University Medical Center, Utrecht, the NL

Gerard H.A.Visser

Chair FIGO Committee Safe Motherhood & Newborn Health

Update on antenatal

corticosteroids

Antenatal Corticosteroids

• How it all began

• Positive effects

• Side-effects

• Repeated courses

• Steroids after 34 wks of gestation

• Unresolved issues

Sir Graham Liggins

Serendipity

Lambs born preterm were more

viable after antenatal glucocorticoid

administration

(Liggins, 1969)

Antenatal corticosteroids

1969 – Liggins

1972 – first RCT ( Liggins & Howie)

1994 – 15 RCT

2006 – 21 RCT

2017 - 27 RCT

So there is a case to give corticosteroids in women at risk of preterm

delivery between 24 weeks and 34 weeks

Betamethasone is more effective than dexamethasone; but be aware of its

effects on FHR variation and movements

(Roberts and Dalziel, Cochrane, 2006)

1970s 1980s 1990s

RDS 0.55 0.71 0.69

PVH 0.50 0.61 0.53

Neonatal death 0.73 0.98 0.50

Antenatal steroids: RCT’s over the decades

Cochrane Systematic Review, 2006

• No consistency in benefit for infants < 26 wks

• Data relate to very few fetuses < 26 wks ( n=49 out of

which 22 were stillborn)

• Doubts as to effectivity because of immature lung

development ( canalicular stage of development; type II pneumocytes)

Roberts & Dalziel, Cochrane 2006

Retrospective cohort study, infants born at 23 wks

• Data from 3 tertiary centers; in total 181 neonates

• Stillbirths, voluntary terminations, parental elected non-

resuscitations excluded

• Death OR 0.32 (CI 0.12-0.84)

• Death, completed course CS 0.18 (CI 0.06-0.54)

• Severe IVH: 21 versus 57% (p=0.17)

Hayes et al, Obstet Gynecol 2008;111: 921-6; data from 1998-2007

Retrospective cohort study, 24- 26 wks gestation

• 82 treated with antenatal CSs before 24 wks, 35 controls

• All infants treated with prophylactic surfactant at birth

Steroid treated Controls

N 82 35

5-min Apgar<7 (%) 30% 51%*

Death 29% 63%*

IVH grade 3 or 4 17% 36%*

Abbasi et al, Am J Perinat.2010, 27:61-66; data from 1998-2008; * sign differences

Population based study; Trent region UK

Wks Steroids YES Steroid NO p

N N Mort (%) N Mort (%)

• 23 102 81 (79) 84 75 (89) 0.07

• 24 330 203 (62) 123 99 (80) 0.0001

• 25 458 169 (37) 120 68 (57) 0.0001

• 26 650 185 (28) 132 60 (46) 0.0001

• 27 741 130 (18) 162 44 (27) 0.005

10 to 20% improved survival; no difference in duration of respiratory support or

CLD; beneficial effects due to effects on tissues outside the lung??

Mantlelow et al, Arch Child Fetal Neonatal Ed 2010, 95: F95-F98; data 1993-2007

Antenatal corticosteroids at

the threshold of viability

Yes, they seem to work

Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• Implementation program of Cs in case of threatened

preterm birth versus standard care (n=98.000)

• Proxi for preterm birth: birthweight< 5th centile (36-

37wks)

• Intervention group CS in 45%, in control group 10%

• Neonatal mortality (<28d; <5th c group): RR 0.96 (0.87-1.06)

• Total mortality : RR 1.12 (1.02-1.22)

• Maternal infections : RR 1.45 (1.33-1.58)

Antenatal CSs in low to middle income countries(Argentina,Guatemala, India, Kenya, Pakistan, Zambia)

Althabe et al, Lancet Febr 14, 2015

• 87% of CS were given to infants weighing> 2000-

2500g, where there is no evidence of its usefulness

• With risks of known steroid side-effects such as

reduced fetal/placental growth, apoptosis in the

brain, CP and maternal infection, which may explain

the overall poorer outcome

• These data stress the importance of adequate dating of

the pregnancy and of identifying women at real risk

of preterm birth (Visser & DiRenzo, correspondence Lancet, 2015)

Corticosteroids are potent drugs, but potent

drug also have potent side-effects

• Reduced placental weight ( human)

• Reduced fetal weight and height ( animals

and human)

• Reduced head circumference, with dominant

effects in the hippocampus area ( animals;

human)

