How Women’s Health Research Can Improve Community Health

Sarah L. Berga, MDDepartment of Gynecology and ObstetricsEmory University School of Medicine

Underscore challenges that compromise reproductive and women’s health in the USA

Outline key research opportunities for fostering better reproductive and women’s health in the USA

Highlight the relationship between individual health and community health

Overview

Challenges◦ Maternal mortality in the USA is higher than most

developed countries and on the rise

◦ Adolescent reproductive health is substandard

◦ Reproductive autonomy varies widely across the nation

◦ Affordability and access are serious barriers to reproductive health

◦ Highly variable health literacy limits implementation

◦ Social and economic inequities between men and women impact health and healthcare access

Women’s and Reproductive Health

Opportunities◦ Understand the social determinants of health and

remediate the health effects of social inequity

◦ Harness the promise of molecular medicine for diagnostics and therapeutics in women’s and reproductive health

◦ Determine how sex, gender, hormones, and reproductive status/history modify diagnosis, treatment, and aging

◦ Ensure that knowledge and discovery are actively translated into health rather than healthcare per se

Women’s and Reproductive Health

Opportunity

Understand the social determinants of health and remediate the health effects of social inequity

Maternal mortality is the traditional marker of comprehensive obstetrical safety• # women who die annually from preventable complications of

pregnancy is 10X > than # deaths from AIDS

• The UN made maternal mortality a sentinel indicator of societal health (Millenium Development Goals)

• The canary in the mineshaft for reproductive and women’s health?

If the goal and purpose of healthcare is to improve health, why is the USA:• 1st in health care expenditure• 45th in life expectancy• 33rd in maternal mortality• 29th in infant mortality?

Background

Copyright ©2000 American Academy of Pediatrics

Maternal Mortality United States 1915-1998

A century of progress in maternal mortality reversed

Guyer, B. et al. Pediatrics 2000;106:1307-1317

Reduced maternal mortality and reliable contraception alter women’s options and societal expectations

High mortality led to limited societal expectations for women

Annual maternal mortality rates in England and Wales, 1880-1980

Loudon, I. Am J Clin Nutr 2000;72:241S-246S

Copyright ©2000 The American Society for Nutrition

CDC 2000 Target :3.3 maternal deaths / 100,000 births

Currently ~16 in USANadir of 8 in1982

1:200

1940

Maternal & fetal survival of pregnancy & delivery was a necessary prerequisite to understanding fetal origins of adult disease & the long-term health consequences to women of childbearing & childrearing

Maternal mortality varies widely around the world

0 10 20 30 40 50 60 70

IrelandDenmark

ItalySweden

AustraliaAustria

IsraelSpain

SwitzerlandJapan

NetherlandsCanadaCroatiaFinland

NorwayUK

USABulgariaGA-USA

RomaniaRussiaGrady

Mexico

Maternal Mortality – Deaths / 100,000 Births

WHO 2005 www.who.int/reproductive-health

US ranks #33 in MM despite being #1 in health care expenditures

Target 3.3 maternal deaths / 100,000 births

Maternal mortality varies widely across the nation

0 5 10 15 20 25

MaineVermont

MassachusettsIndianaVirginia

PennsylvaniaTexas

KentuckyIllinois

Rhode IslandAlabama

South CarolinaWest VA

CaliforniaNew Jersey

North CarolinaTennesseeDelawareArkansas

MississippiLouisianaNew York

New MexicoGeorgia

Maternal Mortality – Deaths / 100,000 Births

WHO 2005 www.who.int/reproductive-health

Georgia ranks 50/50Delaware

ranks 42/50

Maternal Mortality Target 3.3

www.oasis.ga.state.us

US Deaths in Iraq War/100,000 Active Duty US Soldiers

How do we distribute health care services?

ILLNESS $$ILLNESS

$$

Market-driven health care does not guarantee overlap between reservoir of illness and provision of or access to needed health care services

Health outcomes-driven health care seeks to align health care services and activities with health care needs (illness and prevention)

How do we distribute health care services?

