SPTL

 On December 25, 1642 when a widow gave
birth prematurely to a male child, his mother
Hannah Ayscough reportedly described that
child as
“so small that he could have been put into a quart
mug” (≈ 1.3 liters)”
One of the earliest descriptions
of Preterm birth.
The infant survived and grew up to be “Sir Isaac Newton.”
Tan TC. Tocolytic treatment for the management of preterm labour: a systematic review. Singapore Med J. 2006 May;47(5):361-6.
“However, a significant proportion of preterm births do
not survive, let alone grow to become Newton.”

Narendra malhotra
Jaideep Malhotra
Neharika
mnmhagra3@gmail.com
rainbowhospital.org

 Labor and delivery between 28 – 36+6 weeks
 5%-10%
 be the leading cause of perinatal morbidity and
mortality
 Survival rates have increased and morbidity has
decreased because of technologic advances

The preterm parturition syndrome. Multiple pathologic
processes can lead to activation of the common pathway of
parturition.
Ascending intrauterine infections
stage I changing flora vagina/cervix,
II Microorganism alocated between
the amnion and chorion, III intra
amniotic infection, IV fetal invationIn: Creasy, Resnik . Maternal – Fetal Medicine, 2009

40-50% occur spontaneously
[SPTL]
25% occur following preterm
pre-labor rupture of membranes
(PPROM).
Iatrogenic preterm labor :
about 25%1
1. Janet Tucker. BMJ. 2004 September 18; 329(7467): 675–678.
Preterm labor is defined as the presence of contractions of sufficient
strength & frequency to effect progressive effacement & dilatation
of the cervix between 20-37 weeks’ gestation2
2. American College of Obstetricians and Gynecologists, 2003.

COX-2: Cyclooxygenase 2, MLCK: Myosin light chain kinase, OTR: Oxytocin receptors, PG: Prostaglandin, PGDH: Prostaglandin
dehydrogenase
Sunil K. Kota. Endocrinology of parturition. Indian J Endocrinol Metab. 2013 Jan-Feb; 17(1):
‘stimulation’ of the
myometrium
through the
increased production
of uterotonic agonists
such as oxytocin and
prostaglandins

1. Tocolysis: Inhibition of uterine
contractions with drugs
2. Glucocorticoid administration to
promote fetal lung maturation
3. Antibiotics to treat infections, if
present
4. Avoidance of physical exertion—
bed rest and hospitalization.
Dtsch Arztebl Int. Mar 2013; 110(13): 227–
236.

 1970s- β1-agonists (isoxuprine) were introduced.
 FDA approval ritodrine
 1980s- “decade of β 2-agonists” (salbutamol, terbutaline, orciprenaline,
fenoterol & Other- MgSO4, indomethacin.
Expert Opin. Pharmacother. (2014) 15(5):585-
•1960s- the management - bed rest, hydration, opiate analgesia & iv alcohol.
•1990s- Reappraisal of the use of β2-agonists due to concerns about
serious adverse effects e.g. pulmonary edema.
Subsequently, a gradual drift away from -β2-agonists to atosiban,
nifedipine.

 An initial assessment: ascertain cervical length
and dilatation and the station and nature of the
presenting part
 Bed Rest : be placed in the lateral decubitus
position

 Although bed rest is often prescribed for
women at high risk for preterm labor and
delivery, there are no conclusive studies
documenting its benefit.
 A recent meta-analysis found no benefit to bed
rest in the prevention of preterm labor or
delivery.

 Tocolytic therapy
 Magnesium sulfate (Intracellular calcium
antagonism) has become the drug of choice for
initiating tocolytic therapy.
 Terbutaline (Bricanyl) Beta2-adrenergic receptor
agonist sympathomimetic; decreases free
intracellular calcium ions
 Nifedipine(Procardia) Calcium channel blocker

 Tocolytic Therapy
 Prostaglandin synthetase inhibitors: indomethacin,
administered both orally and rectally
 Ritodrine (Yutopar) Same as terbutaline
 Nifedipine Indomethacin (Indocin) Prostaglandin
inhibitor

 Tocolytic therapy may offer some short-term benefit
in the management of preterm labor.
 A delay in delivery can be used to administer
corticosteroids to enhance pulmonary maturity and
reduce the severity of fetal respiratory distress
syndrome,

 also be used to facilitate transfer of the patient
to a tertiary care center
 No study has convincingly demonstrated an
improvement in survival, long-term perinatal
morbidity or mortality, or neonatal outcome
with the use of tocolytic therapy alone.

Potential Complications Associated With the Use
of Tocolytic Agents :
Magnesium sulfate
• Pulmonary edema
• Profound hypotension*
• Profound muscular paralysis*
• Maternal tetany*
• Cardiac arrest*
• Respiratory depression*

Beta-adrenergic agents
• Hypokalemia
• Hyperglycemia
• Hypotension
• Pulmonary edema
• Arrhythmias
• Cardiac insufficiency
• Myocardial ischemia
• Maternal death

Indomethacin (Indocin)
• Renal failure
• Hepatitis
• Gastrointestinal bleeding
Nifedipine (Procardia)
• Transient hypotension

 Corticosteroid Therapy
 Dexamethasone and betamethasone
 for fetal maturation reduces mortality, respiratory
distress syndrome and intraventricular
hemorrhage in infants between 28 and 34 weeks of
gestation.
 benefits start at 24 hours and last up to seven days
after treatment
 The potential benefits or risks of repeated
administration of corticosteroids after seven days
are unknown.

