6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
By Saloni Tanna, Pharm.D; MPH
7 October 2004
6.16-1
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
Table of Contents
6.16.1
6.16.2
Summary ...............................................................................................................................3
Introduction ..........................................................................................................................3
Etiology and Causes ............................................................................................................4
Symptoms of Postpartum Haemorrhage7 .......................................................................5
6.16.3
Size and Nature of Disease Burden .................................................................................5
Incidence and Prevalence ...................................................................................................5
6.16.4
Control Strategy ..................................................................................................................6
Diagnosis ..............................................................................................................................6
Management.........................................................................................................................6
6.16.5
Clinical Evidence and Past Research ...............................................................................9
Oxytocin ................................................................................................................................9
Misoprostol.........................................................................................................................10
Comparative Trials ............................................................................................................10
Studies Assessing the Stability of Uterotonic Agents ..................................................11
Surgery ................................................................................................................................13
6.16.6
Major Problem and Challenges for Disease Control
(Why Does the Disease Burden Persist ?) ....................................................................13
Trends and Scale of the Problem .....................................................................................13
Possible Treatments for Postpartum Haemorrhage in Low-Resource Settings .......13
Oxytocin in Uniject , ..........................................................................................................14
6.16.7
Current Pharmaceutical Product “Pipeline” for AD Treatment ..............................15
6.16.8
Opportunities for Research and Gaps Between Current Research and Potential
Research Issues that Could Make a Difference ..........................................................15
6.16.9
Conclusion..........................................................................................................................16
References ............................................................................................................................................17
Annex
Appendices
6.16-2
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
6.16.1
Summary
Postpartum haemorrhage (PPH) remains a major cause of maternal mortality and morbidity
worldwide. Approximately, half a million women die annually from causes related to
pregnancy and childbirth.2 About one quarter of these deaths are a result of complications in the
third stage of labour-namely postpartum haemorrhage (PPH). The exact contribution of PPH to
maternal mortality is unknown and can range from 17% to 40% of deaths. 2 There are numerous
definitions of postpartum haemorrhage (PPH). The most widely recognized definition is blood
loss after childbirth in excess of 500 ml. Since, it is difficult to accurately measure blood loss, the
true incidence of PPH may be underestimated by up to 50%.1
Most PPH cases occur in the immediate postpartum period-within 24 hours after birth (primary
PPH), and are due to uterine atony, which is a failure of the uterus to properly contract after the
child is born. Consequently, bleeding from the blood vessels in the uterus is not controlled.
Without immediate and proper medical attention, a woman with PPH can die. Administering
intravenous oxytocin immediately after childbirth is the single most important intervention
used to prevent PPH.1 Women given oxytocin lose less blood, resulting in a decreased incidence
of PPH and anemia.2, 4 Oxytocin also allows for a faster delivery of placenta and is therefore less
likely to need manual removal of her placenta. This can be a very painful procedure with in an
increased the risk of infections.4 Oxytocin alone and oxytocin plus ergometrine are generally
equally effective in reducing the incidence of PPH, however they are not easily administered
and require special storage conditions. The parenteral administration, extensive monitoring,
extensive adverse effect profiles and cold chain storage capacity of uterotonic agents are
significant barriers to the effective use of these drugs in many countries.
Medicines and surgical procedures are available for prevention and treatment of PPH. These can
greatly reduce the incidence and sequelae of PPH, however, available medicines, with the
exception of misoprostal, require skilled training, IV administration and are not heat stable. All
these issues severely limit its use in many parts of the world. Pharmaceutical research and
development for heat stable oxytocics, which are easy to administer and heat stable, is severely
lacking and is urgently needed. The etiology and causes of PPH are well understood. There are
however a limited number of agents that can be administered with ease. New agents, with
improved stability, storage, and dosage forms are needed to help prevent and treat PPH.
Furthermore, randomized controlled trials are needed to determine the role, most appropriate
dose and route of administrations for inexpensive and easily used agents like misoprostol.
6.16.2
Introduction
Mortality related to pregnancy and childbirth causes half a million women around the world to
die annually.2 About one quarter of these deaths are a result of complications in the third stage
of labour-namely postpartum haemorrhage (PPH). We do not know the contribution of PPH to
maternal mortality.2,3 In developed countries, the incidence of PPH is lower where there is access
to adequate intensive care, skilled obstetrical care, prompt diagnosis, access to medicines and
blood bank facilities.3 However, while death rates may be lower than developed countries,
6.16-3
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
severe maternal morbidities can arise from severe blood loss such as hypovolaemic shock, renal
and hepatic failure and disseminated intravascualar coagulopathy (DIC).3 At present, the range
of medical options to treat PPH is limited. This paper will review and discuss the currently
available pharmaceutical options in the prevention and management of PPH particularly for
developing countries.
There are numerous definitions of postpartum haemorrhage (PPH). The most widely recognized
definition is blood loss after childbirth in excess of 500 ml. Since, it is difficult to accurately
measure blood loss, the true incidence of PPH may be underestimated by up to 50%.4
Most PPH cases occur in the immediate postpartum period-within 24 hours after birth (primary
PPH), and are due to uterine atony, which is a failure of the uterus to properly contract after the
child is born. Consequently, bleeding from the blood vessels in the uterus is not controlled.
Without immediate and proper medical attention, a woman with PPH can die. Anemic women
are particularly susceptible to such blood loss and consequences of PPH.4, 5
Maternal mortality due to PPH is highest where there is poor access to obstetrical care, skilled
providers, transport systems and emergency services. A woman can die within two hours after
the onset of PPH if she does not receive proper treatment, including appropriate drugs, blood
transfusion or surgical intervention. The following are some statistics provided by the Maternal
and Neonatal care organization for PPH:4





