Lifecourse Approach to Women’s Reproductive Health: Focus on Psychosocial Stress Janet...

Lifecourse Approach to Women’s Reproductive Health:

Focus on Psychosocial Stress

Janet Rich-Edwards, ScD

Assistant Professor

Connors Center for Women’s Health and Gender Biology

Brigham and Women’s Hospital

“With the exception of the stomach, there is no organ that holds such numerous ramifications of sympathy with other organs as the womb.”

J.M. Good, The Study of Medicine, 1826

Lifecourse approach:

• Reproductive success or failure reflects both cumulative and current exposures

• Reproductive events are sentinels of chronic disease in the mother

• Maternal exposures and maternal health predict chronic disease in the child

PastBirthweight

Growth

Social position

Past Present Birthweight

Growth

Social position

Previous pregnancy outcomes

Social position

Pregnancy complications

Stress

Past Present Future Birthweight

Growth

Social position


Social position


Stress

Cardiovascular dz

Diabetes

Cancer

Past Present Future Birthweight

Growth

Social position


Social position


Stress

Cardiovascular dz

Diabetes

Cancer

Next generation



– Theory: reproductive responsiveness– Example: psychosocial stress and pregnancy outcome


Reproduction is expensive:

Lactation

Labor and delivery

Fetal growth

Pregnancy maintenance

Placentation

Conception

Fully competent cycles

Ovulatory failure

Amenorrhea

Physiologic cost

to mother

Adapted from Ellison, 1993

+

-

Reproduction

Survival

Adversity Advantage

Environment

The optimal reproductive system:

• Adapts with agility while expending minimal resources

• Can shut down quickly in response to immediate threat

Childhood Setpoint

Possible in utero or childhood set points:

• Number or quality of ova

• Hormone synthesis

• Hormone receptors

• Uterine vascularization

• Pelvic cavity size

S R

Adult variation

Childhood Setpoint

S

R

Advantageous Adult Environment

S

R

Adverse Adult Environment

The optimal reproductive system:

• Adapts with agility while expending minimal resources

• Can shut down quickly in response to immediate threat

• Customized to early environment

• Retains some plasticity in response to enduring environment

ExamplePregnancy outcome:

preterm birth and low birthweight

9.8 10.010.210.210.610.610.810.711.011.011.011.011.411.611.811.611.912.112.312.512.7

7.6

0

2

4

6

8

10

12

14

1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

Preterm Very Preterm

Preterm (<37 weeks) and Preterm (<37 weeks) and Very Preterm (<32 weeks) BirthsVery Preterm (<32 weeks) Births

United States, 1985-2005United States, 1985-2005

Source: National Center for Health Statistics, final natality dataPrepared by March of Dimes Perinatal Data Center

Percent

Objective

Preliminary preterm birth rates, 2005:

• 11.7% non-Hispanic whites

• 12.4% Hispanics

• 18.4% non-Hispanic Blacks

www.cdc.gov/nchs

Preterm Birth among Singletons by Maternal Education and Race/Ethnicity, U.S. 1999

11 11.210.2 9.4 8.7

11.1 11.79.5

8.47.1

19.818.3

16.214.6

12.9

0

5

10

15

20

25

0-8

year

s9-

11 y

ears

12 y

ears

13-1

5 ye

ars

16+

year

s

0-8

year

s9-

11 y

ears

12 y

ears

13-1

5 ye

ars

16+

year

s

0-8

year

s9-

11 y

ears

12 y

ears

13-1

5 ye

ars

16+

year

s

Percent

Hispanic Non-Hispanic White Non-Hispanic BlackSource: National Center for Health StatisticsPrepared by March of Dimes Perinatal Data Center, 2002

