preterm labour

Tocolysis
in
Preterm Labour
Narendra Malhotra
Jaideep malhotra
Neharika Malhotra Bora
mnmhagra3@gmail.com
www.rainbowhospitals.org

Proprietary and confidential — do not distribute
Preterm Labor
• Preterm labor is defined as the onset of uterine
contraction of adequate strength and frequency
to cause progressive dilatation and effacement of
cervix between 20 and 37 weeks of gestation1
• Preterm labor is one of the leading cause of
perinatal morbidity and mortality2
• Preterm delivery effects almost 23% pregnancies
in developing countries like India3
1. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF
2. BJOG. Volume 120, Issue 13 December 2013 Pages 1588–1598
3. International Journal of Basic and Applied Medical Sciences ISSN: 2277 : An Open Access, Online International Journal2015 Vol. 5 (3) September
2

Epidemiology -The WHO 2013 fact sheet
3519100
1172300
773600
748100
675700
517400
424100
348900
341400
0 500000 1000000 1500000 2000000 2500000 3000000 3500000 4000000
India
China
Nigeria
Pakistan
Indonesia
USA
Bangladesh
Philippines
Congo
3
Internet: 15 Million babies born too soon. http://www.who.int/mediacentre/news/releases/2012/preterm_20120502/en/: Accessed on 14 Jan 2017

The Lancet Editorial 2006;368:339

IOM Report – July 2006
• “Babies born before 32 weeks have the greatest risk for death
and poor health outcomes, however, infants born between 32
and 36 weeks, which make up the greatest number of preterm
births, are still at higher risk for health and developmental
problems compared to those infants born full term
IOM Report page 72

Frequency of
preterm birth by
gestational age
• < 28 weeks : 0.82 %
• < 32 weeks: 2.2 %
• 33-36 weeks: 8.9 %
• < 37 weeks: 11.2
IOM Report-July 2006- page 72/2006
Alexander GR et al 2006 (under review)
Cold Stress
Hypoglycemia
RDS
Jaundice
Sepsis
Complications of “Late
Preterm or Near Term
Infants”

Clinical Circumstances
Associated with Preterm Birth
• Spontaneous preterm labor with intact
membranes
• Preterm PROM
• Indicated preterm delivery
– Maternal (e.g. pre-eclampsia)
– Fetal (e.g. SGA/fetal compromise)

Risk Factors
Clinic Factors in preterm Labor
Maternal
Low socioeconomic
status
Age <18 years or >40
years
Low pregnancy weight
Smoking
Substance abuse
Multiparity
Past Obstetric History
Previous history of
preterm delivery
Previous history of
second trimester
abortion
Uterine Factors
Uterine volume
increased:
Polyhydramnios,
Multifetal gestation
Uterine anomalies
Trauma
Infection
Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 11

Mechanism of Preterm Labor
Causes Mechanism
• Stress
• Premature activation of
physiological effectors
Activation of maternal-fetal
HPA-axis
• CRH → Fetal adrenal
androgens
• Placental estrogen and
progesterone
• Inflammation and infection • Pro-inflammatory cytokines
• Fetal inflammatory response
syndrome
• Ischemia or hemorrhage • Thrombin activation
• Pathological Uterine
distension
• Increased gap junction along
with contraction associated
protiens and upregulation of
prostaglandins and oxytocin
receptorsRevisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF
12

Common Uterine Features of Term
and Preterm Labor
• Increased myometrial contractility
• Cervical ripening (dilatation and effacement)
• Decidual/membrane activation
Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414
Term Labor
Preterm Labor

Common Pathway of Parturition
• Anatomic, physiologic, biochemical,
endocrinologic, immunologic, and clinical events
in the mother and/or fetus in both term and
preterm labor
Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414

Synchronous and Asynchronous
Activation of Labor
Cervical
Ripening
Uterine
Contractility
Membrane-
Decidual
Activation
Preterm
PROM
Preterm
Contractions
Cervical
Insufficiency
© VR RR MM

Common Terminal Pathway
Normal Term
Labor
Physiologic
Activation
Preterm
Labor
Pathologic
Activation
© VR RR MM

What causes pathologic
activation of the pathway ?

