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Antenatal Corticosteroid in Preterm Labor

Muhammad Ilham Aldika Akbar

Dept/SMF OBGYN RSUA RSUD Dr. Soetomo
Fakultas Kedokteran Universitas Airlangga
Surabaya
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Respiratory Distress Syndrome

dr. Aldika Akbar SpOG

+History of Steroid Used in Preterm Birth

Graham Liggins Liggins & Howie

1960 1972
Graham Liggins was investigating factors involved Landmark study
in the initiation of labor in a sheep model. His A controlled trial of
hypothesis was that the fetus produces substances
that trigger labor, possibly steroid hormones. In
antepartum glucocorticoid
postmortem analyses, Liggins incidentally found treatment for prevention of
that preterm lambs exposed to corticosteroids had the respiratory distress
structurally more mature lungs than expected, and syndrome in premature
were also viable at an earlier gestational age and infants. Pediatrics
had less severe respiratory distress at birth. 1970;50:515-25.
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+ Lung Physiology

Surfactant function:
Lower surface tension at air liquid surface
Protect patency of small airways
Prevent movement of fluid into the alveolus
Stimulates lung host defence system
dr. Aldika Akbar SpOG
 Mechanism
+ Improve
of Action lung
mechanics Upregulate
and gas gene
Inducing exchange expression of
fetal lung epithelial Na
antioxidant channel
system

Accelerate
Regulate Cortico development
gene of type 1 & 2
function in steroid pneumocytes
maturation
lung

Inducing
production of
Inducing surfactant
Increase proteins and
pulmonary
surfactant enzyme
beta
receptor production phospholipid
syntetase
dr. Aldika Akbar SpOG
+
Evidence of Short Term Clinical
Benefit of Corticosteroid
Reduction of RDS

2006 systematic review of RCT comparing antenatal corticosteroid vs placebo:

Reduction of RDS (RR 0.66, 95% CI 0.59-0.73)
Reduction in moderate to severe RDS (RR 0.55 95% CI 0.43-0.71)

Reduction of IVH, NEC, NNM, infection

2006 systematic review of RCT comparing antenatal corticosteroid vs placebo:

Intraventricular hemorrhage (IVH) (RR 0.54, 95% CI 0.43-0.69)
Necrotizing enterocolitis (NEC) (RR 0.46 95% CI 0.29-0.74)
Neonatal Mortality Rate (NNM) (RR 0.69 95% CI 0.58-0.81)
Systemic infection in the first 48 hours of life (RR 0.56, 95% CI 0.38-.085)

dr. Aldika Akbar SpOG

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When to Administrate?

< 22 weeks 23-34 weeks > 34 weeks

Reasonable if Recommend to all Controversial

delivery in the next 7 pregnant woman who
days is anticipated will deliver within the Inconsitent data
next 7 days of efficay
Unlikely to
significantly improve Significantly reduce No data about
lung function risk of RDS, IVH, long term safety
neonatal death
Survive with severe
impairment Reduction perinatal
mortality at 23 weeks

dr. Aldika Akbar SpOG

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Corticosteroid Use At 37-39 Weeks

n Empiric use of steroid has been recommended prior to CS at 37-39

weeks

n The ASTECS trial, 1000 women, betamethasone vs placebo, 48 hours

before planned CS:
n Reduction in overall incidence of repiratory problems (Transient
tachypnea of the newborn and RDS) [RR 0.46]
n Similar trial, dexamethasone vs placebo, 48 hours before, 38 weeks
planned CS:
n Reduction in NICU admission for repiratory morbidity
n Reduction in transient tachypnea of the newborn (RR 0.38)
n No difference in RDS, need for mechanical ventilation

dr. Aldika Akbar SpOG

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Corticosteroid Use At 34-36 Weeks
The Antenatal Late Preterm Steroids Trial (ALPS)

Methods:
Women at 34-36 weeks, risk of preterm birth, betamethasone vs placebo

Primary outcome:
Composite of neonatal respiratory treatment in the first 72 hours, stillbirth, or
neonatal death within 72 hours of delivery

