Acta Obstetricia et Gynecologica.

2006; 85: 1310
1314

ORIGINAL ARTICLE

Prevention of postpartum hemorrhage by uterotonic agents:

comparison of oxytocin and methylergometrine in the management
of the third stage of labor

MIKI FUJIMOTO, KYOUSUKE TAKEUCHI, MAKOTO SUGIMOTO &

TAKESHI MARUO

Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan

Abstract
Objectives. To determine the efficacy of intravenous oxytocin administration compared with intravenous methylergometrine
administration for the prevention of postpartum hemorrhage (PPH), and the significance of administration at the end of the
second stage of labor compared with that after the third stage. Methods. A prospective study was undertaken: two major
groups (oxytocin group and methylergometrine group) of 438 women with singleton pregnancy and vaginal delivery were
studied during a 15-month period. These two groups were subdivided into three subgroups: 1. intravenous injection (two
minutes) group immediately after the delivery of the fetal anterior shoulder, 2. intravenous injection (two minutes) group
immediately after the delivery of the placenta, and 3. drip infusion (20 min) group immediately after the delivery of the fetal
head. In each group, quantitative postpartum blood loss, frequencies of blood loss
/500 ml, and need of additional
uterotonic treatment were evaluated. Results. As compared with methylergometrine, oxytocin administration was associated
with a significant reduction in postpartum blood loss and in frequency of blood loss
/500 ml. The risk of PPH was
significantly reduced with intravenous injection of oxytocin after delivery of the fetal anterior shoulder, compared with
intravenous injection of oxytocin after expulsion of the placenta (OR 0.33, 95%CI 0.11
0.98) and intravenous injection of
methylergometrine after delivery of the fetal anterior shoulder (OR 0.31, 95%CI 0.11
0.85). Conclusions. Intravenous
injection of 5 IU oxytocin immediately after delivery of fetal anterior shoulder is the treatment of choice for prevention of
PPH in patients with natural course of labor.

Key words: Prevention of postpartum hemorrhage, oxytocin, methylergometrine

The prophylactic use of oxytocic drugs reduces the Methods

risk of postpartum hemorrhage (PPH) by about 40%
(1) and has been widely adopted as a routine policy
in the active management of the third stage of labor.
Uterotonic agents such as ergot alkaloids (2) and
oxytocin have been used by various routes of
administration and in markedly different doses with
varying success.
We undertook a prospective study in which
women received either intravenous oxytocin or
methylergometrine by bolus injection or drip infu-
sion. These drugs were administered either before or
after the third stage of labor, in order to compare
their safety and efficacy in the prevention of PPH.
A prospective study was undertaken at the Kobe
University Hospital over 40 consecutive weeks
starting from February 2002. Two major groups
(5 IU of oxytocin and 0.2 mg of methylergometrine)
of 438 women with singleton pregnancy and vaginal
delivery without any modes of augmentation of labor
were studied over a 15-month period. Women were
excluded from the study population if they had had a
previous cesarean section, history of antepartum
hemorrhage or postpartum hemorrhage in a previous
pregnancy, or any contraindication for receiving
uterotonic drugs (e.g. hypertension, cardiac disease).
All women had intravenous access in place. These

Correspondence: Kyousuke Takeuchi, Department of Obstetrics and Gynecology, Tsukaguchi Hospital 6-8-17, Minami-tsukaguchicho Amagasaki 661-0012,
Japan. E-mail: kyousuket@dolphin.ocn.ne.jp

(Received 30 January 2006; accepted 4 April 2006)

ISSN 0001-6349 print/ISSN 1600-0412 online # 2006 Taylor & Francis
DOI: 10.1080/00016340600756912

two groups were subdivided into three subgroups: 1.
intravenous injection group immediately after the
delivery of the fetal anterior shoulder, 2. intravenous
injection group immediately after the delivery of the
placenta, and 3. drip infusion group immediately
after the delivery of the fetal anterior shoulder.
These treatment protocols were assigned based on
a temporal manner, with each given exclusively over
a 6-week period. In intravenous injection groups, the
drugs were placed in 20 ml of saline and adminis-
tered for about two minutes. In drip infusion groups,
the drugs were placed in 100 ml of saline and
administered for about 20 min.
Standardized informed consent was obtained from
each participant. As all six protocols had previously
been routinely used in our delivery ward at the
discretion of the midwives, it was thought to be both
ethically and scientifically justified to undertake this
study to compare their relative efficacy and safety.
During the study period, the third stage of labor was
uniformly managed by clamping the cord within 30 s
after delivery. Controlled traction was applied to the
cord only after a lengthening of the umbilical cord
was noticed when the parturient felt uterine con-
tractions again after the baby was born (signs of
separation of the placenta). The third stage was
managed by midwives. In each group, quantitative
postpartum blood loss, frequencies of blood loss

