UTEROTONIC Drugs for ATONIC PPH Prevention in India Dr Sharda Jain , Dr Sangeeta Gupta , Dr Jyoti Agarwal

ATONIC PPH
UTEROTONIC Drugs for
Prevention in India
DR SHARDA JAIN DR SANGEETA GUPTA DR JYOTI AGARWAL

Dr Jyoti Agarwal
MBBS (Gold Medalist)
M.D (Gynae & OBST )
FICOG, PGDMLS
Senior consultant & Director
* Lifecare Centre
* Lifecare IVF
 Ex President of D.G.F.(East)
 Treasurer : Delhi Gynaecologist Forum
 D.G.F. Certified Trainer for
* Infertility - IVF
* Ultrasound
* Colposcopy + Thermal Ablation
 Awards
* APJ Abdul kalam’s Appreciation Award DGF “East” 2015
* “THE TEACHERS EXCELLENCE AWARDS” DGF 2017
* APJ Abdul kalam’s Excellence Award DGF “East” 2020

All pregnant women are at risk of dying
even if no predisposing factors are present

“DYING TO GIVE LIFE
is a reality” !

Table of Contents
• Prevention of PPH
• Uterotonics: Timing and Use
• Guideline Recommendations on uterotonics
for PPH Prevention
• Key Takeaways

Postpartum Hemorrhage: It’s
Unfortunate Yet Common in INDIA
1. Postpartum haemorrhage. Available at: https://www.who.int/medicines/areas/priority_medicines/Ch6_16PPH.pdf?ua=1. Accessed on: 20 July 2021. 2. Postpartum haemorrhage. Available at:
https://www.nhp.gov.in/disease/gynaecology-and-obstetrics/postpartum-haemorrhage. Accessed on: 20 July 2021. 3. Rani PR, Begum J. J Clin Diagn Res. 2017;11(2):QE01.
Maternal mortality1 Global PPH incidence1,2
Leading cause of maternal mortality
accounting for about 35% of all
maternal deaths.
14 million women suffer from PPH.
Incidence of PPH is reported as 2%–4%
after vaginal delivery and 6% after
cesarean section.
PPH: Postpartum hemorrhage
RAPIDLY FALLING
DLY

Types of PPH
• Primary PPH:
• excessive blood loss within 24
hours of delivery.
• Minor and Major PPH
• minor PPH being defined
as blood loss between 500
and 1000 ml,
• and major PPH meaning
blood loss greater than 1
Litre.
• Secondary PPH:
• abnormal or excessive bleeding
that occurs between 24 hours to
12 weeks after delivery
Dey T et al, Identification, prevention and management of postpartum haemorrhage. OBSTETRICS,
GYNAECOLOGY AND REPRODUCTIVE MEDICINE, 2020, 30:8,

PPH – Causes
Pathology Specific cause Approximate
Incidence (%)
Tone Atonic uterus 70
Trauma Lacerations,
Hematomas,
Inversions, Rupture
20
Tissue Retained tissue,
Invasive placenta
10
Thrombin Coagulopathies 1
Am Fam Physician. 2017;95(7):442-449.

ATONIC PPH
• Commonest cause of
Mortality in PPH
In 70 to 75% cases
Dey T et al, Identification, prevention and management of postpartum
haemorrhage. OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE
MEDICINE, 2020, 30:8,
20%
10%
1%
Uterine
atony
Trauma
The commonest cause
of PPH is uterine atony1
70%
So concentrate to
stop atonic PPH

Re emphasising about that every
pregnancy is at Risk for PPH
Am Fam Physician 2017;95(7):442-449
Int J Gynaecol Obstet. 2021 Feb 2. doi: 10.1002/ijgo.13618.
• Occurrence of PPH is often unpredictable
• Possibility of obstetric hemorrhage will always co‐exist with
pregnancy, whether anticipated or not
PPH risk factors identify < 40% of cases of maternal
hemorrhage; therefore, risk factors alone are not adequate
predictors of PPH and active prevention is indicated for every
delivery

HIGH IMPACT OF PPH
Significant
increase in
hospital stay
High
inpatient
mortality
Major
impact
on the
lives of
affected
families
Long term
& physical /
psychologic
al impact
on affected
women

Prevention of atonic PPH
has two parts
• FIRST PART
Care BEFORE preventionTraining +
infrastructure
• SECOND PART
Active managament of 3rd stage of labor +
Uterotonic agents for SUSTAINED
CONTRACTION

Bleeding post-delivery is stopped by clotting in
intrauterine vessels brought about by natural
uterine contractions and is enhanced by oxytocin.
All the medical and uterus conserving surgical
steps attempt to facilitate the clotting and should
be performed before coagulopathy sets in.

