TREATMENT OF POST-PARTUM HEMORRHAGE

INTRODUCTION

Postpartum hemorrhage (PPH) is commonly defined as a blood loss of 500 ml or more within 24 hours
after birth, and affects about 5% of all women giving birth around the world. Globally, nearly one quarter
of all maternal deaths are associated with PPH, and in most low-income countries it is the main cause of
maternal mortality. An estimated 303 000 women and adolescent girls died as a result of pregnancy and
childbirth-related complications in 2015, and around 99% of these deaths occurred in low resource
settings (1). Obstetric hemorrhage, especially postpartum hemorrhage (PPH), is responsible for more than
a quarter of all maternal deaths worldwide.

interventions to prevent PPH is critical to World Health Organization (WHO) strategic priorities
(particularly universal health coverage) for achieving the targets of the third Sustainable Development
Goal (SDG 3) (2,3). As per WHO Recommendations published in 2018 recommends for Improving care
during childbirth to prevent PPH is a necessary step towards the achievement of the health targets of the
third Sustainable Development Goal (SDG 3), particularly target 3.1: “reduce the global maternal mortality
ratio to less than 70 per 100 000 live births by 2030.” 1

In the same document published by WHO, the use of an effective uterotonic for the prevention of PPH
during the third stage of labor is recommended for all births. WHO Recommends that to effectively
prevent PPH, only one of the following uterotonics should be used: "

1) Oxytocin
2) Carbetocin
3) Misoprostol
4) Ergometrine/methylergometrine
5) Oxytocin and ergometrine fixed-dose combination

Products listed at serial No 3 to 5 are supporting therapies whereas In settings where multiple uterotonic
options are available, Oxytocin (10 IU, IM/IV) is the recommended uterotonic agent for the prevention of
PPH for all births.In settings where oxytocin is unavailable (or its quality cannot be guaranteed), the use
of other injectable uterotonics (carbetocin, is recommended for the prevention of PPH.

Oxytocin

Oxytocin is the most widely accepted uterotonic agent, and is widely prescribed across the world for PPH.
However, the product has its inherent challenges in manufacturing, storage and transportation.

The Oxytocin is inexpensive, costing about $0.15 to $0.20 per 10 International Units (IU). Although 10 IUs
is enough to prevent PPH, 40 IUs are required for a treatment dose, costing $0.60 to $1.00. Despite this
low cost, challenges in health sector infrastructure and health service delivery can create barriers to
oxytocin use. Oxytocin must be manufactured in a sterile facility, and the manufacturer must test the
finished pharmaceutical product for drug content and bioavailability (i.e., the rate and extent to which
the active substance is absorbed from the pharmaceutical form), which can be challenging for
manufacturers. Additionally, oxytocin must be included in the cold chain (i.e., storage and transport
equipment that enable medicines to be kept refrigerated from the point of manufacture to the point of
use). The storage requirements for oxytocin are confusing because some labels state storage

1
WHO recommendations: uterotonics for the prevention of postpartum hemorrhage
 TREATMENT OF POST-PARTUM HEMORRHAGE

requirements of 2° to 8° Celsius, but others list ‘‘controlled room temperature,’’ which can be between
20° and 25° Celsius.

Because oxytocin is administered through intravenous or intramuscular injection, thus it require that a
trained health care worker administer the drug. Administration requires specialized skills, sterilized
equipment, and proper disposal of medical waste. This means that women delivering at home or with a
traditional birth attendant probably will not have access to oxytocin. Furthermore, many health workers
are unaware that oxytocin requires cold chain storage.

Although oxytocin is included in most national protocols for health services provision, recent studies in
Ghana and Indonesia showed a large percentage of oxytocin tested did not meet quality standards. In
Ghana, 65.5% of tested samples did not meet quality standards, and, in Indonesia, 11.5% of refrigerated
samples failed assays for active pharmaceutical ingredient content and 15.8% of unrefrigerated samples
failed. To ensure quality, many international tenders require market authorization from a stringent
regulatory authority or prequalification by the WHO through a program that assesses medicines, active
pharmaceutical ingredients, vaccines, diagnostics, injection devices, and quality control laboratories. As
of Now, only two (02) oxytocin products are prequalified, therefore it can be difficult for procurement
agencies to identify quality products.

In Pakistan only one manufacturer is producing Oxytocin for humans, but the quality of the product is
questionable as the manufacturer does not have proper manufacturing facility. Thus there is a severe
shortage of a quality product In Pakistan and an audit into the causes of maternal mortality in public and
private hospitals, points towards postpartum hemorrhage as the main cause of death after childbirth2.
Each year in Pakistan more than 15,000 women die due to pregnancy related complications, among which
Postpartum Hemorrhage (PPH) is accounting for first leading cause of maternal death in Pakistan.3 The
poor quality of Oxytocin available/produced locally is one of the major causes of mortality due to PPH.

Considering the above-mentioned challenges in production, supply and use of Oxytocin, it is clearly
required that a stable product with equal or better efficacy is made available in the country through
reliable manufacturing sources and the product can also be produced locally.