Apoptosis versus cell proliferation

Noorlander et al, 2013; similar findings pren/neon exposure: Zuloaga et al, 2011; Chun-I Sze et

al, 2013

controls

birth

Morris water maze:Hippocampus dependent

learning and memory task

No difference in swimming speed

Behavioural analysis

02468

1012141618

1 2 3 4 5Time (days)

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cit

y (

cm

/sec)

SalineDexamethasone

Camera

Visual Cue

Light

Hidden

Platform

Morris water maze

*

*

*

Hidden platform

*

*

**

Impaired learning and memory after dexamethasone treatment

0

20

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60

80

100

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ncy (

sec)

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1,200

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1 2 3 4 5

Time (days)

Dis

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Behavioural analysis

SalineDexamethasone

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Pericentral areas of fibrosis that extends to portal fields

Saline Dexamethasone

Peripheral analysis: Liver

Dexamethasone

Peripheral analysis: Heart

Saline

Myocytes → thin layer of collagen, indicating

degeneration of myocytes replaced by fibrous tissue

corticosteroids induce precocious

aging and reduced lifespan in mice

Implications for the human…?

Antenatal dex treatment in Rh monkeys (Uno et

al, 19990 and 1994)

• Reduced n pyramidal neurons

and granular neurons in CA

and dendrate regions of

hippocampus, resp. ( at birth)

• Higher plasma cortisol ( at 9m

of age)

• 30% reduction in hippocampus

size ( at 20 months)

• Dose dependent effects

Follow-up after one course of

corticosteroids is reassuring

(McArthur et al, 1990; Smolders – de Haas et al, 1990; Schmand et al 1990;

Dessens et al, 2000; Dalziel et al, 2005 (2x),Karemaker 2006)

• no impairment at the age of 6 (maybe some

impaired visual memory)

. normal behaviour and motor function at 7-10 years

• normal physical and psychological development at

the age of 12 and 20 years

• normal cardiovascular and psychological development at

the age of 30 years (apart from increased insulin resistance)

Impact of corticosteroids on the density of

large neurons in the human hippocampus

(22 infants, 25–32 weeks, who died <4 days after delivery; Thijsseling et al, PLoS One 2012)

Density of neurons Antenatal CS No antenatal CS

High (4) 1 6

Moderate (3) 4 3

Moderate/low (2) 6 2

Low (1) 0 0

Total n of neonates 11 11 (p<0.02)

(data from 19 RCT; Halliday, 2001)

Early neonatal treatment with corticosteroids

• 14 more extubated by 7 days

• 11 less have CLD

• 7 less will die

• 14 avoid late CS treatment

• 6 more have GI bleeding

• 4 more have GI perforation

• 12 have cerebral palsy

• 14 have abnormal

neurological development

at follow-up

For every 100 babies treated…

Early neonatal treatment with corticosteroids

GOOD

BAD

Doyle, Halliday et al, Cochrane 2014

Potent drugs may have potent side effects

0.05–0.20 mg/day for 2 days

0.5 mg/kg/day for many days

Fetal versus neonatal dose

In 40% of 420 European Centres >3 courses will

be given (Eurail, 2001)

37%

22%

14%

0

20

40

60

80

100

120

140

160

1 2 3 4 5 6 7 8 9 10 11 12 20

Number of courses, Europe 2000

It all relates to the fact, that

• Women want to be treated

• And doctors want to treat

• but……………………..

Direct side effects 3 as compared to one course

MACS, Lancet December 2008

Decreased birth weight and head circumference

Single vs repeated corticosteroids

studies

NRR CI

RDS

Severe RDS

Comp sev morb

Use postn ster

8; 3206

6;4826

7;5094

3;3931

0.83

0.80

0.84

1.38

0.75-0.91

0.56-1.14

0.71-0.94

0.99-1.93

IVH

IVH grade 3/4

Peri V Leucom

Patent Duct Art

Chron Lung D

6;3065

6;4819

7;4888

6;4356

8;5393

0.94

1.13

0.77

0.80

1.06

0.75-1.18

0.69-1.86

0.43-1.37

0.64-0.98

0.87-1.30

M birth weight

M head circ

M length

Weight childh

9;5626

9;5626

6;4550

-76g

-0.32 cm

-0.56 cm

-0.03 or -0.20g*

-118, -34

-0.49, -0.15

-0.89, -0.23

Crowther et al, Cochrane, July 5, 2015

No differences in total deaths and/or survival free of any or major

disability or serious outcome

Authors’ conclusions, (Crowther et al, Cochrane, 2015)

The short-term benefits for babies of less respiratory distress and fewer serious

health problems in the first few weeks after birth support the use of repeat

dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven

days or more after an initial course. These benefits were associated with a

small reduction in size at birth. The current available evidence reassuringly

shows no significant harm in early childhood, although no benefit.