Placental Pathology in Prematurity
Arias et al. Obstet Gynecol 1997;69:285.
Acute
Chorioamnionitis
42%
Chronic villitis
0.8%
Villous edema
1.7%
Normal placenta
13.3%
Mixed (inflammation
+ vascular)
20%
Vascular
Lesions
20%
© PJS

And one of the
5 “p” syndromes
(AOFOG)preterm,premature,prom,pih,pph
“Great Obstetrical Syndromes”
Romero R J Prenat Neonat Med 1996;1:8-11

The Preterm Parturition Syndrome
Uterine
Overdistension
Vascular
Infection
Cervical
Disease
Hormonal
Immunological
© VR RR MM
Unknown

• Frequent: 25 % (at presentation)
• Sub-clinical
• Fetal disease
• FIRS
• Host defense
Intraamniotic Infection

• 12% of preterm labor
• 20% of preterm PROM
Sub-clinical
Clinical Chorioamnionitis

Severe neonatal
morbidity
Impending preterm
delivery
Fetal multisystem
involvement
FIRS
© VR RR MM

Fetal Inflammatory Response Syndrome
• Hematologic Abnormalities
• Endocrine System
• Cardiac Dysfunction
• Pulmonary Injury
• Renal Dysfunction
• Brain Injury (PVL)

Prediction of preterm labor
1. Risk factors .
2. Home uterine activity monitoring (HUAM) .
3. Cervical ultrasonography (Cx. Length assessment) .
4. Salivary estriol .
5. Screening for bacterial vaginosis (BV) .
6. Screening for fetal fibronectin (fFN) .
( Edwin and Sabaratnam. 2005)

Screening for PRETERM labour
• Uterine contraction monitoring
– Colton and Associates
– US preventive service task force
• Cervical screening by TVS(sogc)
– Cervical length (less than 25mm)
– Cervical Funneling
• Fetal Fibronectin ( 50ng/ml )RCOG
23rd edition Williams Obstetrics ACOG Practice Bulletin Vol.120 no.4 N Engl J Med
1998;338:15–9. (Level I)

Preterm Management
Management
Preventive
Definitive

Prevention of Preterm
Labor/Delivery

Component Test Treatment
Myometrium Uterine Monitor Tocolysis
Ultrasound CerclageCervix
Approaches for the Prevention of Preterm
Birth
Fetal Fibronectin AntibioticsMembrane/Decidua
© VR RR MM
Is preterm labor simply “labor before its time” ?

Prevention
Progesterone
Cervical Cerclage
PROHYLACTIC TOCOLYSIS
There is no clear evidence that tocolytic drugs improve outcome and therefore it is reasonable not to use
them. However, tocolysis should be considered if the few days gained would be put to good use, such as
completing a course of corticosteroids or in utero transfer.

Progesterone in Pregnancy
Maintenance
• Myometrial quiescence
• Down-regulate gap junction
formation
• Inhibit cervical ripening

Short Cervix with TVS
Singleton Multiple
Low risk Group
Vaginal
Progesteron
e offered if
Cx 20mm or
less at or
before 24
weeks
High risk
Group and
receiving
progesterone
since 16-
34wks
Cerclage
should be
considered if
cervical
length is less
than25 mm
before24
weeks of
gestation
No intervention
improves
outcome
ACOG

Cervical Circlage
• History Indicated Circlage
– Only if 3 or more previous preterm or 2nd Trimester loss (15% vs 32% p<0.005)
– Not offered if 2 or less previous preterm or 2nd trimester loss (14% vs 17% &
12% vs 14%)
– H/O painless cervical dilatation, rupture of membrane before onset of
contraction and additional risk factors are not helpful for decision to place
History indicated circlage
• Usg Indicated
– If Cx is ≤25mm circlage is not indicated if no H/O spontaneous preterm or 2nd
trimester loss ( 22% vs 26%; RR 0.84; 95% CI 0.54 -1.3; p=0.44)
• Women with singleton pregnancy without
– Spontaneous Midterm loss or preterm birth should not be offered usg
indicated circlage IF Cx is ≤25mm before 24 weeks gestation
– USG indicated circlage not recommended for funneling of cervix in absence of
cervical shortening≤25mm
• Rescue Cerclage –
– Cx dilated >1-2cm with or without perceived ut. Contractractions ( with or
wihtout membrane bulging)

“Progesterone deficient state” has
been proposed to be a Mechanism
of Disease
in Preterm Labor

• Progesterone is “indispensable” for normal
pregnancy
• Progesterone withdrawal is a
prerequisite of normal pregnancy termination

A progesterone withdrawal
“prepares” the uterus
for the action of
uterotonic agents

Working Classifications
PRETERM
LABOUR
Extreme
preterm
Early
Preterm
Late
Preterm
< 28 weeks
Cerclage/progesterone
/tocolysis
28 - < 32 weeks
Progesterone/tocolysis
32 - < 37 weeks
tocolysis
The majority of the preterm infants belong to the late preterm subgroup (Marken et al., 2008).