• Healthcare expenditures do not always overlap with healthcare needs

• The sicker an individual, the lower the likelihood that they will be employed and capable of independent care

• A healthcare system based solely on employer based health insurance will of necessity create gaps between healthcare needs and expenditures

• This may explain, at least in part, why the USA is #1 in healthcare expenditure, but #45 in overall health

Health disparities reduce social capital and increase total mortality

• Health disparities track with SES (socioeconomic status) disparity in all countries

• The greater the health disparities in a country, the lower the overall health of everyone

• Highest SES group in USA has health comparable to that of lowest SES in UK

• Sweden has lowest health disparity in world and the best overall health Banks J et al. Disease and Disadvantage in the United

States and England. JAMA 2006;295:2037

Marmot M. Health in an Unequal World. Lancet 2006;368:2081

Income inequality (Gini coefficient) & mortality in men & women aged 45-54 in Britain, 1962-1990. BMJ 2000;320:1200

Social Determinants of HealthSocial Determinants of Health

Figure 2. Under-5 mortality rates per 1000 children by socioeconomic quintile of household Source: Gwatkin, et al.

Behavior40%

Genetics30%

Social 15%

Healthcare10%

Environment5%

Contribution to premature death

Social determinants of health

WHO 2008 Report:Closing the Gap in a Generation

Factors influencing subjective wellbeing

Family47%

Health24%

Location8%

Money7%

Spiritual life6%

Community5%

Work2%

Sustainable Development Commission of UK. Prosperity without Growth?

WHO Report: Closing the Gap in a Generation

3 Action Items: Improve conditions of daily living

Tackle inequitable distribution of power, money, and resources

Measure problems, evaluate action, expand knowledge base, develop workforce that is trained in the social determinants of health, and raise public awareness about SDOH

Social determinants of health

Georgia ranks 37/50 in Women’s Health◦ 39 for health insurance

(25% of women lack)◦ 46 in mental health◦ 46 in sexually transmitted

infections◦ 8 in teen pregnancy◦ 30% of women in need

had access to contraception

◦ 47 in life expectancy◦ 44 in infant mortality◦ 43 in obesity

Delaware ranks 29/50 in Women’s Health◦ 13 for health insurance

(12% of women lack)◦ 28 in mental health◦ 36 in sexually transmitted

infections◦ 6 in teen pregnancy◦ 53% of women in need

had access to contraception

◦ 45 in life expectancy◦ 46 in infant mortality◦ 16 in obesity

National Women’s Law Center State Report Cards

http://hrc.nelc.org/Reports/State-Report-Card

Among the rich countries for which there is data, the USA has:◦ Highest infant mortality◦ Highest teenage birth rate◦ Greatest gap in mortality between rich and rest of

population◦ Largest wealth gap between rich and rest of

population◦ Highest number of persons living alone◦ Lower voter turnout◦ Highest incarceration rate◦ Highest homicide rate

A snapshot of the USA

June 10, 1963 J.F. Kennedy signed the Equal Pay Act to end the gender gap in wages◦ In 1963, women earned 60 cents per $ earned by men◦ In 2010, it is 80 cents

1979 – the term “glass ceiling” introduced to describe low representation of women in management positions

1998 – Newsweek coined the phrase “womenomics”

2006 – The Economist publishes “A Guide to Womenomics” noting that 15% of directors on US corporate boards and 7% worldwide are women

Worldwide, 70% of women regularly work outside the home but hold less than 25% of governmental seats

Womenomics

Opportunity

Harness the promise of molecular medicine for diagnostics and therapeutics in women’s and reproductive health

Maternal milieu = fetal origins of adult disease• Health begins in utero not with birth• Pregnancy = “maternal-fetal-placental unit”

The Barker hypothesis expanded • Risk of CVD in late life related to health of one’s mother• Intrauterine milieu “programs” growth of adipocytes (and other

cells) and gene expression, thereby “imprinting” the next generation

• Epigenetic? Reversible? Plastic?

