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THE BARKER HYPOTHESIS: FETAL ORIGINS OR MATERNAL ORIGINS

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Title: THE BARKER HYPOTHESIS: FETAL ORIGINS OR MATERNAL ORIGINS


1
THE BARKER HYPOTHESIS FETAL ORIGINS OR MATERNAL
ORIGINS?
  • Nigel Paneth MD MPH
  • Departments of Epidemiology and
  • Pediatrics Human Development
  • Michigan State University
  • Hot Topics Symposium
  • Washington, DC
  • December 6, 2005
  • http//www.epi.msu.edu/faculty/paneth.htm

2
PART 1 OF TALK
  • DIFFICULTIES WITH THE FETAL ORIGINS HYPOTHESIS

3
CONCERNS RAISED ABOUT THE BARKER HYPOTHESIS
  • Hypothesis is moving target
  • Conflict of hypothesis with population data
  • Famine studies by and large unsupportive
  • Interventions to raise birthweight not generally
    successful
  • Failure to address confounding
  • Multiple and selective comparisons
  • Weak and inconsistent effects
  • Inappropriate adjustments

4
KEY CRITICAL PAPERS
  • Elford J, Whincup P, Shaper AG Int J Epidemiol
    1991 20833-844 and J Epidemiol and Comm Health
    1992 461-8
  • Joseph KS, Kramer M Epidemiol Reviews
  • Paneth N, Ahmed F, Stein AD J Hypertension
    199614 (suppl) S121-129
  • Huxley R, Neil A. Collins R Lancet
    2002360659-665
  • Huxley R, Owen CG, Whincup P et al JAMA 2004
    2922755-64
  • Tu, Y-K, West R, Ellison GTH et al Am J
    Epidemiol 2005 161 27-32

5
PART 2 OF TALK
  • IS THERE ANOTHER WAY IN WHICH FETAL LIFE MAY BE
    LINKED WITH CARDIOVASCULAR RISK FACTORS?

6
CORE OF THE ARGUMENT
  • Human population groups show different patterns
    of perinatal phenomena, including different
    birthweight distributions and different pregnancy
    complications.
  • Population groups also show different patterns of
    CVD risk factors
  • These two patterns may be linked
  • The perinatal experience may indicate the
    historic adversity the population group had to
    overcome in order to successfully reproduce.
  • The cardiovascular risks may be the price paid
    for the genetic adaptations that helped mothers
    and babies survive

7
THE MEXICAN-AMERICAN PERINATAL PARADOX
  • Even under adverse socio-economic circumstances,
    Mexican-Americans have relatively large babies
    who experience relatively low neonatal mortality
    rates.

8
US INFANT MORTALITY RATE IN HISPANICS,
NON-HISPANIC WHITES AND MEXICAN-AMERICANS (2002)
Per 1,000 live births
9
PERCENT LOW BIRTHWEIGHT (lt 2,500g) BY ETHNICITY
(US 2002)
Per 100 live births
10
METABOLIC SYNDROME
  • Obesity, especially abdominal obesity
  • Dyslipidemia (elevated triglycerides, high LDL
    cholesterol and low HDL cholesterol)
  • Insulin resistance/glucose intolerance
  • Elevated blood pressure

11
PREGNANCY NUTRITIONAL ADAPTATIONS
  • Fat deposition, especially central fat
  • Elevation in lipid fractions, especially
    triglycerides
  • Increased insulin secretion and increased insulin
    resistance
  • Propensity to diabetes

12
THE METABOLIC SYNDROME IN MESO-AMERICAN
POPULATIONS
  • Most Meso-American populations are at high risk
    of the first three components of the metabolic
    syndrome abdominal obesity, dyslipidemia and
    insulin resistance. 50 of Pima Indians have
    type II diabetes by the age of 50
  • The key pregnancy complication in Meso-American
    populations is gestational diabetes
  • However, Meso-Americans are not at especially
    high risk of the fourth component, hypertension

13
THE METABOLIC SYNDROME IN MESO-AMERICANS
PARALLELS PREGNANCY ADAPATIONS TO INCREASE FETAL
NUTRITION
14
FAT OR PSEUDOPREGNANT?
  • The metabolic syndrome is a partial replication
    of the pregnant state
  • It seems likely that the genes that predispose us
    to the non-hypertension parts of the metabolic
    syndrome arose as adaptations to prioritize fetal
    nutrition
  • The metabolic syndrome may be the price we pay
    for large babies with high survival potential,
    seen in an extreme form in Meso-American
    populations