Criteria for Efficacy
• Prevention of preterm birth
– 37 weeks
– 35 weeks
– 32 weeks
• Prolongation of pregnancy
• Neonatal morbidity and mortality

Obstet Gynecol 2003;102:1115-6

Criteria for PTL
Documented uterine Contr. (1/10min)
Ruptured fetal membranes
Documented Cx change (<1cm)
Cx dilatation>2cm
James 4th Edition High Risk Pregnancy Chap. 61 pg-1075

Signs and symptoms of preterm labour
• Frequent contractions (more than four per
hour)
• Cramping
• Pelvic pressure
• Excessive vaginal discharge
• Backache and
• Low back pain
• Non-specific symptoms
Am Fam Physician. 1998 May 15;57(10):2457-2464
46

Diagnosis
Clinical diagnosis is based on uterine contractions and
vaginal examination:
• regular contractions (at least 1/10 minutes) which are
associated with effacement and/or dilatation of the cervix.
A cervical length <15 mm on TVS—is associated with an
increased risk
• of spontaneous preterm birth.
Uterine contractions monitoring by tocometer.
 Contractions of sufficient frequency and intensity to effect
progressive
• effacement and dilation of the cervix: active preterm labor .
Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF
47

Diagnosis Continued ….
• Markers for Diagnosis of Preterm Labor
 Transvaginal ultrasonographic scanning
(TVUSS) of cervical length.
 Assessment of cervicovaginal fetal fibronectin
(FFN) levels has shown a
• sensitivity of about 80%.
48

Fetal fibronectin testing
• Sample :
from the posterior fornix of the vagina
• Indications:
1- Symptomatic preterm labour 24 - 36 weeks
2- Intact membranes and
3- Cervical dilatation less than 3 cm
• Contraindications:
1- Ruptured membranes 2- Vaginal bleeding
3- Cervical cerclage insitu
• Relative Contraindications:
1- After the use of lubricants or disinfectants
2- Within 24 hours of coitus or vaginal examination
(The Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2008)

Management of Preterm Labor
Uterine activity
Rupture of Membrane
Vaginal Bleeding
Presentation
Cervical dilatation &
Effacement
Station
Intravenous tocolytic therapy
( decision based on gestational
age , cause of preterm,
Contraindication ) and monitor
the patient for ADRs
Corticosteriod therapy
( betamethasone 12 mg IM
every 24 hours for 2 doses)
Antibiotic therapy, if indicated
Bed rest
Am Fam Physician. 1999 Feb 1;59(3):593-602
Specific management StrategyAsses the patient
50

Management Contd …..
Negative fFN without any evidence of cervical
change/TVCL > 20 mm:
contractions are infrequent and irregular:
Patient may be discharged with follow-up as an
outpatient within 7 days
contractions are regular and painful:
Admit, offer analgesia reassess in 2 hours
If contractions are persistent and painful:
corticosteroids ,tocolysis
51

Management Contd …..
Positive fFN and/or evidence of cervical change/TVCL <
20 mm:
There is an increased risk of delivery within the next 7
days.
Admit, Offer analgesia,
Administer corticosteroids commence tocolysis (if no
contraindications)
Continuous fetal monitoring with a CTG.
52

Treatment of premature labor
• Inhibition of uterine contractions with tocolysis
• Corticosteroids to induce fetal lung maturation
• Treatment of infection with antibiotics
• Bed rest and hospitalization.
(Schleußner.2013)

Definitive
• Corticosteroid Administration
– Single dose antenatal corticosteroids to women
between 24-34 weeks with High risk of preterm birth
(level 1++)
– Ante-natal corticosteroid can be considered for
women between 23rd and 23+6 (level 2)
– Ante-natal corticosteroid should be given to all
women whom an elective caesarean section planned
prior to 38weeks. (level 2)
Green-top Guideline no.7 RCOG

Antibiotics :
• In PROM
– Routine use reduces maternal and neonatal morbidity
(level 1a)
– Choice of antibiotic any penicillin (except co-
amoxiclav) or erythromycin for 10days
• In Preterm Labour (membrane intact)
– Use of antibiotic is not at all recommended
– Kenyon & colleagues study shows neonatal exposure
to antibiotic more prone to cerebral palsy at age 7
than non exposed

