Joel SegreConsultant to Bill & Melinda Gates FoundationFor the Born Too Soon Care GroupArusha, January 15, 2013

Antenatal Corticosteroids:

A marker of quality of care at birth

Preterm Birth Care Team 1

Antenatal corticosteroids are among the “low hanging fruit” in the management of preterm labor and birth

Antenatal Corticosteroids

Kangaroo Mother Care

Neonatal resuscitation

CPAP / novel surfactant

Cervical pessary

Infection case management

Progesterone

Start here

Preterm Birth Care Team 2

ACS are effective, low cost, and already available in many facilities– they are just underused

Effective Low Cost Under Used

• 19 RCTs with mortality endpoints including ~4000 mothers and babies

• 31% reduction in need for CPAP or ventilation

• 31% reduction in neonatal death across all settings

• Increasing use to 50% could save an estimated 200K lives annually

• Dexamethasone widely available as generic

• Indian dexamethasone prices average <$1 per course

• >80% coverage in developed countries

• Estimates <10% coverage in 75 countries (Lancet 2005)

• Soon to be published data from WHO shows low coverage even at high volume centers with C-section capability

Effective Low Cost Under Used

Preterm Birth Care Team 3

The ACS working group has added ACS to the UN Commission on Life Saving Commodities

Preterm Birth Care Team 4

The ACS 2013 work group is focusing on three main objectives, funded by 10+ partners and the UN Commission

• Data collection form secondary sources (e.g.WHO, MCHIP)• Rapid assessment across 30+ countries • In-depth assessment in 2-4 countries

• Establish a web portal for ACS materials (via HNN)• Host panels at international conferences (GMHC, DELIVER)• Publish critical path analysis (Potentially with UN Commission)• Develop a policy brief for in-country advocacy

• Apply for inclusion in WHO EML• WHO Guidance Review for Mx of preterm labor & baby• Design and deploy accelerated scale up package in 2-4 countries

Gather data

Sharefindings

Take direct action

A

B

C

Preterm Birth Care Team 5

Melinda Gates has identified ACS on her short list of priorities

“Making Kangaroo Mother Care, corticosteroids and other neonatal interventions a priority will prevent incalculable suffering.”-Melinda Gates in The Economist Nov 2012

Preterm Birth Care Team 6

Three paradigm shifts will help to focus our efforts and accelerate uptake of ACS

ACS may be beneficial in many contexts, but current data supports hospital usage

Both betamethasone and dexamethasone are effective, but dexamethasone is less expensive and more commonly available

The balance of risks is in favor of treatment– side effects are minimal while potential benefit is substantial. “If you think of it, give it”

Focus ondexamethasone

for now

Focus onfacility use

for now

Adopt a low threshold for

giving

2

1

3

Preterm Birth Care Team 7

All efficacy data collected to date is in hospital settings

Death in Childhood

1

Respiratory Distress Syndrome

Moderate/Severe RDS

Neonatal Deaths

Maternal (Puerperal) Sepsis

Need for CPAP/Ventilation

0.66 [0.59 , 0.73]

0.55 [0.43 , 0.71]

0.69 [0.53 , 0.9]

0.69 [0.58 , 0.81]

0.68 [0.36 , 1.27]

1.35 [0.93 , 1.95]

Favors InterventionFavors ControlRelative Risk

RR [95% CI]

Summary of “All Babies” included in the 2006 Cochrane Review

1

Preterm Birth Care Team 8

The Global Network’s ongoing trial will build an evidence base for pre-referral use in 6 countries, completing this year

Identification Gestational age assessment

OR

Use Preterm Kit & Refer

1

Preterm Birth Care Team 9

Dexamethasone is more broadly available, inexpensive, and already on many national essential medicines lists

Drug Betamethasone(Phosphate+Acetate) Dexamethasone

Dose /Injection 12 mg 6 mgNo of Injections 2 4Interval btwn injections 24hrs 12hrsTotal Amount 24 mg 24 mgAvg Price/24mg $75.00

Branded Retail$0.51

Indian Generic On WHO Essential Medicines List? No YesSpecialized formulation? Yes No

2

Preterm Birth Care Team 10

There is insufficient evidence to show superior efficacy between betamethasone and dexamethasone