 Antibiotic Therapy
 women who received antibiotics sustained
pregnancy twice as long as those who did not
receive antibiotics
 had a lower incidence of clinical amnionitis.
 poor fetal outcome (death, respiratory distress,
sepsis, intraventricular hemorrhage or necrotizing
colitis) occurred less frequently in women receiving
antibiotics

• Secondary prevention :
Aim :
Early identification of pregnant women at a risk of preterm
labor and helped them to carry their pregnancies to term.
Measures :
1- Self-measurement of the vaginal pH for B.V.
2- Cervix length measurement by TVS .
(The accepted cutoff value for cervix length is ≤ 25 before GW 24 )
3- Cerclage and complete closure of the birth canal
4- Progesterone supplementation
• Queensland Maternity and Neonatal Clinical Guideline (2009)

• Aim of tocolysis :
Suppress uterine contractions and delay preterm
delivery to :
1-allow in-utero transfer to an appropriate level
facility .
2-allow for the administration of corticosteroids.
(King .,et al.2003)
•
•

 The original rationale was to prolong pregnancy and to aim for
term delivery. (This is still what women and the lay public expect from us.)
 This idea -superseded by recent dogma :tocolytics are given to
delay delivery for 48 hours,
 To allow Ante partum glucocorticoids to induce lung maturation &
 In utero transfer to a tertiary care centre with NICU facilities.
 Delay of delivery to permit growth, maturation & to reduce perinatal
mortality & morbidity
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

Contraindications :
• Gestation > 34 weeks
• Labour is too advanced
• In utero fetal death
• Lethal fetal anomalies
• Suspected fetal compromise
• Placental abruption
• Suspected intra-uterine infection
• Maternal hypotension: BP < 90 mmHg systolic
Relative contraindications :
• pre-eclampsia . Multiple pregnancy
• placenta praevia . Rupture of membrane
(Di Renzo et al., 2007)

(SCHLEUßNER 2013)
MECHANISMS OF ACTION OF TOCOLYTIC DRUGS

 Specifically developed to be uterospecific
 Oxytocin receptor antagonist – Atosiban
 Not specifically developed (Not uterospecific)
 Beta-agonists
 NO donors
 NSAIDs
 CCBs
 MgSO4
Gr. tokos: childbirth, lytic: capable of dissolving
Ronald F Lamont. Atosiban as a tocolytic for the treatment of spontaneous preterm labor. Expert Rev. Obstet. Gynecol. 3(2), 163–
174 (2008).

Limitations
of currently
available Tocolytics

Agent Non-myometrial Tissues Responsive
β-adrenergic receptor agonists
Myocardium, Smooth muscles, Juxtaglomerular cells, Skeletal muscle,
Liver
Calcium channel blockers Vascular smooth muscle, Cardiac conduction
Magnesium sulphate Smooth muscle, Brain NMDA receptor, Neuromuscular junction blockage
Nitric oxide donors Vascular smooth muscle
BJOG. 2005 Mar;112 Suppl 1:74-8.
The primary target of tocolytics is the myometrial cell
The wide distribution of responsive tissue is major determinant
of numerous undesired side effects with these agents.

Poor safety profile of currently available Tocolytics
Drug Contraindications Maternal side effects Neonatal side effects
Beta mimetics:
Terbutaline
Ritodrine
Cardiac arrythmias, poorly
controlled thyroid disease and
diabetes mellitus
Cardiac arrythmias,
pulmonary edema, myocardial
ischemia, hypotension,
hyperglycemia, hypokalemia,
tremors etc
Tachycardia, fetal
hyperglycemia, neonatal
hypoglycemia &
hypocalcemia,
hypotension and
myocardial ischemia
CCBs:
Nifedipine
Cardiac disease, caution in
renal impairment, maternal
hypotensionn and with
MgSO4
Headache, flushing, nausea,
dizziness, transient
hypotension and tachycardia
Sudden fetal death &
distress
PG synthetase
inhibitors:
Indomethacin,
ketorolac,
sulindac
Signifiacnt renal or hepatic
impairment, active peptic
ulcer disease, coagulation
disorders, thrombocytopenia,
Heartburn , nausea, gastritis,
impairment of renal function,
increased PPH, dizziness
Constriction of ductus
arteriosus, pulmonary
hypertension,
oligohydramnios intra
ventricular hemorrhage,
necrotizing enterocolitis
NO donors
GTN
Headache Headache, hypertension Neonatal hypotension
Di Renzo GC, J Perinat Med. 2006; 34(5):359-66.

Sites of action of Tocolytic drugs in
the uterine myometrium

 Drug safety and side effect profile : major concern
for both the pregnant women & fetus
 Safety profile of a drug: a real concern, responsible
for therapy discontinuation & choosing alternative
tocolytic drugs
 Gestational age
Hubinont C, Debieve F. Prevention of preterm labour: 2011 update on tocolysis. J Pregnancy. 2011;2011:941057.

 suggested dose of nifedipine is an initial oral
dose of 20 mg followed by 10–20 mg three to
four times daily, adjusted according to uterine
activity for up to 48 hours.
 A total dose above 60 mg appears to be
associated with a three- to four-fold increase in
adverse events.