/500 ml, the need for additional uterotonic treat-
ment, and manual removal of placenta were record-
ed. Changes of hemoglobin concentrations between
admission and 24 h postpartum were calculated.
Other outcomes were side effects such as nausea,
vomiting, headache, chest pain, and hypertension
(diastolic
/100 mmHg or systolic
/150 mmHg).
Blood was collected by covering the area below the
mother’s lower body with plastic sheets that drained
into a basin. Blood loss was carefully determined
until 24 h postpartum, using a measuring receptacle
or weighing the towels used.
Data was prospectively collected using a sheet
attached to the patient’s obstetric chart and com-
pleted by 19 midwives at the delivery room. One of
the researchers prospectively examined the data
sheets and checked that all parameters were an-
swered completely. The information gathered in the
data sheets was then entered into a computerized
database. Statistical analysis was performed by Stat-
View software. Analysis of variance (ANOVA) was
used to compare continuous variables across groups.
Comparison of groups for categorical data was
analyzed with Pearson’s x2 test. Where appropriate,
the odds ratio (OR) with 95% confidence interval
(CI) was calculated. p -values less than 0.05 were
considered statistically significant.
Prevention of postpartum hemorrhage 1311
Results
There were no statistically significant differences in
the six study groups regarding the patients’ mean
age, gravidity, gestational weeks of delivery, duration
of labor, fetal weight, and placental weight. The
duration of the third stage of labor in the intravenous
methylergometrine injection group immediately after
delivery of the fetal anterior shoulder was signifi-
cantly shorter (p B/0.05) than that in the methyler-
gometrine and oxytocin injection group after
expulsion of the placenta (Table I).
There were no significant changes of hemoglobin
concentrations after delivery in the six groups
studied. Blood loss within the first two hours and
24 h after delivery was significantly decreased in the
group of intravenous injection of oxytocin after
delivery of the fetal anterior shoulder, compared
with the other study groups. The risk of PPH was
significantly reduced with intravenous injection of
oxytocin after delivery of the fetal anterior shoulder,
compared with bolus injection of oxytocin after
expulsion of the placenta (OR 0.33, 95%CI 0.11

0.98) and intravenous injection of methylergome-
trine after delivery of the fetal anterior shoulder (OR
0.31, 95%CI 0.11
0.85). The need for repeat
uterotonic injection did not differ significantly in
the six groups studied (Tables II and III). There was
no woman who required manual removal of the
placenta in this study. The incidence of side effects
was low and similar in all the groups studied. There
were no differences in the incidence of high blood
pressure after delivery in the six groups (Table IV).
Discussion
Active management generally involves routine pro-
phylactic administration of uterotonic agents, early
cord clamping and cutting, and controlled cord
traction. In this study, controlled traction was
applied to the cord only after signs of separation of
the placenta. Several large, randomized, controlled
trials (3) suggested that, compared with expectant
management, active management of the third stage
reduces the risk of PPH and the need for therapeutic
uterotonic agents. The administration of uterotonic
agents is one important means to accomplish active
management. Various drugs, routes, and modes
of administration have been tested with varying
success.
This study is unique because we strictly excluded
the patients who received oxytocin infusion for
augmentation or induction of labor, to investigate
the efficacy of uterotonic agents for prevention of
PPH in women with a natural course of labor. The
1312 M. Fujimoto et al.
Table I. Maternal and fetal data presented for each group. Values are shown as mean9/SD. SL/stage of labor, GA/gestational age.

Oxytocin group Ergometrine group

End 2nd SL End 2nd SL After 3rd SL End 2nd SL End 2nd SL After 3rd SL
bolus injection drip infusion bolus injection bolus injection drip infusion bolus injection
n/82 n /95 n/52 n/70 n/79 n /60

Age (years) 29.59/3.72 29.09/4.42 28.29/4.0 28.99/4.24 29.09/5.01 29.69/4.6

Parity 0.939/0.75 0.739/0.76 0.79/0.9 0.599/0.74 0.929/0.98 0.829/0.91
GA (weeks) 39.39/1.09 39.39/1.12 39.19/1.1 39.29/1.01 39.09/1.11 39.19/1.23
Duration of labor (hr) 7.289/6.51 9.109/6.17 9.559/7.08 8.489/6.31 8.119/5.32 8.599/7.55
Duration of 3rd SL (min) 5.59/3.1 5.39/3.7 6.39/2.5* 4.89/2.1 5.19/3.9 6.49/3.0*
Fetal weight (g) 30679/343 30679/310 30429/327 31589/368 30679/348 29649/438
Placental weight (g) 5999/104 5919/113 5869/94.3 6349/108 5939/98 5679/105

*p B/0.01 vs Ergometrine (End 2nd SL) bolus injection.

