# njm 11/13/03

Q. Are there risk factors that suggest a provider should automatically
move to treatment modalities to prevent postpartum hemorrhage?

A. There is not Level I data to support the automatic use of treatment
modalities, other than the active management of labor. See below

Q. Is rectal misoprostol the first line agent for treating postpartum
hemorrhage, now?

A. No, rectal misoprostol is not the first agent for treating PPH, but
there is more to the story.

First, let's distinguish between **treatment modalities**, per se, and
the use of **prophylactic** **modalities**

## [I. Prophylactic modalities]{.underline}

Prophylactic modalities include those management options that seek to
[prevent]{.underline} post partum hemorrhage before it begins.

### Active management of the third stage of labor

Active management involves administration of a prophylactic oxytocic
before delivery of the placenta, and usually early cord clamping and
cutting, and controlled cord traction of the umbilical cord. These
modalities have been well proven in multiple randomized controlled
trials and are standard of care.

Given the benefit of injectable oxytocin in terms of reducing postpartum
haemorrhage and the need for therapeutic oxytocics, when compared to
using no uterotonic, there appears to be a clear practice implication in
favour of using oxytocin.

### Use of prostaglandins

Karkanis et al reported in a randomized controlled trial that "Rectal
misoprostol is of equivalent efficacy to parenteral oxytocin for the
prevention of primary postpartum hemorrhage. Rectal misoprostol is an
appropriate uterotonic agent for routine management of the third stage
of labour."

On balance though, the Cochrane Library still states "Misoprostol should
not replace injectable uterotonics in the routine management of the
third stage of labour." See Resources below.

#### II. Risk Factors

Are there risk factors that suggest a provider should automatically move
to treatment modalities to prevent postpartum hemorrhage?

## Here are some risk factors listed by decreasing odds ratios from case control studies

Prolonged third stage (odds ratio \[OR\] 7.56)\
Mediolateral episiotomy (OR 4.72)\
Previous postpartum hemorrhage (OR 3.55)\
Twins (OR 3.31)

Arrest of descent (OR 2.91)\
Soft tissue lacerations (OR 2.05)

Asian (OR 1.73) or Hispanic (OR 1.66) ethnicity\
Labor augmented by
[oxytocin](../../../../../../../../application/topic.asp%3Ffile=drug_l_z/190133&drug=true)
(OR 1.66)\
Operative delivery (OR 1.66)\
Midline episiotomy (OR 1.58)

Nulliparity (OR 1.45).

Some other factors having an association with hemorrhage were: general
anesthesia (adjusted odds ratio 2.94), amnionitis (odds ratio 2.69),
preeclampsia (2.18), protracted active phase of labor (2.40),
second-stage arrest (1.90), and Hispanic ethnicity (1.82). After
adjustment for these variables, a classic uterine incision had a small
but significant association (odds ratio 1.06) with hemorrhage. (Combs
1991)

Still other risk factors that have been associated with postpartum
hemorrhage include induced labor, obesity, hydramnios, high multiparity,
macrosomia, prolonged labor, rapid labor, intraamniotic infection, and
use of uterine relaxing agents.

As you can see there is some overlap between the lists. There are also
some factors on one list, that are discounted on the other list. On
balance, there is not Level I data to support the automatic use of
treatment modalities, other than the active management of labor,
described above.

## [III. Treatment modalities]{.underline} 

Postpartum hemorrhage (PPH), an estimated blood loss greater than 500
ml. PPH, is subdivided into [primary]{.underline} and
[secondary]{.underline} hemorrhage. Primary PPH is any abnormal or
excessive bleeding from the birth canal occurring between birth and 24
hours.

Secondary PPH is any abnormal or excessive bleeding from the birth canal
occurring between 24 hours and 12 weeks postnatally. In developed
countries, two per cent of postnatal women are admitted to hospital with
this condition, half of them undergoing uterine surgical evacuation; in
developing countries it is a major contributor to maternal death.

Rectal misoprostol does have a role in PPH therapy, but considering the
delayed onset of action of rectal misoprostol, it should be reserved for
use after more rapidly active agents. Here is reasonable approach from
UpToDate.