 Magnesium sulfate acts centrally to decrease
seizures and blocks neuromuscular transmission.
The mechanism for preventing uterine contraction
is unknown but may be related to calcium
antagonist activity.
 A loading dose of 4 to 6 g should be given
intravenously over 15 to 30 minutes.
 A continuous infusion of 1 to 4 g per hour is then
administrated to maintain a magnesium level
between 4 and 6 mEq.
 The infusion is continued until 12 to 24 hours of
uterine quiescence is achieved.

 Ritodrine and terbutaline stimulate the beta2
receptors, resulting in relaxation of the uterine
muscles and the smooth muscles of the lung with
few effects on the beta1 cardiac receptors.
 Intravenous ritodrine is administered in an initial
dose of 0.05 to 0.1 mg per minute and increased at
15 minute intervals to 0.35 mg per minute.
 The usual dosage of terbutaline is 0.25 mg
administered subcutaneously every one to six
hours.oral terbutaline, in a dosage of 2.5 to 5.0 mg,
can be given every four hours,

 A 100-mg dose of indomethacin can be given
by rectum and repeated after one to two hours
if contractions persist.
 An oral dose of 25 mg every four to six hours
should not be continued for longer than 48
hours because of potential fetal side effects.

 Oxytocin is fundamentally involved in the mechanism of preterm labour.
 Oxytocin receptors are crucial for the onset of human labor.1
 Plays two important roles in :
 the initiation of labour &
 the expulsive phase of labour
 The “choice/ideal” tocolytic agent- could improve
neonatal outcome with no maternal or neonatal
side-effect
 Atosiban was developed specifically to treat preterm labor
 Atosiban “an advance” in currently available tocolytics &
 Should be a first-line tocolytic for the management of spontaneous preterm
labour.2
2. Experimental Physiology (2001) 86.2, 297–302.1. Science. 1982 Mar 12;215(4538):1396-8.

 Licensed preparations
 Oxytocin receptor antagonist – Atosiban
 Beta agonist – Ritodrine, isoxsuprine, Terbutaline, salbutamol, fenoterol
 Unlicensed preparations/not approved by regulatory
authority
 Calcium channel blockers [CCBs] - Nifedipine, Nicardipine
 Nitric oxide donors (No donors)- glyceryl trinitrate [GTN]
 PG synthetase inhibitors – Indomethacin, sulindac,
COX-2 inhibitors
 MgSO4 (magnesium sulfate)
Ronald F Lamont. Atosiban as a tocolytic for the treatment of spontaneous preterm labor. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

• DOSAGE AND ADMINISTRATION :
30 MG LOADING DOSE,|THEN 10–20 MG EVERY 4–6 H.
• CONTRAINDICATIONS :
. CARDIAC DISEASE . . RENAL DISEASE .
. MATERNAL HYPOTENSION (< 90/50 MM HG) .
. AVOID CONCOMITANT USE WITH MAGNESIUM
SULPHATE .
• MATERNAL SIDE EFFECTS :
. FLUSHING, HEADACHE . . NAUSEA .
. TRANSIENT HYPOTENSION . . TRANSIENT
TACHYCARDIA .
• FETALAND NEONATAL SIDE EFFECTS :
. SUDDEN FETAL DEATH . . FETAL DISTRESS .
(CONDE ET AL.,2011)

During the second half of pregnancy, uterus
shows an increase in the expression of
oxytocin receptors (100-200fold) &
increasingly sensitive to oxytocin.
Oxytocin also secreted by Decidua
(Placenta), Extra embryonic fetal
tissue.
Terzidou V. Mechanical stretch up-regulates the human oxytocin receptor in primary human uterine
myocytes.
J Clin Endocrinol Metab. 2005 Jan;90(1):237-46.

ATOSIBAN
A Novel
tocolytic agent

Recommended
atosiban as first
line agent in the
management of
Preterm labor .
[2,3]
1. Guidelines for the management of spontaneous preterm labor. J Perinat
Med. 2006;34(5):359-66.
2. Rcog. Tocolytic drugs for women in preterm labour: Royal College of Obste-
tricians and Gynaecologists (RCOG). 2002.
3. Expert Opin Pharmacother. 2014 Apr;15(6):787-97.
Atosiban should be considered a first-line tocolytic for
the management of Spontaneous Preterm Labor. [1]
Spanish SPTL International guideline recommend

Systemic name-
1-(3-mercaptopropanoic acid)-2-(o-ethyl-D-ornithine)-
4-L-threonine-8-L-ornithine-oxytocin.
Formula—
C43H67N11O12S2
Molar mass-
994.199 g/mol.

Differen
ce at
Position
s- 1,2,4,8
Atosiban (INN) is a synthetic peptide ([Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin)
Atosiban = structure similar to oxytocin -> inhibit uterus contractions

Vrachnis N. Int J Endocrinol. 2011;2011:350546.