515,000 women die during pregnancy and childbirth every year
99% of maternal deaths occur in developing countries
130,000 women bleed to death each year while giving birth
2/3 of women with PPH have no identifiable risk factors
90% of cases of PPH are due to uterine atony
Etiology and Causes
PPH can be classified as early or late. Early PPH occurs within the first 24 hours after delivery
and late PPH occurs 24 to 6 weeks after delivery.6 PPH has several potential causes, some of
which are listed in Table 6.16.1 below.7 90% of early PPH occurs due to uterine atony-a failure
of the uterus to contract and retract following delivery of the baby. Once a baby is delivered, the
uterus normally continues to contract and removes the placenta. After the placenta is delivered,
contractions help to compress the bleeding vessels in the area where the placenta was attached.
If the uterus does not contract strongly enough, as in the case of uterine atony, the blood vessels
will continue to bleed freely and haemorrhage occurs. If small pieces of the placenta remain
attached, bleeding is also likely. It is estimated that as much as 600 ml of blood flows through
the placenta each minute in a full-term pregnancy.7, 8 Recognizing risk factors for PPH can help
caregivers identify who at risk for PPH, however 20% of women may not have a preexisting risk
factor, therefore all caretakers need to promptly diagnose and manage PPH.8
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6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
Table 6.16.1: Risk Factors for Uterine Atony8
Risk factors
Prolonged labour
Retained placenta products
Chorioamnionitis
Oxytocin used in labour
Preeclampsi/eclampsia
Multiple gestation
Hydroamnios
Halogenated anesthesia
Previous episode of uterine atony
Some women are at greater risk for postpartum haemorrhage than others are. Some conditions
that may increase the risk for postpartum haemorrhage are listed in Annex 6.16.1. 4,6 7, 8
Symptoms of Postpartum Haemorrhage7
The following are the most common symptoms of postpartum haemorrhage. Symptoms vary
with each woman and include the following:
 uncontrolled bleeding
 decreased blood pressure
 increased heart rate
 decrease in the red blood cell count (hematocrit)
 swelling and pain in tissues in the vaginal and perineal area
6.16.3
Size and Nature of Disease Burden
Incidence and Prevalence
According to a report on the global burden of maternal death and disability, PPH continues to
be a major cause of maternal deaths in both developing and developed countries. The estimated
incidence rate of PPH globally is estimated to be 10.5% of live births. 9 The incidence is lower in
developed countries where active management during the third stage of labour is routinely
practiced and where most women deliver in hospitals. Based on a global average, the WHO
report estimates that nearly 14 million women suffer from severe blood loss during labour and
postpartum. It is estimated that 140,000 women die consequently, with a global case fatality rate
of 1%. Table 6.16.2 below shows the estimated incidence of major obstetric complications and
main the maternal sequelae for maternal morbidity and mortality (2000 data). 9
Table 6.16.2: Estimated Incidence of Major Obstetric Complications and Main
Maternal Sequelae9
Complication
Incidence
Cases
6.16-5
Case
Maternal
Main
6.16: Postpartum Haemorrhage
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PPH
Sepsis
Preeclampsia/ecl
ampsia
Obstructed
labour
Abortion



