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
December 6 2005
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
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 1000 live births 9 PERCENT LOW BIRTHWEIGHT (lt 2500g) 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
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.
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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