THE BARKER HYPOTHESIS: FETAL ORIGINS OR MATERNAL ORIGINS

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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

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PART 1 OF TALK

• DIFFICULTIES WITH THE FETAL ORIGINS HYPOTHESIS

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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

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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

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PART 2 OF TALK

• IS THERE ANOTHER WAY IN WHICH FETAL LIFE MAY BE
  LINKED WITH CARDIOVASCULAR RISK FACTORS?

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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

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THE MEXICAN-AMERICAN PERINATAL PARADOX

• Even under adverse socio-economic circumstances,
  Mexican-Americans have relatively large babies
  who experience relatively low neonatal mortality
  rates.

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US INFANT MORTALITY RATE IN HISPANICS,
NON-HISPANIC WHITES AND MEXICAN-AMERICANS (2002)
Per 1,000 live births
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PERCENT LOW BIRTHWEIGHT (lt 2,500g) BY ETHNICITY
(US 2002)
Per 100 live births
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METABOLIC SYNDROME

• Obesity, especially abdominal obesity
• Dyslipidemia (elevated triglycerides, high LDL
  cholesterol and low HDL cholesterol)
• Insulin resistance/glucose intolerance
• Elevated blood pressure

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PREGNANCY NUTRITIONAL ADAPTATIONS

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

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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

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THE METABOLIC SYNDROME IN MESO-AMERICANS
PARALLELS PREGNANCY ADAPATIONS TO INCREASE FETAL
NUTRITION
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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

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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

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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

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CAN THE PERINATAL AND CARDIOVASCULAR PATTERNS OF
AFRICAN-AMERICANS BE LINKED?
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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

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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

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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.

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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

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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.

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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.

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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.

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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

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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