A competitive antagonist of human oxytocin receptor
Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).
Atosiban

 Atosiban is specifically developed as tocolytics/uterospecific
 Acts only on Myometrium/myoepithelial tissue.
 Best maternal and fetal safety profile
 Only tocolytic drug without serious ADR
 Safest choice In:
 Multiple pregnancies,
 Expanded blood volume &
 Anemia
Where use of other tocolytics
predispose to pulmonary
edema.

 Decreases the frequency & tone of uterine
contractions.
 Antagonizes uterine contractions & induces
uterine quiescence.
 The onset of uterine relaxation is rapid,
contractions significantly reduced within 10 min
to achieve stable uterine quiescence (≤ 4
contractions/hour) for 12 hours.
Ronald F Lamont. Atosiban as a tocolytic for the treatment of spontaneous preterm labor. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).
http://www.medicines.org.uk/emc/medicine/4305/SPC/Tractocile+7.5+mg+ml+Concentrate+for+Solution+for+Infusion/

Parameters Values
Time to Steady state conc. 1 hour after infusion (range 298 to 533 ng/ml).
Terminal (tβ) Half-life 1.7 ± 0.3 hours
Clearance 41.8 ± 8.2 litres/h
Volume of distribution 18.3 ± 6.8 litres.
Plasma Protein Binding 46 to 48%
fetal/maternal atosiban conc.
Ratio
0.12.
No dose adjustment in Renal impairment.
Tractocile International prescribing information.

 Indicated to delay imminent pre-term birth in pregnant adult
women with:
 Regular uterine contractions of at least 30 seconds duration at a rate of
≥ 4 per 30 minutes
 Cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of ≥
50%.
 Gestational age from 24 until 33 completed weeks
 Normal foetal heart rate

• DOSAGE AND ADMINISTRATION :
INITIAL BOLUS DOSE 6.75 MG OVER ONE MINUTE,
FOLLOWED BY AN
INFUSION OF 18 MG/H FOR 3 H AND THEN 6 MG/H
FOR UP TO 45 H.
• CONTRAINDICATIONS :
. NONE .
• MATERNAL SIDE EFFECTS :
. NAUSEA .
. ALLERGIC REACTION .
. HEADACHE .
• FETALAND NEONATAL SIDE EFFECTS :
. NONE
( DE HEUS ET AL.,2009 )

TOSIBAN
Tosiban
(37.5 mg/5 ml)
Tosiban
(37.5 mg/5 ml)
Tosiban

Step Regimen Dose Infusion rate Duration
1 0.9 ml I.V.
injection
6.75 mg Bolus Given over 1 minute
2 I.V. loading
infusion
54 mg /3 hrs (18mg/hr) 24 ml/hr
(300µg/min)
3 hr
3
I.V.
infusion.
Up to 270 mg (6 mg/hr) 8ml/hr
(100 µg/min)
Up to 45 hours
Administered Intravenously in Three Successive Stages
The total dose should not exceed 330.75 mg.

− Gestational age : < 24 or > 33
completed wks.
− PROM >30 wks of gestation
− Abnormal foetal heart rate
− Antepartum uterine
hemorrhage
− Eclampsia & severe pre-
eclampsia
− Intrauterine foetal death
− Suspected intrauterine infection
(chorioamnionitis)
− Placenta praevia, Abruptio placenta
− Any other conditions of the mother or
foetus, in which continuation of pregnancy
is hazardous
− Hypersensitivity to the atosiban or
excipients

 ADRs were generally of a mild severity.
 The most commonly reported adverse reaction
in the mother is Nausea (11 %).
 No specific ADR in newborn.
Di Renzo GC, Roura LC; European Association of Perinatal Medicine-Study Group on Preterm Birth. Guidelines for the management of spontaneous preterm
labor. J Perinat Med. 2006; 34(5):359-66.
Adverse Reactions

Grzesiak M, Wilczynski J. Preliminary report of 48-hours Atosiban administration in spontaneous preterm labor - Doppler blood flow
assessment of placental and fetal circulation. Neuro Endocrinol Lett. 2013;34(7):681-6.
Atosiban doesn't alter uterine nor fetal arterial blood
flow pattern.
Hemodynamic cardiac activity in fetuses remains
unaffected.

 Patients with renal or hepatic impairment
a) Renal impairment is not likely to warrant a dose adjustment.
b) Should be used with caution in impaired hepatic function
 Paediatric population
a) The safety and efficacy in pregnant women < 18 yrs have not
been established.
 Atosiban is not involved in CYP450 mediated drug-drug
interactions.
 No clinically relevant interaction was found between atosiban and
bethamethasone or labetalol

 Jan. 2000 :Atosiban approved in the European Union.
 On 30 May 2013 The EMA granted a marketing authorisation
for atosiban SUN (Sun Pharmaceutical) a generic of Tractocile.
 Oct. 2014 : Approved In India.(Zuventus health care ltd)
 As of June 2007 atosiban is approved in 67 countries, excluding
the USA, Japan.

 Following the launch of atosiban in 2000, the
calculated cumulative patient exposure to
atosiban (Jan 2000 to Dec 2005) is estimated at
156,468 treatment cycles.
 To date, routine monitoring of drug safety has
revealed no important safety issues.

