1

Current Recommendation For Antenatal Corticosteroids

Ronald Wapner, MD

Beneficial Effects of Antenatal Corticosteroids

0.2-0.90.4IVH

0.5-0.80.6Neonatal Mortality

0.4-0.60.5RDS

95% CIOR

Steroids

Induction ofProteins and

EnzymesInduced Structural

Changes

• Increased Tissue and AlveolarSurfactant

• Accelerated antioxidant production• Induction of β-receptor expression in

Alveolar cells

• Increased compliance and maximallung volume

• Decreased vascular permeability• More mature parencyhmal structure

2

Fetal Lung Fluid Dynamics

Bland RD, AJOG,1979,80.

The Paradigm for Alveolar Salt Transport

Na+

K+

Na+K+

Na+,K+ Cl-

Cl-

Na,K-ATPase

ENaCHSC

ENaCNSC

K Channels

CFTR

CLC

T2 Cell

Interstitium

Na+,K+,Cl-

H2OH2O

AQP5 AQP5T1 Cell

Paracellular

Salt and Water

Term laborCatecholamines

OxygenSteroids

Recommended Use of Corticosteroids

NIH Consensus Panel - 1994

• Benefits outweigh risks: RDS, mortality, IVH• All fetuses 24-34 weeks gestation are candidates• Decision to use should not be altered by race, gender,

or surfactant• Use: Betamethasone 12 mg, q24h x 2 or

dexamethasone 6mg q12h x 4• Use with pPROM <32 weeks - Reduces IVH• Optimal benefit at 24 hrs to 7 days post treatment

- Treatment <24 weeks reduces risk

Quandaries in Antenatal Steroid Use:2008

• Benefits and Risks of Repeat Dosing ?• Treatment Window ?

• Over 34 weeks

• Under 24 weeks

• Does the effect vary by obstetrical Condition ?

3

32 year old G4P1203admitted at 26 weeks for PTL and cervical length of 1.2cm. Treated with indocin and given betamethasone 12mg X2 doses. Preterm contractions resolve and patient discharged to bed rest. Now readmitted at 30 weeks contracting irregularly with cervix 3cm and 80% effaced.

You would:

Tre

at with

toco

lytic b

ut n..

Tre

at w

ith to

coly

tic and...

No re

-treat

men

t req

uired...

51%

6%

43%1. Treat with tocolytic but not repeat steroids

2. Treat with tocolytic and repeat whole course of steroids

3. No re-treatment required since she had been receiving weekly steroids since 26 weeks

Potential Types of Fetal Lung Maturational Response

36 wks

36 wks

36 wks

36 wks

Term

Steriod Induced Repetitive Steroids in Preventing RDS

Sheep Studies

Weekly Course: Sequential improvement in compliance (150%), ventilatory efficiency and lung volume (4-fold) following multiple weekly doses. (Ikegami, Am J Resp, Crit Care Med 1997)

Improvement %Thoracic Compliance

Control -

1 Dose 28%

2 Dose 77%

3 Dose 100%

4 Dose 150%104 111 118 124 125(69%gest)

Del

(83%gest)

4

Crowther CA, Cochrane Review 2007

Respiratory Distress Syndrome

Crowther CA, Cochrane Review 2007

Severe Lung Disease

Crowther CA, Cochrane Review 2007

Composite Serious Morbidity(variously defined)

Crowther CA, Cochrane Review 2007

Biweekly Antenatal Corticosteroids

1.04(0.77-1.39)

OR

(95% CI)

12.5%

Repeat

0.8312.9%Morbidity/Mortality Composite

pSingle Course

Composite: Mortality, severe RDS, IVH (III/IV), PVL, BPD, NEC

MACS Study

Murphy SMFM 2007

N = 1858

5

Repetitive Antenatal Corticosteroids andNeonatal Cushing Syndrome

Antenatal Betamethasone: Effect on Maternal and Fetal Hypothalamic Pituitary Adrenal Axis

Maternal: Decrease in cortisol levels within 2 hours, nadir at 12 hours with return to normal within 2 days

Fetal: Decrease in cortisol levels within 6 hours with return to normal by 7 days

Effect of Single Course

Ballard, JCI 1975 and Ped Res 1980

Compared to single, repeat courses:• Reduce maternal adrenal function with the effect lasting 3 wks

or longer

• Reduce fetal adrenal function:

– fetal cortisol returns to normal in pregnancies remaining in-utero >3 wks

These effects are not associated with any detectable clinical effect

6

Large Animal Studies of Impact ofRepetitive Corticosteroids on Fetal Growth

Sheep

Decrease in BirthweightControl -1 Dose 15%2 Dose 19%3 Dose 27%4 Dose 27%

Control - -1 Dose 11% 14%3 Dose 25% 19%

Ikegami, Am J Resp Crit Care Med, 1997104 111 118 124 125(69% gest)

Del Day 125 Del Day 145 (term)

***

Jobe, AJOG,1998104 111 ll8 125 145

* approx 4 days growth arrest**approx 9 days growth arrest

Del

(83% gest)

(69% gest)

(83% gest)

(term) Crowther CA, Cochrane Review 2007

Mean Birthweight (g)

Crowther CA, Cochrane Review 2007

Small-for-Gestational Age at Birth Safety:Frequency of SGA Infants

Birth Weight % <10%tile

Repeat ACS Placebo p

SGA 23.0% 16.0% .03

SGA – Singleton 19.3% 8.5% .002

1-3 Study Courses 9.4% 12.0% 0.9

> 4 Study Courses 30.7% 18.6% 0.01

7

13.7

91.1

49.1 49.0

90.5

13.5

0102030405060708090

100

Weight Length HeadCircumference

Placebo (N=238) Repeat (N=248)