Neuroprotection
Magnesium Sulphate
• Administration of MgSO4 significant reduction in cerebral
palsy in gestation age before 28weeks (rouse et al)
• Administration of MgSO4 before 30weeks of gestation
(University of Adelaide)
• Administration even for multiple gestation
• For expected delivery within 24hour
• Even in PROM
• Can be administer 4hour before delivery (Australian guidelines)

The perfect tocolytic
is uniformly effective with
complete
fetomaternal safety
Does it exist ??
does not exist

Tocolysis :
There is no clear evidence that tocolytic drug improve
outcome therefore it is reasonable not to use them.
(level A)
-Use them only to gain few days would be put to good use
such as corticosteroid course or in-utero transfer
• Tocolytic drug not associated with clear reduction in
perinatal or neonatal mortality or morbidity (level A)
• Not recommended in suspected preterm labour who
had otherwise uncomplicated pregnancy
- Only in those who benefit by gaining time to Hosiptal or
NICU transfer or not completed steroid course

Tocolysis
• 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 and
MAG SULF for neuroprotection
(King .,et al.2003)
•
•

Tocolysis
• Tocolytic therapy may offer some short-term benefit
in the management of preterm labor.
• Can offer time to
– Administer corticosteroids to enhance pulmonary maturity
– Reduce the severity of fetal respiratory distress syndrome,
and
– To reduce the risk of intraventricular haemorrhage.
– Facilitate transfer of the patient to a tertiary care center.
Am J Obstet Gynecol. 2004;190:702-706

Tocolysis Contd ….
Indications of Tocolytics
Acute Preterm Labor
Completing a course of
corticosteroids or in utero
transfer
Reduce the proportion of
births occurring within 7
days
Maintenance - Acute
Preterm labor
Both oral and parenteral
may be for maintenance
therapy beyond 48–72
hours
Prophylaxis of Preterm
Labor
prophylaxis of preterm
labor in women who are at
high risk for Preterm labor
61

Tocolysis
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)

Tocolytic Drugs
Class Examples
Beta agonists Isoxsuprine, Ritodrine,
Terbutaline
Oxytocin Antagonist Atosiban
Nitric oxide donors GTN
Calcium Channel Blockers Nifedipine
Others Magnesium Sulphate
Drugs. 1983 Sep;26(3):243-61
International Journal of Basic and Applied Medical Sciences ISSN: 2277 An Open Access, Online International Journal 2015 Vol. 5 (3)
63

Tocolytic Drugs contd …
MECHANISMS OF ACTION OF DIFFERENT
TOCOLYTIC DRUGS
Beta
mimetic s
CCBs and
Magnesium
NO donors
Oxytocin antagonists
COX inhibitors
64

Tocolytic Drugs :
• Nifedepine and Atosiban has comparable effectiveness
(levelA)
• Compared to β agonist nifedepine improves neonatal
outcome (levelA)
• β agonist have higher side-effects (levelA)
• Nifedepine, Atosiban and COX inhibitor lesser side-
effects(levelA) comparing effectiveness is unclear
• There is insufficient evidence for any firm conclusions
about whether or not tocolysis leads to any benefit in
preterm labour in multiple pregnancy
• Maintenace therapy in threatened preterm is not
recommended

Calcium channel blockers
(Nifedipine)
• 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 .
• Fetal and neonatal side effects :
. Sudden fetal death . . Fetal distress .
(Conde et al.,2011)

Atosiban (Tractocile)
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.
. None .
. Nausea .
. Allergic reaction .
. Headache .
. None
( De Heus et al.,2009 )

Prostaglandin synthetase inhibitors
( Indomethacin )
loading dose of 50 mg rectally or 50-100 mg orally, then
25-50 mg orally every 6 hr × 48 hr.
. Renal or Hepatic impairment
. Nausea, heartburn gastritis . Renal impairment function
. Increased PPHge . Headache, dizziness
. Constriction of ductus arterious . Pulmonaryhypertension
. Oligohydramnios, . Intraventricularhemorrhage
. Hyperbilirubinemia, . Necrotizing enterocolitis
( Haas et al.,2009 )

Nitric oxide donors
10 mg patch for every 12 hr continuing until contraction
cease up to 48 hours
. Headache
. Headache .
. Hypotension .
. Neonatal hypotension
( Smith et al.,2007 )
•
•

