic injection of urea J. Obstet. Gynaec. Brit. C’wlth. 80 : 1095-1099 and prostaglandin E2.
Anderson, G. G. and Hobbins, for therapeutic abortion. (1972).
(1974).
7.
Puri, C. P., Rahman, S.A., Jain, A.K., Bhaduri, R., Singh, C.M. Hingorani, V. and Laumas, K.R. Serum hormone levels in women underextra-amniotic or intramuscular admingoing abortion with intraqmniotic, istration of 15(S) 15methyl prostaglandin F2,. Prostaglandins 11 : 905923 (1976).
8.
Jouppila, P., Ylikarkala, O., Karvonen, P., Haapalahti, J. and Suonoja, L. The placental and fetal response to the intraqmniotic injection of Brit. J. Obstet. Gynaec. ~~st;~~;d$ F2a in mid-trimester abortions.
:
9.
Craft,
-
I. L.
(1976). Intro-amniotic
PGE2 and urea for abortion.
Lancet 1
: 779
(1973). 10.
Golbus, M.S. and Erickson, R.P. Mid-trimester abortion induced b intra: fetal tissue viability. Amer. J. Obstet. Gynec. lib : amniotic PGF 268-270 (1974:
11.
Fraser, I.S. and Brash, J.H. prostaglandins for therapeutic (1974).
1176
Comparison of -extra- and intra-amniotic abortion. Obstet. Gynec. 43 : 97-103
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
12.
I.S., Leask, R., Drife, J.O., Bacon, L. and Michie, E.A. Fraser, Plasma estrogen response to dehydroepiandrosterone sulphate injection in normal and complicated pregnancy. Obstet. Gynec. 47 : 152-158(1976).
13.
Scaramuzzi, R.J., Corker, C.S., Young, G. and Baird, D.T. In ‘Steroid Immunoassay’, Proceedings of the Fifth Tenows Workshop, Cardiff, April 1974, pp. 111-122, Eds. E.H.D. Cameron, S.G. Hillier and K, Griffiths, Alpha Omega, Cardiff.
14.
Renou, P. and Wood, C. Interpretation record.
Clinics
in Obstetrics
of the continuous fetal heart rate and Gynaewlogy 1 : 191-216 (1974).
15.
Lauersen, N. l-l. and Wilson, K.H. Mid-trimester abortion induced with Amer.J. a single intro-amniotic instillation of prostaglandin F2,. Obstet. Gynec. 118 : 210-217 (1974).
16.
Fraser,
17.
Galen, R.S., Chauhan, P., Wietzner H. and Navarro, pathology and mechanism of fetal death in saline-induced Amer. J. Obstet. Gynec. 120 : 347-355 (1974).
18.
Kovacs, L., Pesch, B., Szollosi, J. and Herczeg, J. The role of fetal death in the process of therapeutic abortion induced by IAS. J. Obstet. (1970). Gynaec. Brit. C’wlth. 77 : 1132-1136
19.
Raud, H.R., Balsdon, M.J. and Collins, J.A. Serum human chorionic gonadotropin and progesterone following intra-crmniotic in’ection of hypertonic urea. Amer. J. Obstet. Gynec. 113 : 887-864 (1972).
20.
Alsat, E. and Cedard, L. The stimulating action of the prostaglandins on the production of oestrogens by the human placenta perfused in vitro. Prostaglandins 3 : 145-153 (1973).
21.
Siiteri, P.K. and MacDonald, P.C. Placental estrogen biosynthesis durin human pregnancy . J. Clin. Endocrinol. Metab. 26 : 751761 ($966).
22.
Embrey, M.P,, Hillier, K. and Mahendran, P. Induction of abortion Advances in the Biosciences, by extra-amnrotic PGE2 and F2a. 9 : 507-513 (1973).
I.S.
Unpublished observations. Fetal C. abortion.
Received 6/17/75 - Approved 3/d/77
JUNE 1977 VOL. 13 NO. 6
1177
HORMONE DEATH
I.S.
Fraser:
CHANGES AFTER
IN
RELATION
TO
THE TIME
PROSTAGLANDIN-INDUCED
Katherine
M.
