1. Intergenerational Nutritional Effects & Fetal Growth and Chronic Disease
2010

3. Intergenerational Effects
Cohort studies
maternal birthweight and fetal grown
Dutch famine studies
Experimental Study
Supplementation in Guatemala

4. Godfrey KM, Barker DJP, Robinson S, Osmond C
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 1997;104:663–7

5. Illinois Study Coutinho et al. Am J Epi, 1997 146:804-809
N=15,287 Black and 117,708 white matched pairs of infants and mothers.
Mothers were born between , infants between

6. Results
Father’s 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
Each 100 g increase in maternal birthweight was associated with g increase in infant birthweight

7. FIGURE 3 Mean offspring birth weight (g) for categories of paternal birth weight in selected strata of maternal birth weight
Bouchard, C. Am J Clin Nutr 2009;89:1494S-1501S
Copyright ©2009 The American Society for Nutrition

8. Dutch Famine Studies Susser and Stein, Nutrition Reviews, 1994
Dutch famine winter lasted 6 months, from November 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

9. Dutch Hunger Winter: Calories

10. 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 days

11. Birth Cohorts

12. Obesity in Young Men after Famine Exposure in Utero and early Infancy (Ravelli et al NEJM, 1976)
N=300, 000 Dutch military inductees at age 19
Famine exposure in first 2 trimesters lead to 80% higher prevalence of overweight (p<0.0005)
Famine exposure in last trimester or famine exposure in first 5 months of life associated with 40% lower prevalence of overweight (p<0.005)

13. Adult Obesity

14. Interpretation? Cohort B1 Cohort D1
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

15. 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.

16. 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;

17. 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.

18. 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.

19. 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;

20. 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

21. 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.

22. Intergenerational Impact of Dutch Famine
A mother's exposure to famine prior to conception of her offspring was associated with lower self-reported measures of mental health and quality of life in her adult offspring.
Stein et al. Epidemiology Nov;20(6):909-15
The expected increase in offspring birth weights with increasing birth order was not seen after maternal intrauterine exposure in the first trimester of pregnancy
Lumey and Stein. Am J Epidemiol Nov 15;146(10):810-9

23. Reproductive performance and nutrition during childhood
Nutrition Reviews; Washington; Apr 1996; Martorell, Reynaldo; Ramakrishnan, Usha; Schroeder, Dirk G; Ruel, Marie;

24. 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

25. 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.

26. 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.”

32. Follow-Up data s
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.

33. Role of intergenerational effects on linear growth
U Ramakrishnan; R Martorell; D G
Schroeder; R Flores; The Journal of Nutrition; Bethesda; Feb 1999;

34. Methods
The sample was restricted to singleton, term (>37 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 ( )
Complete data were available for 215 mother-child pairs, and 60% of the mothers (n = 140)

35. 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 < 0.001)
For every centimeter increase in maternal birth length, her child's birth weight increased by 53 g.

36. Metabolic “Programming” in an Age of Plenty

37. Recent Studies on Impact of GWG on Offspring Obesity
Zilko et al. Am J Obset Gynecol, 2010
In NLSY: GWG associated with child overweight
Mamun et al. Circulation, 2009
In Australian cohort : Greater GWG associated with greater offspring BMI in early adulthood
Von Kries et al.
Int J Pediatr Obes, 2010
Large German cross-sectional study: higher than average GWG accounts for moderate increase in offspring overweight at ages 3-17

38. Fig. 1. Obesity and pregnancy are associated with insulin resistance and inflammatory changes that exacerbate in combination, increasing lipid transfer earlier in gestation
Heerwagen, M. J. R. et al. Am J Physiol Regul Integr Comp Physiol 299: R711-R ;
Fig. 1. Obesity and pregnancy are associated with insulin resistance and inflammatory changes that exacerbate in combination, increasing lipid transfer earlier in gestation. Obesity is associated with adipose tissue inflammation and systemic insulin resistance, resulting in increased adipose tissue lipolysis and hepatic very-low-density lipoprotein (VLDL) secretion. When combined with pregnancy, this leads to an increase in maternal circulating lipids with advancing gestation. Subsequent hydrolysis of maternal triglycerides (TGs) by placental lipoprotein lipase (LPL) and increased free fatty acid (FFA) uptake and transport by the placenta results in excess lipid transfer to the developing fetus. This increase in fetal lipid exposure may impact the liver, skeletal muscle, adipose tissue, brain, and pancreas to increase the risk for metabolic disease in childhood. MCP-1, monocyte chemotractant protein-1; CM, chylomicron; NAFLD, nonalcoholic liver disease.
Copyright ©2010 American Physiological Society

39. Fetal Nutrition and Chronic Diseases of Adulthood
Developmental Origins of Health & Disease

40. UN Standing Committee on Nutrition, 2006
While undernutrition kills in early life, it also leads to a high risk of disease and death later in life. This double burden of malnutrition has common causes, inadequate foetal and infant and young child nutrition followed by exposure (including through marketing practices) to unhealthy energy dense nutrient poor foods and lack of physical activity.
The window of opportunity lies from pre-pregnancy to around 24 months of a child’s age.