# UpToDate

**Treatment of postpartum hemorrhage, by [Allan J Jacobs,
MD](../../../../../../../../application/author.asp%3FID=480338)**

The initial procedures to follow upon diagnosis of excessive vaginal
bleeding are:

Begin fundal massage.\
\
Ensure intravenous access, preferably with a large bore catheter (eg, 16
gauge).\
\
Administer uterotonic drugs such as:

i\.
[Oxytocin](../../../../../../../../application/topic.asp%3Ffile=drug_l_z/190133&drug=true)
10 to 40 U in 1 liter of normal saline

ii\. Methergine 0.2 mg intramuscularly if no hypertension (never
intravenously)

iii\. [Carboprost
tromethamine](../../../../../../../../application/topic.asp%3Ffile=drug_a_k/43540&drug=true)
(Hemabate) 250 µg IM every 15 to 90 minutes, as needed, to a total dose
of 2 mg.

iv\.
[Misoprostol](../../../../../../../../application/topic.asp%3Ffile=drug_l_z/169662&drug=true)
800 to 1000 µg rectally has also been reported to be effective in one
randomized and one nonrandomized study. Unlike methergine and
carboprost, misoprostol can be given to women with hypertension or
asthma.

Infuse large amounts of crystalloid to prevent hypotension.\
\
Transfuse blood products, as needed, to maintain adequate tissue
perfusion and oxygen delivery and prevent coagulopathy. ([See
\"Indications for red cell
transfusion\"](../../../../../../../../application/topic.asp%3Ffile=transfus/8375)
and [see \"Use of red blood cells for
transfusion\"](../../../../../../../../application/topic.asp%3Ffile=transfus/5967)).

If these measures are not immediately successful in controlling
hemorrhage, the woman is placed in stirrups in a room with facilities
for general anesthesia and both vaginal and abdominal surgery.

## 

## UpToDate

**Treatment of postpartum hemorrhage, by [Allan J Jacobs,
MD](../../../../../../../../application/author.asp%3FID=480338)**

<http://www.uptodateonline.com/application/topic.asp?file=postpart/4483&type=A&selectedTitle=1~8>

## 

## [I. Resources: Prophylaxis / Prevention of PPH]{.underline}

##### UpToDate

**Management of the third stage of labor, by [Frank Silverman,
MD](../../../../../../../../application/author.asp%3FID=542873)**

<http://www.uptodateonline.com/application/topic.asp?file=labordel/10159&type=A&selectedTitle=4~8>

**Prendiville WJ, Elbourne D, McDonald S** Active versus expectant
management in the third stage of labour (Cochrane Review). In: *The
Cochrane Library*, Issue 4, 2003. Chichester, UK: John Wiley & Sons,
Ltd.

<http://www.ihs.gov/MedicalPrograms/CIR/cir-cochrine-library-gateway.asp>

### Background 

Expectant management of the third stage of labour involves allowing the
placenta to deliver spontaneously or aiding by gravity or nipple
stimulation. Active management involves administration of a prophylactic
oxytocic before delivery of the placenta, and usually early cord
clamping and cutting, and controlled cord traction of the umbilical
cord.

### Reviewers\' conclusions 

Routine \'active management\' is superior to \'expectant management\' in
terms of blood loss, post partum haemorrhage and other serious
complications of the third stage of labour. Active management is,
however, associated with an increased risk of unpleasant side effects
(eg nausea and vomiting), and hypertension, where ergometrine is used.
Active management should be the routine management of choice for women
expecting to deliver a baby by vaginal delivery in a maternity hospital.
The implications are less clear for other settings including domiciliary
practice (in developing and industrialised countries).

### Implications for practice 

Routine \'active management\' is superior to \'expectant management\' in
terms of blood loss, PPH and severe PPH and other serious complications
of the third stage of labour. When ergometrine is a component of the
oxytocic, active management is associated with an increased risk of
unpleasant side effects (eg nausea and vomiting), and hypertension.
Active management should be routine for women expecting a vaginal
delivery in a maternity hospital. There is no evidence to suggest that
this recommendation should not also include home births and birth centre
births in a developed country situation.

**Elbourne DR, Prendiville WJ, Carroli G, Wood J, McDonald S**
Prophylactic use of oxytocin in the third stage of labour (Cochrane
Review). In: *The Cochrane Library*, Issue 4, 2003. Chichester, UK: John
Wiley & Sons, Ltd.

<http://www.ihs.gov/MedicalPrograms/CIR/cir-cochrine-library-gateway.asp>

### Background 

Many maternal deaths across the world result from complications of the
third stage of labour (when the placenta is delivered).

### Reviewers\' conclusions 

There are strong suggestions of benefit for oxytocin in terms of
postpartum haemorrhage, and the need for therapeutic oxytocics, but
without sufficient information about other outcomes and side-effects it
is difficult to be confident about the trade-offs for these benefits,
especially if the risk of manual removal of the placenta may be
increased. There seems little evidence in favour of ergot alkaloids
alone compared to either oxytocin alone, or to Syntometrine, but the
data are sparse. More trials are needed in domiciliary deliveries in
developing countries, which shoulder most of the burden of third stage
complications.

