Prevention of Prematurity and Stillbirth - Epidemiology, Evidence, and Research

James A. Litch, MD, DTMHDirector, Perinatal Interventions Program Global Alliance for Prevention of Prematurity and Stillbirth (GAPPS)

Clinical Assistant Professor,Department of Global HealthDepartment of Epidemiology

jlitch@yahoo.com james.litch@seattlechildrens.org

Outline

• Millennium Development Goals (MDGs) progress • Definitions• Epidemiology• What we know - Evidence review for interventions• What we don’t know - Research activities

• Note - All numbers reported in this presentation are estimates impeded by a variety of assumptions and classification/reporting systems

Millennium Development Goals (MDGs)

Global <5 child mortality rate has declined by a third, from 89 deaths per 1,000 live births in 1990 to 60 in 2009.

All regions, except sub-Saharan Africa, Southern Asia and Oceania, have seen reductions of at least 50 per cent.

Number of deaths in children under five worldwide declined from 12.4 million in 1990 to8.1 million in 2009.

Nearly 12,000 fewer children dying each day.

Millennium Development Goals (MDGs)

In developing regions, maternal mortality ratio dropped by 34% between 1990 and 2008, from 440 maternal deaths per 100,000 live births to 290 maternal deaths.

Despite proven interventions that could prevent disability or death during pregnancy and childbirth, maternal mortality remains a major burden.

Connected MNCH OutcomesRequire a New, Interdisciplinary Approach

Maternal

Fetal

Newborn

Child

Prematurity & Stillbirth

Connected MNCH OutcomesRequire an Interdisciplinary Approach

Maternal

Fetal

Newborn

Child

Prematurity & Stillbirth

Preterm birth and stillbirth are

inextricably linked with maternal,

newborn and child health.

Interventions aimed at reducing

preterm births and stillbirths will

accelerate efforts toward

achieving MDGs 4 and 5.

Definitions

Definition of preterm birth: Babies born alive before 37 completed weeks of pregnancy

What is preterm birth?

Late and moderate

preterm

32 to <37 weeks

84%

Very preterm28 to <32 weeks10%

Extremely preterm

< 28 weeks

5%

Source: Chap 5, Born Too Soon

Born Too Soon Report

Source: Lawn JE, Blencowe H, Pattinson R, et al, for The Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; published online April 14. DOI:10.1016/S0140-6736(10)62187-3.

What is stillbirth?

• Classification for most LMIC is a birthweight of at least 1000 g or a gestational age of at least 28 weeks (third trimester stillbirth)– Essential for international comparability, poorly applied – New stillbirth estimates for 193 countries published in Lancet

Series use this definition – WHO definition — a "fetal death late in pregnancy" and allows each

country to define the gestational age at which a fetal death is considered a stillbirth for reporting purposes. Some countries define stillbirth as early as 16 weeks of gestation, whereas others use a threshold as late as 28 weeks (1000 g).

• In some high-income countries other definitions are used – In UK stillbirths are counted from 24 weeks– In USA, Australia and New Zealand from 20 weeks

If high income country stillbirth definitions were used for all countries then the global total would be much higher

eg for USA with WHO definition 13,070, USA definition 27,500

Epidemiology

Major Causes of Under-5 Deaths Globally

Cause of Mortality Annual <5 Deaths

Respiratory infections 2 million

Diarrheal diseases 1.6 million

Malaria 1.1 million

Preterm births 1 million

Childhood-cluster diseases

1 million

HIV/AIDS 340,000

Tuberculosis 40,000 Sources: Jamison, Sonbol, Jamison et al. 2006; Lawn, Wilczynska-Ketende et al. 2006; Stanton, Lawn et al. 2006

3.2 millionStillbirths

Not counted

Changes in Causes of Newborn Deaths

Note: rates by country are available on the accompanying wall chart. Not applicable=non WHO Members StateSource: Blencowe et al National, regional and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications

Of the 11 countries with the highest rates, 9 are in Africa

First ever national estimates of preterm birth for 192 countries – where are the highest rates?

11 countries with preterm birth rates over 15% 1.Malawi2.Congo3.Comoros4.Zimbabwe5.E. Guinea6.Mozambique7.Gabon8.Pakistan9.Indonesia10.Mauritania11.Botswana

Born Too Soon Report

Note: rates by country are available on the accompanying wall chart. Not applicable=non WHO Members StateSource: Blencowe et al National, regional and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications

Preterm births – where are the biggest numbers?