41. Barker’s Fetal Origins Theory
Coronary heart disease, stroke, type 2 diabetes, hypertension and osteoporosis, originate through developmental plasticity, in response to malnutrition during fetal life and infancy. Certain cancers, including breast cancer, also originate in fetal life.

42. Fetal Origins Concepts Barker 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.

43. The Barker Hypothesis Fetal Origins of Adult Disease
Adverse intrauterine events
permanently “program” postnatal
structure/function/homeostasis
“Adapted Birth Phenotype”
* 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

44. FETAL ORIGINS OF ADULT CVASC DISEASE
Adverse Intrauterine
Events
In Utero
Birth
Childhood
Adulthood
Low Birthweight/IUGR
MODIFIERS
COFACTORS
Adult “Metabolic Syndrome”
Abd’l Obesity
HTN
CAD
Diabetes
 TG/ HDL
Renal Failure

45. 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 1993;307:1519–24)

47. Age-adjusted Relative Risk of Non- fatal
Coronary Heart Disease and Stroke
5.0
7.5
10.0
0.50
0.75
1.00
1.25
1.50
Birthweight
Relative Risk
Mean ± 95% CL
121,700 American Nurses, self report study BMJ 315:396,1997

48. Catch-up growth in childhood and death from coronary heart disease: longitudinal study (Eriksson et al, BMJ, 1999)
Subjects: men born in Helsinki between
Followed with school data for weight and height
Deaths from coronary heart disease from (standardized mortality ratios) were endpoints.

49. Catch-up growth in childhood and death from coronary heart disease: longitudinal study (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

50. David J.P. Barker, F.R.S., Clive Osmond, Ph.D., Tom J. Forsén, M.D.,
Eero Kajantie, M.D., and Johan G. Eriksson, M.D. Trajectories of Growth among Children Who Have Coronary Events as Adults. N Engl J Med 2005;353:

51. Diabetes in Low-Birth-Weight Men
Birth Weight (lbs)
% Impaired Gluc Tol or DM
< >9.5 40 30 20 10
370 men
Age 64 yrs
Odds Ratio/Adj for BMI 8 6 4 2
Gestat’l DM
Hales et al. BMJ 303: 1019, 1991

52. Fetal Milieu Affects Obesity Risk
Trouble at Both Ends of the Birth Weight Spectrum
Birth Weight (kg)
Odds
Ratio
For
Obesity
Eriksson J et al Internatl J Obesity 2001

53. Birth Weight Predicts Blood Pressure at Age 31
Birth Weight (gm)
< >4500
130
128
126
124
122
Sys BP (mmHg)
Birth Weight Predicts Blood Pressure at Age 31
1966 Northern Finland Birth Cohort
+/- adjust for current BMI
Jarvelin M et al. Hypertension 2004
Variables:
Birth Weight
Ponderal Index
Sex
Gestational age
Mat’l Ht, Wt
Parity
Socioeconomic
Current BMI
n = 5960 offspring

54. Birthweight and Adult HTN in US Women
Nurses Health Study I
Birthweight Category (lbs)
<
HTN Prevalence (%) 40 30 15 10
Age
46-71
8.4%
30-55
3.1%

55. Early Growth Patterns Predict Adult HTN
Barker et al. J HTN 20:1951, 2002.
Cohort
Average
(n=8760) }

56. Animal Models (Waterland and Garza)
“Overall the data from animal models of metabolic imprinting support the observed epidemiological associations.”

57. Effect of Gestational Type 2 Diabetes on Body Weight in Adult Offspring

58. Framework for understanding the maternal regulation of fetal development and programming
Godfrey & Barker. Fetal nutrition and adult disease. Am J Clin Nutr :

60. Asymmetric Growth Restriction
Adverse Intrauterine
Events
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

61. Fetal Origins of Adult Disease
* Thin
* Small abdominal
girth ( liver size)
* Low arm cir-
cumference
( muscle mass)
* Preserved
central fat mass
From Barker, 1998
Asymmetric Growth Restriction
“More powerful predictor than other risk factors”

62. ? % Growth-Restricted Phenotype in Lower Birth Weight Categories
Conceptual Graph

63. Structural Deficits  Reduced Functional Units in Organs
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

64. 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 :335-47; 2Am J Kid Dis : 171

65. New Nephrons Form in Concentric Layers during Gestation
Branching Morphogenesis  Nephrogenesis
New Nephrons Form in Concentric Layers
during Gestation
Condensing Mesenchyme
Comma Shaped Bodies
Outer Nephrogenic Layer
Glomeruli

