3 Intergenerational Effects Cohort studiesmaternal birthweight and fetal grownDutch famine studiesExperimental StudySupplementation 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 ResultsFather’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 careEach 100 g increase in maternal birthweight was associated with g increase in infant birthweight
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 occupationStrong evidence for critical stages of development in several physiological systems
10 Affects of Famine Fertility decreased Maternal weight fell during pregnancy with famine exposureThird trimester famine exposure had strong effect on birthweightThird trimester famine exposure was associated with infant mortality at days
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 19Famine 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)
14 Interpretation? Cohort B1 Cohort D1 Conceived and gestated at time of moderate caloric restrictionBorn into time of famineLow rates of adult obesityCohort D1Conceived and gestated at a time of famineBorn into food sufficiencyHigh 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 MethodsNine 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 MethodsCompared 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 ResultsThe 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):909-15The expected increase in offspring birth weights with increasing birth order was not seen after maternal intrauterine exposure in the first trimester of pregnancyLumey and Stein. Am J Epidemiol Nov 15;146(10):810-9
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 sThe 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 GSchroeder; R Flores; The Journal of Nutrition; Bethesda; Feb 1999;
34 MethodsThe 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 ResultsFor 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.
37 Recent Studies on Impact of GWG on Offspring Obesity Zilko et al. Am J Obset Gynecol, 2010In NLSY: GWG associated with child overweightMamun et al. Circulation, 2009In Australian cohort : Greater GWG associated with greater offspring BMI in early adulthoodVon Kries et al.Int J Pediatr Obes, 2010Large German cross-sectional study: higher than average GWG accounts for moderate increase in offspring overweight at ages 3-17
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 effectsUndernutrition has different effects at different times of life.Rapidly growing fetuses and neonates are vulnerable to undernutritionUndernutrition results from inadequate maternal intake, transport, or transfer of nutrients.
43 The Barker Hypothesis Fetal Origins of Adult Disease Adverse intrauterine eventspermanently “program” postnatalstructure/function/homeostasis“Adapted Birth Phenotype”* Better chance of fetal survival* Increased risk of adult diseaseSusan P. Bagby, MD, Professor of Medicine & Physiology/PharmacologyDivision of Nephrology & Hypertension OHSU, Portland, OR
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 Stroke5.07.510.00.500.751.001.251.50BirthweightRelative RiskMean ± 95% CL121,700 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 betweenFollowed with school data for weight and heightDeaths 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, 1999Men who had low birth weight or were thin at birth have high death rates from coronary heart diseaseDeath rates are even higher if weight "catches up" in early childhoodDeath from coronary heart disease may be a consequence of prenatal undernutrition followed by improved postnatal nutritionPrograms 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< >9.540302010370 menAge 64 yrsOdds Ratio/Adj for BMI8642Gestat’lDMHales et al. BMJ 303: 1019, 1991
52 Fetal Milieu Affects Obesity Risk Trouble at Both Ends of the Birth Weight SpectrumBirth Weight (kg)OddsRatioForObesityEriksson J et al Internatl J Obesity 2001
53 Birth Weight Predicts Blood Pressure at Age 31 Birth Weight (gm)< >4500130128126124122Sys BP (mmHg)Birth Weight Predicts Blood Pressure at Age 311966 Northern Finland Birth Cohort+/- adjust for current BMIJarvelin M et al. Hypertension 2004Variables:Birth WeightPonderal IndexSexGestational ageMat’l Ht, WtParitySocioeconomicCurrent BMIn = 5960 offspring
54 Birthweight and Adult HTN in US Women Nurses Health Study IBirthweight Category (lbs)<HTN Prevalence (%)40301510Age46-718.4%30-553.1%
55 Early Growth Patterns Predict Adult HTN Barker et al. J HTN 20:1951, 2002.CohortAverage(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 :
63 Structural Deficits Reduced Functional Units in Organs Potential Mechanisms ofDevelopmental ProgrammingStructural Deficits ReducedFunctional Units in OrgansKidney Nephron # HTNPancreas Islet Cell # Insulin secretion GlucoseMuscle muscle mass Basal met rate Exercise capacityHeart myocyte # Risk CHFLiver cells # ? lipid metabolism
64 What Conveys Risk of HTN in Lower Birth-weight Offspring ? Brenner et al. 1988,1994Low Birth Wt, Low Nephron Number and HTN“… retardation of renal development as occursin individuals of low birth weight gives rise toincreased postnatal risks for systemic andglomerular hypertension as well as enhanced riskof expression of renal disease.”21Am J HTN :335-47; 2Am J Kid Dis : 171
65 New Nephrons Form in Concentric Layers during Gestation Branching Morphogenesis NephrogenesisNew Nephrons Form in Concentric Layersduring GestationCondensing MesenchymeComma Shaped BodiesOuter Nephrogenic LayerGlomeruli
66 Birth Weight Predicts Nephron Number 230,000 nephronsper kg increasein birth weightIn Term Births:Ages 1-17 yrsAll Ages Hughson et al,Kid Internat (2003) 63, 2113Also:Merlet-Benichou et al, 1999Manalich et al, 2000
67 Asymmetric Growth Restriction in Utero Maternal Protein DeficiencyAsymmetric Growth Restriction in Utero“The ThriftyPhenotype”Impaired KidneyDevelopment# Nephrons(permanent)FOODCATCH-UPGROWTH#NephronsBPBODYMASS
68 Rethinking “FOAD” Programming events may act: PericonceptuallyPrenatallyPostnatally: infancy, childhoodCardiovascular outcomes may appear:In childhood, adolescenceIn midlifeIn elderly
69 and Risk of Childhood Adiposity Rapid Infant Growthand Risk of Childhood AdiposityStettler et al, Ped.109, 2002.BirthweightRate of Wt GainIn first 4 moPrevalence ofOverweightat Age 7 Yrs
70 Barker DJ. TRENDS Endo Metab 13; Nov 2002 Infant Growth Rate and Coronary DiseaseBMIWeightHeightCohortAge in YearsStandard Deviation (Z) Score0.05- 0.05- 0.10- 0.15- 0.20- 0.254630 Helsinki boys357 developed CHDBarker DJ. TRENDS Endo Metab 13; Nov 2002
71 DEVELOPMENTAL ORIGINS OF Infant Undernutrition 0-1 yr HEALTH & DISEASEIn UteroBirthChildhoodAdulthoodLow Birthweight/IUGRFetalUndernutrition“Metabolic Syndrome”Abd’l ObesityHTNCADDiabetes TG/ HDLRenal FailureAcceleratedGrowth+Infant Undernutrition 0-1 yrFood:AccessPalatabilityInter-Generational Transmission
72 EpigeneticsEpigenetics = the study of stable alterations in gene expression that arise during development and cell proliferation Epigenetic phenomena do NOT change the actual, primary genetic sequenceEpigenetic phenomena are important because, together with promotor sequences and transcription factors, they modulate when and at what level genes are expressedThe 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 RNASome “marks” can be inheritedExamples of the impact of this inheritance:Grandmother’s smoking in pregnancy & risk of asthma in grandchildrenBrains from suicide victims, methylation of 5’ regulatory region of genes encoding ribosomal RNA associated with early childhood abuse & neglect
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 siblingsMethylation 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 effectsID genes; research on genomics, metabolomics and epigeneticsUnderstand imbalanced nutrition; focus on overnutrition during critical periodsUnderstand social/environmental factors that influence critical windowsID how and when to intervene to prevent later disease