(% of live
births)
10.5
4.4
3.2
13,795,000
5,768,000
4,152,000
fatality
rate
1.0
1.3
1.7
deaths (2000)
Sequelae
132,000
79,000
63,000
Severe anemia
Infertility
Eclampsia
4.6
6,038,000
0.7
42,000
14.8
19,340,000
0.3
63,000
Urinary
incontinence,
fistula
Infertility
PPH remains a major cause of maternal mortality and morbidity worldwide it is responsible
for over 130,000 deaths each year with a morbidity of 20 million women per year.10
PPH is the second leading cause of maternal mortality in France, and the third in the US.
In the UK while the risk of death from obstetric haemorrhage is 1 in 100,000 deliveries, the
associated morbidities are significant, which include coagulopathies, renal failure, fluid
overload and surgical interventions.2
6.16.4
Control Strategy
To prevent and manage PPH several systems need to be functioning in concert: trained birth
attendants, emergency transport systems, availability of blood transfusions, essential obstetrical
care and availability of effective oxytocic medicines. Management of PPH often requires an
obstetrician to initiate a series of non-operative and operative interventions promptly while
assessing the success and or failure of the intervention. If an intervention does not succeed, the
next treatment should be instituted.2
Diagnosis
Diagnosis of PPH includes a complete medical history and physical examination and diagnosis
is usually based on symptoms listed above. Laboratory tests may help with the diagnosis and
these include:7
 estimation of blood loss
 pulse rate and blood pressure measurement of the mother
 hematocrit (red blood cell count) measurement
 clotting factors in the blood
Management
Active versus Expectant Management (Pharmacological management)
The third stage of labour is the period from the birth of the child until the placenta is delivered.
Expectant management of the third stage of labour involves allowing the placenta to deliver
6.16-6
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
spontaneously or aiding by gravity or maternal effort. Uterotonic agents are given only if there
is excessive bleeding, and the cord is clamped later.
A series of procedures, conducted during the third stage known as active management,
enhances the uterus’s ability to contract immediately thereby decreasing the amount of time
necessary to deliver the placenta. Active management involves administration of a prophylactic
oxytocin, combination oxytocin plus ergometrine or ergometrine alone before delivery of the
placenta, and usually early cord clamping and cutting and controlled cord traction of the
umbilical cord.4,6
Active management of the third stage of labor can substantially decrease the following2, 4:
 Incidence of PPH due to an atonic uterus by about 60%
 Length of the third stage of labor
 Need for additional drugs to treat excessive bleeding by about 70%
 Need for a blood transfusion
 Need for surgical intervention
 Incidence of anemia and other problems associated with excessive blood loss