PPH PREVENTION :involves the practice of active
management of the third stage of labor for all patients
irrespective of mode of delivery & place of delivery.
IDENTIFICATION of those at high risk for postpartum
hemorrhage , such as patients with prolonged labor, pre
eclampsia, previous postpartum hemorrhage and
multiple pregnancy is loosing credibility now as 60 %
have NO risk factors

Prophylactic
uterotonic agents
ACTIVE MANAGEMENT
Cord
clamping
and
cutting
Controlled
traction of
umbilical
cord
Uterine
massage

Management of third stage of labor incorporates
three main interventions:
• Administration of oxytocin / carbetocin or
misoprostol or another uterotonic drug
within 1 minute after the birth of the baby
• Controlled cord traction (not essential with
oxytocin) and
• Uterine massage after delivery of the
placenta

Uterine massage
every 5-10 mins
is recommended to
confirm that the uterus is
contracted .
Women should be taught
to self massage and also
advised to warn staff if
uterine fundus is soft ,
also increasing in size or
continuing to bleed.
Uterine massage

NB :if oxytocin /carbetocn is not available  administering a single
dose of misoprostol 600μg orally immediately after delivery of the
newborn is indicated .It is a good practice to first do an abdominal
palpation to confirm that there are no additional babies in utero

Training programs and simulation training
It s recommended that simulations of postpartum
haemorrhage prevention therapy should be
included in
in-service training programs for NURSES & MBBS
Doctors.
It has also been demonstrated that good
communication between healthcare providers and
their patients (and families) can have a beneficial
result

Various UTEROTONICS available in INDIA

USE OF UTEROTONIC AGENT
• Time of Administration:
– At the crowning of baby’s head xx
– At the delivery of anterior shoulder
– At the end of second stage of labour √
– Following the delivery of placenta
• Prophylactic Use:
– Prevention of PPH
– Active management of third stage of labour
• Therapeutic Use:
– Management of PPH
Molecules
Oxytocin
Carbetocin
Ergometrine
Syntometrine
(500 mcg ergometrine
+ 5 IU oxytocin)
Misoprostol

Uterotonics
Class of drug Example Half-life Mechanism of action Side-effects
Oxytocin Oxytocin • 3-5 mins • Binds to oxytocin receptors and
stimulates myometrial smooth
muscle contractions1
• Tachycardia
• Hypotension
• Myocardial ischaemia
• Free water retention
Long-acting
oxytocin
agonists
Carbetocin • 40 mins • Same as oxytocin, but duration of
uterine activity is longer1
• Significantly fewer
adverse events
• Headache, Nausea,
Abdominal Pain
Ergot alkaloids Ergometrine • 2-4 hours • Significantly increase motor activity1
• Produces myometrial contractions
via calcium channel mechanism and
actin–myosin interaction1
• Nausea, vomiting
• Hypertension
• Arteriolar constriction
Ergot alkaloids
and oxytocin
Syntometrine
(500 mcg
ergometrine
+ 5 IU
oxytocin)
• - • Same as ergometrine (sustained
myometrial contractions) and
oxytocin (rapid onset of action)2
• Headache, dizziness
• Hypertension, chest pain
• Abdominal pain
Prostaglandins Misoprostol • - • Involved in cervical ripening3
• Increases myometrial contractions
via cervical smooth muscle relaxation
and increasing intracellular calcium1
• Fever, chills
• Nausea, vomiting
• Diarrhoea

SYNTOCINON / OXYTOCIN
Syntocinon /oxytocin requires refrigeration and
must always be administered by injection. The
usual dose is 20 IU in 500 ml of crystalloid
solution.
The intravenous route is used with the dosage
rate adjusted according to the response (typical
rate 250 ml/h)

Intramuscular administration of 10 IU result in a
slower onset of action (3-7 min) but with a
longer – lasting effect (up to 60 min)
Syntocinon / Oxytocin
Intramuscular Route
IMPORTANT FACT
The preferred storage to oxytocin is refrigeration
but it may be stored at temperature of up to
30*C for up to 3 months without
significant loss of potency

SYNTOMETRINE / ERGOMETRINE
Syntometrine requires refrigeration .
It can be administered intramuscularly or
intravenously , at a dose of
1 ampule (500 μg of ergometrine and 5 IU of
syntocinon) .
Syntometrine is contraindicated in women with
• Hypertension
• Cardiac disease.

CARBETOCIN
Carbetocin is a synthetic oxytocin analogue that binds to
the same oxytocin receptors in the myometrium with an
affinity similar to that of oxytocin.
Its main advantage over oxytocin is a
FOUR FOLD longer uterotonic activity
(up to 2 hours).
This means there is no necessity for a continuous
infusion.

Carbetocin in PPH Prevention in
cesarean section
Carbetocin 100μg as an IV bolus over 1 minute
instead of continuous oxytocin infusion
Robust Evidence in elective cesarean section
for the prevention of PPH has been shown to
decrease the need for addional therapeutic
uterotonics & thus saver of money aswell.