Table II. Outcome variables in each study group. Values are shown mean9/SD or n (%). SL/stage of labor, PPH/postpartum
hemorrhage.

Oxytocin group Ergometrine group

End 2nd SL End 2nd SL After 3rd SL End 2nd SL End 2nd SL After 3rd SL
bolus injection drip infusion bolus injection bolus injection drip infusion bolus injection
n/82 n/95 n/52 n/70 n /79 n /60

Decrease in Hb before and 0.419/0.88 0.899/0.90 0.889/1.03 0.619/0.82 0.869/0.88 0.839/0.98

after delivery (g/dL)
Blood loss within the first 2 h 2079/185 2889/219 3549/298 3389/211 2769/150 3299/255
after delivery (g)
Blood loss within the first 24 h 3269/206 4179/263 5269/408 4929/256 3959/208 4369/257
after delivery (g)
No. patients with PPH of 6 (7.3) 11 (11.6) 10 (19.2) 13 (18.6) 6 (7.5) 9 (15.0)
]/500 g (%)
No. patients who required 7 (8.5) 9 (9.5) 6 (11.5) 6 (8.6) 3 (3.8) 2 (3.3)
additional oxytocics (%)

main observation in this study is that intravenous
injection of oxytocin immediately after the delivery
of fetal anterior shoulder is more effective in
preventing PPH than other routes and timing of
administration of methylergometrine and oxytocin.
The use of ergot alkaloids increases the risk of
elevated blood pressure and unpleasant maternal
side effects, including nausea, vomiting, and chest
pain. Begley (4) reported that ergotamine induces an
unphysiologic uterine spasm and may interfere with
normal physiologic placenta separation from the
uterine wall, resulting in partial retention of the
placenta. However, in all groups studied, a very low
incidence of side effects was noted and no patients

Table III. Outcome variables in comparative trial of bolus injection of oxytocics. Values are shown mean9/SD or n (%). SL /stage of labor,
PPH/postpartum hemorrhage.

Oxytocin-Oxytocin Oxytocin-Ergometrine

Oxytocin Oxytocin Oxytocin Ergometrine

End 2nd SL After 3rd SL t test or OR End 2nd SL End 2nd SL t test or OR
n/82 n/52 (95% CI) n/82 n/70 (95% CI)

Blood loss within the first 2 h after 2079/185 3549/298 p/0.00058 2079/185 3389/211 p/0.0001
delivery (g)
Blood loss within the first 24 h after 3269/206 5269/408 p/0.00026 3269/206 4929/256 p/0.0002
delivery (g)
No. patients with PPH of ]/500 g (%) 6 (7.3) 10 (19.2) 0.33 (0.11
0.98) 6 (7.3) 13 (18.6) 0.31 (0.11
0.85)
No. patients who required additional 7 (8.5) 6 (11.5) 0.72 (0.22
2.26) 7 (8.5) 6 (8.6) 1.00 (0.31
3.11)
oxytocics (%)
 Prevention of postpartum hemorrhage 1313
Table IV. Side effects in each group. Values are shown as n (%). SL/stage of labor, SBP/systolic blood pressure, DBP/diastolic blood
pressure.

Oxytocin group Ergometrine group

End 2nd SL End 2nd SL After 3rd SL End 2nd SL End 2nd SL After 3rd SL
bolus injection drip infusion bolus injection bolus injection drip infusion bolus injection
n/82 n/95 n/52 n /70 n /79 n /60

Nausea 1 (1.2) 0 (0) 1 (1.9) 2 (2.8) 1 (1.3) 2 (3.3)