Severe IVH (2 Trials, 563 Infants)

1

RDS (5 Trials, 767 Infants)

IVH (4 Trials, 463 Infants)

Death (4 Trials, 610 Infants) 1.28 [0.46,3.52]

0.44 [0.21,0.92]

0.4 [0.13,1.24]

1.06 [0.88,1.28]

Favors Dexa Favors BetaRelative Risk

RR [95% CI]

Meta analysis of the effectiveness of beta and dexa from 2008 Cochrane Review

2

Preterm Birth Care Team 11

Antenatal steroids are safe for mother and baby3

Fever Req Antibiotics (1 Trial, 118 Women)

Puerperal Sepsis (4 Trials, 536 Women)

1

Chorioamnionitis (4 Trials, 575 Women) 1.35 [0.89,2.05]

1.74 [1.04-2.89]

2.05 [1.14, 3.69]

Favors Dexa Favors ControlRelative Risk

RR [95% CI]

Meta analysis of the maternal safety of dexa from 2008 Cochrane Review

Preterm Birth Care Team 12

Even partial doses of antenatal corticosteroids confer benefit

3

Relative risks using partial doses of dexamethasone in infants <1kgN=124

Dexa dose 1 versus 0 2 versus 0 3-4 versus 0RDS 0.6 (0.2 to 2.3) 0.1 (0.0 to 0.7) 0.2 (0.1 to 0.5)Surfactant 1.0 (0.3 to 3.4) 0.4 (0.1 to 1.7) 0.2 (0.1 to 0.5)IVH1 0.4 (0.1 to 1.6) 2.1 (0.4 to 11.2) 0.2 (0.0 to 0.5)CLD & death 0.7 (0.2 to 2.6) 0.2 (0.0 to 0.9) 0.4 (0.1 to 1.1)

Sources: Salhab W et al. Partial or complete antenatal steroids treatment and neonatal outcome in extremely low birth weight infants 1000 g: Is There a Dose-Dependent Effect? Journal of Perinatology (2003) 23, 668–672.; Elimian A. Antenatal corticosteroids: Are incomplete courses beneficial? obstetrics & gynecology: 2003

Note: Data from seven infants not included secondary to early death. RDS = Respiratory Distress Syndrome, IVH = Intraventricular hemorrhageCLD = Chronic lung disease

Preterm Birth Care Team 13

WHO data suggests huge opportunities to increase usage

10

20

30

40

50

60

70

80

90

100

Cambodia

Sri Lanka

Mexico

ACS Coverage (%)

Nepal

Pakistan

Peru

Philippines

Viet Nam

Thailand

Uganda

5 10 20 25 30 35 40 4515 55 60 65 70 75 8050

Nicaragua

Mongolia

Nigeria

Niger

Angola

Paraguay

Institu

tional R

ate (%

)

Democratic Republic of the Congo

Ecuador

ChinaBrazil

85

Afghanistan

95 100

India

JordanJapan

Kenya

90

Notes: ACS coverage rates are preliminary figures from WHO MCS Survey, 2011Hospitals surveyed had >1000 births annuallyCoverage rate is defined as % of live births 24-34wks GA with childbirth taking place after 3hrs in hospitalNo data is available on the type of ACS used, protocol, or completion of dosing

Circle area corresponds to total annual preterm births

Preterm Birth Care Team 14

The ACS work group has identified Malawi, Uganda, India and Brazil as first candidates for assessment and implementation

Country Salient Feature Existing policy Potential impact

Malawi Highest preterm rate in the world

ACS are part of the national guidelines, high level support for preterm work

High facility birth rate and only 28 district hospitals to cover initially create an opportunity to shift practice across the entire country quickly

Uganda Strong gov’t support No guidelines to date

Anecdotally, ACS coverage rate is close to zero, suggesting a great opportunity to save lives

Brazil 6th largest number of preterms, enabling infrastructure

ACS are part of the national guidelines, high level support

Nearly 200K preterm births are modeled to currently take place in facilities but do not receive ACS. Coverage rate is low at 30%

India Largest number of preterm babies and deaths

ACS are part of national guidelines

300K+ preterm births are modeled to currently take place in facilities but to do not receive ACS, even though the ACS rate is high at 87%

Preterm Birth Care Team 15

Discussion