Result:
Primary outcome occur less in treatment groups (RR 0.80; 95% CI
0.66-0.97)
Severe respiratory complications, transient tachypnea of the newborn,
surfactant use, and bronchopulmonary dysplasia, occurred significantly
less frequently in the treatment group
Neonatal hypoglicemia more frequently in treatment groups
RDS and use of Mechanical Ventilation is similiar
dr. Aldika Akbar SpOG
Gyamfi Bannerman et al, 2016. BEJM
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Corticosteroid Use At 34-36 Weeks
Many approach

The Society for MFM Specialists:

Two doses of betamethasone for women 34-36 wk with symptoms of preterm
labor, cervical dilatation > 3 cm, eff 75%, no tocolysis

The American College of Obstetricians and Gynecologists:

Administer betamethasone in women at 34-36 wk with imminent risk of
preterm delivery within 7 days
Chorioamnionitis is contraindication
Tocolysis shouldnt be used

The Royal College of Obstetricians and Gynecologists:

Routine administration of antenatal glucocorticoids for:
(1)All women at risk of preterm birth (include 34-36 weeks)
(2)All women who must undergo CS before 39 weeks

dr. Aldika Akbar SpOG

 UPTODATE Recommendation:

Administer first course corticosteroid for women

scheduled CS at 34-36 weeks

Not administer second course of corticosteroid for above

condition, to women already received corticosteroid < 34
weeks

Not administer corticosteroid for women undergoing CS

at >37 weeks

For vaginal delivery >34 weeks, not administer steroid

(TTN is less common in vaginal delivery)

dr. Aldika Akbar SpOG

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Timing of Administration Before
Delivery
n A statistical benefit was observed among infants born
between one and seven days after the first treatment dose
(RR 0.46, 95% CI 0.35-0.60; 9 trials, 1110 infants) (Crowley PA,
1995)

n In one study, only one-quarter of women delivered within the

optimal window of after steroid administration (Mahkija NK et
al, 2016)

n Observational data suggest neonatal benefits begin to

accrue within a few hours of corticosteroid administration
(Elimian et al, 2003)

dr. Aldika Akbar SpOG

 2 x 12 mg im 24 hours apart
Betamethasone
Choices
of Drugs 4 x 6 mg im 12 hours apart
Dexamethasone

Why ?
These steroids are less extensively metabolized by the placental
enzyme 11 -hydroxysteroid dehidrogenase type 2

The efficacy of alternative dosing regimen is unproven

dr. Aldika Akbar SpOG

 Betamethasone Dexamethasone

2013 Cochrane review of 12 trials:

No statistical differences between dexamethasone and betamethasone
were observed for respiratory distress syndrome (RDS) or neonatal
death

Both are effective, similar efficacy

dr. Aldika Akbar SpOG
+ Potential Side Effect of A Single Course of
Antenatal Corticosteroid Therapy < 34 weeks

Fetal Infants Children Maternal

Transient FHR Didnt increase No report any Most women

changes (non any adverse adverse effect tolerate well
reassuring) infant outcome on growth, lung No increase risk
within 2-3 days function, of death,
administration psychosexual, chorioamnionitis,
Transient motor, & puerperal
improvement in cognitive, sepsis
umbilical artery neurologic & Transient
end diastolic opthalmologic hyperglicemia
flow (EDF)

dr. Aldika Akbar SpOG

 Repeated
Course of
Corticosteroid
Therapy

Single
VS Risk
Multiple Single VS
Repeated VS Benefit
Course Full dose

dr. Aldika Akbar SpOG

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Efficacy of Repeated Course of
Steroid Therapy
n 2015systematic review RCT, repeated doses
betamethasone vs placebo

n RESULT
n For the neonate:
n Reduced risk of RDS (RR: 0.83)

n Reduced risk composite serious infant outcome [RR 0.84]