Commonplace examples of maternal determinants of adult disease “acquired” in utero abound, but physician and public awareness is low• Awareness precedes action• Whose job is it to screen?

From Molecules to Motherhood

Reproductive “alignment” occurs when physiological and pathophysiological responses to the external milieu modulate reproductive function • This plasticity is necessary for adaptation• To what extent is the resulting state reversible or plastic?• What are the consequences of pregnancy in a compromised

maternal milieu?

Stress, metabolic states (diabetes, over- & undernutrition, nutrient deficiency, GI enteropathies, obesity), and environmental exposures (infection, toxins) alter reproductive physiology and trigger reproductive compromise

• Both women & men experience reproductive compromise when metabolically or psychologically “stressed”

From motherhood to molecules: mechanisms underlying gene x milieu

How fares weight homeostasis?

• Excess body weight is the 6th most important risk factor for global disease burden• Primarily due to physical activity + passive

overconsumption of energy dense foods• Reflects gene x environment interaction with ↑

risk of obesity greatest in disadvantaged populations

• Consequences:• Metabolic syndrome• CVD• Diabetes• Life expectancy• Reproductive compromise

McMillen IC et al Adv Exp Med Biol 2009;646:71

Social Determinants of HealthSocial Determinants of Health

Figure 7. Women's obesity by quartiles of education. Prevalence ratios based on prevalence of obesity in lowest quartile of education set at 1 for each group of countries. Source: Monteiro, et al.

Copyright restrictions may apply.

Gesink Law, D.C. et al. Hum. Reprod. 2007 22:414-420; doi:10.1093/humrep/del400

The predicted probability of conception with changing body mass index (BMI kg/m2), after adjusting for age, smoking, race, education, occupation and study centre

BMI and pregnancy outcome in nulliparous women

• Compared to Scottish women with BMI 20-24.9

• Obese women had elevated risk of:• Pre-eclampsia (OR 7.2 for BMI > 35)• Induced labor (OR 1.8)• Emergency CS (OR 2.8)• Postpartum hemorrhage (OR 1.5)• Preterm delivery (OR 2.0)• Macrosomia (>4000gm) (OR 2.1)

• Thin women (BMI < 20) showed:• SGA infants (<2500gm) (OR1.7)• Macrosomia (OR 0.5)

Bhattacharya S et al. BMC Public Heath 2007;7:168

A unifying hypothesis• Both undernutrition / low weight and

overnutrition / obesity compromise reproductive function• Different states elicit a different constellation

of endocrine and epigenetic changes• Different - but nonetheless deleterious - fetal

impact

• Social stress may elicit undernutrition or overnutrition

• Overnutrition is more common when energy dense food is readily available

Mechanisms mediating genomic plasticity Variation in alleles (polymorphisms)

resulting in modified mRNAs and proteins

Variation in cis or trans regulatory (enhancer) DNA

• (Science 2009; 326:1612)

Alterations in promoter sequences

Differential expression of co-activators and co-repressors modulate DNA transcription

Altered imprinting• Methylation of DNA and histones• Acetylation of histones

Micro RNA (miRNA) altered gene transcription or translation

Altered RNA trafficking / turnover altered gene translation

Transposons and endogenous retrovirus (ERVs)

Changes in DNA methylation and histone acetylation in twins across lifespan

Epigenetics of experience

Anatomical and physiological differences between queen and worker bees conferred epigenetically

• Health begins in utero• By altering cortisol and thyroxine levels, maternal

stress and disease modify the genome including fetal DNA methylation (epigenetics)

• Long-term health consequences for women after pregnancy and the fetus as an adult

• Many conditions clinically occult

• Maternal milieu = molecular milieu = fetal milieu

• Maternal milieu = fetal origins of adult disease + generational transmission via epigenetic mechanisms

Molecules to Motherhood

Public health implications are obvious

• To reduce disease burden, we must invest in maternal and paternal health before, during, and after conception

• Focus of care must be more than the fetus or the postnatal individual

• Obstetricians need to be more than surgeons

• All physicians must understand impact of diseases upon reproduction in men and women

• Women’s health specialists are held back by a reductionistic appreciation of the importance of the maternal milieu

Whose Job? – Molecules to Motherhood

Reduction of health inequities is certainly not a goal of federal policy in the USA, even in these days of health-care reform.