Carbetocin in Vaginal Delivery
For women delivering vaginally carbetocin 100μg
IM decreases the
• Need for uterine message to prevent PPH when
compared with continuous infusion of oxytocin.
• Need for other uterotonic agents
• Need for blood transfusion

Carbetocin is More Effective than
Syntometrine
Reduction in postpartum blood loss, smaller drop in hemoglobin levels and
less adverse effects makes Carbetocin more effective than Syntometrine.
Askar AA, et al. Arch Gynecol Obstet. 2011;284(6):1359–65.
Significant difference
between mean blood loss
(mL):
Carbetocin group:
224.6±110.6 mL
Syntometrine group:
306.1±95.65 mL
Lesser Mean drop of
hemoglobin
concentration
24 h after delivery=
Carbetocin group: 0.8
g/dL
Syntometrine group:
1.1 g/dL
Better Hemoglobin levels
on postpartum day 1=
Carbetocin group: 10.9
g/dL
Syntometrine group: 10.6
g/dL

35
Cochrane Database Syst Rev. 2018 Dec 19;12(12):CD011689
2018

196 studies involving 135,559 women
 Compared 7 Uterotonic agents against each other and against women receiving no
uterotonic
3 most effective drugs for prevention of PPH
≥ 500 mL were
* Ergometrine+ oxytocin combination,
*Carbetocin Alone
*Misoprostol + oxytocin combination

 These Three drugs were more effective at
preventing PPH ≥ 500 mL compared with
oxytocin alone the current standard
Two combination drugs ( ergometrine + oxytocin ,
oxytocin & misoprostol ) are associated with SIDE
EFFECTS that women might find disturbing compared
with oxytocin
CARBETOCIN –has additional benefits
compared with oxytocin and appears to
be without an increase in side effects.
196 studies - 135,559 women

Guidelines recognise the benefits of carbetocin
for preventing uterine atony
Society of
Obstetricians and
Gynaecologists of
Canada (2009)1
Mexican
National Center
for Health
Technology
Excellence
(2008)3
Danish Society
of Obstetrics
and Gynecology
(2013)2
Ministry of Health
of the
Russian
Federation (2013)6
Expert Group of
the Polish
Gynaecological
Society (2013)5
Queensland
Maternity and
Neonatal Clinical
Guidelines Program
(2013)4
Philippine
Obstetrical and
Gynecological
Society (2014)8
Chinese Society of
Obstetrics and
Gynecology (2014)7

CARBETOCIN VS
OXYTOCIN IN VAGINAL
DELIVERY IN HIGH-
RISK CASES
Carbetocin could be considered as a good alternative agent
to oxytocin in the PPH prevention

Misoprostol PGE1 for prevention of
PPH in field setting
• Misoprostol does NOT required
refrigeration.
• Is easy to administer
• inexpensive and widely available for the
treatment of PPH
• A single dose of misoprostol 800μg
administered sublingually, immediately
following delivery if IV oxytocin is not
immediately for prevention of PPH

Misoprostol PGE1 for Control of PPH
• A single dose of misoprostol 800μg administered
sublingually in vaginal delivery if IV oxytocin is
already given for treatment of PPH.
• Evidence suggests that adjunct (simultaneous) use
of misoprostol has no added benefit.
Important Tip
Repeat doses of misoprostol for PPH
treatment are not recommended

Misoprostol PGE1- Side effects
The side effect of temperature
changes and gastrointestinal effects
are transient and can be simply
treated using anti-pyretics and anti-
emetics respectively

Prostaglandin F2α
Prostaglandin F2α requires refrigeration.
it is administered intramuscularly 
in a dose of 250μg ; the maximum number of
doses is 8 (15 minutes apart) ie 2mg maximum .
It is contraindicated in women asthma and cardiac
disease.
Caution :Prostaglandin F2α is not effective after
giving 2 doses  do not go on & on

Tranexamic Acid
• Tranexamic acid 1-2 g hourly will reduce
fibrinolysis and will stabilize the clot in the
uterine vessels.
• It is given via the intravenous route ,
• It is best used when the bleeding continues
despite oxytocin and when prostaglandin has
become necessary.

Recombinant factor Vlla
(rFVlla)
rFVIIA is very expensive and required refrigeration
it is used when uterine message and uterotonic
medications (oxytocin, ergometrine prostaglandins)
have all failed to control postpartum hemorrhage .
The recommended dose is 40-6 μg/kg administered
intravenously.
Clinical Tip  In clinical practice this drug is used as a
last resort because of its possible side effects and
expense

Future INNOVATIONS Uterotonics
in Pipe line
• Develop HEAT STABLE OXYTOCIN preferably in
the form of fast dissolving tablets(FDTs) to be
administered sub lingually.
• Carbetocin Room Temperature Stable (RTS)
tablets needed for field use.

Protocol: A65870A phase III, randomized, double-blind,
active, controlled, multinational, multicentre, non-
inferiority trial using carbetocin room temperature stable
(RTS)
for the prevention of postpartum haemorrhage during
the third stage of labour in women delivering vaginally
Future INNOVATIONS Uterotonics
in Pipe line

CARBETOCIN + ALL OTHER UTERUTONICS

GOI & state GOVT should made the
availability of Carbetocin /
sysntocinon and other drugs available
in every delivery units

UTEROTONIC Drugs for ATONIC PPH Prevention in India Dr Sharda Jain , Dr Sangeeta Gupta , Dr Jyoti Agarwal

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