Preconception Health & Health Care:A Life-Course Perspective

Mi h l C L MD MPHMichael C. Lu, MD, MPHAssociate Professor

Department of Obstetrics & GynecologyDavid Geffen School of Medicine at UCLA

Department of Community Health SciencesUCLA School of Public Health

August 3, 2010

Why Why Preconception Care?p

Why Preconception Care?

Early prenatal care is too lateEarly prenatal care is too late.

Early Prenatal Care Is Too LateEarly Prenatal Care Is Too LateTo Prevent Some Birth Defects

The heart begins to beat at 22 days after conceptionThe heart begins to beat at 22 days after conceptionThe neural tube closes by 28 days after conceptionThe palate fuses at 56 days after conceptionCritical period of teratogenesis – Day 17 to Day 56

Early Prenatal Care Is Too LateEarly Prenatal Care Is Too LateTo Prevent Implantation Errors

Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001 Nov 8;345(19):1400-8.

Early Prenatal Care Is Too Late yfrom A Life-Course Perspective

A way of looking at life not as disconnected A way of looking at life not as disconnected stages, but as an integrated continuum

Early Programming

Barker HypothesisBarker HypothesisBirth Weight and Coronary Heart Disease

1.5

1

1.25Age Adjusted Relative Risk

0.75

1

0.25

0.5

0<5.0 5.0-5.5 5.6-7.0 7.1-8.5 8.6-10.0 >10.0

Birthweight (lbs)Birthweight (lbs)

Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. Br Med Jr 1997;315:396-400.

Barker HypothesisBarker HypothesisBirth Weight and Hypertension

170

51

mm

Hg)

165

Pres

sure

(m

160

Syst

olic

P

155

<=5.5 5.6-6.5 6.6-7.5 7.6-8.5 >8.5Birthweight (lbs)Birthweight (lbs)

Law CM, de Swiet M, Osmond C, Fayers PM, Barker DJP, Cruddas AM, et al. Initiation of hypertension in utero and its amplification throughout life. Br Med J 1993;306:24-27.

Barker HypothesisBarker HypothesisBirth Weight and Insulin Resistance Syndrome

18

12

14

16 Odds ratio adjusted for BMI

8

10

12

2

4

6

0

2

<5.5 5.6-6.5 6.6-7.5 7.6-8.5 8.6-9.5 >9.5Birthweight (lbs)Birthweight (lbs)

Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS. Type 2 (non-insulin-dependent) diabetes mellitus,hypertension and hyperlipidaemia (Syndrome X): Relation to reduced fetal growth. Diabetologia 1993;36:62-67.

Maternal Stress & Fetal Programming

Prenatal Stress & e a a S ess &Programming of the Brain

Prenatal stress (animal model)Prenatal stress (animal model)Hippocampus

Site of learning & memory formationStress down-regulates glucocorticoid receptorsLoss of negative feedback; overactive HPA axis

Amygdala

Site of anxiety and fearStress up regulates glucocorticoid receptorsStress up-regulates glucocorticoid receptorsAccentuated positive feedback; overactive HPA axis

Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain.J Neuroendocrinol 2001;13:113-28.

Prenatal Programming of the Prenatal Programming of the Hypothalamic-Pituitary-Adrenal Axis

Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain.J Neuroendocrinol 2001;13:113-28.

EpigeneticsEpigenetics

Gibbs WW. The Unseen Genome: Beyond DNA. Scientific American 2003

EpigeneticsEpigeneticsSame Genome, Different Epigenome

R.A. Waterland, R.A. Jirtle, "Transposable elements: targets for early nutritional effects on epigenetic gene regulation," Mol Cell Biol, 23:5293-300, 2003. Reprinted in the New Scientist 2004

Prenatal Programming of g gChildhood Obesity

Epidemic of Childhood Overweight & Obesity

25

20

25Children 6-18 Overweight

10

15

Perc

en

t

5

10

01976-1980 1988-1994 1999-2002

Black Hispanic Whitep

Source: National Center for Health Statistics, National Health and Nutrition Examination Survey