15
THE AFRICAN-AMERICAN PERINATAL SITUATION
  • African-Americans babies tend to have the
    following characteristics
  • Relatively high neonatal mortality
  • Lower mean birthweight, and higher frequency of
    low birthweight.
  • Lower mean gestational age, and higher frequency
    of preterm delivery
  • Relatively favorable neonatal survival for a
    given birthweight or gestational age below the
    mean.
  • Relatively unfavorable neonatal survival for
    birthweights and gestational ages above the mean
  • Relatively high risks of pre-eclampsia

16
CARDIOVASCULAR RISK IN AFRICAN-AMERICANS
  • Unlike Meso-Americans, the most distinctive
    cardiovascular risk factor in African-Americans
    is hypertension
  • Insulin resistance and abdominal obesity occur,
    but less commonly than in Meso-Americans
  • Dyslipidemia is less severe BMI-adjusted HDL-C
    levels are actually higher in African-Americans
    than in whites

17
CAN THE PERINATAL AND CARDIOVASCULAR PATTERNS OF
AFRICAN-AMERICANS BE LINKED?
18
DELIVERY HEMORRHAGE
  • In underdeveloped countries, bleeding is the
    leading cause of maternal death.
  • Even in the US, 5 of mothers lose more than a
    liter of blood in delivery. (Magann EF et al
    South Med J. 2005 98419-22)
  • Delivery bleeding is the most important
    hemorrhagic stress ordinarily encountered by
    humans.
  • It is likely that adaptations to prevent
    hemorrhage in labor may be important determinants
    of genes controlling vasoconstriction and
    thrombosis

19
PREGNANCY ADAPTATIONS DESIGNED TO REDUCE RISK OF
DELIVERY BLEEDING
  • Dominance of pro-coagulant state
  • ? thrombin, PAI, thromboxane, factors VII, VIII,
    X
  • Thromboxane/prostacyclin balance favors
    vasoconstriction
  • Greatly enhanced risk of thrombotic disorders in
    pregnancy

20
PRE-ECLAMPSIA AS PROTECTION AGAINST DELIVERY
BLEEDING?
  • Pre-eclampsia may be an exaggerated version of
    ordinary pregnancy adaptions to reduce the risk
    of delivery bleeding.
  • In pre-eclampsia, the mother seems to be trying
    to prevent the baby from so remodeling the
    uterine vasculature that she risks dying in labor
    from bleeding.

21
PREGNANCY ADAPTATIONS IN AFRICAN-AMERICANS
  • Higher rates of pre-eclampsia, indicating a
    tendency towards vasoconstriction
  • Shorter mean gestation and slower fetal growth
    will also produce less delivery bleeding
  • A predisposition to early delivery may also
    protect the mother from experiencing full-blown
    eclampsia

22
WHY SHOULD PEOPLE OF WEST AFRICAN ORIGIN NEED
SPECIAL PROTECTION FROM DELIVERY BLEEDING?
  • Possibly because of a high prevalence of anemia
    in pregnancy due to malaria infection.
  • Malaria is known to have altered the gene pool to
    produce the sickle-cell trait
  • Delivery bleeding is likely to especially
    threaten maternal survival in anemic women.

23
SAVING MOTHER OR SAVING BABY?
  • For each set of genes that have evolved
    because of perinatal pressures, one must consider
    whether they are designed for optimal fetal or
    for optimal maternal survival, which may be in
    competition.
  • In Meso-Americans, genes seem to be favored that
    protect the fetus, by transferring nutrients and
    producing big babies. The price paid is diabetes
    and obesity.
  • In African-Americans, genes seem to be favored
    that protect the mother, by producing a smaller,
    less mature baby, and a tendency to
    pre-eclampsia. The price paid is hypertension and
    somewhat lower neonatal survival.
  • These two populations are best seen as
    illustrating processes that are universal and
    found to some degree in all populations.

24
IMPLICATIONS FOR CARE AND PREVENTION
  • This hypothesis is only designed to understand
    how population predispositions to different
    components of the cardiovascular risk profile may
    have developed as a result of perinatal survival
    pressures.
  • It does not minimize in any way our continuing
    public health need to find environmental ways to
    prevent and ameliorate the human consequences of
    our shared evolutionary history, particularly in
    populations at risk.

25
APOLOGIA
  • I have thought it better to publish my
    inquiry in its present imperfect state, than to
    wait till I should be able to make such a
    complete research as I could wish, more
    especially as, by directing the attention of the
    profession to the question, it may be earlier
    decided.
  • John Snow On the Adulteration of Bread as a
    Cause of Rickets. Lancet 1857ii4-5

26
PERINATAL EPIDEMIOLOGY TRAINING PROGRAM AT MSU
(T-32)
  • Two NIH-supported post-doctoral positions
    available for US citizens/green card holders as
    of June 1, 2006
  • If interested, contact me at paneth_at_msu.edu
  • 517-353-8623, x 112
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