Indeed, today’s most vocal critics of social inequalities are not Marxists but scholars of public health.

In the UK, the mechanism chosen to tackle inequalities is some form of state-sponsored national health-care system.

The USA has an enviable public health infrastructure.

What it does not have is universal medical care, and my country’s record on health inequalities is abysmal.

Who owns health inequities?Nathanson CE. Lancet 2010;375:274-275

Opportunity

Determine how sex, gender, hormones, and reproductive status/history modify diagnosis, treatment, and aging

Two key modifiers of health & disease are sex & age

Every cell has a sex

Sex differences are more than hormones◦ New journal launched Biology of Sex Differences

We need to understand:◦ Conditions found only in women◦ Conditions more common in one sex over the other◦ Conditions that present differently in men and women◦ How sex modifies treatment responses

Sex Differences

Brain region size in adults correlated with fetal sex steroid activity. Cahill L. His Brain, Her Brain. Scientific American. May 2005.

Larger in females

Larger in males

Core concepts:•Hormone-dependent sexual differentiation•Hormone-independent sexual differentiation•Sex-specific hormone action

Using microarray analysis, 2000 more hormone-responsive genes were detected in female than in male rats given a standard dose of a synthetic glucocorticoid

◦ 70 genes showed opposite changes in expression in males and females

◦ Inflammatory genes more suppressed in males

◦ Male rats had higher survival when given GC after exposure to infection

Stressing sex differences

Duma et al. Sci Signal 3 ra74 2010

August 25, 2005Page 39

Women’s HealthVision – Emerging Services

The range of services would expand to include those conditions that are more common and/or biologically different for women in order to provide specialized, thus higher quality, care.

Conditions That Exist Only in Women

Pregnancy Post-Partum

depression

Cervical Cancer Ovarian Cancer Uterine Cancer

Uterine fibroids Endometriosis Menopause

Conditions That Occur More Frequently in Women

Breast cancer Endocrine disorders Cholecystitis Thyroid disease

Pelvic ulcer disease Kidney and urinary

tract infection Multiple sclerosis Seizures and

headaches

Pelvis fractures Obesity Bronchitis and

asthma Arthritis

Conditions That Are Biologically Different in Women

Infertility Cardiac disease Stroke

Migraine headaches Pulmonary emboli

Osteoporosis Psychiatric disorders

TraditionalWomen’sServices

EmergingWomen’sServices

Many health conditions reflect a combination of biological sex differences and gendered social determinants

Action priorities include:◦ Access to services◦ Recognition of women’s roles as health care providers◦ Building accountability for gender equality and equity into

health systems

Important barriers:◦ Lack of awareness ◦ Lack of acknowledgement ◦ Absence of effective accountability mechanisms

2007 WHO Commission of Social Determinants of Health

Women and Gender Equity Knowledge Network

Opportunity

Ensure that knowledge and discovery are actively translated into health rather than health care per se

The Patient Protection and Affordable Health Care Act created PCORI

Nonprofit corporation that is neither an agency nor an establishment of the US gov’t◦ Build on the efforts of the Agency for Healthcare Research and

Quality (AHRQ) and NIH

Mission is to support the production of well-validated scientific evidence to assist in health care decisions◦ Set research priorities◦ Identify evidence and evidence gaps◦ Relevance of evidence and economic effects◦ AHRQ and NIH will disseminate findings

Patient-Centered Outcomes Research Institute (PCORI): The Intersection of Science and Health Care

Implementation science

Basic Science (foundations)

Translational Science(mechanisms of disease and pharmacogenomics)

Valley of funding death

Implementation science / Clinical effectiveness research (improved care, delivery, access)

Chasm of doomPCORI? NCATS?