Authors MACS trail ( comment in Cochrane, 2015, p205)“Although the short term neonatal benefits of repeated courses of antenatal

corticosteroids support their use, long-term benefits have not been

demonstrated and long-term adverse effects have not been ruled out. The

adverse effect of repeated doses of antenatal corticosteroids on birth weight and

weight at early childhood follow-up is a concern. Caution should therefore be

exercised to ensure that only those women who are at particularly high risk of

very early preterm birth are offered treatment with repeated courses of antenatal

corticosteroids.”

Should steroids be repeated?

• If you think so (Crowther et al), than give only a single repeat course ( WHO, August 2015)

• And only before 32 weeks of gestation

RCT Steroids before elective CS<39wks

Stutchfield et al, BMJ 2005; n=1000

RR in intervention group

• RDS 0.21 (0.03-1.32)

• Transient Tachypnea NICU 0.54 (0.26-1.12)

• RDS NICU admission 0.46 (0.23-0.93)

Arch Dis Child

Fetal Neonatal

2013

RCT Steroids before elective CS<39wks

Stutchfield et al, BMJ

2005

Steroids before elective CS<39 wks

• Why do we give these potent drugs with potent side-

effects instead of waiting for 39 wks

• Or, why don’t we first determine fetal lung maturation by

amniocentesis

NEJM Febr 4, 2016

RCT, n=2.800

Betam. Placebo

• N 1429 1402

• CPAP/Oxygen,Mech Vent 11.6% 14.4% 0.80(0.66-0.97)

• ECMO - -

• Stillbirth/neon d<72h - -

• RDS 5.5% 6.4% 0.87(0.65-1.17)

• Comp RDS/Tachypnea/apnea 13.9% 17.8% 0.87(0.66-0.93)

• Hypoglycemia<2.2mmol/l 24% 15% 1.60(1.37-1.87)

34-37 wks

Steroids for women at risk for late preterm birth

• Implemented in the USA

However,

• It will result in more than doubling of steroid use.

Uncertain if positive effects prevail over long term side

effects?

• Improved morbidity at all ages or only at 34-35 wks ?

• No follow-up data yet.

• So, what is wise ??

French College of O&G: NO

Antenatal corticosteroids

Poison with some positive side effects

And I would also suggest to wait

with implementation, until more

information is obtained

The future

Co-treatment to prevent steroid induced

side-effects ??

The future

Co-treatment with statins, which improve

NO bioavailability

• Paravastatin prevents alterations of

cardiovascular system and brain

development (volume, cortical and hypocampal neuronal numbers,

GFAP-positive astrocyte density in the white matter) in rat pups

treated neonatally

Thijsseling, PhD Utrecht, January 2014; in collaboration with D Giussani,

Cambridge. Thijsseling et al, Ped Res 2013

The future

• Co-treatment with allo-pregnanolone (AP); a

neurosteroid and GABAA receptor antagonist

that influences fetal brain development and has

neuroprotective properties.

• Co-administration of AP prevented changes in

the n of myelinating cells in subcortical white

matter, in fetal sheep

Yawno et al, Neuropharmacology 2014

But, in the meantime we have to find out

• The optimal dose

• If correction for maternal BMA is necessary

• And if steroids are useful in IUGR fetuses

So, with steroids it remains an unfinished story

Finally,

• Use of corticosteroids should be reduced by a better

identification of women who really are at increased risk of late

preterm delivery (CL measurement, fibronectin)

• 24-34 wks, preterm contractions n=665, PTD 12%; Van Baaren et al, O&G 2014

n PTD<1wk

• CL >30mm 255 2 0.7%

• CL 15-30mm 297 25 8 %• CL 15-30 FN- 139 4 3 %

• CL 15-30 FN+ 148 21 14 %

• CL < 15 mm 113 53 47 %

Corticosteroids; poison with some

positive side-effects.

So, only use it with wisdom and

only if really indicated

Women want to be treated and

doctors want to treat,

But doctors should know better

THANK YOU