Transcript Slide 1

Sarah L. Berga, MD
Department of Gynecology and Obstetrics
Emory University School of Medicine
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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
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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
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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
Understand the social determinants of
health and remediate the health
effects of social inequity
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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?
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If the goal and purpose of healthcare is to improve
health, why is the USA:
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1st in health care expenditure
45th in life expectancy
33rd in maternal mortality
29th in infant mortality?
A century of progress in maternal mortality reversed
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
High mortality
led to limited
societal
expectations
for women
CDC 2000 Target :
3.3 maternal deaths / 100,000 births
Currently ~16 in USA
Nadir of 8 in1982
1:200
1940
Reduced maternal
mortality and reliable
contraception alter
women’s options and
societal expectations
Annual maternal mortality rates in
England and Wales, 1880-1980
Maternal Mortality United States 1915-1998
Loudon, I. Am J Clin Nutr 2000;72:241S-246S
Guyer, B. et al. Pediatrics 2000;106:1307-1317
Copyright ©2000 The American Society for Nutrition
Copyright ©2000 American Academy of Pediatrics
Maternal mortality varies widely around the world
Mexico
Grady
Russia
Romania
GA-USA
Bulgaria
USA
UK
Norway
Finland
Croatia
Canada
Netherlands
Japan
Switzerland
Spain
Israel
Austria
Australia
Sweden
Italy
Denmark
Ireland
US ranks #33 in MM despite being #1 in
health care expenditures
Target 3.3 maternal deaths / 100,000 births
WHO 2005 www.who.int/reproductive-health
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10
20
30
40
50
60
Maternal Mortality – Deaths / 100,000 Births
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Maternal mortality varies widely across the nation
Georgia
New Mexico
New York
Louisiana
Mississippi
Arkansas
Delaware
Tennessee
North Carolina
New Jersey
California
West VA
South Carolina
Alabama
Rhode Island
Illinois
Kentucky
Texas
Pennsylvania
Virginia
Indiana
Massachusetts
Vermont
Maine
Delaware
ranks 42/50
Georgia ranks
50/50
WHO 2005 www.who.int/reproductive-health
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5
10
15
20
Maternal Mortality – Deaths / 100,000 Births
25
www.oasis.ga.state.us
US Deaths in Iraq War/100,000
Active Duty US Soldiers
Maternal Mortality Target 3.3
How do we distribute health care services?
ILLNESS
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ILLNESS
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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
Banks J et al. Disease and Disadvantage in the United
and the best overall health
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 Health
Figure 2. Under-5 mortality rates per 1000 children by socioeconomic quintile of
household Source: Gwatkin, et al.
Environment
5%
Healthcare
10%
Behavior
Social
40%
15%
Genetics
30%
Contribution to premature death
WHO 2008
Report:
Closing the
Gap in a
Generation
Spiritual life
Community
Work
5%
2%
6%
Money
7%
Family
Location
48%
8%
Health
24%
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
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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
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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
http://hrc.nelc.org/Reports/State-Report-Card
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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
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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
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1979 – the term “glass ceiling” introduced to describe
low representation of women in management positions
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1998 – Newsweek coined the phrase “womenomics”
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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
Harness the promise of molecular
medicine for diagnostics and
therapeutics in women’s and
reproductive health
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Maternal milieu = fetal origins of adult disease
• Health begins in utero not with birth
• Pregnancy = “maternal-fetal-placental unit”
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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?
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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?
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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”
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:
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Metabolic syndrome
CVD
Diabetes
Life expectancy
Reproductive compromise
McMillen IC et al Adv Exp Med Biol 2009;646:71
Social 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.
The predicted probability of conception with changing body mass index
(BMI kg/m2), after adjusting for age, smoking, race, education,
occupation and study centre
Gesink Law, D.C. et al. Hum. Reprod. 2007 22:414-420; doi:10.1093/humrep/del400
Copyright restrictions may apply.