### Implications for practice 

Before making major changes to practice based on the current review,
further information from other reviews considering the role of active
management ([Prendiville 2000](#O-16)), of any uterotonic (Elbourne et
al forthcoming), of prostaglandins ([Gülmezoglu 2000](#O-9)), and of
ergot alkaloids ([McDonald 1999](#O-12)) needs to be taken into account.

Nevertheless, given the benefit of oxytocin in terms of reducing
postpartum haemorrhage and the need for therapeutic oxytocics, when
compared to using no uterotonic, there appears to be a clear practice
implication in favour of using oxytocin. This has to be tempered,
however, by the knowledge that there is insufficient information about
most other outcomes and side-effects, and that all the trials were
conducted in hospitals and/or developed country settings.

Similarly, although the data are sparse, the balance of evidence
suggests does not support the prophylactic use of ergot alkaloids alone
(in contrast to either oxytocin alone, or to Syntometrine).

**Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ** Prostaglandins for
prevention of postpartum haemorrhage (Cochrane Review). In: *The
Cochrane Library*, Issue 4, 2003. Chichester, UK: John Wiley & Sons,
Ltd.

<http://www.ihs.gov/MedicalPrograms/CIR/cir-cochrine-library-gateway.asp>

### Background 

Prostaglandins have mainly been used for postpartum haemorrhage when
other measures fail. Misoprostol, a new and inexpensive prostaglandin E1
analogue, has been suggested as an alternative for routine management of
the third stage of labour.

### Reviewers\' conclusions 

Neither intramuscular prostaglandins nor misoprostol are preferable to
conventional injectable uterotonics as part of the active management of
the third stage of labour especially for low-risk women. Future research
on prostaglandin use after birth should focus on the treatment of
postpartum haemorrhage rather than prevention where they seem to be more
promising.

### Implications for practice 

Misoprostol should not replace injectable uterotonics in the routine
management of the third stage of labour. Misoprostol for this indication
is less effective, has more side-effects and is not necessarily less
costly in developing countries ([Mozambique 2001](#S-10)). The choice of
injectable uterotonic should be decided upon by considering the
advantages and disadvantages of oxytocin, ergometrine, or a combination.

There is currently insufficient evidence to justify the use of
misoprostol prophylactically when other uterotonics are not available.
Efforts should be devoted to making injectable uterotonics available
especially using strategies such as that of disposable prefilled
syringes, e.g. Uniject ([PATH 2001](#O-12)). Developing the skills to
administer injections in areas where this is not currently available
will have the additional benefit of enabling other effective treatments
such as parenteral antibiotics or anticonvulsants to be used.
Misoprostol has several other effective indications in obstetrics and
gynaecology for which it should be used.

Neither intramuscular prostaglandins nor misoprostol are preferable to
conventional uterotonics in the management of the third stage of labour
especially for low-risk women.

It should be remembered that even when the best preventive strategy for
postpartum haemorrhage is offered, three per cent to four per cent of
all women in different populations will still have \>= 1000 ml of blood
loss after delivery. Even in developed countries, severe postpartum
haemorrhage is still the most prevalent obstetric morbidity.

**McDonald S, Prendiville WJ, Elbourne D** Prophylactic syntometrine
versus oxytocin for delivery of the placenta (Cochrane Review). In: *The
Cochrane Library*, Issue 4, 2003. Chichester, UK: John Wiley & Sons,
Ltd.

Background

The routine prophylactic administration of an oxytocic agent is an
integral part of active management of the third stage of labour. These
agents help prevent postpartum haemorrhage.

Reviewers\' conclusions

The use of the combination preparation syntometrine (oxytocin and
ergometrine) as part of the routine active management of the third stage
of labour appears to be associated with a statistically significant
reduction in the risk of postpartum haemorrhage when compared to
oxytocin where blood loss is less than 1000ml. No difference was seen
between the groups using either five or 10 international units for blood
loss equal to or greater than 1000 millilitres. This needs to be weighed
against the more common adverse effects associated with the use of
syntometrine.

Implications for practice

The evidence from this review suggests a small risk reduction when
ergometrine-oxytocin (Syntometrine) is used and blood loss exceeds 500ml
but not 1,000ml. There are significant side-effects of vomiting and
hypertension associated with the use of ergometrine-oxytocin. The
implications for practice in this situation of competing risks must
depend on the different weights placed upon these outcomes.

