Different Doses of Sublingual Misoprostol versus Methylergometrine for the Prevention of Atonic Postpartum Haemorrhage

Abstract

In the poor underdeveloped countries, anaemia is very common in pregnant women. Maternal mortality is four times higher in severely anaemic women than non-anaemic ones and postpartum haemorrhage (PPH) is the most common cause of death. Its main cause is uterine atony, which accounts for more than 70%. The objective of this study is to evaluate the use of sublingual misoprostol in different doses of 600, 800 and1000μg in management of the third stage of labor, with regards to blood loss and incidence of atonic postpartum haemorrhag (APPH).
Double blind randomized controlled study
One thousand and two hundred parturient were studied in a control and three study groups, each composed of 300 women. Methylergometrine 0.2 mg IM injection and sublingual misoprostol 600, 800 and 1000 μg tablets were given to women in control and the three study groups respectively, immediately after delivery.
Duration of the third stage of labour, Blood loss in the third stage of labour, Outcomes in anaemic compared to non-anaemic women, Incidance of atonic postpartum haemorrhage in different groups, Haemoglobin deficit after 24 hrs of delivery, Changes in the women's blood pressure during the study, Side effects of the drug, and, Women's acceptability of sublingual misoprostol administration.
Only significant reduction in blood loss and haemoglobin deficits were seen in the third stage of labour and after delivery in women used misoprostol doses of 800 μg and 1000 μg. The incidences of PPH in studied women and controls were almost similar, ranging between 2 and 3%. Similar results were seen in anaemic and non-anaemic women with a higher incidence of APPH in the non-misoprostol user anaemic women. Side effects of the drug were dose related.
Misoprostol in high dose may be used for managing third stage of labour to reduce maternal morbidity and mortality due to APPH particularly, in the poor underdeveloped countries where, facilities to deliver in health centers, purchase and store the oxytocic ampoules or medically trained persons are not readily available in all places. Benefits of large dose misoprostol outweigh its side effects.

Full text

Different Doses of Sublingual 
229
Different Doses of Sublingual Misoprostol versus Methylergometrine for the Prevention of
Atonic Postpartum Haemorrhage.
Soltan, M.H., El-Gendi, E., Imam, H. H. and Fathi, O
Department of Obstetrics and Gynaecology, El-Menia Faculty of Medicine, El-Menia
University, Egypt.
Abstract:
Objective: In the poor underdeveloped countries, anaemia is very common in pregnant women. Maternal mortality is four times
higher in severely anaemic women than non-anaemic ones and postpartum haemorrhage (PPH) is the most common cause of
death. Its main cause is uterine atony, which accounts for more than 70%.The objective of this study is to evaluate the use of
sublingual misoprostol in different doses of 600, 800 and1000µg in management of the third stage of labor, with regards to
blood loss and incidence of atonic postpartum haemorrhag (APPH).
Study Design: Double blind randomized controlled study
Methods : One thousand and two hundred parturient were studied in a control and three study groups, each composed of 300
women. Methylergometrine 0.2 mg IM injection and sublingual misoprostol 600, 800 and 1000 µg tablets were given to w omen
in control and the three study groups respectively, immediately after delivery.
Outcome Measures:
Duration of the third stage of labour, Blood loss in the third stage of labour, Outcomes in anaemic compared to non-anaemic
women , Incidance of atonic postpartum haemorrhage in different groups,
Haemoglobin deficit after 24 hrs of delivery, Changes in the women’s blood pressure during the study,
Side effects of the drug, and, Women’s acceptability of sublingual misoprostol administration.
Results : Only significant reduction in blood loss and haemoglobin deficits were seen in the third stage of labour and after
delivery in women used misoprostol doses of 800 µg and 1000 µg. The incidences of PPH in studied women and controls were
almost similar, ranging between 2 and 3%. Similar results were seen in anaemic and non-anaemic women with a higher
incidence of APPH in the non-misoprostol user anaemic women. Side effects of the drug were dose related.
Conclusion : Misoprostol in high dose may be used for managing third stage of labour to reduce maternal morbidity and
mortality due to APPH particularly, in the poor underdeveloped countries where, facilities to deliver in health centers, purchase
and store the oxytocic ampoules or medically trained persons are not readily available in all places. Benefits of large dose
misoprostol outweigh its side effects.
Corrospondance :
Prof. Mohamed H. Soltan
Director General
Suzan Mubarak Maternity University Hospital
El-menia, Egypt
email: mohamedsoltan552@hotmail.com
International Journal of Health Sciences, Qassim University, Vol. 1, No.2, (July 2007/Jumada II 1428H)
229