Magnesium sulfate
Loading dose: 4g MgSO4 as a SLOW BOLUS over 15-30 minutes
Maintenance dose: 1g/hr. for 24/hr.
( Stop infusion if: RR<12 ,Hypotension ,loss of Patellar reflexes & UOP<100ml in 4hours )
1- Hypersensitivity .
2- Hypermagnesemia & Hypercalcemia .
3- Myocardial damage, Diabetic coma, Heart block .
• Side effects :
Magnesium toxicity include :
1- Hypotension & Hypothermia .
2- Cardiac and Central nervous system depression
3- Respiratory paralysis .
( Overdose is treated with 10ml of 10% Calcium Gluconate i.v. over 10 minutes )
(Lowes 2013)

Betamimetics
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
. Uncontrolled thyroid desease, & diabetes mellitus
. Cardiac arrythmias (Anotayanonth et al.,2010 )
. Hypokalemia . Hyperglycemia . Hypotension
. Pulmonary edema . Arrhythmias . Myocardial ischemia
. Tachycardia. . Hyperinsulinemia . Hyperglycemia

Isoxsuprine
Beta-sympathomimetics have been most
frequently used to arrest preterm labour
Isoxsuprine hydrochloride was the first beta-
agonist used to arrest preterm labour
Potent Vasodilator
DCGI Approved drug
ACOG Recommends Beta Sympathomimetic as
first line treatment in the management of
preterm labor
Evidence includes positive reviews on tolerability
of the drug when used both as acute and
maintenance therapy
72

Isoxsuprine Dose
IV infusion : 0.2 to 0.5 mg /min to be adjusted to the
patient’s response until symptoms are controlled
6 X 2ml ampoules can be diluted in 500 ml of 5%
dextrose
The drip rate should be 30 to 45 drops /min , gradually
increased to 50 to 80 drops/min
Monitor the BP
Dose can be titrated as per the response of the patient
Prescribing Information of Duvadilan
73

Contd ….
 I.M injections : Administered at the
onset of premature labor , only if
facilities for IV administration are not
available and continued until control
is obtained on symptoms of preterm
labor .
 Dose is 10 mg every 1-2 hours
 Oral: Oral administration of
isoxsuprine should be subsequent to
IV or IM administration provided
uterine activity has completely
subsided .
 60 to 80 mg daily in divided doses is
the usual maintenance dose
Prescribing Information of Duvadilan
74

Adverse Effects
Central Nervous System - Dizziness.
Cardiovascular - Low blood pressure, palpitations,
tachycardia, and flushing.
 Gastrointestinal - Nausea, vomiting and abdominal
distress.
 Miscellaneous - Rash and allergic reactions such as
hives, difficulty breathing, tightness in the chest.
Obs and Gynecology . 2002 : VII : 10
75

Contraindications
• General Contraindications of Tocolytics
A.Known lethal congenital or chromosomal
abnormalities
B.Intrauterine infections
C.Severe pre-eclampsia
D.Placental abruption
E. Advanced cervical dilatation
F. Fetal demise
G.Chorioamnionitis
76

Regulatory Status
European Medicines Assesment
WHO Guidelines
Ministry of Health & Family
Welfare
77

Regulatory Status of Tocolytics
• Ministry of Health and Family Welfare (MOHFW)
Indicated in preterm labor
Schedule H drug (prescription drug) approved by
CDSCO
Monograph given in National Formulary list 2016
published by Indian Pharmacopoeia Commission,
Ministry of Health and Family Welfare
• Note: In India use of nifedipine for preterm labor is off label
78

Regulatory Status Contd ….
• European Medicines Agency (EMA) Assessment
• –– EMA assessment report for short-acting beta-adrenergic
agonists
(salbutamol, terbutaline, fenoterol, ritodrine, hexoprenaline,
isoxsuprine) containing medicinal products for obstetric indication
(2013) concluded that benefits of parenteral formulations outweigh
risk in short-term management of uncomplicated tocolysis
–– Parenteral products should only be administered for up to 48 hours,
in patients between 22 weeks and 37 weeks of gestation
79

Regulatory Status Contd …
• WHO Guidelines
• –– Evidence-based guidelines for preterm labor—WHO
recommendations
• (2015) on interventions to improve preterm birth outcomes have
stated
• that tocolytic treatment, acute and maintenance are not
recommended
• for women at risk of imminent preterm birth for the purpose of
• improving newborn outcomes.
• --- Conditional recommendations are given
• based on very low quality evidence
80