-Caliskan E, Dilbaz B, Meydanli MM, Ozturk N, Narin MA, Haberal A. Oral
misoprostol for the third stage of labor: a randomized controlled trial.
Obstet Gynecol. 2003 May;101(5 Pt 1):921-8.

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12738151&dopt=Abstract>

[CONCLUSION:]{.underline} Oral misoprostol alone is as effective as
oxytocin alone for the prevention of postpartum hemorrhage; it is less
effective than oxytocin plus methylergonovine maleate and oral
misoprostol plus oxytocin.

-Karkanis SG, Caloia D, Salenieks ME, Kingdom J, Walker M, Meffe F,
Windrim R.\
Randomized controlled trial of rectal misoprostol versus oxytocin in
third stage management. J Obstet Gynaecol Can. 2002 Feb;24(2):149-54.

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12196880&dopt=Abstract>

[CONCLUSION:]{.underline} Rectal misoprostol is of equivalent efficacy
to parenteral oxytocin for the prevention of primary postpartum
hemorrhage. Rectal misoprostol is an appropriate uterotonic agent for
routine management of the third stage of labour.

#### II. Resources: Risk factors for of Post partum hemorrhage

##### UpToDate

**Management of the third stage of labor, by [Frank Silverman,
MD](../../../../../../../../application/author.asp%3FID=542873)**

<http://www.uptodateonline.com/application/topic.asp?file=labordel/10159&type=A&selectedTitle=4~8>

### UpToDate,Table 1 Causes of postpartum hemorrhage

<http://www.uptodateonline.com/application/image.asp?file=obst_pix/cause54.gif>

Combs CA, Murphy EL, Laros RK Jr. Factors associated with hemorrhage in
cesarean deliveries. Obstet Gynecol. 1991 Jan;77(1):77-82.\
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1984231&dopt=Abstract>

A case-control study was performed to study risk factors for hemorrhage
in cesarean deliveries. Hemorrhage was defined by a pre- to
post-delivery hematocrit decrease of 10 points or more or by the need
for red-cell transfusion. Patients with antenatal bleeding were
excluded. Among 3052 cesarean deliveries, hemorrhage occurred in 196
cases (6.4%). Three controls were matched to each case and multiple
logistic regression was used to control for covariance among predictor
variables. Factors having a significant association with hemorrhage
were: general anesthesia (adjusted odds ratio 2.94), amnionitis (odds
ratio 2.69), preeclampsia (2.18), protracted active phase of labor
(2.40), second-stage arrest (1.90), and Hispanic ethnicity (1.82). After
adjustment for these variables, a classic uterine incision had a small
but significant association (odds ratio 1.06) with hemorrhage. Previous
cesarean, parity, gestational age, and several other factors had no
association with hemorrhage. These data allow one to anticipate
hemorrhage in patients at risk and may be useful in planning appropriate
use of blood bank resources, including antepartum autologous blood
donation.

[III. Resources: Treatment of PPH]{.underline}

Khan RU, El-Refaey H. Pharmacokinetics and adverse-effect profile of
rectally administered misoprostol in the third stage of labor. Obstet
Gynecol. 2003 May;101(5 Pt 1):968-74.

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12738159&dopt=Abstract>

The rectal route group had a mean maximum serum concentration 144 pg/mL
lower than that for the oral route (95% CI 63, 225). This maximum was
achieved on average 23 minutes later than in the oral group (95% CI 10,
35).

[CONCLUSION:]{.underline} Misoprostol administered rectally is
associated with lower peak levels and a reduction in adverse effects
compared with the oral route. Increasing rectal doses may achieve higher
efficacy without reducing the acceptability of the treatment.**\
**

**Mousa HA, Alfirevic Z** Treatment for primary postpartum haemorrhage
(Cochrane Review). In: *The Cochrane Library*, Issue 4, 2003.
Chichester, UK: John Wiley & Sons, Ltd.

<http://www.ihs.gov/MedicalPrograms/CIR/cir-cochrine-library-gateway.asp>

### Background 

Primary postpartum haemorrhage is one of the top five causes of maternal
mortality in both developed and developing countries.

Reviewers\' conclusions

Rectal misoprostol in a dose of 800 micrograms could be a useful \'first
line\' drug for the treatment of primary postpartum haemorrhage. Further
randomised controlled trials are required to identify the best drug
combinations, route, and dose for the treatment of postpartum
haemorrhage.

### Implications for practice 

Rectal misoprostol in a dose of 800 micrograms may be a useful \'first
line\' drug for the treatment of primary postpartum haemorrhage.