No alternative tocolytics were required during the entire study
No retreatment with Atosiban was required during the entire study
No cases of AEs reported or observed during the entire study
No SAEs or deaths reported
All patients tolerated Atosiban well
90% 89.09% 89.09% 88.18%
0%
20%
40%
60%
80%
100%
24 hrs 48 hrs 72 hrs At discharge
Percentage of Undelivered patients till discharge
Out of 110 patients, 98 patients (89.09%) remained
undelivered up to 72 hrs after completion treatment. Ninety
seven patients (88.18%) remained undelivered till the end of
their hospital stay (≤7 days).

The strong evidence base for atosiban in SPTL
 >350 research articles, earliest 1985 compared to nifedipine
(poor quality evidence) & β-agonist (ritodrine, Isoxsuprine,
Terbutaline, fenoterol).
From its clinical introduction in open-label pilot studies through
Phase II, Phase III, worldwide comparative studies and Phase IV
studies a robust evidence base for atosiban has established.
Lyndrup J, Lamont RF. The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban.
Expert Opin Investig Drugs. 2007 Jun;16(6):843-53.

BJOG: An International Journal of Obstetrics & Gynaecology
pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1471-0528.2003.00056.x/full#f1

pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x

pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
The overall mean number of days gained after the start of tocolysis was 31 days,
whereas in the subgroup of women with PPROM the interval until delivery was
9.3 days and in women with preterm labour 41.0 days

Percentage of patients who remained undelivered
0
10
20
30
40
50
60
70
80
Percentage of
undelivered patients
at 24 hours.
Percentage of
at 48 hours.
Percentage of
at 7 days.
58 55
48
74
69
65
Placebo
Atosiban
Am J Obstet Gynecol..2000 May;182(5):1173-83.
Percentageofpatients

Mean Percent Changes in the Number of Uterine contractions before & after treatment (2 hr)
Am J Obstet Gynecol. 1994 Feb;170(2):474-8.
-26.4
-55.3-60
-50
-40
-30
-20
-10
0
%DecreaseinUterine
contractions
Placebo
Atosiban

SN Title Test
&compara
tor drug
Study design n Remark
1. Hadar E.
Am J Obstet Gynecol. 2013
Jun 15. pii: S0002-
9378(13)00542-5.
Atosiban Open label
Comparative
21 atosiban (Tractocile) reduces uterine electrical activity in women
with preterm labor.
2.
Wu MY.Taiwan J Obstet
Gynecol. 2010 Dec;49(4):495-
9.
Atosiban Case report 1
Atosiban has few side effects and assisted in prolonging a
pregnancy involving twins that experienced extremely preterm
premature rupture of membranes.
3.
Moraloglu O. Reprod Biomed
Online. 2010 Sep;21(3):338-
43.
atosiban RCT 180 Results have indicated that atosiban increases the implantation
rate and pregnancy rate after IVF-embryo transfer.
4. Maagaard M. Ugeskr Laeger.
2009 Mar 9;171(11):907.
Case report Long-term treatment with a combination of tocolytics, Atosiban and
diclofenac inhibited labour until week 26 + 3 where both babies
were born.
5. Pierzynski P. Fertil Steril. 2007
Jul;88(1):213.e19-22.
Atosiban Case report. The treatment decreased the uterine contractile activity and
resulted in successful embryo implantation and a normal twin
diamniotic pregnancy.
6 Husslein P. BJOG. 2006 Dec;
113 Suppl 3:105-10.
Atosiban open-label,
RCT
105 The use of atosiban was effective for the delay of preterm labour
and presented no safety concerns irrespective of the time it was
administered.

SN Title Test
&compara
tor drug
7 Richter ON. Arch Gynecol
Obstet. 2005 Jun;272(1):26-30.
Epub 2004 Jul 23.
Atosiban prospective,
randomized
pilot study
20 In summary, atosiban showed itself to be effective for tocolytic
treatment for premature labor, even during 18 and 24 weeks of
pregnancy, while exhibiting its known, favorable profile of side
effects.
8 Lurie S. J Perinat Med.
2004;32(2):137-9.
Atosiban prospective
observational
study
15 Atosiban may be an effective treatment of uterine hyperactivity
during active labor.
9 Helmer H. BJOG. 2003 Apr;110
Suppl 20:113-5.
atosiban retrospective
study
208 Atosiban is an effective tocolytic drug in the treatment of preterm
labour and preterm rupture of the membranes. It has significantly
less side effects due to its lack of cardiovascular activity.
10 Herbst A. Eur J Obstet Gynecol
Reprod Biol. 2003 May
1;108(1):109-10.
atosiban Case report 1 Tocolytic therapy with a continuous infusion of the oxytocin
antagonist, atosiban, during 154 h. The delivery was postponed
for 12 days. The prolonged treatment was not associated with
maternal or fetal side effects.
11 Coomarasamy A. Med Sci
Monit. 2002 Nov;8(11):RA268-
73.
atosiban Meta-analysis
Cochrane
Oxytocin antagonists appear to be effective and safe for tocolysis
in preterm labour.