Nicholson,
Gail
OF
FETAL
ABORTION
Graham and
H. Boyle
Department of Obstetrics and Gynaecolo ~,.Universi~y of Edinburgh and Simpson Memorial Maternity avrlron, Edmburgh. ABSTRACT The changes in unconjugated estradiol-178 and estriol, progesterone and chorionic somatomammotropin (HCS) in peripheral plasma have been studied in adminis18 women at 30minute intervals following intra-terine prostaglandin tration for therapeutic termination of second trimester pregnancy. The Eaormonal changes were related to the time of fetal death detected by the disappearance of was given by the intra-amniotic route with fetal heart pulsations. Prostaglandin urea (5 patients) or with intravenous o% ocin (5 patients), or by the extra-amniotic route with intravenous oxytocin (8 patients). Fetal death occurred rapidly with intra-amniotic PGE2, but usually at a late stage with extra-amniotic PG . Three fetuses in the extra-amniotic group died at or just before abortion. A vart‘a ty of fetal heart changes were noted and the time of fetal death did not appear to influence the time of abortion within each treatment subgroup. Estradiol and estriol showed a slight but persistent fall over 24 hours prior to induction of abortion. A more rapid fall usually occurred after induction, with a consistent fall around the time of fetal death. Progesterone and HCS usually fell much less before and immediately after fetal death. A marked rise in estradiol sometimes occurred before fetal death, particularly in the intraamniotic PGE and urea subgroup. Estriol levels declined more rapidly before than after fet 4 death, whereas fetal death had less consistent effects on the other hormones. All hormones had usually fallen considerably at the time of abortion, and in some individuals marked fluctuations in hormone levels were seen. ACKNOWLEDGEMENTS The authors are garteful to the consultant staff of the hospital for permission to study their patients, to Sister Revolta and her staff for dedicated nursina care of the wtients. to Dr. Rex Scaramuzzi and Dr. Georae Wilson for gifts 07 the antibodies used \n the radioimmunoassay, to the Upjohi Company for a grant, to Mrs. E.A. Michie for assistance with the endocrine aspects of the study and to Miss Rose Leask for expert technical assistance. Present address and address for correspondence Department of Obstetrics University of Sydney, Australia.
JUNE 1977 VOLi 13 NO. 6
:
and G naecology, New Youth Wales,
2006,
1161
PROSTAGLANDINS
IMRODUCT
ION
Numerous papers have reported changes in plasma hormone concentrations following prostaglandin (PG) therapy for induction of abortion (for example l-8) Most of these report that hormones of fetal and placental origin show a variable fall by the time of abortion but there is much disagreement about details. Differences in the reported results may be due to differences in dosage, types and route of administration of prostaglandins, the use of additional drugs including oxytocin and urea, and to the infrequency of sampling of maternal plasma in some of the studies. The hormone changes have not been closely correlated with the time of fetal death although it has been postulated that the efficacy of intraamniotic PGE when combined with urea is partly due to rapid fetal demise (9). in culture of fetal tissue obtained after On the other Kand, good cell viability suggests that fetal death occurred abortion induced with intro-amniotic PGF shortly before abortion (10). This suggest!%?I is supported by the occasional abortion of a fetus with a heartbeat after intro-uterine PG administration. In this investigation fetal heart rate changes and the time of fetal death have been related to alterations in the levels in maternal plasma of unconjugated estradiol-17R, unconjugated estriol,progesterone and chorionic somatomammotropin (HCS) for three different regimes of PGE2administration. CLINICAL
MATERIAL
AND
METHODS
In a small preliminary study 3 normal primigravid patients were followed and with 1 to 2 hour1 blood samples for 24 hours prior to induction of abortion, with hourly sampr es following induction of abortion with intro-amniotic PGE2. During this time the patients were mainly resting in bed or sitting in a comfortable chair. These samples were assayed for unconjugated estradiol-170 and estriol. In the main study eighteen patients (age 16 to 27) had their pregnancies Statutory approval for therapeutic abortion terminated using intro-uterine PGE . The under the 1967 United Kingdom Ab&tion Act had previously been given. following prostaglandin regimes were used : -
1)
Intro-amniotic PGE2(5 mg) and urea (40 g or 80 g) given single dose by transabdominal amnioover 5 minutes in a centesis.
2)
Intro-amniotic PGE mented by intraven &I Oxytocin was started to a maximum of 240
3)
Extra-amniotic
(10 mg) given in a single dose supples oxytocin starting at the same time. at 30 mu/minute and increased hourly mu/minute.