Mean Anthropometric Measurements at Follow-up Exam

(kg) (cm)Head Circumference

(cm)

96

87

99

88

80

85

90

95

100

PDI MDI

Placebo (N=236) Repeat (N=248

Median BayleyValues

Two Year Follow-up Nothing is Certain

• A none significant increase in the rate of CP seen in NICHD study in neonates exposed to more than 4 courses:

– (RR 5.7, 95%CI0.69 – 46.8)

• Animal data shows delayed myelination, decreased brain growth and decreased number of neurons with repeat courses

• Results of RCTs evaluating early postnatal dexamethasonetreatment consistently show increased risk of CP: – OR:4.62 (95%CI:2.38 -8.98)*

• Children Exposed To Repeat Doses Of Corticosteroids Were More Likely To Warrant Assessment For Attention Problemsin ACTORDS (P = 0.04). *Shinwell 2000

What to Do

●

●

Reduced birth weight and increased SGA

Improved acute

Pulmonary status

CLD

Severe RDS

IVH/PVL

Death

26.9%0.4%

19.2%0.0%

5.8%0.0%

9.6%0.4%

Delivery

< 32 weeks

Delivery

>32 weeks

More Than 70% Of Patients Treated With Steroids Delivered Beyond 32 Weeks

Based on these findings weekly administration of ACS should not be used

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A Rescue Course?

• May not be efficacious• May not be feasible• May not be safe

●Ability To Re-treat Patients with

Corticosteroids

Delivery <34 weeks

Received “Optimal” Corticosteroid Treatment - 38%

If Corticosteroids routinely given on admission Additional percent receiving optimal treatment- 4%

Not receiving “Optiminal” Treatment- 58%

Mercer, SPO, 1998

What We Do

• Low Threshold for Initial Course of Steroids

• No further Steroids if over 32 weeks

• Repeat Once if 7-10 days has passed and delivery within 7 days is imminent

35 yo G1P0 admitted at 23 weeks with membranes prolapsed into the vagina. Scan reveals AGA fetus with EFW of 650gms. Patient requests neonatal resuscitation at delivery. After counseling you would:

Not

adm

inist

er st

eroids

a...

Give

full c

ours

e of b

etam

...

83%

17%

1. Not administer steroids at this gestational age since they are not effective at this age but Await 24 weeks and if still pregnant administer steroids

2. Give full course of betamethasone now

9

Retrospective Comparison of Single vs. Repeat ANCS in Very Low Birth Weight Neonates

N=4047

Single vs. Repeat

OR 95% C.I.Death .77 (.54 – 1.1)Severe IVH/PVL .79 (.58 – 1.1)Sepsis 1.2 (.65 – 2.2)BPD 1.3 (1.0 – 1.7)Weight <10th %tile .89 (.56 – 1.4)NDI <70 .89 (.49 – 1.6)CP .77 (.37 – 1.6)NDI .93 (.57 – 1.5)Death or NDI .67 (.46 - .97)

NICU Network, 2001Wright et al, SPR Abstract

Benefit of Antenatal Corticosteroids in the Extremely Premature Newborn

1.33

Gest Age Equivalent Effect(wks)

0.53(0.42-0.66)

1.230.54

(0.44-0.66)1.14

0.55(0.45-0.66)

Odds Ratio

(95%CI)

Gest Age Equivalent Effect (wks)

Odds Ratio

(95%CI)

Gest Age Equivalent Effect (wks)

Odds Ratio

(95%CI)

Death or ImpairmentDeath or Profound

ImpairmentDeath

22-25 completed weeks

Tyson, NEJM 2008

42 yo G1P0 patient conceived twins by IVF. Now 30 weeks pregnant with ROM. You would:

Induce

labo

r

Adm

inis

ter s

tero

ids and d

...

Adm

inis

ter s

tero

ids and...

Awai

t onse

t of s

pontaneo

..

0% 1%

90%

9%

1. Induce labor

2. Administer steroids and deliver in 24 hours

3. Administer steroids and await onset of spontaneous labor or 34 weeks

4. Await onset of spontaneous labor or 34 weeks

Data since 1994 NIH Consensus� Lewis et al., Obstet Gynecol 1996

� PPROM 24-34 wks� Randomized to betamethasone or no rx� RDS: 18% v. 44%, p=0.03� Qublan et al., Clin Exp Obstet Gynecol

2001� PPROM 27-34 wks� Randomized to dexamethasone or no rx� RDS: RR 0.54 (95% CI 0.31, 0.95)

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PPROM: Morbidity with steroids?� Auckland Meta-Analysis

� 15 randomized trials� >1400 women with PPROM

� Maternal infection 0.86 (0.61, 1.20)� Neonatal infection 1.05 (0.66, 1.68)

Harding et al., AJOG 2001

ACOG Practice Bulletin: Apr 2007

Recent data suggest that antenatal corticosteroids reduce the risk of RDS without increasing risks of maternal or neonatal infection regardless of gestational age

Multiples, Steroids and RDSStudy RR for RDS 95% CILiggins 1972 0.63 0.29, 1.35Collaborative 1981

0.98 0.54, 1.77

Gamsu 1989 0.44 0.02, 8.35Silver 1996 0.97 0.65, 1.46Total:167 cases, 153 controls

0.85 0.60, 1.20Cochrane Database, 2006