66. Birth Weight Predicts Nephron Number
 230,000 nephrons
per kg increase
in birth weight
In Term Births:
Ages 1-17 yrs
All Ages
 Hughson et al,
Kid Internat (2003) 63, 2113
Also:
Merlet-Benichou et al, 1999
Manalich et al, 2000

67. Asymmetric Growth Restriction in Utero
Maternal Protein Deficiency
Asymmetric Growth Restriction in Utero
“The Thrifty
Phenotype”
Impaired Kidney
Development
# Nephrons
(permanent)
FOOD
CATCH-UP
GROWTH #
Nephrons BP
BODY
MASS

68. Rethinking “FOAD” Programming events may act:
Periconceptually
Prenatally
Postnatally: infancy, childhood
Cardiovascular outcomes may appear:
In childhood, adolescence
In midlife
In elderly

69. and Risk of Childhood Adiposity
Rapid Infant Growth
and Risk of Childhood Adiposity
Stettler et al, Ped.
109, 2002.
Birthweight
Rate of Wt Gain
In first 4 mo
Prevalence of
Overweight
at Age 7 Yrs

70. Barker DJ. TRENDS Endo Metab 13; Nov 2002
Infant Growth Rate and Coronary Disease
BMI
Weight
Height
Cohort
Age in Years
Standard Deviation (Z) Score
0.05
- 0.05
- 0.10
- 0.15
- 0.20
- 0.25
4630 Helsinki boys
357 developed CHD
Barker DJ. TRENDS Endo Metab 13; Nov 2002

71. DEVELOPMENTAL ORIGINS OF Infant Undernutrition 0-1 yr
HEALTH & DISEASE
In Utero
Birth
Childhood
Adulthood
Low Birthweight/IUGR
Fetal
Undernutrition
“Metabolic Syndrome”
Abd’l Obesity
HTN
CAD
Diabetes
 TG/ HDL
Renal Failure
Accelerated
Growth +
Infant Undernutrition 0-1 yr
Food:
Access
Palatability
Inter-Generational Transmission

72. 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.

73. Examples of the impact of this inheritance:
Epigenetic mechanisms for nutrition determinants of later health outcomes. (Zeisel, Am J Clin Nutr, 2009)
“epigenetic code is a series of marks added to DNA or to proteins (histones) around which DNA is wrapped.”
Methylation, covalent modifications of histones and chromatin and RNA
Some “marks” can be inherited
Examples of the impact of this inheritance:
Grandmother’s smoking in pregnancy & risk of asthma in grandchildren
Brains from suicide victims, methylation of 5’ regulatory region of genes encoding ribosomal RNA associated with early childhood abuse & neglect

74. FIGURE 1 Epigenetic marks alter gene expression
Zeisel, S. H Am J Clin Nutr 2009;89:1488S-1493S
Copyright ©2009 The American Society for Nutrition

75. Fig. 2. General example of epigenetic regulation of gene transcription
General example of epigenetic regulation of gene transcription. Epigenetic regulation of gene expression is characterized by stable changes to DNA and chromatin structure that alter gene expression independent of gene sequence. The primary forms of epigenetic control involve DNA methylation by DNA methyl-transferase (DNMTs), and histone tail modifications, such as acetylation/deacetylation, by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities, respectively. Additionally, microRNAs have recently been shown to regulate DNA methylation as well. Histone tail acetylation promotes an open-chromatin conformation, and is associated with regions of active gene expression, while histone tail deacetylation promotes a closed-chromatin conformation and is associated with gene silencing. DNA methylation of cytosine guanine (CpG) dinucleotides in the 5' promoter region of genes generally induces transcriptional silencing, both by blocking transcription factor binding and by promoting the recruitment of transcriptional corepressors or histone-modifying complexes. MeBP, methyl-CpG binding protein; TF, transcription factor; Pol II, DNA polymerase II.
Heerwagen, M. J. R. et al. Am J Physiol Regul Integr Comp Physiol 299: R711-R ;
Copyright ©2010 American Physiological Society

76. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Tobi et al, Hum Mol Genet Nov 1;18(21):
Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings
Methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher
“persistent changes in DNA methylation may be a common consequence of prenatal famine”

77. Are Nutrition-Induced Epigenetic Changes the Link Between Socioeconomic Pathology and Cardiovascular Diseases? Lopez-Jaramillo et al. Am J Ther Jul-Aug;15(4):

78. Are Nutrition-Induced Epigenetic Changes the Link Between Socioeconomic Pathology and Cardiovascular Diseases? Lopez-Jaramillo et al. Am J Ther Jul-Aug;15(4):

79. Early Risk Determinants and Later Health Outcomes: Research Priorities (Field, Am J Clin Nutr, 2009)
ID biological mechanisms responsible for lasting and later health effects
ID genes; research on genomics, metabolomics and epigenetics
Understand imbalanced nutrition; focus on overnutrition during critical periods
Understand social/environmental factors that influence critical windows
ID how and when to intervene to prevent later disease