PGE2 given as described previously
(11)
in a &sage of 2OOpg hourly (total dose 0.4 to 2.5 mg). Simultaneous intravenous oxytocin was given as above.
1162
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
in Table
Parity, 11.
gestation and numbers of patients for each regime are shown
The fetal heart was recorded using a Sonicaid D 205 M ultrasonic fetal heart detector for 4 to 10 minutes every 15 minutes until fetal death. Maternal blood samples were collected in heparinised tubes from an indwelling catheter in the ante-cubital vein every 30 minutes until fetal death (or every 60 minutes if the fetus was still alive after 6 to 8 hours), and every 1 to 2 hours after fetal death until after the abortion of the fetus. In several patients some placental tissue remained in the uterus after abortion and was removed by curettage several hours later. Each blood sam le was centrifuged at 4’C shortly after collection and the plasma stored in - 159C. and estriol were PI asma unconjugated estradiol-178 measured in duplicate by radioimmunoassay using antibodies raised in sheep to estradiol-178-17-hemisuccinate-bovine serum albumen and to estriol 16, 17dihemisuccinate bovine serum albumen(12). Plasma pools run with each assay gave a within-assay variation of 7.9O% for estradiol and 8.4% for estriol, and an interassay variation of 8.5% for estradiol and 15.9% for estriol. Plasma progesterone raised in sheep was measured in duplicate by radioimmunoassay using an antibo to progesterone-l la-bovine serum albumen (13) and giving a wit“k in-assay variation of 8% and an inter-assay variation of 15.7%. Plasma HCS was measured in unextracted plasma in duplicate using a commercially available radioimmunoassay kit (The Radiochemical Centre, Amersham, Bucks, England) and giving a withinassay variation of 9.4% and an inter-assay variation of 14.1%. Samples from each individual patient were usually run in the same assay. RESULTS In the preliminary study plasma estradiol and estriol levels showed a to fall progressively during the 24 hours prior to induction of abortion r and Table 1). Estriol fell slightly in all three patients and estradiol fell ;(,FiKZt of 3 [mean = 27pg/mI/h our for estradiol ; 17 pg/mI/hour for e.strioIJ. Moderate fluctuations in the levels were seen in all three patients(with coefficients of variation of 10.9%, 14.9% and 15.9% for estradiol and 8.9%, 12.0% and 21.4% for estriol). Following induction of abortion both hormones fell markedly prior to abortion.
tendenc
The relationship of the times of fetal death and abortion to the mode of prostaglandin administration in the main study are shown in Table 11. There was no significant difference in the induction+bortion intervals between the three different regimes, and no difference in the time to fetal death for the two intraamniotic regimes. However, the induction to fetal death interval was significantl longer for the extra-amniotic regime than for the other two methods. The tota r cbse of PGE given by the extra-amniotic route was usually considerably less than for the i&ra-amniotic route (11). The fetal heart recordings showed a variet y of patterns which did not appear to be related to changes in plasma hormone eve s or to mode of PG administration :
64
Fairly steady prior to sudden terminal disappearance (9 cases)
JUNE 1977 VOL. 13 NO. 6
bradycardia and
1163
PROSTAGLANDINS
TABLE REGRESSION
EQUATIONS
I
FOR PLASMA
UNCONJUGATED
ESTRIOL FOR 24 HOURS BEFORE TREATMENT ABORTION
INTERVAL
AND
ESfRADlOL
DURING
IN 3 PATIENTS TREATED WITH
INTRA-AMNIOTIC
Estradiol Before Treatment
I
Regression Coefficient (r)
PGE2
Estriol
During InductionAbortion Interval
-0.066
AND
THE INDUCTION-
Before Treatment
During induction kzn
-0.272
I
7
4
\j
dml
(I
‘r
3
I I I I
2
a- ---------
--_____________ -------0
i
II II
I
P-L___
1.
I
0 --__
I 1 I 0
2
1
6
8
ICI
II
I8
22
II
---a1 ’
hf lb
2
4
6
8
10
nom
FIGURE
1
Changes in plasma unconjugated estradiol and estriol levels jn 3 patients admitted to hospital 24 hours before induction of abortion with intra-amniotic PGE (10 mg.). The figure shows the regression lines for one t 2 two hourly blood samples prior to initiation of therapy and during the induction-abortion period.