Soltan, M.H. et al
230
Introduction
In the poor underdeveloped countries,
anaemia is very common in pregnant women. (1)
Maternal mortality is four times higher in severely
anaemic women than non-anaemic ones (2) and
postpartum haemorrhage (PPH) is the most
common cause of death. (3) Its main cause is
uterine atony, which accounts for more than 70%. (4)
Active management of the third stage of labor is
recommended for all parturient women. It is the
most effective mean of preventing atonic
postpartum hemorrhage (APPH). It reduces more
than 50% of the PPH risk, and routine prophylaxis
reduces 70% of the need for therapeutic oxitocics
to treat excessive postpartum bleeding. (5)
Several drugs reduce PPH by
stimulating the uterus to contract. Ergot
derivatives have been used for decades,
although oxytocin is the drug of choice in some
centers, methylergometrine is still been used in
some places. Several prostaglandins are used
as second or third line agents. These drugs,
however, must be refrigerated to remain
effective. Moreover, most uterotonics must be
administered by injection, which requires sterile
equipment and training in safe administration,
prerequisites which are unavailable for most
women delivering in poor undeveloped
countries. (6)
Misoprostol, a prostaglandin E1
analogue, is heat stable and can be
administered orally, rectally, or sublingually. A
multicentre study found that misoprostol was
less effective for prophylaxis than intravenous or
intramuscular injections of oxytocin but did not
investigate the possible benefit of misoprostol to
the large number of women who give birth
outside health facilities. (7) Distribution of
misoprostol in Indonesia in certain areas
reduced the frequency of excessive bleeding
and the need for emergency referral to hospitals
for PPH compared with the data from a control
area where misoprostol was not available. (8)
Most of the randomized studies of
prophylactic misoprostol have used oral and
rectal administration, though a recent
pharmacokinetic study showed that sublingual
administration secures the highest peak
concentration and the best bioavailability. (9) A
recent pilot study found that sublingual
misoprostol and intravenous syntometrine have
comparable effects on blood loss in the third
stage of labour. (10) All studies tried misoprostol
doses from 200 to 600 µg and the reported
results were either less effective or similar to the
results of standard oxytocics in reducing third
stage blood loss and PPH incidences. Therefore,
it was necessary to study higher doses of
misoprostol and to compare them with the
oxytocic drug that still been used in some poor
undeveloped countries, methylergometrine. (11)
The aim of the study was to evaluate
the efficacy and safety of various doses of
sublingual misoprostol 600, 800 and 1000 µg
and compare them to methylergometrine for
management of the third stage of labor, with
special emphasis on PPH prevention.
Methods
A prospective randomized controlled
study was carried out on 1200 parturient
delivered in Mallawy general hospital, El-Menia,
Egypt, in the period from April 2002 to Feb.
2003. The study was approved by the ethical
committee of the faculty of medicine, El-Menia
University, Egypt. The husband’s of all women
signed an informed consent before admission of
their wives into the study.
Inclusion criteria were
Full term single living fetus, no medical
disorders associated with pregnancy,
spontaneous and instrumental vaginal
deliveries with or without episiotomy.
Exclusion criteria were
Traumatic postpartum haemorrage,
Cesarean section delivery, blood diseases,
women with chorioamnionities, placenta previa
and abruptio placenta.
Multiple gestation and previous history
of PPH were not excluded.
Cases and controls were subjected to
thorough history taking, physical examination
and routine investigations such as complete
blood count and abdominal ultrasound
examination.
Randomization and allocation of women
to study groups and controls were done through
a computer generation; the study officer handled
out an opaque closed envelope containing the
orders to manage the women according to
planned protocol.
Each of control and the three study
groups was composed of 300 women. The women
in control group were given 0.2 mg IM
methylergometrine, which has been used routinely
in the hospital as part of active management of the