**Alexander J, Thomas P, Sanghera J** Treatments for secondary
postpartum haemorrhage (Cochrane Review). In: *The Cochrane Library*,
Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.

<http://www.ihs.gov/MedicalPrograms/CIR/cir-cochrine-library-gateway.asp>

### Background 

Secondary postpartum haemorrhage is any abnormal or excessive bleeding
from the birth canal occurring between 24 hours and 12 weeks
postnatally. In developed countries, two per cent of postnatal women are
admitted to hospital with this condition, half of them undergoing
uterine surgical evacuation; in developing countries it is a major
contributor to maternal death

### Reviewers\' conclusions 

No information is available from randomised controlled trials to inform
the management of women with secondary postpartum haemorrhage. This
topic may have received little attention because it is perceived as
being associated with maternal morbidity rather than mortality in
developed countries; it is only recently that the extent and importance
of postnatal maternal morbidity has been recognised. A well designed
randomised controlled trial comparing the various drug therapies for
women with secondary postpartum haemorrhage against each other and
against placebo or no treatment groups is needed.

### Implications for practice 

No information is available from randomised controlled trials to inform
the management of women with secondary postpartum haemorrhage.

OB/GYN Chief Clinical Consultant's Corner, Volume 1, No. 7, July 18,
2003

<http://www.ihs.gov/MedicalPrograms/MCH/M/MCHdownloads/CCCCorner71803.doc>

# George Gilson: Postpartum Hemorrhage and rectal misoprostol

"Several providers have discussed with me the use of rectal misoprostol
for the [treatment]{.underline} of PPH. Some feel it has become the drug
of choice for this situation. I\'d like to disagree (!) and present some
of the evidence of which I\'m aware.

While rectal misoprostol is an inexpensive and readily available agent,
the evidence for its use for the *treatment* of PPH comprises several
case reports, totaling all of 14 patients, as far as I\'ve been able to
ascertain. It certainly has a use in the *prevention* of PPH (active
management of the third stage of labor), especially in developing
countries, and good evidence exists, although it appears to be slightly
inferior to oxytocin for that indication.

The most recent green journal had the paper we\'d been waiting for on
the pharmacokinetics of rectal misoprostol. They are actually identical
to those of vaginally administered misoprostol. Levels begin to rise by
30 minutes, peak at 60 minutes, and are sustained for at least 4 hours.
This makes it a great agent for the prevention of delayed PPH, but not
very helpful for the treatment of acute hemorrhage, where you need
something that will work immediately. I believe the supposed benefit you
are seeing represents the effect of the other agents you have given and
the ongoing massage you are doing, and are not the result of the drug.

# I would not count on it when you have much more rapid acting, and effective, agents available."

# [**http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12738159&dopt=Abstract**](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12738159&dopt=Abstract)

# [OB/GYN CCC Editorial comment]{.underline}

# 515,00 women die worldwide of complications of childbirth. Hemorrhage is the single most important cause of maternal death worldwide. One quarter of those deaths are due t hemorrhage. Active management of the third stage of labor will significantly reduce the incidence of PPH with uterotonic drugs, early cord clamping, and controlled cord tension. In the ITU system we should rely on those injectable rapid acting agents that are readily available, e.g, oxytocin. 

# 

# In the case of PPH, Methergine should be your first choice after oxytocin, if the patient is not hypertensive. The second tier of uterotonic agents that would be used for treatment of PPH may be chosen by the patient's clinical course and their side effect profile. Hemabate can produce dramatic uterotonic results, but is also accompanied copious diarrhea. Rectal misoprostol has less side effects, but has a delayed onset of action. 

# The Advanced Life Support in Obstetrics Course (ALSO) offers an excellent step-wise approach for treatment of hemorrhage. I recommend the ALSO Course for all providers who provide maternity care.

I have also provided several online resources for guidelines and
background of the active management of the 3^rd^ stage of labor and the
treatment of PPH below.

###### 

###### 

###### 

###### Active management of 3rd stage of labor and postpartum hemorrhage management (PPH)

Outlook: Preventing PPH

<http://www.reproline.jhu.edu/english/2mnh/2articles/otlkpph.pdf>

3^rd^ stage of labor: Family Practice Notebook

<http://www.fpnotebook.com/OB109.htm>

3^rd^ stage of labor: ReproLine MCH

<http://www.reproline.jhu.edu/english/2mnh/2ppts/3rdstage/>

3^rd^ stage of labor: US Agency for International Development

<http://www.mnh.jhpiego.org/best/pphactmng.asp>

PPH treatment: Family Practice Notebook

<http://www.fpnotebook.com/OB14.htm>