I = induction of abortion
1164
A = abortion
JUNE 1977 VOL. 13 NO. 6
PGE2 + oxytocin
Extra-amniotic
PGE2 + oxytocin
Intra-amniotic
Intra-amniotic PGE2 + urea
Multiparas
4
2
3
4
1
4
(12-16)
14.1wks
(13-l 8)
15.8wks
Plwk (18-25)
Mean (Range)
GESTATION
(04°0-2550hrs) f 7hrs lmin
9hrs 34mins (08l 0-2550hrs) f 6hrs 1Smins
14hrs 42mins
2hrs 26mins
12hrs 05 mins
(G015-a430h~s) f lhr 39mins
(01 15-0330ht.s) f 55 mins
(0655-2230hrs) f 6hrs 4 mins
(0715-1620hrs) * 4hrs lmin
Phrs 23mins
5kTF
(00 -14 hrs) f 5hrs 44mins
(070°-1 230hrs) f Phrs 3Omins
9hrs 39mins
(0325-2000hrs) f 6hrs 19mins
1Ohrs 2Omins
f SD
f SD
f SD 12hrs 43mins
Mean (Range)
Mean (Ran*)
FETAL DEATH ABORT ION I NT ERVAL
Mean (Range)
INDUCTIONFETAL DEATH INTERVAL
ABORTION
ADMINISTRATION
INDUCTIONABORT ION INTERVAL
OF PROSTAGLANDIN
OF TIMES OF FETAL DEATH AND
-I-
Primi paras
NUMBERS
TO METHOD
RELATIONSHIP
TABLE II
PROSTAGLANDINS
(b)
Increasingly wide swings in rate sometimes progressing to deceleration with contractions (2 cases)
(c)
Increasing tachycardia (2 cases)
before sudden fall and disappearance
(d)
Increasing bradycardia
(2 cases)
(e)
Normal
heartbeat
until 30 minutes before abortion
(3 cases).
One fetus from the extra-amniotic group was born with a heartbeat and two others died within 30 minutes before abortion (Group (e)). All fetuses in the intra-amniotic groups died within 44 hours of PGE2 administration. The hormone than s in maternal plasma immediate1 after fetal death and after abortion are detar.Ye ed in Table III as oercentaaes o r the basal levels. The difference in basal levels is consistent with’the diffgrent gestations of the three treatment groups. The data have been analysed in more detail (Table IV) by calculating the regression equations for each hormone in each treatment group prior to fetal death, and after fetal death but prior to abortion (Figures 2a and 2b). The samples collected immediately after fetal death and immediately after abortion were not included in the pre-fetal death and pre-abortion equations respectively. In the extra-amniotic treatment group (Group III ) there was no overall change in hormone levels during the first few hours of treatment in those cases where fetal death occurred late, so the regression equation for the whole group has been calculated for a period of five hours prior to fetal death. The chcmges in plasma hormone levels in six individual patients are shown in Figures 3 to 5. These have been included in order to illustrate the individual variations in response. Figures detailing changes in plasma levels of all these hormones at such frequent intervals and in relation to fetal death have not been published previously. The main findings of this study were -
1166
(a)
a consistent fall in estradiol and estriol levels during the 30 minutes around fetal death (Figure 2), but little or no fall in progesterone or HCS levels over the same period (except for HCS in the extra-amniotic group) ;
(b)
all hormones had fallen considerably at the time of abortion and usually the major part of this fall had occurred well In some individuals very ra id falls in all before abortion. hormone levels were sometimes seen around t g e time of abortion (Figs. 3a and Sa).
(c)
Progesterone and HCS fell comparatively little prior to fetal death particularly when the fetal death occurred early, except in 3 individual cases (e.g. Fig. 4b). Persistently high levels of HCS and progesterone after abortion were usually related to retained placental tissue (Fig. 3b).