Different Doses of Sublingual 
231
third stage of labour. While women in the study
groups I, II, III were given 600, 800 and 1000 µg of
sublingual misoprostol respectively. The above
medications were given to the mothers
immediately after delivery of the baby.
The outcome measures in the study were
- Duration of the third stage.
- Estimation of blood loss, collected by
graduated plastic bag (7), as well as
weighing the towels, linens, and gauzes.
- Incidence of PPH in different groups.
- Effect of misoprostol on the women’s blood
pressure.
- Haemoglobin deficit after 24 hrs of delivery.
- Outcome in anaemic compared to non-
anaemic women.
- Side effects of misoprostol
- Acceptability of the drug sublingually by the
women.
Placentas were delivered by Brandt’s
Andrew technique. Retained placentas for
more than 30 minutes were removed manually
under general anesthesia. Excess bleeding
before and after placental expulsions was
evaluated and treated according to WHO
recommendation (8).Blood samples were taken
on admission and after 24 hours of delivery for
haemoglobin estimation. Side effects observed
or complained of by studied women and
controls were reported to the nurses and
recorded. Women in the study were asked, if
they had any difficulties or problems tolerating
the drug with the sublingual route.
Calculation and analysis
The average blood loss in the third
stage of labour is 250-350 ml, and 12% of
women will loose > 500 ml (10). Use of
uterotonics should reduce this proportion to 5 %.
(10). According to our calculations we needed 300
women in each group to have a power of 80% (1
- ) with a risk of type 2 error ( ) of 5%.
Data were collected and analyzed using
SPSS program version 11 for windows using
relative risk (RR), t and chi square tests for
statistical significance.
ResultsOne hundred and forty four women
were excluded from analysis because they were
exposed to trauma to the perineum, vagina or
cervix during labour and had traumatic
excessive bleeding. Blood loss in these women
hardly exceeded 500 ml and treated by dealing
with the cause. Table (1) shows that the age
and parity of women in studied and control
groups are not statistically significantly different.
There was no significant difference among study
groups and controls with regards to women with
previous history of PPH, Chi square P = 0.09.
The duration of the third stage of labour
was not significantly different in studied women
compared to control group (Table 2), there were
five cases of retained placenta required manual
removal under general anesthesia. These cases
were distributed as follow: one in control group,
one in studied group I (RR 0.9), one in studied
group II (RR 0.98) and two cases were in study
group III (RR 2.05).
Table (1). Comparison of age and parity between studied groups and controls.
GROUPS AGE
Mean ±SD T P Parity
Mean ±SD T P
Controls 25±5.9 - - 1.7±1.9 - -
group I 26±6.4 1.64 0.1 1.7±1.76 0.29 0.77
Group II 26.4±5.9 1.29 0.197 1.7±1.78 0.07 0.94
Group II 26±5.6 0.521 0.603 1.8±2.02 0.66 0.504
Table (2). Comparison between the duration of the third stage in minutes in the four groups.
Groups Mean ± SD T P
Controls 8.6±3.1 - -
Group I 8.3±3.3 1.3 0.19
Group II 8.5±3.36 0,302 0.76
Group III 8.4±3.16 0.68 0.32

Soltan, M.H. et al
232
Table (3) shows that third stage blood
loss in women of study group I is not statistically
different from women in control group, while,
blood loss in women of studied groups II and III
are significantly reduced in comparison to
women of the control group. Cases of atonic
PPH in the whole study were 29, an incidence of
2.7%, they were distributed as follow: seven
cases in control group, in one case, the PPH
was severe with blood loss exceeding 1000 ml
and the women had blood transfusion. The other
six cases had average blood loss between 500
– 1000 ml. In studied group I, there were seven
cases, their blood losses were average amount
between 500 – 1000 ml.
In studied group II there were nine cases
of APPH; in one case the PPH was severe and
intractable required total abdominal hysterectomy.
She received 3000 ml of blood transfusion, and
the remaining eight cases had an average blood
loss. In group III, APPH occurred in six cases with
average blood loss, without need for blood
transfusion. Extra oxytocic drugs particularly,
intravenous oxytocin infusion was used in all 29
cases developed APPH.
Table (4), shows the haemoglobin
deficit between the admission and the 24 hrs
post-delivery levels. It can be seen that there
are no significant differences between studied
group I and control group; however, this deficit is
statistically significantly reduced when studied
groups II, III are compared with controls.
Table (3). comparison between amounts of blood loss in ml among the four groups.
Groups Mean ± SD T P
Controls 149.3±104 - -
Group I 143±111.1 0.66 0.508
Group II 131.2±92 2.11 0.03
Group III 128±67 2.7 0.006
Table (4). Comparison between haemoglobin deficit in g/dL among the four groups.
Groups Hb deficit Mean ± SD T P
Controls O.46±0.4 - -
Group I 0.4±0.42 1.8 0.06
Group II 0.38±0.4 2.2 0.02
Group III 0.3±0.4 2.3 0.01