The International Confederation of Midwives (ICM) and The Federation of Gynecology and
Obstetrics (FIGO), representing midwives and obstetric physicians from around the world,
released a Joint Statement on the Management of the Third Stage of Labor to Prevent
Postpartum Haemorrhage in November 2003.23 Based on a review of the literature, the joint
statement recommends that active management of third-stage labor be offered to all women.
Uterotonic Drugs: oxytocin, ergometrine or methergine, 15-methyl prostaglandin F2 , and
misoprostol.
The use of uterotonic agents to prevent postpartum haemorrhage can reduce maternal mortality
by 40% and administering intravenous oxytocin immediately after childbirth is the single most
important intervention used to prevent PPH.1, 11 Uterotonic agents of choice are oxytocin with or
without supplemental ergot preparations such as ergometrine or methergine. Both oxytocin and
methergine are unstable at room temperature and thus require special temperature and light
storage conditions to remain effective. Moreover, such preparations must be administered
intramuscularly. In many settings, lack of trained personnel and of refrigeration to store
oxytocic agents undermines the potential for implementing the active management of thirdstage labor.
Utertonic drugs include oxytocin, ergometrine or methergine, 15-methyl prostaglandin F2 ,
and misoprostol. For decades uterotonic agents of choice have been oxytocin with or without
supplemental ergot preparations such as ergometrine or methergine. Misoprostol, an oral
preparation of prostaglandin (PGE1) analogue, is candidate given its uterotonic properties; ease
of use as an oral, vaginal, or rectal preparation; relative low cost in some areas; and stability at
high temperature.23,29. There is some evidence that misoprostol is effective in the management of
PPH when IV agents are unable.3
6.16-7
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
Oxytocin is the only uterotonic agent listed on the essential medicines list. Women given
oxytocin lose less blood, resulting in a decreased incidence of PPH and anemia. Oxytocin also
allows for a faster delivery of placenta and is therefore less likely to need manual removal of her
placenta. This can be a very painful procedure, resulting in an increased the risk of infections.4
Timing of Administration
Timing of oxytocin administration is critical. It is most effective when administered within one
minute after the birth of the baby. Waiting to give oxytocin until after the placenta is delivered
may increase the woman’s risk of uncontrolled bleeding.4
The parenteral administration, extensive monitoring, extensive adverse effect profile and
specific storage requirements of oxytocic agents are significant barriers to the effective use of
these drugs in many countries. The reviews below provide an overview of some the
characteristics of the agents, which may limit is effective use in many countries.
1.
Oxytocin 12
Oxytocin is a hormone used to help start or continue labor and to control bleeding after
delivery. It is also sometimes used to help milk secretion in breast-feeding.
Oxytocin is available only in the following dosage forms:
 Nasal Solution : Indication for increasing milk production in breast feeding (not indicated
for PPH)
 Parenteral Injection: Indicated for PPH
Adverse Effects
Oxytocin can be very useful for helping labor. However, there are certain risks with using it.
Oxytocin causes contractions of the uterus. In women who are unusually sensitive to its effects,
these contractions may become too strong. In rare cases, this may lead to tearing of the uterus.
Also, if contractions are too strong, the supply of blood and oxygen to the fetus may be
decreased.
Oxytocin has been reported to cause irregular heartbeat and increase bleeding after delivery in
some women. It has also been reported to cause jaundice in some newborn infants.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of
these side effects may occur, if they do occur they may need medical attention:
 Rare (with use of injection): Confusion; convulsions (seizures); difficulty in breathing;
dizziness; fast or irregular heartbeat; headache (continuing or severe); hives; pelvic or
abdominal pain (severe); skin rash or itching; vaginal bleeding (increased or continuing);
weakness; weight gain (rapid)
 Other side effects: Nausea; vomiting
Storage:
 Refrigerated at 2 to 8 degrees C or up to 30 degrees C for 3 months
Storage
 2 to 8°C away from light. It may be kept up to 25°C for 2 months away from light.
6.16-8
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
2.
Misoprostol
Other than oxytocin and ergot preparations, prostaglandins are the only group of drugs that
have a potential for use in PPH. 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.2 Prostaglandins are effective in controlling haemorrhage but most have the
disadvantages of being more expensive and having increased side effects (e.g., diarrhea,
vomiting and abdominal pain). One notable exception is misoprostol, a prostaglandin analogue
with a potential uterotonic drug for use in active management of the third stage of labour.
Studies to date indicate that misoprostol may be effective in reducing the incidence of PPH
without the side effects associated with other uterotonic drugs where other agents are not
available.29 Furthermore, misoprostol is inexpensive, stable at room temperature and can be
given orally – all of which are tremendous advantages over currently available uterotonic
drugs.2,8 Additional information on misoprostol include the following:
 Unlike ergometrine, misoprostol is not hypertensive
 Misoprostol is approved for PPH, however its therapeutic use is widely known and
clinicians have had to take the leadership in its use and development for PPH.
 Misoprostol is available as an oral, vaginal and rectal dosage form. The rectal route is the
most optimal form of administration for PPH. There are several small studies (pilot and
observational) to show the effectiveness of rectal misoprostol in PPH.10, 29
 The use of rectal misoprostol is largely based on clinical studies and is now included on
many hospital guidelines for the management of PPH. For example, a survey from Norway
showed that 20% of obstetricians now use misoprostol in the treatment of PPH. This is
despite the fact that no pharmacokinetic studies have been conducted on this medicine. 2
 There is a great deal of controversy about the role and uses of misoprostol in the
management of PPH. Additional RCTs are needed to address the dose, timing and role of
misoprostol in the management of PPH. Studies to date indicate that injectable oxytocin or
oxytocin-ergometrine preparations are more effective than misoprostol as part of the active
management of the third stage of labor. Furthermore, misoprostol may have a role in lowrisk patients or as a last resort where oxytocics are not available.13, 29
6.16.5
Clinical Evidence and Past Research
Oxytocin
The routine prophylactic administration of utertonic agents is an integral part of active
management of the third stage of labour, helping to prevent PPH. The two most widely used
agents are ergometrine-oxytocin (Syntometrine), a combination product and oxytocin alone
(Syntocinon).
A Cochrane review evaluated the effects of ergometrine-oxytocin to oxytocin in reducing the
risk of PPH and other maternal and neonatal causes. Six RCT were found, and results of the
review concluded that the use of ergometrine-oxytocin as part of the active management of the
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third trimester appears to have a small, but statistically significant, reduction in the risk of PPH
when compared to oxytocin for a blood loss of 500ml. No difference was noted for blood loss
greater than 1000ml. Also, a statistically significant difference was seen in the adverse effects
associated with ergometrine-oxytocin versus oxytocin alone. These include elevated blood
pressure, vomiting, and nausea. Therefore, the advantage of a reduction in PPH must be
outweighed with the side effects associated with this is agent.14 At present, oxytocin is the only
uterotonic agent on the Model World Health Organization Essential Medicines List.
Misoprostol