Maternal age

Preterm birth by maternal ageUS, 2002-2004 Average

15.7

13.011.6

10.6 11.012.4

15.1

11.6

0

3

6

9

12

15

18

17 andunder

18-19 20-24 25-29 30-34 35-39 40+ AllAges

Percent

Preterm is less than 37 competed weeks gestation

Source: National Center for Health Statistics, 2000 final natality data

Prepared by March of Dimes Perinatal Data Center, 2002

Preterm BirthsPreterm Birthsby Maternal Age, United States, 2000by Maternal Age, United States, 2000

• Absolute black:white differences in risk of poor pregnancy outcomes at any age

• Different slopes for blacks and whites

with age

The next slides show associations of maternal age with poor pregnancy outcomes, stratified by maternal race/ethnicity. Pay attention to:

0

5

10

15

20

25

15-17

18-19

20-24

25-29

30-34

35-45

15-17

18-19

20-24

25-29

30-34

35-45

Percent low birthweight (<2500 gm) by maternal age, births to Black and White mothers, Chicago 1994-1996

White mothers Black mothers

Per

cent

Rich-Edwards, IJE

Preterm Birth among Singletons by Maternal Age and Race/Ethnicity, United States, 1999

11.3

9.28.1 7.9

910.5

12.3

10.19.3 10

12.3

14.7

17.5

14.8 1516.4

18.7

21.6

0

5

10

15

20

25

15-1

920

-24

25-2

930

-34

35-3

940

-44

15-1

920

-24

25-2

930

-34

35-3

940

-44

15-1

920

-24

25-2

930

-34

35-3

940

-44

Percent

Non-Hispanic White Hispanic Non-Hispanic BlackSource: National Center for Health StatisticsPrepared by March of Dimes Perinatal Data Center, 2002

• Absolute black:white differences in risk of poor pregnancy outcomes at any age

– effect of factors before reproductive maturity– genes?

– early environment of girls: birthweight, nutrition, stress, etc.

• Different slopes for blacks and whites with age

– exposures more prevalent with age– cumulative exposures

Weathering Hypothesis, Geronimus 1992

Health of African Americans “may begin to deteriorate in early adulthood as a physical consequence of cumulative socioeconomic disadvantage”

• Financial stress

• Chronic strain

• Family function

• Neighborhood function

• Violence

• Racism

Measurable elements of weathering

Weathering

Poverty, racism, family fx

Preconceptional VulnerabilityStress-related behaviors

Altered endocrine reactivity to stress

Immune defense degradation

Underlying chronic disease

Preterm/FGR Risk FactorsCRH, BV, inflammation, HTN, preeclampsia

Preterm/LBW

PSYCHOSOCIAL STRESS

NEUROENDOCRINE FACTORS

IMMUNE FACTORS

VASCULAR FACTORS

PRETERM/LBW

?

Three Propositions

Weathering manifests during pregnancy as:

1) neuroendocrine maladaptations 2) immune dysfunction3) vasculopathy

Proposition 1:Weathering manifests as

neuroendocrine maladaptations in pregnancy

MOTHER

CRH

ACTH

CORTISOL

Mean peak ACTH responses to laboratory stressor by childhood abuse history and

adult depression status

0

24

6

8

1012

14

16

Controls Depressed Abuse only Abuse/Dep

AC

TH p

eak

(pm

ol/L

)

Heim et al., JAMA, 2000

Changes in maternal CRH in human pregnancy

MOTHER PLACENTA FETUS

CRH

ACTH

CORTISOL CRH CORTISOL

Physiologic stressors raise CRH levels:

• Infection

• Inflammation

• Preeclampsia

• Pregnancy-induced hypertension

• Fetal growth restriction

• Hemorrhage

• Uteroplacental vascular insufficiency

MOTHER PLACENTA FETUS

CRH

ACTH

CORTISOL CRH CORTISOL

NE

Does psychologic stress raise CRH?

• 2 out of 3 studies report ‘yes’(Hobel 1999, Hermann 2001, Petraglia 2001)

• 1 study: higher CRH with lower income(Hermann 2001)

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Prenatal depressive symptoms

Odd

s r a

t io

Odds ratios for prenatal depression for a one standard deviation increase in mid-pregnancy ln CRH, Project Viva

Rich-Edwards et al., submitted

Is race/ethnicity associated with CRH levels?