S
N
Title Test
&compara
tor drug
12 Goodwin TM. Am J Obstet
Gynecol. 1994 Feb;170(2):474-8.
atosiban RCT 120 A 2-hour infusion of the oxytocin antagonist atosiban resulted in a
significantly greater decline in contraction frequency compared
with controls.
13 Valenzuela GJ. Am J Obstet
Gynecol. 1995 Apr;172(4 Pt
1):1304-6.
atosiban Open label 8 Our results show minimal placental transfer of atosiban.
Administration of atosiban even at high doses up to the time of
delivery did not increase maternal blood loss at cesarean section.
14 Am J Perinatol. 1996
Apr;13(3):143-6.
Goodwin TM.
atosiban. An open-
labeled
62 Successful tocolysis was noted in 43 of 61 (70.5%). A decrease
in uterine contraction frequency of 50% or more was noted in 50
of 61 patients (82.0%).

Atosiban
Vs
β- Agonists
(Ritodrine, Isoxuprine, Fenoterol,
Magnesium sulphate, Terbutaline)
Superior efficacy and safety compared to β-Receptor Agonist

 β-Agonists are not uterospecific and hence have multiorgan side effects.
 Atosiban have superior efficacy without the conventional cardiovascular
side effects compared to β-agonist.
 β-Agonists are gradually being phased out of use because of less efficacy
and higher rate of maternal adverse drug reaction.
 Atosiban is very useful in patients with heart disease and multi-fetal
pregnancies (twins), anemia where β-agonist are contraindicated.

• Dosage and administration :
1-Terbutaline 0.25 mg subcutaneously every 20 min. to 3 hr .
2-Ritodrine initial dose of 50-100 μg/min i.v., increase 50 μg/min
every 10 min until contractions cease or side effects develop,
maximum dose = 350 μg/min
• Contraindications :
. Uncontrolled thyroid desease, & diabetes mellitus
. Cardiac arrythmias (Anotayanonth et al.,2010 )
• Maternal side effects :
. Hypokalemia . Hyperglycemia . Hypotension
. Pulmonary edema . Arrhythmias . Myocardial
ischemia
• Fetal and neonatal side effects :
. Tachycardia. . Hyperinsulinemia . Hyperglycemia

ATOSIBAN vs. RITODRINE
BJOG. 2006 Nov;113(11):1228-34. Epub 2006 Sep 15.
60
8
35
71
0
10
20
30
40
50
60
70
80
Efficacy Rate at 7 days (%) Maternal side effects (%)
Atosiban
Ritodrine

SN Title Test
&comparato
r drug
Study
design
n Remark
1. Wex J.
Eur J Obstet Gynecol Reprod
Biol. 2011 Aug;157(2):128-35.
Atosiban vs
ritodrine or
isoxuprine
Meta-
analysis
9
RCTs Owing to its superior safety profile, Atosiban is cost-
saving versus ritodrine or isoxuprine.
2.
Fabry IG. Eur J Clin
Pharmacol. 2011
Jun;67(6):573-80.
Atosiban
vs
Ritodrine
Double-
blind,
randomized
trial
20 Atosiban without clinically relevant cardiovascular
effects, may be a good alternative for ritodrine in
pregnant women at risk of cardiovascular complications.
3.
Fabry I. Eur J Clin Pharmacol.
2011 Jan;67(1):11-7.
Atosiban vs
Ritodrine
double-
blind,
randomized,
crossover
trial
20 Atosiban has no significant effects and may be an
appropriate alternative to tocolyticum, particularly in
cardiovascularly complicated pregnancies.
4.
Nonnenmacher A. Z
Geburtshilfe Neonatol. 2009
Oct;213(5):201-6.
Atosiban
Vs.
fenoterol
open-label,
RCT
Atosiban was comparable in clinical effectiveness and
was associated with fewer maternal and fetal adverse
effects, so that fenoterol cannot be recommended.
5.
Wex J.
BMC Pregnancy Childbirth.
2009 Jun 19;9:23.
Atosiban and
betamimetics
meta-
analysis
3 RCT In a German setting, atosiban is cost saving versus
betamimetics in the treatment of preterm.
Cost savings stem from the superior safety profile
of atosiban.

SN Title Test
&comparat
or drug
Study
design
n Remark
6. Wu MY, J Formos Med
Assoc. 2011
Dec;110(12):800.
Atosiban
and
Ritodrine
33 From 2004 to 2010, we treated 33 first-trimester pregnancies with
vaginal bleeding after ART with evident uterine contractions using
ritodrine and/or atosiban, and there was no preterm delivery before 30
weeks.
7. Lin CH. J Formos Med
Assoc. 2009 Jun;
108(6):493-501.
Atosiban
Vs
Ritodrine
RCT 45 These results indicate that atosiban is an effective
tocolytic drug without the conventional cardiovascular
side effects often seen with beta-agonist treatment.
8. de Heus R, BMJ. 2009 Mar
5;338:b744.
Atosiban,
Indometacin,
Nifedipine,
Beta
agonists.
Prospective
cohort study.
192
0
atosiban & Indometacin were the only drugs not
associated with serious adverse drug reactions.