ACOG Recommendations
Practice Bulletin interim update on
Management of Preterm Labor Jan2016 –
Evidence Supports Beta – adrenergic drug as
the first line therapy in Preterm Labor
Practice Bulletin interim update on
Management of Preterm Labor Oct2016 –
Evidence Supports Beta – adrenergic drug as
the first line therapy in Preterm Labor
81

Isoxsuprine Vs Nifedipine: Clinical study
Success rates in delaying delivery
Isoxsuprine (%) Nifedipine%) P - Value
Less than 24
hours
61% 70% Not significant
7 days 36% 31% Not significant
Upto 34 weeks 27% 29% Not significant
Both drugs had similar success in inhibiting PTL.
Maternal side effects were higher in the Isoxsuprine group in this study
Cepeda T D et al. Tocólisis con clorhidrato de isoxuprina o nifedipina en la amenaza de parto pretérmino. NIFEDIPINA Vol. 70, Nº 1, marzo 2010 11 Rev Obstet Ginecol Venez 2010;70(1):11-17 For internal
Abbott use only

Take Home Message
• TVS preferred modality for Cx length at 20 weeks and also at 13
weeks NT NB scan
• Fibronectin level positivity between 24-34 wks-asso with PTL
No usefulness of routine uterine monitoring (cost-benefit)
• Vaginal Progesterone recomm. for singleton pregnancy(lowrisk) with
CxL <2cm at 24 weeks or more
High risk group should given 17alpha Hydroxy Progesterone Caproate
• Only if 3 or more previous preterm or 2nd Trimester loss - History
indicated cerclage
• Tocolysis used to buy time ……….isoxsuprine in India the largest
experience,and clinically may be first line …
• If pain is there then oral isoxsuprin is a reasonale
startup choice
• Administration of MgSO4 before 30weeks of gestation for Fetal
neuroprotection.

Take home message
• Fetal fibronectin is a promising predictive test. (Honest et al.,2009) but
it may have limited accuracy in predicting preterm birth
within 7 days for women with symptoms of preterm labour .
(Sanchez-Ramos et al.,2009)
• Ultrasound assessment of cervical length is also a promising
predictive test for symptomatic women . ( Crane and hutchens .2008)

Take home message
• There is no indication in routine clinical practice for
continuing tocolytic therapy for more than 48 hours. Except in
some cases (e.g., placenta previa hemorrhage, amniotic sac
prolapse). (Schleußner.2013)
• Using multiple tocolytic drugs associated with a higher risk of
adverse effects and should be avoided.
• Use isoxsuprin as first line is accepted (experience)
(De Heus et al.,2009)

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)

Take home message
• FDA warns against magnesium sulfate injections to pregnant
women for more than 5-7 days to stop preterm labor, as this agent
can lead to hypocalcemia and bone abnormalities in the fetus.
(Lowes.2013)
• Antenatal corticosteroid therapy should be initiated between 24
and 34 weeks gestation to reduce fetal morbidity.
(Porto et al.,2011)

Take home message
• Routine administration of antibiotics in premature labor
without premature rupture of the membranes is not
recommended .because the rate of maternal infection is lower ,
but pregnancy is not prolonged, nor reduction of the neonatal
complications . (Subramaniam et al.,2012)
• There is no evidence that bed rest actually lowers the rate of
preterm birth. (Crowther and Han. 2012)

Revisiting the use of tocolytics in the
Management of Preterm Labor
Certain questions need to be answered ?

Why tocolysis?
• To allow for a course of corticosteroids
• To allow for in utero transfer (women go
to tertiary center)

Questioning Tocolysis!!!!
• Patient oriented outcome: neonatal mortality
????

What a surprise!!!
• No clear evidence was found for the relative
effectiveness of any tocolytic versus placebo
being beneficial for neonatal mortality

No evidence !!
• No evidence of beneficial effect does not
mean Evidence of no value
• No evidence could be due to small number of
patients (type II error), or heteregeneity of
studies, or different entry point at time of
study

What to do now??
• we have become accustomed to the fact that
tocolytics buy us time.
• The question is : Does it Worth?

To get an answer
• is a large scale multi-centred randomised non-
blinded trial, analysed by intention to treat.

Till then
• Tocolysis will continue
• So use the most cost effective modality : CCB
THIS IS OFF LABEL IN INDIA
• Or simpler to use are B mimetics
(agonists)(isoxsuprine)specialy
the retrad oral preperations

preterm labour

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