Estimate the impact of science investment in 4 areas:

Economic growth – measured by patents and start-ups

Workforce outcomes – measured by student mobility into workforce

Scientific knowledge – measured by publications and citations

Social outcomes – measured by overall health and environmental health

STAR METRICS a new approach to measure the impact of federally funded research

• Most obstetrical emergencies are survivable with prompt and appropriate management• Not predictable• Occur predominantly in “low risk” patients• “Decision to incision” for C-section < 30

min• “Crash” C-section < 5 min• Most occur during labor, delivery, and the

first 24 hours postpartum

North Carolina Pregnancy-Related Mortality Review 1995-1999• 40% of pregnancy-related mortality was

preventable• Improved safety of medical care single

most important factor• Racial disparity - 46% of deaths

preventable in black vs 33% in white women

• Factors to manage:• Access• Obstetrician

availability and alertness

• Nursing engagement• Communication /

process / teamwork• Resource availability

• Space• Anesthesia

coverage• Pediatric

resuscitation team• Blood

Maternal mortality is a implementation rather than medical knowledge gap

Berg CJ (CDCP). Obstet Gynecol 2003;101:289; Obstet Gynecol 2005 ; Chang J (CDCP). MMWRSurveill Summ 2003;52:1; Ho E. Am J Ob Gyn 2002;187:1213.

The big picture

• Unassisted birth results in high maternal mortality in humans

• Humans are the only species in which fetal head > maternal pelvic diameter (inherent cephalopelvic disproportion) • Postpartum hemorrhage• Eclampsia / pre-eclampsia• Puerperal sepsis• Obstructed labor• Fistula formation / pelvic floor dysfunction

• Humans are the only species requiring birth attendants

• Trade-off between fetal brain size and need for “premature” birth• Cultural adaptations to care for highly dependent offspring• Humans are only species with “childhood” (provisioning of food after

weaning)• Childhood facilitates child survival AND allows shortest interbirth interval of

all primates• Adaptations have fostered explosive growth of human population

Social Determinants of Health

Social Determinants of Health

“If medicine is to fulfill her great task, then she must enter the political and social life.

Do not we always find the diseases of the populace traceable to defects in society?”

Since disease so often results from poverty, then physicians are the “natural attorneys of the poor” and social problems should be solved by them.

Rudolf Virchow in DeWatt DA, Pincus T. The legacies of Rudolf Virchow: cellular medicine in the 20th century and social medicine in the 21st century. IMAJ 2003;5:395

Knowledge Gaps Autoimmune dx Breast ca causes Preterm labor cause Sex-specific cardiac

presentation Sex differences in

stress, neuropsych, neurodegeneration

Risks and benefits of hormones

Implementation Gaps Maternal mortality Breast ca treatment Preterm labor tx Sex-specific cardiac

care Teenage pregnancy Adolescent gyne STIs Contraception

Knowledge vs Implementation Gaps in Reproductive and

Women’s Health

GYNONC

Menopause

GENETICS

FAMILYPLAN

NEUROPSY

REI/IVF

UROGYN

OB

GYN

Transforming Health and Healing…. Together

Build a comprehensive portfolio of Obstetrical, Gynecological, and Women’s Health services

Collaborate with other disciplines to achieve best practices for men, women, and offspring and expand research activities

Increase academic approach and enterprise to improve standard of care, teaching and training, to implement best practices, and to personalize care

Harnessing the promise of molecular medicine for reproductive and women’s health

MFM

Comprehensive portfolio should encompass sex specific diagnosis

and treatments

We are all in this together!

Individual Health

Family Health

Community Health