BMI and pregnancy outcome in nulliparous women
• Compared to Scottish women with BMI 20-24.9
• Obese women had elevated risk of:
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Pre-eclampsia
Induced labor
Emergency CS
Postpartum hemorrhage
Preterm delivery
Macrosomia (>4000gm)
(OR
(OR
(OR
(OR
(OR
(OR
7.2 for BMI > 35)
1.8)
2.8)
1.5)
2.0)
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
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Variation in alleles (polymorphisms)
resulting in modified mRNAs and proteins
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Variation in cis or trans regulatory
(enhancer) DNA
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(Science 2009; 326:1612)
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Alterations in promoter sequences
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Differential expression of co-activators and
co-repressors modulate DNA transcription
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Altered imprinting
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Methylation of DNA and histones
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Acetylation of histones
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Micro RNA (miRNA)  altered gene
transcription or translation
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Altered RNA trafficking / turnover  altered
gene translation
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Transposons and endogenous retrovirus
(ERVs)
Epigenetics of experience
Changes in DNA methylation and histone
acetylation in twins across lifespan
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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
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Maternal milieu = molecular milieu = fetal milieu
Maternal milieu = fetal origins of adult disease +
generational transmission via epigenetic
mechanisms
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
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Reduction of health inequities is certainly not a goal of
federal policy in the USA, even in these days of healthcare 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.
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The USA has an enviable public health infrastructure.
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What it does not have is universal medical care, and
my country’s record on health inequalities is abysmal.
Determine how sex, gender,
hormones, and reproductive
status/history modify diagnosis,
treatment, and aging
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Two key modifiers of health & disease are sex & age
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Every cell has a sex
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Sex differences are more than hormones
◦ New journal launched Biology of Sex Differences
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We need to understand:
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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
Larger in females
Larger in males
Brain region
size in adults
correlated with
fetal sex
steroid activity.
Cahill L. His
Brain, Her
Brain.
Scientific
American. May
2005.
Core concepts:
•Hormonedependent sexual
differentiation
•Hormoneindependent sexual
differentiation
•Sex-specific
hormone action
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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
Duma et al. Sci Signal 3 ra74 2010
Women’s Health
Vision – 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.
Traditional
Women’s
Services
Conditions That Exist Only in Women
 Pregnancy
 Cervical Cancer
 Uterine fibroids
 Post-Partum
 Ovarian Cancer
 Endometriosis
 Uterine Cancer
 Menopause
depression
Conditions That Occur More Frequently in Women
 Breast cancer
 Pelvic ulcer disease
 Pelvis fractures
 Endocrine disorders
 Kidney and urinary
 Obesity
 Cholecystitis
tract infection
 Multiple sclerosis
 Seizures and
headaches
 Bronchitis and
 Thyroid disease
asthma
 Arthritis
Conditions That Are Biologically Different in Women
Emerging
Women’s
Services
Page 39
 Infertility
 Migraine headaches
 Osteoporosis
 Cardiac disease
 Pulmonary emboli
 Psychiatric disorders
 Stroke
August 25, 2005
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Many health conditions reflect a combination of
biological sex differences and gendered social
determinants
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Action priorities include:
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Important barriers:
◦ Access to services
◦ Recognition of women’s roles as health care providers
◦ Building accountability for gender equality and equity
into health systems
◦ Lack of awareness
◦ Lack of acknowledgement
◦ Absence of effective accountability mechanisms
Ensure that knowledge and discovery
are actively translated into health
rather than health care per se
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The Patient Protection and Affordable Health Care
Act created PCORI
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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
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Mission is to support the production of wellvalidated scientific evidence to assist in health care
decisions
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Set research priorities
Identify evidence and evidence gaps
Relevance of evidence and economic effects
AHRQ and NIH will disseminate findings
Basic
Science
(foundations)
PCORI?
NCATS?
Translational
Science
Valley of
funding
death
(mechanisms of disease
and pharmacogenomics)
Chasm of doom
Implementation science /
Clinical effectiveness research
(improved care, delivery, access)
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Estimate the impact of science investment in 4 areas:
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Economic growth – measured by patents and start-ups
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Workforce outcomes – measured by student mobility into
workforce
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Scientific knowledge – measured by publications and
citations
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Social outcomes – measured by overall health and
environmental health
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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
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Factors to manage:
• Access
• Obstetrician
availability and
alertness
• Nursing engagement
• Communication /
process / teamwork
• Resource availability
• Space
• Anesthesia
coverage
• Pediatric
resuscitation team
• Blood
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.
• Unassisted birth results in high maternal mortality in humans
• Humans are the only species in which fetal head > maternal
pelvic diameter (inherent cephalopelvic disproportion)
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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
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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
 “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
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
REI/IVF
UROGYN
MFM
NEUROPSY
OB
FAMILY
PLAN
GYN
GENETICS
GYNONC
Menopause
Comprehensive portfolio should
encompass sex specific diagnosis
and treatments
Individual Health
Community
Health
Family Health