Truly a global problem, affecting all countries60% are in South Asia and sub-Saharan Africa but with

less care

10 countries account for 60% of the world’s preterm births1.India2.China3.Nigeria4.Pakistan5.Indonesia6.United States of America7.Bangladesh8.Philippines9.Dem Rep Congo10.Brazil

Born Too Soon Report

Preterm Births by Gestational Age and Region for 2010

• 75% of preterm deaths are in Sub-Saharan Africa and Southern Asia

• 80% of 32-37 week preterm babies can survive with essential care

• Level of care determined by gestational age

Causes of Death Due to Preterm Birth

Underlying Pathology Cause of DeathLung immaturity Hypoxia

Acute respiratory distress syndrome (ARDS)

Inability to tolerate labor Birth asphyxia

Poor temperature regulation Hypothermia

Infection SepsisPneumonia

Poor feeding HypoglycemiaDehydrationPour weight gain

Challenges for Preterm Prevention: Multiple Social, Biological, and Clinical Risk Factors• Chorioamnionitis • Bacterial vaginosis• Periodontal disease• Maternal morbidity• Incompetent cervix• Low pre-pregnancy weight• Poor weight gain• Twins, triplets• Congenital malformations• Genetics• Prior preterm birth

• Poor nutrition• Poor pregnancy weight gain• Maternal age• Marital status• Poverty• Black race• Tobacco use• Substance use• Stress • Physical exertion

Country variation in stillbirth rates

Source: The Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; published online April 14. DOI:10.1016/S0140-6736(10)62187-3.

10 countries account for 66% of the world’s stillbirths – and 66% of neonatal deaths and 60% of maternal deaths  1. India2. Pakistan3. Nigeria4. China5. Bangladesh6. Dem Rep Congo7. Ethiopia8. Indonesia9. Tanzania10. Afghanistan

Stillbirth rates (deaths per 1000

livebirths) 

Lowest countries•Finland (2)•Singapore (2)

 Highest countries192. Nigeria (42)193. Pakistan (47)

Stillbirth rates (deaths per 1000

livebirths) 

Lowest countries•Finland (2)•Singapore (2)

 Highest countries192. Nigeria (42)193. Pakistan (47)

2.6 million stillbirths 98% occur in low-income and middle-income countries

Stillbirths during labor – 1.2 million a year

Source: The Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; published online April 14. DOI:10.1016/S0140-6736(10)62187-3.

Approximately of 40% of stillbirths are during labor

Causes of stillbirths

Major causes:1. Childbirth complications2. Maternal infections in pregnancy (eg

syphilis, malaria)3. Maternal conditions, especially

hypertension and diabetes4. Fetal growth restriction5. Congenital abnormalities

Source: Lawn JE, Blencowe H, Pattinson R, et al, for The Lancet’s Stillbirths Series steering committee. Stillbirths: Where? When? Why? How to make the data count? Lancet 2011; published online April 14. DOI:10.1016/S0140-6736(10)62187-3.

These overlap with the causes of maternal and neonatal deaths

What we do know – Evidence for Interventions

• Identified evidence-based interventions to prevent preterm birth and stillbirth

• About 2,000 studies on preterm birth, stillbirth or

related interventions were evaluated.

• Out of 82 existing interventions, 49 were selected

for in-depth reviews. • Selection was based on the presence of a reasonable amount of evidence and relevance

to low- and middle-income countries.

• Commissioned by Gates Foundation

• Available at www.gapps.org

2010 Global Report on Preterm Birth & Stillbirth

Summary of assessments for INTRAPARTUM preterm birth and stillbirth interventions (based on GRADE system)

Premature baby carePrevention of preterm birth • Essential and extra newborn care

(thermal care, feeding support, early breastfeeding, and vitamin K at delivery

• Neonatal resuscitation

• Prolonged Skin-to-Skin Care

• Management of premature babies with complications especially respiratory distress syndrome, infections and jaundice

• Progressing towards neonatal intensive care

Management of preterm labor

•Prophylactic corticosteroids

•Antibiotics for pPROM

•Tocolytics to slow down labor

Reduction of preterm birth

Mortality reduction among babies born preterm

• Preconception care package especially family planning

• Smoking cessation and employment safeguards of pregnant women (PG to prevent recurrent preterm birth)

• Antenatal care package

• Effective childbirth care

Quality evidence and strong recommendation for LMICs to reduce the burden of preterm birth

Priority interventions for preterm baby care team due to unique capability of driving significant preterm mortality reduction in a cost-effective manner

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Estimated Lives Saved of Premature Babies in Settings with Universal Coverage of Basic Interventions (without NICU)

520,000 lives (55%) saved of premature babies could be prevented if adequate management of preterm labor and birth.

760,000 lives (80%) saved if family planning included in model.

Prevention of intrapartum stillbirth

Prevention of antepartum stillbirth

•Effective childbirth care

•Neonatal resuscitation

•Progressing towards comprehensive Emergency Obstetric Care

Management of intrapartum

complications

•Management of prolonged labor•Magnesium sulfate•Antibiotics•Active management of third stage•Induction of labor at or beyond 41 completed weeks

Reduction of antepartum stillbirth

Reduction of intrapartum stillbirth

• Preconception care package especially family planning

• Antenatal care package/BPP• Periconceptual folic acid and

maternal nutrition• Malaria in pregnancy (IPTp/ITN)• Syphilis screening and treatment• Diabetes screening and

management• Smoking cessation and fetal

growth restriction management

Quality evidence and strong recommendation for LMICs to reduce the burden of stillbirth

Born Too Soon Report

Modeling reduction in stillbirth 10 evidence-based interventions

Interventions considered in the model99%

coverage Stillbirths

Reduction

1 Periconceptual folic acid fortification 27,000 1%

2 Malaria in pregnancy - ITNs & IPTp 35,000 1%

3 Syphilis screening and treatment 136,000 5%

4 Hypertensive diseases in pregnancy and management 57000 2%

5 Diabetes screening and management 24,000 1%

6 Fetal growth restriction management 107,000 4%

7 Induction of labor at or beyond 41 completed weeks 52,000 2%

8,9,10 Obstetric Care (3 levels of care) 696,000 28%

Total Stillbirths Averted1,134,00

0 45%

Basic antenatal

care

Advanced antenatal

care

Childbirth care

Source: Pattinson R et al. Stillbirths: how can health systems deliver for mothers and babies? Lancet 2011.