Note: Estimate not available for 1976-1980 for Hispanic; overweight defined as BMI at or above the 95th percentile ofr the CDC BMI-for-age growth charts

Prenatal Programming ofPrenatal Programming ofChildhood Overweight & Obesity

Prenatal Programming of Childhood e a a og a g o C d oodObesity

Maternal Diabetes & Intrauterine Hyperglycemia

Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells)β )

Prenatal& PostnatalHyperleptinemia

Preadipocyte Differentiation

Programmed Insulin

ResistanceAdipocyte

Hyperplasia

Hypothalamic Pancreatic β-

Postnatal Hyperinsulinemia

ypLeptin Resistance

βCell Leptin Resistance

HyperphagiaHyperinsulinism

Adipogenesis

C l ti P thCumulative Pathways

Photo: http://www.lam.mus.ca.us/cats/encyclo/smilodon/

Allostasis: Maintain Stability through Change

McEwen BS. Protective and damaging effects of stress mediators. N Eng J Med. 1998;338:171-9.

Allostastic Load:os as c oadWear and Tear from Chronic Stress

McEwen BS. Protective and damaging effects of stress mediators. N Eng J Med. 1998;338:171-9.

Stressed vs. Stressed OutStressed Stressed OutStressed

Increased cardiac output

Stressed Out

Hypertension & cardiovascular diseases

Increased available glucose Glucose intolerance &

insulin resistance

Enhanced immune functions

Infection & inflammation

Growth of neurons in hippocampus & prefrontal cortex

Atrophy & death of neurons in hippocampus & prefrontal cortex

Allostasis & Allostatic Load

McEwen BS, Lasley EN. The end of stress: As we know it. Washington DC: John Henry Press. 2002

Rethinking Preterm Birth

Sequelae of Preterm BirthSequelae of Preterm Birth

75%Perinatal Perinatal MortalityMortality

12%

NeurologicNeurologic50%

Term Births

NeurologicNeurologicDisabilitiesDisabilities

Preterm Birth

Racial & Ethnic DisparitiespPreterm Births < 37 Weeks

18

14

16

18Percent of Live Births

17.9

10

12

14

11.5

6

8 Year 2010 Goal

2

4

0African American White

NCHS 2006

Racial & Ethnic DisparitiespVery Preterm Births < 32 Weeks

4 5 P t f Li Si l t Bi th

3.5

4

4.5 Percent of Live Singleton Births

4.05

2.5

3

3.5

1 631.5

2 Year 2010 Goal

1.63

0.5

1

0African American White NCHS 2006

Racial & Ethnic DisparitiespInfant Mortality

14

12

14Deaths Per 1,000 Live Births

13.78

10

4

6 Year 2010 Goal

5.72

4

0African American White

NCHS 2006

Rethinking Preterm BirthRethinking Preterm Birth

Vulnerability to preterm delivery may be traced to not only exposure to stress & infection during pregnancy, but host response to stress & infection (e.g. stress reactivity & inflammatory dysregulation) patterned over the life course inflammatory dysregulation) patterned over the life course (early programming & cumulative allostatic load)

An important objective of preconception care is An important objective of preconception care is to restore allostasis to women’s health before pregnancy

Preterm Birth &Maternal Ischemic Heart Disease

Smith et al Lancet 2001;357:2002-06

Kaplan-Meier plots of cumulative probability of survival without admission or death from ischemic heart disease after first pregnancy in relation to preterm birth

Why Preconception Care?Why Preconception Care?Summary

Early Prenatal Care Is Too LateEarly Prenatal Care Is Too LateTo prevent some birth defectsTo prevent implantation errorsTo restore allostasis quickly enough to optimize fetal programming

Why Preconception Care?

Before, Between, and Beyond PregnancyPregnancy

Put the W Back in MCH

INTERCONCEPTION CARECARE