SN Title Test
&comparato
r drug
Study
design
n Remark
9. Cabar FR. Rev Bras Ginecol
Obstet. 2008 Feb; 30(2):87-
92.
Atosiban,
Vs.
terbutaline
RCT 80 The therapeutic approach used showed to be effective for
tocolysis, with low incidence of maternal, fetal and neonatal
side effects.
10 Neri I.Am J Perinatol. 2009
Apr;26(4):259-63.
Ritodrine
And
atosiban
Atosiban induced higher gestational ages at delivery and higher
birth weights than ritodrine.
With respect with atosiban, ritodrine treatment induces
tachycardia and a lower variability of fetal heart rate.
11. Tan JP. Zhonghua Fu Chan Ke
Za Zhi. 2008 Feb;43(2):81-4.
Atosiban,
ritodrine,
magnesium
sulphate
35 Oxytocin antagonist atosiban could be given as alternative rescue
therapy if therapy with ritodrine or magnesium sulphate fails in
the treatment of preterm labor, and it is safe and effective.
12. de Heus R. Eur J Obstet
Gynecol Reprod Biol. 2008
Aug; 139(2):139-45.
atosiban
and
ritodrine
RCT 140 Considering the maternal effects, our results suggest a possible
role for atosiban bolus in acute tocolysis in term labour.
13. Grignaffini A.
Minerva Ginecol. 2007
Oct;59(5):481-9.
atosiban
and
ritodrine
91 Atosiban efficacy was comparable to ritodrine, but with a
superior safety profile.
14. Stergiotou I. Acta Obstet
Gynecol Scand.
2007;86(8):927-9.
Atosiban
and
ritodrine
review Atosiban is a safe choice for ECV with less maternal side
effects.

S
N
Title Test &
comparator
drug
Study
design
n Remark
16 Husslein P. BJOG. 2006
Dec; 113 Suppl 3:105-10.
Atosiban open-
label,
RCT
105 The use of atosiban was effective for the delay of
preterm labour and presented no safety concerns
irrespective of the time it was administered.
17 Shim JY, BJOG. 2006
Nov;113(11):1228-34.
Epub 2006 Sep 15.
Atosiban
Or
ritodrine
RCT 63 The efficacy and safety of atosiban in the treatment of
preterm labour were superior to those of ritodrine.
18 Locci M, J Obstet
Gynaecol. 2006
Jul;26(5):396-401.
atosiban
and
ritodrine
retrospecti
ve study
16 We conclude that atosiban is associated with a
significantly lower incidence of maternal tachycardia
and improved neonatal outcome compared with ritodrine.

Take home message
• Atosiban and Nifedipine appear to have comparable
effectiveness in delaying delivery, with fewer adverse effects
than alternatives such as Ritodrine or Indomethacin.
(RCOG Green-top Guideline. 2011)
• Ritodrine and Atosiban are licensed in the UK. for the treatment
of threatened preterm labour. Although the use of Nifedipine for
preterm labour is an unlicensed indication, it has the advantages
of oral administration and a low price. (British National Formulary)

 Atosiban as effective as nifedipine with fewer cardiovascular side
effects.
 Nifedipine is not uterospecific and hence have multiorgan side
effects.
 Nifedipine has no licence or approval for use in pregnancy or
spontaneous preterm labour. Pregnancy category C by the Food and
Drug Administration (FDA) so is not recommended before 20 weeks, or
in the first trimester.Husslein P,.Atosiban versus usual care for the management of preterm labor. J Perinat Med. 2007;35(4):305-13..
Wu MY, Chen SU, Yang YS. J Formos Med Assoc. 2011 Dec;110(12):800.

Nifedipine can be administered orally but rapid onset preparations
compromise safety and slow-release preparations compromise efficacy
and lead to the use of additional tocolytics such as magnesium sulfate or β
-agonists, which further compromise safety .
Increasing number of reports of fetomaternal adverse effects with the use
of nifedipine.
Nifedipine: not useful in multiple pregnancies, expanded blood volume ,
anemia & patients with heart disease.
Poor quality of clinical evidence. [mostly retrospective, small sample size]

Atosiban Vs nifedipine for the treatment of preterm labor
83
75
17.5
75
65
40
0
10
20
30
40
50
60
70
80
90
Efficacy Rate for 48 hours(
%)
Efficacy Rate at 7 days (%) Maternal side effects (%)
Atosiban
Nifedipine
Int J Gynaecol Obstet. 2005 Oct;91(1):10-4.

S
N
Title Test
&comparato
r drug
1. Saleh SS.
J Obstet Gynaecol. 2013 Jan;
33(1):43-5.
Atosiban
Vs.
Nifedipine
Retrospective
study
comparing the
efficacy and
safety
75 A total of 68.3% of women in the atosiban group remained
undelivered, Vs. 64.7% in the nifedipine group at 7 days .
Only the nifedipine group showed flushing, palpitation and
hypotension.
2. Salim R.
Obstet Gynecol. 2012 Dec;
120(6):1323-31.
Atosiban
Vs.
Nifedipine
Randomized
Controlled
Trial
145 Atosiban has fewer failures within 48 hours.
68.6% women in atosiban Vs 52% to nifedipine did not deliver
and did not require an alternate agent at 48 hours.
3. de Heus R. J Matern Fetal
Neonatal Med. 2009
Jun;22(6):485-90.
Atosiban or
nifedipine
RCT 31 Tocolysis with either atosiban or nifedipine combined with
betamethasone administration appears to have no direct fetal
adverse effects.
4. de Heus R, BMJ. 2009 Mar
5;338:b744.
Atosiban,
Indometacin,
Nifedipine,
Beta
agonists.
Prospective
cohort study. 1920
Atosiban & Indometacin were the only drugs not associated
with serious adverse drug reactions.
5. Kam KY. Expert Opin
Pharmacother. 2008
May;9(7):1153-68.
Nifedipine,
or Atosiban,
Review The evidence to support atosiban is much superior to that
of nifedipine and there have been recent safety concerns
over nifedipine.