Different Doses of Sublingual 
233
Table (5), shows the third stage
outcome in anaemic and non-anaemic
subgroups. The incidence of anaemia
(haemoglobin less than 10.5 g/ ml) in the
studied population was 28.5%. It can bee seen
from this table that the third stage blood loss is
non-significantly higher in the anaemic than the
non-anaemic women. The incidence of APPH in
control group (misoprostol non-user) is higher in
anaemic than non-anaemic women (4.5% Vs
2%), while these incidences are similar in the
three studied groups.
Table (6), shows the side effects of both
methylergometrine and misoprostol used in the
study. It can be seen that the differences
between side effects in studied women and
controls is highly statistically significant and they
are dose related. The incidence of shivering in
the 600µg, 800µg, 1000µg and control groups
are29%, 33% 35% and 10.6% respectively.
Similarly, fever incidences follow the same
pattern, it is 8%, 9.6%, 13.6 and 2%
respectively. None of the studied women
complained of headache or chest pain.
Table (5). The outcome in anemic and non-anemic women of the study. G=group ,M=mean,* Chi 2 =6.3 P=0.09.
Anemic status Controls N=266 Study G (I)
N=271 Study G(II) N=269 Study G (III) N=278
Anemic:
Number
M. blood loss
PPH cases
66 (24.8%)
152.5±97.2
3 (4.5%)
75 (27.6%)
154.9±99.3
2 (2.6%)
82 (30.4%)
149.5±101.3
3 (3.6%)
97 (30.3%0
158.5±100.5*
2 (2.5%)
Non-anemic:
Number
M. blood loss
PPH cases
200(75.2%)
139.6±105
4 (2%)
196(72.4%)
122.7±102.1
5 (2.5%)
187 (69.6%)
123.6±150
6 (3.5%)
181 (69.7%)
119.4±102.1
4 (2.5%)
Table (6). Side effects of sublingual misoprostol among study groups and control. *Chi 2= 63.1, P=0.0001,
G=group.
Side effect Control G. Study G.(I) Study G. (II) Study G.(III)
Shivering 32 (12.1%)
88 (32.5%)
RR= 3.57
100 (37.1%)
RR= 4.3
121 (46.5%)*
RR= 6.3
Fever 6 (2.3%)
25 (9.2%)
RR= 4.4
29 (10.7%)
RR= 5.2
41 (15.7%)*
RR= 8.1
Vomiting 12(4.6%) 10 (3.6%) 21 (7.8%) 41 (15.7%)*
Diarrhea 4 (1.5%) 2 (0.8%) 5 (1.9%) 3 (1.2%)*

