Intergenerational Nutritional Effects

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Intergenerational Nutritional Effects Fetal
Growth and Chronic Disease

• 2007

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Effect of Womens own Intrauterine Nutritional
Experience her Offspring
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Two Studies of Effects of Maternal Birthweight on
Infant Birthweight
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Godfrey KM, Barker DJP, Robinson S, Osmond C.
Mother's birthweight and diet in pregnancy in
relation to the baby's thinness at birth. Br J
Obstet Gynaecol 19971046637
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Illinois StudyCoutinho et al. Am J Epi, 1997
146804-809

• N15,287 Black and 117,708 white matched pairs of
  infants and mothers.
• Mothers were born between 1956-75, infants
  between 1989-1991

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Results

• Fathers birthweight had effect on infant
  birthweight but not as strong as mothers.
• In multiple linear regression for infants who
  weighed more than 2500 g, parental birthweight
  accounted for 5 of variance among black infants
  and 4 among white infants.
• (adjusted for parental age, years of schooling,
  marital status and adequacy of prenatal care)

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Results, cont.

• Each 100 g increase in maternal birthweight was
  associated with 24-27 g increase in infant
  birthweight

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Influence of Maternal Intrauterine Childhood
Nutrition on Outcomes of Pregnancy
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Reproductive performance and nutrition during
childhood

• Nutrition Reviews Washington Apr 1996
  Martorell, Reynaldo Ramakrishnan, Usha
  Schroeder, Dirk G Ruel, Marie

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Longitudinal Supplementation Trial (1969-1977)

• Guatemala, 4 Villages, one pair of villages had
  about 900 people each and the other about 500
  each.
• 2 each randomized to
• Atole (Incaparina, a vegetable protein mix
  developed by INCAP, dry skim milk, sugar, and
  flavoring, 163 kcal/cup, 11/5 g protein)
• Fresco (flavored drink with sugar, vitamins and
  minerals, 59 kcal/cup)

Institute of Nutrition of Central America and
Panama
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• Feeding center was open daily for over 7 years,
  from 1969 to 1977.
• Anyone in the village could attend, but careful
  recording of consumption, including of additional
  servings as well as of leftovers, was done only
  for women who were pregnant or breastfeeding and
  for children 7 years or younger.
• Supplements were available twice daily, in
  midmorning and midafternoon, so as not to
  interfere with meal times.

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Conceptual framework

• Malnutrition in early childhood constrains the
  future capacity of women to bear healthy newborns
  and their ability to feed and care for them, and
  through these mechanisms the growth and
  development of the next generation.

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Follow-Up data - 1990s

• The prevalence of low birthweight is currently
  12 in Atole villages (n 65) and 28 in Fresco
  villages (n 58) among women exposed to the
  supplements during the intrauterine period and
  the first 3 years of life.
• Mean birthweights are 2.90 kg in Atole villages
  and 2.73 in Fresco villages.

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Role of intergenerational effects on linear
growth

• U Ramakrishnan R Martorell D G
• Schroeder R Flores The Journal of Nutrition
  Bethesda Feb 1999

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Methods

• The sample was restricted to singleton, term (gt37
  wk of gestation) births that occurred in the four
  study villages between 1991 and 1996, to women
  who were born during the original longitudinal
  study (1969-1977)
• Complete data were available for 215 mother-child
  pairs, and 60 of the mothers (n 140)

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Results

• For every 100 g increase in maternal birth
  weight, her infant's birth weight increased by 29
  g after adjusting for the effects of maternal
  age, gestational age and sex of the infant. This
  relationship was highly significant (P lt 0.001)
• For every centimeter increase in maternal birth
  length, her child's birth weight increased by 53
  g.