SN Title Test
&comparator
drug
Study
design
n Remark
6 Al-Omari WR. Eur J Obstet
Gynecol Reprod Biol. 2006
Sep-Oct;128(1-2):129-34.
atosiban
or
nifedipine
RCT 63
Both drugs are equally effective and efficacious in acute
tocolysis. The maternal side effects were higher with
nifedipine.
7 Kashanian M. Int J Gynaecol
Obstet. 2005 Oct;91(1):10-4.
atosiban
and nifedipin
randomized
controlled
trial
80 Atosiban is an effective and safe drug for the acute
treatment of preterm labor with minimal side effects, and it
can be an option in the treatment of preterm labor,
especially in patients with heart disease and multi-fetal
pregnancies.
8 Thornton JG. BJOG. 2005
Mar;112 Suppl 1:118-21.
beta-agonists
and
magnesium
sulphate
nifedipine,
atosiban.
systematic
reviews
The only tocolytic that has been shown to prolong gestation
when used as maintenance therapy is atosiban.
9 Husslein P. J Perinat Med.
2007; 35(4):305-13.
atosiban or
beta-agonists,
CCBs,
magnesium
sulphate,
and/or bed
rest
open-label,
RCT
295 Atosiban was associated with fewer maternal and fetal
adverse events compared with other tocolytics, and
presented no safety concerns for either the mother or the
unborn baby.
10. Vercauteren M. Acta
Anaesthesiol Scand. 2009
Jul;53(6):701-9.
Atosiban,
CCB,
Magnesium
sulphate,
Nitroglycerin.
Review
Atosiban and CCB are at least as effective tocolytic agents
as beta-mimetics but have significantly less side effects.

11. Lyndrup J. Expert
Opin Investig Drugs.
2007 Jun;16(6):843-53.
Review
I. The evidence base for atosiban is
strong but the evidence is of poor
quality for nifedipine.
II. The balance of evidence indicates
that atosiban is as effective as
nifedipine and more effective than beta-
agonists and is significantly safer than
both.

Atosiban:
in Assisted
Reproductive
Technology
(ART)

 Evidence suggest that atosiban is useful in
improving the pregnancy outcome of in vitro
fertilization-embryo transfer (IVF-ET) in patients
with repeated implantation failure (RIF).
 The pregnancy rate improved from zero to
43.7%.
Lan VT. Reprod Biomed Online. 2012 Sep;25(3):254-60.

SN Title Test
&compar
ator drug
1. Hadar E.
Am J Obstet Gynecol. 2013
Jun 15. pii: S0002-
9378(13)00542-5.
Atosiban Open label
Comparative
21 Atosiban (Tractocile) reduces uterine electrical activity in women
with preterm labor.
2. Lan VT. Reprod Biomed
Online. 2012 Sep;25(3):254-
60.
Atosiban
Prospective
cohort study
71 Atosiban was given at the time of embryo transfer to women
undergoing IVF/embryo transfer. The pregnancy rate went from
zero to 43.7%.
3. Kalmantis K.
Arch Gynecol Obstet. 2012
Jan; 285(1):265-70.
Atosiban RCT 26 Women who have taken oxytocine receptor antagonist presented
an endometrium with characteristics more predictive of
implantation.
4. Chou PY.
Taiwan J Obstet Gynecol.
2011 Jun;50(2):136-40.
Atosiban
Retrospective
study
150 These results suggest that IVF-ET using lower dosage
of atosiban may improve pregnancy outcomes of patients with
repeated implantation failure.
5.
Moraloglu O. Reprod Biomed
Online. 2010 Sep;21(3):338-
43.
atosiban RCT 180 Results have indicated that atosiban increases the
implantation rate and pregnancy rate after IVF-embryo
transfer.

Summary
 Most of the tocolytics are not uterospecific & hence have multi-organ side
effects.
Atosiban:
 A new advance in the management of preterm labor.
 Uterospecific, has placebo-level side effects and was developed solely for the
treatment of spontaneous preterm labor.
 More efficacious than β-agonists & much safer, with a 10-fold decrease in
cardiovascular side effects and a 15-fold decreased need to discontinue treatment
owing to unacceptable side effects.

 β –agonists use is decreasing worldwide due to safer alternative: Atosiban.
 Atosiban is as effective as nifedipine with fewer cardiovascular side effects.
 Nifedipine (oral) : rapid onset preparations compromise safety and slow-
release preparations compromise efficacy. [fetomaternal adverse effects]
 The high quality evidence base & serious concerns about the safety of other
agents : Guidelines recommend atosiban as first-line therapy for the
treatment of spontaneous preterm labor.
Summary

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