Carbetocin

Carbetocin is a long-acting synthetic oxytocin analogue, 1-deamino-1-monocarbo-(2-O-Methyltyrosine)-

oxytocin, firstly described in 1987. It has a half-life of 40 minutes (around 4–10 times longer than oxytocin)
and uterine contractions occur in less than two minutes after intravenous administration of optimal
dosage of 100 μg. A single dose of Carbetocin has been hypothysed to act as a 16 hours intravenous
oxytocin infusion regarding the increase in uterine tone and the reduction of the risk of PPH in elective
caesarean section.
Several data of literature suggest that prophylactic administration of Carbetocin will be a good alternative
to oxytocin to prevent post-partum hemorrhage,

2
Haemorrhage and Maternal Morbidity and Mortality in Pakistan (JPMA Dec 2017
3
Pakistan National Forum on Women’s Health (PNFWH/USAID
 TREATMENT OF POST-PARTUM HEMORRHAGE

In a comparative study of Oxytocin Vs Carbetocin, none from the carbetocin group needed additional
Oxytocics (oxytocin, methylergometrine, sulprostone). Whereas, significantly more women required
additional uterotonic agents in the oxytocin group.
At the same, there was a significant difference in the uterine tone and in the fundal height as shown in.
The uterine contractility was better in the Carbetocin group at 2, 12 and 24 hours after caesarean section,
and the difference was statistically significant at 24 hours. The fundus was significantly below 2 cm from
the umbilical point (-2UP) in patients of Carbbetocin group at 2 and 12 hours with respect to patients
undergoing oxytocin administration.4
It was concluded in the study that despite the Carbetocin is a synthetic oxytocin analogue, the small
difference in the molecular structure could determine not only the uterotonic stronger action, but also
the difference in the biologic function as the absence of antidiuretic effect, and this is an important result
in the attempt to define a more comprehensive Carbetocin profile.
It is therefore concluded that a single injection of Carbetocin appears to be more effective than a
continuous infusion of oxytocin to maintain adequate uterine tone, with a similar safety profile and minor
antidiuretic effect, in the third stage and in the first 24 hours after delivery defined “four stage of
labor”5Thus the study proves that Carbetocin is more effective than oxytocin in the prevention of PPH
and significantly reduces the necessity to administer therapeutic uterotonics during caesarean delivery.
Other critical issue with Oxytocin is its temperature requirement for production, transportation & Storage
storage. The temperature requirement for Oxytocin is 2-8°C, This low temperature requirement has been
the reason for the low quality of Oxytocin supplied in the countries like Pakistan where the environment
remains hot and humid during most of the year. On the other hand the storage requirement for
Carbetocin is below 30°C that is more suited to the local environment.
Further to that the difficulty in administration of Oxytocin for Prevention of postpartum uterine
haemorrhage require the product to be administered in hospital settings only as the usual dose is 5 IU (8.3
micrograms) by i.v. infusion (5 IU diluted in physiological electrolyte solution and administered as an i.v.
drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes) after delivery of
the placenta. On the other hand Carbetocin can be given as soon as possible after delivery, preferably
before removal of the placenta. No further doses of carbetocin are required.
Conclusion
The challenge that will be faced is the per unit cost of a single dose of both drugs, where the cost of one
dose of Oxytocin is very low and in Pakistan the product is priced at Rs.17.0/ dose of 10IU which
corresponds to US$ 0.13 only. Where as the likely cost of Carbetocin injection of 100mcg is likely to be
around Rs.2500/. corresponding to US& 18.50.

But the cost of single dose does not determine the cost of treatment as the actual dose of Oxytocin
ranges from 5IU to 100IU as confirmed in a study published in Am J Perinatol, the study concludes that
“Oxytocin, the most commonly used uterotonic agent in the United States to prevent postpartum
hemorrhage, has no established standard dose. The study also confirms that data on oxytocin dosing for
the prevention of postpartum hemorrhage confirms that the dose of oxytocin used ranged from 5 to

4
Carbetocin versus oxytocin in caesarean section with high risk of post-partum hemorrhage J Prenat Med. 2013 Jan-Mar; 7(1): 12–18
5
Carbetocin versus oxytocin in caesarean section with high risk of post-partum hemorrhage J Prenat Med. 2013 Jan-Mar; 7(1): 12–18
 TREATMENT OF POST-PARTUM HEMORRHAGE

100 IU and duration of administration ranged from 5 to 30 seconds (intravenous bolus) to 8 hours diluted
in crystalloid.”6
Another study published in “ARCHIVES OF GYNECOLOGY AND OBSTETRICS7” The proportion of subjects needing
additional uterotonic treatment was 3.1 % (95 % CI 1.7–5.1 %) after carbetocin and 7.2 % (5.8–8.9 %) after
oxytocin; relative risk 0.41 (0.19–0.85); p = 0.0110. The study concluded that, Carbetocin was most
effective compared with the oxytocin bolus subgroup with less need for additional uterotonic medication.
Thus, compared with Oxytocin, Carbetocin diminished the need for additional uterotonics by more than
50 %.

Based on the conclusion of the two studies that Carbetocin has a better efficacy and is more suitable for
the countries like Pakistan due to its stability in the higher temperatures and ease of administration as
any clinic having a qualified doctor can administer the injection of Carbetocin, whereas the Oxytocin
infusion is required for a hospital setting where the infusion is given for a certain period of time. Price of
the

6
Am J Perinatol. 2013 Aug;30(7):523-8. doi: 10.1055/s-0032-1329184. Epub 2012 Dec 3
7
Carbetocin in comparison with oxytocin in several dosing regimens for the prevention of uterine atony after elective caesarean section in the Netherlands (Arch Gynecol Obstet. 2013 Jun;
287(6): 1111–1117)