1.1 million stillbirths (45%) could be prevented.1.6 million (70%) if family planning included in model.

0.7 million (30%) could be prevented by obstetric care alone.But need higher coverage and quality of care

What we know about what works?

Potential for lives saved through steroid injections for women in preterm labor

Respiratory complications due to lung immaturity (RDS) are the commonest cause of death in preterm babies.

Single course of antenatal steroids to women in preterm labour: •31% Mortality reduction (RR 0.69, 95% CI 0.58 to 0.81) for babies in settings where ventilation (+/-surfactant is standard of care (Cochrane review))

•53% reduction in mortality in 4 studies in middle income countries (RR 0.47, 95% CI 0.35 to 0.64)

Could save about 400,000 babies each year if reached 95% of women in preterm labor (LiST analysis)

Dexamethasone is low cost (<$1) and available in many settings but low coverage in low and middle income settings

One of the 13 priority medicines listed by UN Commodities Commission

Born Too Soon Report

Source: Chap 6 , Born too soon,

Potential for lives saved through continuous skin-to-skin care

Baby is tied skin to skin with mother 24 hours a day for days/weeks providing

•thermal care, •increased breastfeeding, better weight gain•reduced infections and links to additional supportive care, if needed, and earlier discharge

Mortality reduction 51% for babies < 2000 gm, in facilities, clinically stable and started within one week compared to incubator care

Effective entry point for care of preterm babies

Chap 5 and 5, Born too Soon>Impact data from Lawn et al ‘Kangaroo mother care’ to prevent neonatal deaths due to preterm birth complications. Int J Epid: 2010,Conde Aguedelo Cochrane review 2011

Could save about 450,000 babies each year if reached 95% of preterm babies (LiST analysis)

Born Too Soon Report

What We Want to Know - current research efforts

Missed delivery opportunities to reach preterm babies with essential interventions

Availability Gap

Development Gap

Information Gap

33

Thank you

Global Alliance for the Prevention of Prematurity and Stillbirth (GAPPS) leads a collaborative, global effort to increase awareness and accelerate innovative research and development to make every birth a healthy birth.jlitch@yahoo.com james.litch@seattlechildrens.org

Highly cost effective

Source: Pattinson R, Kerber K, Buchmann E, et al, for The Lancet’s Stillbirths Series steering committee. Stillbirths: how can health systems deliver for mothers and babies? Lancet 2011; published online April 14. DOI:10.1016/S0140-6736(10)62306-9.

• Childbirth care cost analysis• Cost per maternal death prevented is US$54,350 • Counting newborns and stillbirths this becomes $3,920 per

death prevented

• Total additional running cost of $10.9 billion for the 68 priority countries per year for full coverage of care with

• 10 interventions for women, newborns and stillbirths• plus 5 maternal and newborn specific interventions

US $2.32 per year per person in the 68 priority countriesAffordable especially given results of 2.7 million lives

savedInvestment in maternal health should count the full effect

Lawn JE, et al, Lancet 2005;365(9462):891-900

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Day of life

Risk of Death, by Day,During the First Month of Life

Developing an Indicator to Measure Intrapartum Stillbirth and Immediate Neonatal Death

• GAPPS and MHTF sponsored meeting to: • Re-evaluate the Intrapartum Stillbirth and Early Neonatal Death indicator

described in “Monitoring emergency obstetric care: a handbook”• Establish a protocol for a prospective multi-country pilot study• Results:

Working group developed a standardized protocol

Pilot study performed by Global Health Network

Intrapartum mortality, early neonatal mortality and peripartum mortality indicators are all feasible with provision of fetal heart monitor assessment at admission to labor ward

New indicator allows collection of robust data to improve intervention trials

Practical Tools for Immediate and Near-term Impact•Scale up and improved quality of evidence-based interventions and childbirth decision tools •Accelerate new interventions coming down the pipeline•Shift awareness and attitudes of families and HCWs

Preventing Preterm Birth (PPB) Initiative

• GAPPS stewarding $20 million Gates Foundation grant

• Advances research into causes and mechanisms of preterm birth

• First of the Family Health Grand Challenges in Global Health

• Received applications from 320 researchers in 50 countries

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• Collection of vital resources

– Maternal data linked to tissue specimens

• Fosters pioneering research

– Leads to diagnostics, prevention, therapeutics

• Expanding, becoming global model

– Launched with Washington hospitals: UW, Swedish, Yakima Valley Memorial

– Designed to be self-sustaining

The GAPPS Repository