(d)
In the intra-amniotic
PGE2with
urea group (Group I)
JUNE
1977
VOL. 13 NO. 6
Z O
ug/ml
HCS
0.93 ±0.40
0.96 ±0.41
100.0 -+~18.5
77.8 ±48.5
36.1 ±8.7
43.2 4-10.2
122.1 ±63.0
0.80 ±0.46
4.38 ±1.75
J (3)
83.9 4-35.5
80.5 4-21.8
36.4 ±25.0
70. 0 :k37.9
30.2 ±!3.5
56.6 4-27.8
42.5 4-18.8
36.1 4-16.4
% OF CONTROL LEVELS Immediately after Fetal Death (1) (3)
56.2 :~)4.6
31.9 4-26.4
12.7 +-4.9
29.5 ±25.6
(1)
2.2 4-2.2
19.1 4-10.9
12.1 +-4.5
30.5 :1:49.9
5.5 ~:8.4
24.7 ±15.4
28.8 4-26.3
15.8 4-13.5
J
(3)
% OF CONTROL LEVELS Immediately after Abortion
(1) Intra--amniotic PGE2 + urea (5 patients) (2) Intra-amnlotlc PGE2 + oxytocin (5 patients) (3) Extra-amniotic PGE2 + oxytocln (8 patients)
±0.48
1.30
53.4 4-20.0
64.7 4-26.0
ng/'ml
Progesterone
1.32 ±1.20
2.45 4-1.12
ng,/ml
Estriol (unconjugated)
8.12 ±5.48
ng/ml
9.37 ±3.78
I (2)
Estradiol-17B (unconiugated)
J (I)
BASAL LEVELS
HORMONAL CHANGES IN MATERNAL PLASMA IMMEDIATELY FOLLOWING FETAL DEATH AND ABORTION IN 18 PATIENTS UNDERGOING THERAPEUTICABORTION BY THREE DIFFERENTMETHODS OF PROSTAGLANDIN ADMINISTRATION (Mean ± SD)
TABLE III.
c~
~a o
O~
Z O
t-
--.I
O~ OO
111
GROUP
11
GROUP
r
intercept ng/ml regression coefficient
slope n~ml//hr
r
regression coefficient
intercept ng/ml
slope ng/ml/hr
r
1.23 -0.581
-0.292
-0.143
-0.125
5.64
-0.146
3.49
-0.230
-0.020
6.89
-0.084
-0.138
0.78
-0.047
-0.127
0.91
-0.071
-0.444
0.23
-0.024
-0.293
0.44
-0.036
-0.225
30.8
-1.35
-0.205
46.9
-1.97
-0.485
24.5
-2.28
-0.092
35.9
-0.44
-0.385
840
-71
+0.128
850
+37
-0.339
262
-25
-0.347
780
-39
TABLE IV REGRESSION EQUATIONS FOR FOUR HORMONES BEFOREAND AFTER FERAL DEATH AFTERTREATMENTWITH PROSTAGLANDINS (GROUP 1 - INTRA-AMNIOTIC PGE? AND UREA ; GROUP 11 - INTRA-AMNIOTIC PGE2 WITH OXYTOCIN; GROUP 111 - EXTRA-AMNIOTIC PGE2 WITH OXYTOCIN). Estriol Estradiol Progesterone HCS Before After After i Before After Before After Fetal Fetal Feta I Fetal Fetal Fetal Fetal Fetal Death Death Death Death Death Death Death Death slo~ +2.230 -0.860 -0.330 -0.072 -2.67 -4.00 -+25 -74 ng~ml/hr GROUP intercept 8.02 10.94 2.49 0.87 59.1 57.9 1230 1290 n~/ml 1 regression coefficient +0.490 -0.459 -0.398 -0.564 -0.080 -0.392 +0.047 -0.417
==
PROSTAGLANDINS
(a)
Gmupl
14
i
I
12
I
10 n&d
8
I
q
6
I
4 2
-------s
0 I
* ‘0. --_____
1
J
4
- ________ 3
6
I
I
_ _____ 8
7
______ II 12
ItI
8 7 6 5 4 3 2 1
-_____q
0
*---
-__-__
-___-________~,a 7 ",&
d
4
9
Group Ill
ID
i
1'1 lr
13
b"
3
I I I
2 1 0
FIGURE 2(a)
L
5
*____-___-___aM 4
3
10
12
3 tiwn
4
5
Changes in plasma unconjugated estradiol and estriol levels related to fetal death and abortion following treatment with intraamniotic PGE and urea (Group l), intra+mniotic PGE and intraPGE a r-8 intravenaus oxyto a n(Group 11) and extradmniotic venous oxytocin (Group 111). The graphs are derr‘dd from the regression equations of the plasma hormone levels for all patients before fetal death and after in each separate treatrt;; gra x
F/D
JUNE 1977
2
= fetal death
VOL. 13 NO. 6
A = abortion
1169
PROSTAGLANDINS
40 Progesterone ng/ml
30 20
‘0
I
0
I
I
I
I
I
I 10
(123456789
II
12
13
HOUIX Group
P/D 50 40
N
n9hI
i
I
;
_..a.