A RCT study conducted in Turkey compared misoprostol 600 mcg intrarectally with
conventional oxytocics in the management of third stage of labour.15 Results of the study
showed that the incidence of PPH was 9.8% in the misoprostol group compared to 3.5% in
the oxytocin-methylergometrine group. More women required oxytocin in the misoprostol
only group than the oxytocin-ergometrine group and the incidence of shivering and
hyperthermia was higher in the misoprostol group. Conclusion of the studies showed that
this was a good RCT model for study, which could serve as a model for research for other
studies. Rectal misoprostol was comparable to IV oxytocin alone but less effective that
oxytocin plus methylergometrine. 15
Comparative Trials


A Cochrane review evaluated randomized and quasi-randomized controlled trials
comparing pharmacological, surgical and radiological interventions for the treatment of
primary PPH. Only one trial, comparing rectally administered misoprostol versus
syntometrine combined with an oxytocin infusion, met the eligibility criteria and was
reviewed. However, the study was still not large enough to evaluate the effects of maternal
mortality, serious maternal morbidity or hysterectomy rates in women with primary
postpartum haemorrhage. Compared with a combination of intramuscular syntometrine
injection and oxytocin infusion, rectal misoprostol administration showed a statistically
significant reduction in the number of women who continued to bleed after the intervention
and those who required medical co-interventions to control the bleeding. However, there
was no significant difference between the two groups regarding surgical interventions to
control intractable haemorrhage including hysterectomy, internal iliac artery ligation and/or
uterine packing. Reviewers of the review concluded that rectal misoprostol in a dose of 800
micrograms could be a useful as a first line drug for the treatment of PPH. However, further
randomized controlled trials are required to identify the best drug combinations, route, and
dose for the treatment of postpartum haemorrhage. 16
A Cochrane review was conducted on randomized or quasi-randomized trials comparing a
prostaglandin agent with another uterotonic or no prophylactic uterotonic (nothing or
placebo) as part of management of the third stage of labour. Results of the review showed
that oral misoprostol 600 mcg are less effective than conventional injectable uterotonics in
reducing blood loss greater than 1000 mls. The authors commented that data comparing
oral misoprostol to no uterotonics/placebo were from three trials involving 1700 women and
difficult to interpret because of the heterogeneity between trials. However, the data do not
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“Opportunities to Address Pharmaceutical Gaps”