(perinatal death, bronchopulmonary dysplasia, IVH, NEC,
sepsis, periventricular leucomalacia, & ROP)
n For the mothers: no difference in chorioamnionitis & puerpural
sepsis
n For the young child: no significant benefit & harm

dr. Aldika Akbar SpOG

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Concern About RISK in Multiple
Course Corticosteroid Therapy
n Maternal Fetal Medicine Networks Unit trial:
n Higher percentage of SGA fetuses in repeated course group
n Smaller placenta

n Increase incidence of cerebral palsy

n MultipleCourses of Antenatal Corticosteroid for

Preterm Birth Study:
n Dose response relationship between number of corticosteroid
course with decrease in fetal growth

dr. Aldika Akbar SpOG

 Multiple Course of Steroid Therapy

Benefit
Reduced RDS
Reduced
Risk composite infant
morbidity

SGA
Reduced HC
Smaller
placenta
dr. Aldika Akbar SpOG Cerebral palsy?
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Salvage/Rescue/Booster Therapy

DEFINITION:
One additional course of therapy for women at high risk of
delivering within 7 days

RATIONALE:
Reduction of RDS without increasing RISK of potentially adverse
outcomes

EVIDENCE:
Three RCT, 2 report significant reduction in RDS, and 1 trial report
significantly increased repiratory compliance

dr. Aldika Akbar SpOG

At this gestational age, the ACS group had fewer cases of RDS,
less need for surfactant, and less frequent need for ventilator
dr. Aldika Akbar SpOG support (Garite TJ et al, 2009)
 CONCLUSION: Infants randomized to rescue antenatal steroids have a
significantly increased respiratory compliance compared with placebo
dr. Aldika Akbar SpOG
 Recommend single course of salvage steroids in
women:
ACOG (1)Who remain at risk of preterm delivery < 34 weeks
(2) Whose prior course was administered at least 7
days previously

Weekly repeat dosing with single injection of

ACTORDS betamethasone was effective after initial therapy

Single Dose Two Dose

dr. Aldika Akbar SpOG

+ RCOG Recommendation
Recommendation Evidence
Antenatal steroid (ANS) are associated with significant reduction A
in neonatal death, RDS, IVH and safe for mother
Single course of ANS to women 24-34 weeks who are at risk of A
preterm birth
ANS are most effective in reducing RDS in pregnancies that A
deliver 24 hours t days after adminisitration
ANS isnt associated with any signifiant shor term maternal or fetal A
adverse effects
Caution when giving corticosteroid in women with systemic A
infection
ANS should be given to all women at risk of preterm birth up to 34 A
weeks
ANS should be given to all women for whom an elective CS A
planned prior to 39 weeks
Betamethasone 2 x 12 mg im or dexamethasone 4 x 6 mg im are A
the steroid of choice to enhance fetal lung maturity
Weekly repeat course of ANS isnt recommended
dr. Aldika Akbar SpOG A
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Take Home Messages
1. Steroid is beneficial in preterm labor
2. 22 34 weeks
3. Betamethasone = dexamethasone
4. Salvage/booster therapy: < 34 weeks in labor,
already received steroid > 7 days before
5. Steroid > 34 weeks is optional for cesarean
delivery
dr. Aldika Akbar SpOG
+ Refference
n Baud O, Sola A. 2007. Corticosteroid in perinatal medicine: how to improve
outcomes without affecting the developing brain?. Seminar in Fetal & Neonatal
Medicine (2007) 12, 273-279.

n Bonanno C, Wapner RJ. 2009. Antenatal corticosteroid treatment: what happened

since Drs Liggins and Howie?. American Journal of Obstetrics and Gynecology.
April 2009.

n Garite TJ, Kurtzman J, Maurel K, Clark R. 2009. Impact of a rescue course of

antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J
Obstet Gynecol 2009;200:248.e1-248.e9

n Lee MJ, Guinn D. Antenatal corticosteroid therapy for reduction of neonatal

morbidity and mortality from preterm delivery. UpToDate. Apr 08, 2016.

n McEvoy C, Schilling D, Peters D, Tillotson C, Spitale P, Wallen L, Segel S, Bowling S,

Gravett M, Durand M. 2010. Respiratory compliance in preterm infants after a
single rescue course of antenatal steroids: a randomized controlled trial. Am J
Obstet Gynecol 2010;202:544.e1-9.

n RCOG, 2010. Antenata; Corticosteroids to reduce neonatal morbidity and

mortality. Green top Guideline no 7, Oct 2010.

dr. Aldika Akbar SpOG