.---30 c
p---_____ I I
10
I I II
1
2
1.0
I
20
0
II.
4I
I 3
rdml
3’
--.__
---__
----___
----___al,
:I
0.5
:It
4
5
6
7
8
9
1’011
Group
Ill.
A
Ill 12I((
’
13
Hours
F/D 40 q/ml
P _
30;
__---..
I .o.
t
20
FIGURE 2(b) Changes in plasma levels of progesterone and HCS related to fetal death and abortion as detailed in the legend for figure 2(a).
1170
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
4
24
WEEKS
1.0 -
-
~9 /ml
nq /ml 60 0.5
c--o 5
n9M
3
I
24
WEEKS i
i” 2.0
1.5 -
C-l
I.0
nglml
P9lml o-5
.-.
o---o
nqlml
nqlml S 3
I
-&&_-o--v-__._~ 0
4
a
. I2
16
-e10
HOu?S
FIGURE 3
Plasma hormone changes after intraannioticPGE2 and urea in two patients.
1 = Induction of abortion; FD = Fetal Death; A = Abortion; *--a Progesterone; e HCS; Estradiol ; o - - -0 Estriol .
JUNE 1977 VOL. 13 NO. 6
1171
PROSTAGLANDINS
60
40
I.0
20
0.5
-
9-4
lr9lml
nglml
I
16
I
I
LA&
I2 8 4
0
2
b
4
8
16
12
20
HOURS
*--. nglml
------L I
Ii
.-
IZ-
/I
8
I
I.0 o---o nghl
n5hl -0.5
4.41 s\:.-* \b&+_-C_
____-____-__
I I 0
FIGURE 4
2
6
10
14
18
2:
Plasma hormone changes after intramniotic PGE2 with intravenous oxytocin therapy in two patients. Symbols as in Figure 3
1172
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
I.0
40.
hd
m---s nqlm1
P9/‘1 0.5 20.
FIGURE
5
Plasma hormone changes during extraamniotic PGEz and intravenous oxytocin therapy in two patients. Symbols
JUNE 1977 VOL. 13 NO. 6
as in Figure
3
1173
PROSTAGLANDINS
plasma estradiol showed a consistent rise up to and sometimes beyond the time of fetal death (Figure 3). (e)
In all groups following the start of treatment (except initially in Group 1) plasma estradiol and estriol fell more steeply than in the preliminary study group over the 24-hour control period before treatment.
(f)
Marked fluctuations (Figures 3 to 5).
(s)
The rates of decline of each hormone were not consistently altered b fetal death except for estriol which declined faster be rore fetal death than after.