suggest a significant reduction in the rate of postpartum haemorrhage or other measures of
blood loss so far. Injectable prostaglandins are associated with reduced blood loss in the
third stage of labour when compared to conventional injectable uterotonics but are
associated with more side effects. Authors of the review conclude that neither intramuscular
prostaglandins nor misoprostol are favorable agents compared to conventional injectable
uterotonics as part of the active management of the third stage of labour. However, it seems
reasonable to use prostaglandins as a last resort for the management of intractable
postpartum haemorrhage refractory to other measures. Future research needs to focus on
management of postpartum haemorrhage where prostaglandins seem to be more
promising.17
The objective of one Cochrane review was to assess the effects of active versus expectant
management on blood loss, postpartum haemorrhage and other maternal and perinatal
complications of the third stage of labour. Randomized trials comparing active and
expectant management of the third stage of labour in women who were expecting a vaginal
delivery were included for review. Only five studies were included and four of the trials
were of good quality. Compared to expectant management, active management (in the
setting of a maternity hospital) was associated with the following reduced risks:



maternal blood loss;
postpartum haemorrhage of more than 500 mls and;
prolonged third stage of labour.
The review showed that active management was however associated with an increased risk of
maternal nausea vomiting and raised blood pressure (probably due to the use of ergometrine).
No advantages or disadvantages to these forms of management were apparent for the baby.
Authors of the review concluded that routine 'active management' is better than 'expectant
management' in terms of blood loss, postpartum haemorrhage and other serious complications
of the third stage of labour. Active management is, however, associated with an increased risk of
side effects such as nausea, 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. However, the implications for this form of
management are less clear for other settings in developing and industrialized countries.18
Studies Assessing the Stability of Uterotonic Agents
The World Health Organization, (WHO) conducted a series of field studies and laboratory
simulated studies in order to determine the stability and efficacy of injectable utertonics namely
oxytocin. 19 (See Appendix 6.16.1) Some of the research questions addressed by this study
included:


The pattern of stability of injectable oxytocics
The short-term and long-term effects of storage at 25 and 30 degrees centigrade, exposure to
higher temperatures and light
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

Correlation of solution color to level of active ingredient
Correlation between pH and stability in topical conditions.
The field survey was conducted in Gambia, Malawi, Sudan and Zimbabwe. Samples were taken
from, health facilities, medical stores, and rural health centers. The second component,
evaluated the stability of 11 brands of uterotonic agents, under stimulated topical laboratory
conditions.
Results of the study showed the following:19





For oxytocin there is no loss of potency of the active ingredient after twelve months
refrigerated storage. There was however, 14% loss after one year at 30 degrees C, stored in
the dark. No destabilizing effect of light was found.
Stability of ergometrine injection is a problem. Only 31%of the collected samples complied
with the USP standards.
Stimulation studies showed that when refrigerated for 12 months about 4-5 % of the active
ingredients were lost. When stored at 30 degrees C in the dark, 25% of the active ingredient
was lost after twelve months. When stored at 21-25 degrees C under light exposure, 21-27%
of the active ingredient was lost after 1 month, and over 90% over 1 year.
There is a correlation between color of the solution and level of active ingredient. The WHO
study suggests that any discoloration of ergot preparations implies that the agent is below
the USP standards of the 90% stated content.
Oxytocin is more stable than (methyl)ergometrine, mainly because it lacks adverse effects to
light exposure and also it is more stable than (methyl)ergometrine when stored in the dark
with or without refrigeration.
Recommendations by the WHO regarding these agents state that oxytocin, and
(methyl)ergometrine be stored under refrigeration as much as possible. 19 These agents must be
clearly marked to instruct to keep under refrigerated conditions, and ergot preparations should
have additional instruction to protect from light. Where a cold chain storage capacity is
unavailable, the WHO recommends that short periods of transport are acceptable, not exceeding
one month at 30 degrees centigrade or two weeks at 40 degrees centigrade. (See Appendix
6.16.1)
Stability of Oral Oxytocics in Topical Climates 20(See Appendix 6.16.2)
The stability of oral oxytocics in topical climates was part of a WHO research program whose
objective was to reduce PPH. The stability of four oral oxytocic agents which included
ergometrine tablets (E), methylergometrine (ME), buccal oxytocin (OT) and buccal desaminooxytocin (DOT) were evaluated under simulated topical conditions. The tablets were exposed to
artificial temperature conditions ranging from 6-40 degrees centigrade. Samples were then
assessed on the content of the active ingredient. Results of the study showed that none of the
oral oxytocics were stable under the simulated conditions. Oral ergometrine was the least stable.
A further study in Zimbabwe of a number of essential drugs demonstrated that while the initial
quality of injectable ergometrine (an oxtocic product) was often sub standard in a high
6.16-12
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proportion of cases the product deteriorated to be ineffective within six months.21 (See Appendix
6.16.3) The authors concluded that oral oxytocics are ineffective in the prevention and
management of PPH.20
Surgery
Surgical interventions are required for patients who do not respond to medical management or
who have existing lacerations, large hematomas or a ruptured uterus. If interventional radiology
is available arterial embolization, may be done on hemodynamically stable patients, as an
alternative to surgery. 8
6.16.6
Major Problem and Challenges for Disease Control
(Why Does the Disease Burden Persist ?)
Trends and Scale of the Problem
Today there is an increasing awareness of gender related medical problems in the world and
maternal mortality figures have increasingly become a political issue. However, this has not
affected mortality rates due to PPH particularly in developing countries. Even in developed
countries, estimates are surprisingly high. For example, the Netherlands, PPH cases 13% of all
recorded maternal deaths. 2 In the US, obstetric haemorrhage is responsible for 13% of maternal
deaths with PPH as the cause in over one third of the cases. 2 PPH remains the leading cause of
maternal mortality today and there is no evidence in the literature to suggest that these figures
will decline, especially in countries with the following problems to contend with: 2, 22, 23