• 1 study: African Americans have higher CRH (Hermann, 2001)

• 1 study: African Americans have same CRH (Holzman, 2001)

• 1 study: Latinas have lower CRH (Ruiz, 2001)

Proposition 2:Weathering manifests as

immune dysfunction in pregnancy

• Vaginal and uterine infections associated with preterm delivery (especially BV)

• However, antibiotic treatment trials have equivocal results

• Suggests that infection/inflammation starts before pregnancy

Infection and preterm delivery

• Non-pregnant state: psychosocial stress raises risk of viral illness, slows healing time (Kiecolt-Glaser, Cohen)

• High stress and low social support associated with depressed lymphocyte activity in pregnancy (Herrera 1998)

• High chronic stress associated with bacterial vaginosis during pregnancy (Culhane 2001)

Stress and Infection

Maternal stress and bacterial vaginosis status Maternal stress and bacterial vaginosis status

21

22

23

24

25

BV- Intermediate BV+

Mean

Ch

ron

ic S

tress S

co

re

Culhane, MCH Journal 2001

Preterm delivery associated with higher levels of proinflammatory cytokines in maternal blood, amniotic fluid, and umbilical cord blood(IL-6, CRP, TNFα)

Inflammation and preterm delivery

• Lower social position associated with higher levels of CRP, IL-6, and TNFα(Steptoe 2002, Owen 2003)

• Depression associated with higher IL-6, IL-1ß (Licinio 1999)

• Burnout and ‘vital exhaustion’ associated with higher TNFα(Grossi 2003, Appels 200)

Stress and Inflammation

• Inflammatory cytokines higher among women with hx of preterm delivery (Amory 2001)

• Periodontitis associated with preterm delivery and higher CRP levels (Pitiphat)

• Genes associated with high inflammatory response are associated with preterm PROM among African Americans (but not whites)(Roberts 1999; Dizon-Townson 1997)

Inflammation predates pregnancy?

Is proinflammatory state an:• Appropriate response to infection? • Ineffective downregulation? • Chronic inflammation?

Inflammation and preterm delivery

Proposition:Weathering manifests as

vasculopathy in pregnancy

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 15 25 35 45

Es

tim

ate

d O

dd

s

Black White

Estimated odds of hypertension among US women by age and race

Geronimus, 1992

• Uterine artery blood flow is lower in anxious women (Teixeria1999)

• Anxious mothers have blood flow patterns indicative of fetal hypoxia (Sjostrom1997)

Psychosocial stress and vasculopathy during pregnancy

Prenatal blood pressure response to laboratory stressor

Correlation with

DBP response

(mm Hg) p-value

Birthweight (gm) - 0.44 < 0.01

Gestational age (weeks) - 0.39 < 0.05

Fetal growth (gm/wk) - 0.36 < 0.05

McCubbin, AJOG 1996

Diastolic blood pressure reactivity to two types Diastolic blood pressure reactivity to two types of stressor, according to history of racial of stressor, according to history of racial discrimination, African American women discrimination, African American women

02

46

810

1214

Mirror Task Speech Task

DB

P r

eact

ivit

y (m

m H

g)

No discriminationDiscrimination

Guyll, Health Psychol, 2001

0.50

0.75

1.00

1.25

1.50

1.75

2.00

5 6-10 11-15 16+

Od

ds

Ra

tio

Odds ratios for hypertension by childhood emotional and physical abuse, Nurses’ Health Study II

Childhood Trauma Questionnaire Score

PSYCHOSOCIAL STRESS

NEUROENDOCRINE FACTORS

IMMUNE FACTORS

VASCULAR FACTORS

PRETERM/LBW

?