in hormone levels in some individuals
DISCUSSION Knowledge of the approximate timing of fetal death and the chances of delivery of a living fetus after therapeutic abortion using prostaglandins are of relevance in obtaining fresh fetal tissue for tissue culture and histological work and to the current concern about delivery of a live fetus with potential for longterm survival in a damaged state. This study indicates that fetal demise occurs at an early stage following intra-amniotic PGE augmented by urea or oxytocin, whereas fetal death usually occurs at a late sta 8 e with extra-amniotic PGE even when it is augmented with oxytocin. In three out of eight in the extra-am r?rotic group the fetus survived until around delivery with a normal fetal heart pattern. The fetal heart patterns showed similar wide variations to those recorded prior to fetal death in labour at term (14). Two other studies using ultrasonic fetal heart detectors have recorded the mean time of fetal death following intra-amniotic PGF (40 mg) as 14 to 2 hours in and 10.4 hours (8 ; 15). One of these groups expert *Q%zed some difficulty being certain of-the disappearance of the fetal heart due to strong contractfons. This difficulty was not noted in the present study. It seems likely that the time of fetal death is related to the intra-terine pressure changes associated with Following intra-amniotic PGE2 administration prostaglandin administration. (10 ma) there is usuallv a marked increase to 60-90 mmHa in baseline intra;terinYe’pressure within’ 1 to 2 hours, and contractions are”superimposed on this(l6). This could be expected to cause considerable impairment of placental and fetal perfusion. Indeed it has been suggested that combined intra-crmniotic PG and urea exert their effect on steroid levels in maternal plasma b anoxic impa4 ment of the fetoplacental unit leading to early fetal death (6). &th extra-clmniotic PGE administration there is genemlly a much smaller rise in baseline tone which e likely to permit continued placental perfusion between contmctions. The is& h rtonic intra-amniotic urea may have an additional, more direct, deleterious e !pe feet on fetal survival as has been observed with hypertonic saline (17), although in this study fetal death did not occur any earlier in the intra+mniotic urea subIn this study there &es not appear to be any clear relationship between group. the time of fetal death and the time of abortion, which is in agreement with studies PGF2a (8) and hypertonic saline (18). using intra-amniotic
1174
JUNE 1977 VOL. 13 NO. 6
PROSTAGLANDINS
Hormonal changes measured in maternal plasma in this investigation are in general agreement with most other published studies, in spite of the infrequency hormones in of sampliny in many of these _studies. Almost all feto-placentat maternal p asma fa I by the trme of abortion except in rare cases where the fetus survives until abortion. Hormones solely of placental origin tend to fall less than those requiring a fetal contribution. Some fluctuation of the levels of all hormones was seen and may indicate episodic release. This fluctuation (outwith the intro-assay coefficient of variation) was also seen for estradiol and estriol prior to initiation of prostaglandin therapy. Fluctuations have been noted by others (1) but have not been studied by relatively frequent sampling. It is important to note that maternal estradiol and estriol levels may show a small but progressive fall over a 24-hour period before any treatment when the second trimester patient is first admitted to hospital. The large fall in estriol levels at the time of fetal death was not surprising for a hormone which requires continued fetal production of precursors for its synthesis by the placenta, and suggests that changes in fetal probction of precursors are fairly rapidly reflected by changes in circulating levels of maternal hormone. Progesterone is produced mainly, and HCS entirely, by the placenta, and the usual finding of only a small or negligible fall in maternal plasma levels prior to fetal death, and even abortion, indicates that placental synthesis of these hormones is largely unaffected by intro-uterine PGE administration and the presumed uterine hypertonicity associated with rapiBfetal death. This finding is at variance with published data (3) which indicates that there is a dmmatic fall in HCS levels following PGF . It is ssible that PGF and PGE may have differing actions on HCS s$‘thesis. It Pas been reporte d% at hyper 8. nrc urea does not have a specific effect on placental synthesis of these hormones (19), but this study has demonstrated an early sustained rise in estradiol in patients treated with intro-amniotic urea and This might have been due to a stimulatory action of the PGE on PGE plac 3’ntal estrogen synthesis (20) accentuated by urea or to a stress-In *?i uced increase in circulating maternaldehydm~piandmsterone sulphate precursor of adrenal origin(12). The moderate1 elevated levels of estmdiol continuing after fetal death are consistent wit 1: the observation that 50% of circulating estradiol comes from precursors of maternal origin (21). The use of intro-amniotic urea or intravenous oxytocin with intrauterine PGE shortens the induction-abortion interval corn ared with PGE2 alone (9, d, but it ap ears unlikely that they greatly of Pect the time of fetal death. It is more Y.rkelybat these substances potentiate the direct action of PGE on myometrial contractility, and it is only during the latter part of the a bL?r. tron process that declining levels of estradiol and progesterone in the uterus may also affect myometrial contractility.
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REFERENCES
1.
Symonds, E.M., Fahmy, D., Morgan, C., Roberts, G., Gomersall, R. and Maternal plasma oestrogen and progesterone levels during Tumbull, A.C. therapeutic abortion induced by intra-amniotic injection of prostaglandin F2 a. J. Obstet. Gynaec. &it. C’wlth. 79 876-980 (1972).
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Speroff, L., Caldwell, B.V., Brock, W.A., J.C. Hormone levels during PGF2ainfusions 531-536 J. Clin. Endocrinol. Metab. 34 :
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Ylikorkala, 0. and Pennanen, S. Human placental lactogen levels in maternal serum during abortion induced by intra- and extra-amniotic injection of prostaglandin F2,. J. Obstet. Gynaec. Brit. C’wlth. 80 : 927-931 (1973).