poorly functioning health care systems,
no trained physicians,
poor emergency transport systems,
lack of availability of blood transfusions,
availability and knowledge of administering medicines
and lack of essential obstetric functions as the first referral level
Intravenous or intramusular administration of oxytocin and
Specific storage requirements i.e. lack of a cold chain to store oxytocin.
PPH still remains a major problem and there is no evidence in the literature to suggest that
maternal mortality will likely be reduced in the near future especially in developed countries.
Possible Treatments for Postpartum Haemorrhage in Low-Resource Settings
Health care providers involved in the Safe Motherhood Initiative, and organizations like The
International Confederation of Midwives (ICM) and The International Federation of Gynecology
and Obstetrics (FIGO) work towards safe birth practices for women in all countries. These
organizations are also looking for new strategies, techniques, technologies, and adaptations of
underused technologies to reduce maternal mortality attributable to postpartum haemorrhage.
6.16-13
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
Some promising technologies for treatment of PPH that are relatively simple, which can be used
by personnel with limited skills and training and can be available in remote and/or rural areas of
less developed countries include:23





universal use of active management of third-stage labor,
oxytocin in Uniject (BD Pharmaceutical Systems) as a way of overcoming some of the
barriers to oxytocin use in low-resource settings,
the use of oral and/or rectal misoprostol for prevention and treatment of postpartum
haemorrhage,
the non-inflatable antishock garment (NI-ASG) for stabilization and resuscitation of
hypovolemic shock secondary to postpartum haemorrhage, and
the hydrostatic condom balloon catheter to control intractable postpartum haemorrhage
secondary to uterine atony.
Oxytocin in Uniject 23, 24
Guidelines for the active management of third-stage labor recommend oxytocin, given IM or IV,
as the "preferred" uterotonic for prevention of postpartum haemorrhage.1 However, in many
low-resource settings, safe injection is not always possible due to the need for injection skills and
training, lack of sterile equipment, and difficulty measuring the correct dose and availability of a
cold chain to store the agents. To overcome some of these barriers to safe injection, the Program
for Appropriate Technology in Health (PATH) developed the Uniject device for safer oxytocin
administration. The device comes as a single dose, individually packed prefilled, non-refillable,
sterile injection, which is easy to use, with a fixed needle that can be "activated" for use after
opening the sterile packet. The Uniject deliver device has also been used to administer tetanus
toxoid to pregnant women in Bolivia, Indonesia, and Mali and to deliver Cyclofem (a monthly
injectable contraceptive. Studies were conducted on its use to administer oxytocin in Indonesia
and were designed to assess:



If Uniject could be safely used in home settings by skilled attendants (trained village
midwives),
if the technology of the Uniject improved the delivery of oxytocin, and
if it was acceptable to providers and women.
The study compared the experiences of 140 midwives who attended 2200 home births using
prophylactic oxytocin in Uniject with the midwives' previous experiences with oxytocin in
standard syringes. The authors found that unsafe reuse of syringes ceased once the midwives
were supplied with Uniject. In addition, dosage accuracy increased slightly, and mothers found
the Uniject less painful than regular syringe injections. The study also reports that 98% of
midwives preferred the Uniject and were willing to pay a small additional amount (over
standard syringes) for the convenience of using the Uniject.24
Possible situations where Uniject Oxytocin could be helpful include: 23
6.16-14
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”





routine prophylactic use in deliveries by skilled attendants
improved injection safety,
dose accuracy and convenience,
selected or emergency use by specially trained providers at community level to prevent or
treat PPH and/or
and/or outreach for use in areas with high rates of postpartum haemorrhage or difficult
access to referral care.
Cold and Storage Capacity for Uniject Oxytocin
The Uniject oxytocin still requires cold chain storage. With the introduction of this device a
larger cold chain volume will be required. For this reason, it is the recommendation of the
Program for Appropriate Technology in Health (PATH)) that developers of this technology
evaluate refrigeration ability and volume estimates are needed to see if current cold chain
storage capacity is adequate to accommodate singe-dose dosage forms (as opposed to multi
dose vials).24
6.16.7
Current Pharmaceutical Product “Pipeline” for AD Treatment
An exhaustive search looking at the scientific literature, Pharmaceutical Research and
Manufacturers of America, European Agency for the Evaluation of Medicinal Products,
academic organizations and professional organization related to maternal, obstetrics and
gynecological revealed that there is no current research in this field. Furthermore, there are no
products under research or development for PPH reported in any database. 25,26, 27
At present, new advances in the management of haemorrhage rely on surgical procedures or
transfusion of blood and blood products, all of which require highly skilled staff and expensive
equipment. In addition, skilled staff and specific nomograms and laboratory values of
hematocrit are needed to determine how much blood can be drawn. The argon beam coagulator,
an electrosurgical device, may also be used in obstetric haemorrhage. The procedure involves a
contact free cautery to coagulate 2 to 3 mm of tissue that then sloughs off. The procedure allows
for clearing of blood with minimal internal tissue damage. 28
6.16.8
Opportunities for Research and Gaps Between Current Research
and Potential Research Issues that Could Make a Difference



There is a lack of agreement on how much blood loss constitutes a clinical problem and
hence the parameters of the definition of PPH are unclear. 29
The methodology to estimate the blood loss is unclear. Perhaps other indicator such as a
drop in hemoglobin level holds more clinical value and the measurement is objective and
reproducible.29
Active management of PPH requires early umbilical cord clamping, administration of
uterotonic agents and controlled cord traction. The prophylactic use of uterotonic agents is
of particular importance, particularly in developing countries. In many countries, the use of
uterotonic agents is impractical. The available agents are not stable at high ambient
6.16-15
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”



temperatures and therefore require special storage conditions, which remain to be
developed. 29 We need heat-stable formulations of these agents.
Randomized controlled clinical trial are required to identify the best way to manage PPH.29
Rectal and vaginal misoprostol needs to be investigated in the management of PPH as well
combination therapies in PPH management.29
Additional dosage forms which will allow for ease of administration, improved stability and
storage need to be developed. 30
6.16.9
Conclusion
PPH is the leading cause of maternal mortality and morbidity in developing countries. 9
Medicines and surgical procedures are available for prevention and treatment of PPH that can
greatly reduce its incidence and sequelae but the available medicines, with the exception of
misoprostol, require skilled training, IV administration and are not heat stable.
Novel drug delivery technologies and new agents, particularly heat stable oxytocics are
desperately needed. In addition clinical and operations research is needed to demonstrate the
effectiveness, efficacy, acceptability and cost-effectives/sustainability in developing countries of
therapeutic agents for the management of PPH.
6.16-16
6.16: Postpartum Haemorrhage
“Opportunities to Address Pharmaceutical Gaps”
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