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Influence of Maternal Nutrition in Pregnancy
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Dutch Famine StudiesSusser and Stein, Nutrition
Reviews, 1994

• Dutch famine winter lasted 6 months, from
  November 1944- when nazis imposed transport
  embargo on west Holland until-
• May 7, 1945 when Holland was liberated from the
  occupation
• Strong evidence for critical stages of
  development in several physiological systems

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Dutch Hunger Winter Calories
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Affects of Famine

• Fertility decreased
• Maternal weight fell during pregnancy with famine
  exposure
• Third trimester famine exposure had strong effect
  on birthweight
• Third trimester famine exposure was associated
  with infant mortality at 30-90 days

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Birth Cohorts
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Obesity in Young Men after Famine Exposure in
Utero and early Infancy(Ravelli et al NEJM, 1976)

• N300, 000 Dutch military inductees at age 19
• Famine exposure in first 2 trimesters lead to 80
  higher prevalence of overweight (plt0.0005)
• Famine exposure in last trimester or famine
  exposure in first 5 months of life associated
  with 40 lower prevalence of overweight (plt0.005)

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Adult Obesity
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Interpretation?

• Cohort B1
• Conceived and gestated at time of moderate
  caloric restriction
• Born into time of famine
• Low rates of adult obesity
• Cohort D1
• Conceived and gestated at a time of famine
• Born into food sufficiency
• High rates of adult obesity

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Second Generation

• Modest association found in this cohort between
  birthweights of mothers and their offspring.

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Other Results for Infants Exposed to Famine

• Excess central nervous system disorders (such as
  NTD)
• Famine exposure associated with twofold risk of
  schizophrenia in 50 year old women.

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Prenatal exposure to famine and brain morphology
in schizophrenia

• Hulshoff Pol HE Hoek HW Susser E Brown AS
  Dingemans A Schnack HG van Haren NE Pereira
  Ramos LM Gispen-de Wied CC Kahn RS American
  Journal of Psychiatry , Jul 2000

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Methods

• Nine schizophrenic patients and nine healthy
  comparison subjects exposed during the first
  trimester of gestation to the Dutch Hunger Winter
  were evaluated with magnetic resonance brain
  imaging, as were nine schizophrenic patients and
  nine healthy subjects who were not prenatally
  exposed to the famine.

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RESULTS

• Prenatal famine exposure in patients with
  schizophrenia was associated with decreased
  intracranial volume.
• Prenatal Hunger Winter exposure alone was related
  to an increase in brain abnormalities,
  predominantly white matter hyperintensities.

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Further evidence of relation between prenatal
famine and major affective disorder.

• Alan S Brown Jim van Os Corine Driessens Hans
  W Hoek et al The American Journal of
  Psychiatry Washington Feb 2000

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Methods

• Compared the risk of major affective disorder
  requiring hospitalization in birth cohorts who
  were and were not exposed, in each trimester of
  gestation, to famine during the Dutch Hunger
  Winter of 1944-1945.

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Results

• The risk of developing major affective disorder
  requiring hospitalization was increased for
  subjects with exposure to famine in the second
  trimester and was increased significantly for
  subjects with exposure in the third trimester,
  relative to unexposed subjects.

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Fetal Nutrition and Chronic Diseases of Adulthood

• Developmental Origins of Health Disease

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Fetal Origins ConceptsBarker et al

• Nutrition in early life has permanent effects
• Undernutrition has different effects at different
  times of life.
• Rapidly growing fetuses and neonates are
  vulnerable to undernutrition
• Undernutrition results from inadequate maternal
  intake, transport, or transfer of nutrients.

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The Barker Hypothesis
Fetal Origins of Adult Disease
Adverse intrauterine events permanently
program postnatal structure/function/homeostasis

Better chance of fetal survival Increased
risk of adult disease
Susan P. Bagby, MD, Professor of Medicine
Physiology/Pharmacology Division of Nephrology
Hypertension OHSU, Portland, OR
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FETAL ORIGINS OF ADULT CVASC DISEASE
Adult Metabolic Syndrome
? TG/? HDL Renal Failure
Abdl Obesity HTN
CAD Diabetes
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Coronary heart disease death rates, expressed as
standardized mortality ratios, in 10,141 men and
5585 women born in Hertfordshire, United Kingdom,
from 1911 to 1930, according to birth weight.
(Osmond C, Barker DJP, Winter PD, Fall CHD,
Simmonds SJ. Early growth and death from
cardiovascular disease in women. BMJ
1993307151924)
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Age-adjusted Relative Risk of Non- fatal
Coronary Heart Disease and Stroke
121,700 American Nurses, self report study BMJ
315396,1997
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Catch-up growth in childhood and death from
coronary heart disease longitudinal study
(Eriksson et al, BMJ, 1999)

• Subjects 3641 men born in Helsinki between
  1924-1933
• Followed with school data for weight and height
• Deaths from coronary heart disease from 1971-95
  (standardized mortality ratios) were endpoints.