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Shutt, D.A., Smith, I.D. and Shearman, R. P. Changes in oestrogen levels in maternal venous plasma after intra-crmniotic infusion of PGF2, for therapeutic abortion. Prostaglandins 4 : 291-299 (1973).
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Newton, J. and Collins, W. Plasma hormone changes during infusions of prostaglandins F2aand E2 for therapeutic abortion. Adv. Biosci. 9 : 689699 (1973).
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Craft, I. L., Fer usson, I.L.C., Smith, B. and Youssafnejdian, E. Sex steroid hormone aevels in plasma following intra-amniotic injection of urea J. Obstet. Gynaec. Brit. C’wlth. 80 : 1095-1099 and prostaglandin E2.
Anderson, G. G. and Hobbins, for therapeutic abortion. (1972).
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Puri, C. P., Rahman, S.A., Jain, A.K., Bhaduri, R., Singh, C.M. Hingorani, V. and Laumas, K.R. Serum hormone levels in women underextra-amniotic or intramuscular admingoing abortion with intraqmniotic, istration of 15(S) 15methyl prostaglandin F2,. Prostaglandins 11 : 905923 (1976).
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Jouppila, P., Ylikarkala, O., Karvonen, P., Haapalahti, J. and Suonoja, L. The placental and fetal response to the intraqmniotic injection of Brit. J. Obstet. Gynaec. ~~st;~~;d$ F2a in mid-trimester abortions.
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Craft,
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(1976). Intro-amniotic
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Golbus, M.S. and Erickson, R.P. Mid-trimester abortion induced b intra: fetal tissue viability. Amer. J. Obstet. Gynec. lib : amniotic PGF 268-270 (1974:
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Fraser, I.S. and Brash, J.H. prostaglandins for therapeutic (1974).
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12.
I.S., Leask, R., Drife, J.O., Bacon, L. and Michie, E.A. Fraser, Plasma estrogen response to dehydroepiandrosterone sulphate injection in normal and complicated pregnancy. Obstet. Gynec. 47 : 152-158(1976).
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Scaramuzzi, R.J., Corker, C.S., Young, G. and Baird, D.T. In ‘Steroid Immunoassay’, Proceedings of the Fifth Tenows Workshop, Cardiff, April 1974, pp. 111-122, Eds. E.H.D. Cameron, S.G. Hillier and K, Griffiths, Alpha Omega, Cardiff.
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Renou, P. and Wood, C. Interpretation record.
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of the continuous fetal heart rate and Gynaewlogy 1 : 191-216 (1974).
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Lauersen, N. l-l. and Wilson, K.H. Mid-trimester abortion induced with Amer.J. a single intro-amniotic instillation of prostaglandin F2,. Obstet. Gynec. 118 : 210-217 (1974).
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Galen, R.S., Chauhan, P., Wietzner H. and Navarro, pathology and mechanism of fetal death in saline-induced Amer. J. Obstet. Gynec. 120 : 347-355 (1974).
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Kovacs, L., Pesch, B., Szollosi, J. and Herczeg, J. The role of fetal death in the process of therapeutic abortion induced by IAS. J. Obstet. (1970). Gynaec. Brit. C’wlth. 77 : 1132-1136
19.
Raud, H.R., Balsdon, M.J. and Collins, J.A. Serum human chorionic gonadotropin and progesterone following intra-crmniotic in’ection of hypertonic urea. Amer. J. Obstet. Gynec. 113 : 887-864 (1972).
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Alsat, E. and Cedard, L. The stimulating action of the prostaglandins on the production of oestrogens by the human placenta perfused in vitro. Prostaglandins 3 : 145-153 (1973).
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Siiteri, P.K. and MacDonald, P.C. Placental estrogen biosynthesis durin human pregnancy . J. Clin. Endocrinol. Metab. 26 : 751761 ($966).
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Embrey, M.P,, Hillier, K. and Mahendran, P. Induction of abortion Advances in the Biosciences, by extra-amnrotic PGE2 and F2a. 9 : 507-513 (1973).
I.S.
Unpublished observations. Fetal C. abortion.
Received 6/17/75 - Approved 3/d/77
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