Soltan, M.H. et al
234
Table (7) shows statistically significant
drop in systolic and diastolic blood pressure in
the studied group III in comparison to control
group, while the other two studied groups do not
show such change. This drop in blood pressure
was commonly associated with shivering and
fever and did not require treatment.
Twenty eight women (4.6%) in studied
groups II and III (11 {3.6%} in group II and 17
{5.6%} in group III) reported unpleasant
sensation of having too many tablets under the
tongue, this had made them nauseated and
sometime they swallowed some particles of the
tablets, however, none of these women spitted
the tablets out of their mouth nor requested
discontinuation of the trial.
Discussion
Reduction of postpartum blood loss at
primary care level, in rural areas and first line
health care units has been thought of for
decades. Because the misoprostol drug is
cheap, stable at room temperature, rapidly
absorbed after oral, rectal and sublingual routes;
and has strong uterotonic effect, it was thought
to be ideal for this purpose especially in poor
underdeveloped countries.
Multiple controlled trials investigating
misoprostol as a prophylactic agent to prevent
postpartum bleeding have been reported (14 – 20).
A systematic review of randomized controlled
trials of oral or rectal misoprostol to prevent
postpartum hemorrhage concluded that the
traditional injectable preparations were more
effective than misoprostol as part of active
management of the third stage of labor. (21) The
results of this study showed that sublingual
misoprostol in a dose of 600 µg was as good as
methylergometrine and higher doses (800 and
1000 µg) were significantly better than the
injectable methylergometrine in reducing third
stage blood loss and haemoglobin deficit.
Therefore, it is possible that the effect of
misoprostol is a dose related one.
High doses of misoprostol have been
used to treat the established postpartum
haemorrhage without serious side effects. (12, 16)
As well as the reported results of using low or
average doses of misoprostol, which produced
an effect either less or similar in reducing third
stage blood loss and PPH incidence compared to
injectable oxytocics, this has encouraged us to
take the initiative to try high doses of misoprostol
for management of the third stage of labour. (22)
The results of this study show that third
stage blood loss, haemoglobin deficit were
significantly reduced in women used high doses of
misoprostol. This has not been reported with 600µg
or less neither in this study nore in previous other
studies. (22) The PPH incidence in our study
population is 2.7% which is remarkably less than
the reported incidences in general obstetric
population 5 – 15% (23), therefore, the sublingual
route of high dose misoprostol may have more
potential forboth prophylactic and active postpartum
hemorrhage treatment.
Anaemia is prevalent in pregnant women
worldwide, particularly, in the poor underdeveloped
countries; it was interesting to look at the
performance of anaemic women receiving
misoprostol in the study. It is not surprising to see
that there was no significant difference between
anaemic and non-anaemic women with regards to
third stage blood loss, as misoprostol acts to
stimulate uterine muscle contractions after reaching
its peak concentration. However, the incidence of
APPH in anaemic control group (women not using
misoprostol) in this study was higher than non-
anaemic women, which suggests that misoprostol
may have a protective effect against APPH in third
stage in anaemic pregnant women.
Table (7). Comparison of the changes in mean blood pressure in mmHg among the four groups.
Groups Mean change in
systolic BP T P Mean change in
diastolic BP T P
Controls 1.4±6.5 - - 0.67±9.2 - -
Group I 0.8±8.4 0.53 .53 0.2±9.5 0.88 0.3
Group II 0.69±9.2 1.02 0.3 0.32±6.2 1.2 0.2
Group III 0.67±9.2 2.3 0.01 0.67±7.4 3.4 0.001

Different Doses of Sublingual 
235
Duration of the third stage of labour was not
statistically different between study and control groups.
This is in agreement with results of all previous
misoprostol studies. Because the cease of bleeding in
uncomplicated third stage of labour normally occurs
within 10 min after delivery, and the peak
concentration of sublingual misoprostol is usually
reached after 26 min (9) , Therefore one would not
expect that the drug effect the third stage duration. (24)
It is difficult to explain the drop in blood
pressure that occurred in the 1000µg group,
especially, the majority of these women had
simultaneous shivering and fever. However, the
blood pressure of these women had returned to
normal within short time without treatment.
Adverse effects of misoprostol are dose
related this fact has been supported by the results of
our study. Lumbiganon et al (25) reported that of 843
women treated with 600 µg of oral misoprostol, 13%
had shivering within 1 hour of delivery and more than
11% had pyrexia between 2 and 6 hours postpartum.
Another study investigating 600 µg of oral misoprostol
given in the third stage of labor reported an incidence
of shivering of 22%. (17) A more recent study reported
the incidence of shiveringand fever decreased to 11%
and 4%, respectively with 400 µg of misoprostol given
orally at cord clamping. (26) One small studyevaluating
70 women who received either 400 µg or 200 µg of
rectal misoprostol in the postpartum period reportedan
overall incidence of shivering in 7%, but whether the
patient received 400 or 200 µg was not clearly noted.
(27) The incidences of shivering and fever reported in
our study are higher than other studies. However,
these adverse effects of misoprostol were of temporary
nature lasting only for short time, they neither cause
serious or permanent damage nor require a specific
treatment; therefore, the mother should be informed
that she would expect a temporarily shivering and
fever after delivery. And higher doses of misoprostol
should not be dismissed from the routine evaluation to
prevent PPH.
The problem of unpleasant feeling of
having too many tablets under the tongue,
observed in our study may be overcome by
manufacturing the 800 and 1000µg in a single
tablet for comfortable easy use.
Conclusion
The benefits of using large dose
misoprostol to prevent maternal morbidity and
mortality due to APPH outweigh the temporary
side effects, especially in the poor
underdeveloped countries, where giving birth in
health facilities is not available at all places for
more than half of obstetric population.
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