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Catch-up growth in childhood and death from
coronary heart disease longitudinalstudy
(Eriksson et al, BMJ, 1999

• Men who had low birth weight or were thin at
  birth have high death rates from coronary heart
  disease
• Death rates are even higher if weight "catches
  up" in early childhood
• Death from coronary heart disease may be a
  consequence of prenatal undernutrition followed
  by improved postnatal nutrition
• Programs to reduce obesity among boys may need to
  focus on those who had low birth weight or who
  were thin at birth

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Early Nutrition Chronic Disease in Adulthood
(Waterland Garza, Am J Clin Nutr, 199969179-97)

• Epi studies BMI, CVD, Htn, IGT
• Animal studies
• Potential mechanisms of metabolic imprinting

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Diabetes in Low-Birth-Weight Men
Gestatl DM
Hales et al. BMJ 303 1019, 1991
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Preadult Influences on Cardiovascular Disease and
Cancer (Leon Ben-Shlomo in A Lifecourse
approach to chronic disease epidemiology, 1997)

• 5 large retrospective studies - 4 found inverse
  relationship between birth weight and adult CVD
• Confounding issues include SES and BMI
• The relationship between birth weight and BMI
  complicates studies of birth weight and chronic
  disease

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Fetal Milieu Affects Obesity Risk
Trouble at Both Ends of the Birth Weight Spectrum
Eriksson J et al Internatl J Obesity 2001
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CVD

• The preponderance of data suggest an inverse
  association between birth weight and adult CVD
  risk. (Waterland and Garza)

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Blood Pressure

• Retrospective studies in diverse populations
  have found that birth weight is inversely
  correlated with adult blood pressure. Although
  each of the studies has some weaknesses, together
  they support a biological link between
  intrauterine growth and adult blood pressure
  (Waterland and Garza)

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Early Growth Patterns Predict Adult HTN
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Impaired Glucose Tolerance

• Several large retrospective cohort studies in
  several countries have found relationship between
  bw and IGT.
• 266 men and women at age 50 odds ratio for ITG
  or type II diabetes were 3.5 for men and 12 for
  women with birth weights lt 2.5 compared to gt3.4
  (Phillips et al, Diabetologia, 1994)

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Impaired Glucose Tolerance, cont..

• In some populations (ex Pima Indians) both high
  and low birth weights are associated with IGT in
  adults.

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Animal Models (Waterland and Garza)

• Overall the data from animal models of metabolic
  imprinting support the observed epidemiological
  associations.

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Effect of Gestational Type 2 Diabetes on Body
Weight in Adult Offspring
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Framework for understanding the maternal
regulation of fetal development and programming.
Keith M Godfrey and David JP Barker (Fetal
nutrition and adult disease Am J Clin Nutr 2000
71 1344-1352)
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Asymmetric Growth Restriction

• Low Birth Weight for Gestational Age
• Low Wt Height Ratio (thinness)
• Relative sparing of heart, brain, adrenal
• Disproportionate reduction of kidney, liver,
  pancreas, skeletal muscle mass
• Reduced abdominal girth