Summary

Psychosocial stressors may affect reproductive function through:

• Acute or chronic exposure

• Conditioned pathways

• Neuroendocrine function

• Immune response

• Vasculopathy

• Other pathways

In other words:

• Reproductive success or failure reflects both cumulative (weathering) and current exposures



Relative risk of mortality among mothers and fathers by offspring birthweight, Renfrew and Paisley (n=794)

0

0.2

0.4

0.6

0.8

1

1.2

1 2 3 4 5Quintile of Offspring Birthweight

Rel

ativ

e ri

sk o

f m

ort

alit

y

Mothers

Fathers

Adapted from Davey Smith, 1997

Relation between infants’ birthweight and mothers’ mortality, England and Wales, 1976-1997, n~45,000

Relative risk mothers’ death

Birthweight # births All cause Cardiovascular

<2500g 3,891 3.1 (2.2-4.4) 7.1 (2.6-18.8)

2500-3499 27,360 1.8 (1.0-1.7) 2.0 (0.8-4.8)

>3500 13,562 1.0 (referent) 1.0 (referent)

Per 1000g 1.6 (1.4-1.9) 2.3 (1.5-3.4)

Davey Smith, BMJ, 2000

Relative risks for premenopausal breast cancer by characteristics of first pregnancy, Nurses’ Health Study II

Relative Risk (95%CI)

1st pregnancy at 20 1st pregnancy at 30

Birthweight (gm), p-trend=0.005

2500 0.90 (0.89-0.96) 0.77 (0.64-0.93)

3500 1.00 1.00

4500 1.11 (1.03-1.20) 1.29 (1.08-1.55)

Gestation length (weeks), p-trend=0.02

37 (preterm) 1.07 (1.01-1.13) 1.17 (1.03-1.33)

40 (term) 1.00 1.00

42 (post-term) 0.96 (0.92-0.99) 0.90 (0.83-0.98)

0

50

100

150

200

250

300

350

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Inc

ide

nc

e p

er

10

0,0

00

py

37 weeks

40 weeks

42 weeks

Assumes menarche at 13, no family history, no benign breast disease, average height, average BMI, nondrinker, birthweight=3.5 kg

Age-specific incidence of breast cancer by gestation length among women with first pregnancy at age 20, Nurses’ Health Study II

0

50

100

150

200

250

300

350

Inc

ide

nc

e p

er

10

0,0

00

py

37 weeks

40 weeks

42 weeks

Assumes menarche at 13, no family history, no benign breast disease, average height, average BMI, nondrinker, birthweight=3.5kg

Age-specific incidence of breast cancer by gestation length among women with first pregnancy at age 30, Nurses’ Health Study II

0

50

100

150

200

250

300

350

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Inc

ide

nc

e p

er

10

0,0

00

py

2.5 kg

3.5 kg

4.5 kg

Assumes menarche at 13, no family history, no benign breast disease, average height, average BMI, nondrinker, gestation length=40 weeks

Age-specific incidence of breast cancer by first offspring birthweight among women with first pregnancy at age 20, Nurses’ Health Study II

0

50

100

150

200

250

300

350

30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Inc

ide

nc

e p

er

10

0,0

00

py

2.5 kg

3.5 kg

4.5 kg

Age-specific incidence of breast cancer by offspring birthweight among women with first pregnancy at age 30, Nurses’ Health Study II

Assumes menarche at 13, no family history, no benign breast disease, average height, average BMI, nondrinker, gestation length=40 weeks

0.5

0.75

1

1.25

1.5

1.75

<5.5 5.5-<7 7-<8.5 8.5-<10 >=10Birthweight, lbs

Haz

ard

Rat

io

Own Offspring

Adjusted hazard ratios for breast cancer by own birthweight and offspring birthweight

Broad strokes:

• Reproductive status reflects childhood and adult exposures

• Reproductive health may be an early warning of chronic disease processes

• Safeguarding the health of girls may yield future benefits in the health of women and future generations

Lifecourse Approach to Women’s Reproductive Health: Focus on Psychosocial Stress Janet...

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