Vomiting 0 (0) 0 (0) 1 (1.9) 1 (1.4) 0 (0) 1 (1.7)
Headache 0 (0) 0 (0) 1 (1.9) 2 (2.8) 1 (1.3) 1 (1.7)
Chest pain 0 (0) 0 (0) 0 (0) 1 (1.4) 0 (0) 0 (0)
SBP
/150 mmHg 1 (1.2) 1 (1.1) 0 (0) 3 (4.3) 2 (2.5) 1 (1.7)
DBP
/100 mmHg 0 (0) 0 (0) 0 (0) 1 (1.4) 1 (1.3) 1 (1.7)

required manual removal of the placenta in the study
period. These discrepant findings could be attribu-
ted to the differences of administered dose or
subtypes of ergot alkaloids: in the present study
0.2 mg of methylergometrine was administered be-
cause it had been widely used for prevention of PPH
in Japan, while in the other studies the use of 0.5 mg
ergometrine was used.
The major limitation of the present study is the
rather small sample size and the fact that drugs were
administered in a nonblinded manner, which was
adopted because the immediate nature of care
provided in the delivery room demands complete
knowledge of any drug given to the patient during
delivery. The assessment bias can be limited by
reducing the impact of personal bias towards a
certain drug regimen when determining outcome
parameters because many midwives participated in
this study.
The demonstration of a significant influence of the
timing of uterotonic administration is important, as
few data are available regarding this issue. Jackson
et al. (5) suggest that if controlled cord traction is
used, the timing of oxytocin administration (with
presentation of the anterior shoulder or immediately
following placental delivery) does not alter the rate
of PPH, manual removal of the placenta, and other
outcomes. Because the need for manual removal was
not increased in our trial, the practice of adminis-
tering oxytocin at the time of delivery of the baby is
supported. Soriano et al. (6) reported that both
oxytocin and a mixture of oxytocin and ergometrine
administered after delivery of the fetal head are
associated with a significantly lower rate of PPH,
compared with after placental expulsion. In the
present study, intravenous injection of oxytocin after
the delivery of the fetal anterior shoulder signifi-
cantly reduced blood loss within the first two hours
oxytocin after the placenta was expelled. However,
no significant difference was found in the effective-
ness of methylergometrine administration after the
delivery of the fetal anterior shoulder in decreasing
postpartum blood loss and preventing PPH, com-
pared with methylergometrine administration after
the placenta was expelled.
In this study we also elucidated whether the
administration speed of uterotonic agents had any
influence on the prevention of PPH or the occur-
rence of side effects. Intravenous injection of oxyto-
cin significantly decreased postpartum blood loss
compared with drip infusion of oxytocin. No sig-
nificant difference was found in the effectiveness of
intravenous injection of methylergometrine com-
pared with drip infusion in decreasing postpartum
blood loss. The likely explanation for those differ-
ences is that the half-life of oxytocin is shorter than
ergometrine: when given intravenously, the half-life
of oxytocin is 10 min, while that of methylergome-
trine is 120 min (2). Furthermore, in this study we
strictly excluded women with cardiovascular com-
plications. This might lead to the low incidence of
side effects regardless of administration speed of
uterotonic agents.
In conclusion, our preliminary data suggest that in
the hospital setting intravenous injection of 5 IU
oxytocin after the delivery of the fetal anterior
shoulder can be the drug of choice for prevention
of PPH in women with a natural course of labor. A
larger randomized study is needed to prove its
efficacy.
References
1. Prendiville W, Elbourne D, Chalmers I. The effects of routine
oxytocic administration in the management of the third stage of
labour: an overview of the evidence from controlled trials. Br J
Obstet Gynaecol. 1988;95:3
16.
/ /

and 24 h after delivery, and was more effective in 2. de Groot ANJA, van Dongen PWJ, Vree TB, Hekster YA, van
preventing PPH, compared with administration of Roosmalen J. Ergot alkaloids. Current status and review of
1314 M. Fujimoto et al.
clinical pharmacology and therapeutic use compared with
other oxytocics in obstetrics and gynecology. Drugs. 1998;56:
/ /
523
35.
3. Prendiville WJ, Elbourne D, McDonald S. Active versus
expectant management in the third stage of labour (Cochrane
Review). In: The Cochrane Library, Issue 2. Oxford, UK:
Update Software; 2002.
4. Begley CM. A comparison of ‘active’ and ‘physiological’
management of the third stage of labour. Midwifery. 1990;6: /
3
17.
5. Jackson KW Jr, Allbert JR, Schemmer GK, Elliot M, Hum-
phrey A, Taylor J. A randomized controlled trial comparing
oxytocin administration before and after placental delivery in
the prevention of postpartum hemorrhage. Am J Obstet
Gynecol. 2001;185:873
7.
/ /
6. Soriano D, Dulitzki M, Schiff E, Barkai G, Mashiach S,
Seidman DS. A prospective cohort study of oxytocin plus
ergometrine compared with oxytocin alone for prevention of
/ postpartum haemorrhage. Br J Obstet Gynaecol. 1996;103: / /
1068
73.