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Fetal Origins of Adult Disease
From Barker, 1998
Asymmetric Growth Restriction
More powerful predictor than other risk factors
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? Growth-Restricted Phenotype in Lower Birth
Weight Categories
Conceptual Graph
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Potential Mechanisms of Developmental
Programming
Structural Deficits ? Reduced Functional Units in
Organs
Kidney ? Nephron HTN Pancreas ? Islet Cell
? Insulin secretion ??
Glucose Muscle ? muscle mass ? Basal
met rate ? Exercise capacity Heart
? myocyte ? Risk CHF Liver ? cells
? ? lipid metabolism
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What Conveys Risk of HTN in Lower Birth-weight
Offspring ?
Brenner et al. 1988,1994
Low Birth Wt, Low Nephron Number and HTN
retardation of renal development as occurs in
individuals of low birth weight gives rise to
increased postnatal risks for systemic and
glomerular hypertension as well as enhanced risk
of expression of renal disease.2
1Am J HTN 1988 1335-47 2Am J Kid Dis 1994 23
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Maternal Protein Deficiency
The Thrifty Phenotype
FOOD
CATCH-UP GROWTH
BODY MASS
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Rethinking FOAD

• Programming events may act
• Periconceptually
• Prenatally
• Postnatally infancy, childhood
• Cardiovascular outcomes may appear
• In childhood, adolescence
• In midlife
• In elderly

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Rapid Infant Growth and Risk of Childhood
Adiposity
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Infant Growth Rate and Coronary Disease
Barker DJ. TRENDS Endo Metab 13 Nov 2002
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Early Nutrition Chronic Disease in Adulthood
(Waterland Garza, Am J Clin Nutr, 199969179-97)

• Potential mechanisms of metabolic imprinting

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Epigenetics

• Epigenetics the study of stable alterations in
  gene expression that arise during development and
  cell proliferation Epigenetic phenomena do NOT
  change the actual, primary genetic sequence
• Epigenetic phenomena are important because,
  together with promotor sequences and
  transcription factors, they modulate when and at
  what level genes are expressed
• The protein context of a cell can be understood
  as an epigenetic phenomena.
• Examples include DNA methylation, histone
  hypo-acetylation, chromatin modifications,
  X-inactivation, and imprinting.

http//cnx.rice.edu/content/m11532/latest/
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Metabolic Imprinting

• the basic biological phenomena that putatively
  underlie relations among nutritional experiences
  of early life and later diseases.

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Metabolic Imprinting Characteristics

• Susceptibility limited to a critical ontogenic
  window early in development
• Persistent effect lasting through adulthood
• Specific and measurable outcome
• Dose-response or threshold relation between
  exposure and outcome

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Metabolic Imprinting Potential Mechanisms

• Organ structure
• Cell number function
• Clonal selection
• Metabolic differentiation

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Organ Structure

• Organogenesis starts early by 5 weeks
  rudimentary organs are in place, by 8 weeks
  organogenesis is nearly complete
• Driven by inductive signals from adjacent cells
  and morphogen gradients (ex retinoic acid/vit.
  A)
• Local concentrations of nutrients and metabolites
  may modulate this process.

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Cell Number

• Tissues go through limited periods of
  hyperplastic and hypertrophic growth
• Rate of growth is dependent on nutrient
  availability
• Winnicks rat studies found severe malnutrition
  during critical periods limited brain cell number
  
• An organs metabolic activity is limited by cell
  number

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Cell Function

• Early nutrition may influence the cascade that
  establishes cell specific patterns.
• Ex hepatocyte polyploidization - in adults
  hepatocytes often have gt normal complement of
  chromosomes and increased metabolic activity.
  Lack of polyploidization could limit hepatic
  metabolic activity.

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Clonal Selection

• Each organ is based on a finite number of founder
  cells which may have slight differences
• Founder cells that divide the most rapidly may
  disproportionally make up a tissue
• Nutrient availability may select cells with
  certain characteristics
• Ex cells with more active lipogenic pathways
  could grow faster if access to fatty acids was
  limited

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Metabolic Differentiation

• Process cells develop stable patterns of basal
  and inducible gene expression
• Cells are characterized by the ability to express
  a limited number of genes.
• Mechanisms of control include
• chromatin structure (DNA packaging)
• transcription factors (maintained through cell
  divisions)
• DNA methylation

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Gluckman et al. Biology of the Neonate, 2005