Undernutrition during conception and gestation: Increased risk for the next generation

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1 Undernutrition during conception and gestation: Increased risk for the next generation Reinoud J.B.J. Gemke VU University Medical Center Amsterdam

2 Genetic disorders One gene => one phenotype => one disease Autosomal recessive Cystic fibrosis Sikkel cel anemia X linked Duchenne s muscular dystrophia Daltonism

3 Developmental Origin of Cardiovascular Risk Fetal and early postnatal cardiovascular risk factors Fetal growth retardation birth weight < p10, SGA Preterm birth Born < 37 wks gestational age Accelerated post natal growth Weight gain > 1 SDS

4 Genetic and epigenetic factors DNA 99% identical Gene polymorfism Epigenetic factors Affecting geneexpression without DNA differences DNA methylation DNA acetylation Histone modification

5 Epigenetics and the life cycle: lifelong remodeling

6 Genetic identical, different phenotype: Which mechanisms in early life? Phenotype determined by development in environment Role of insulin signaling pathway in gene-expression and phenotype of bee (queen) Wolschin, 2010

7 Gestational epigenetics affecting phenotype Genetically identical agouti mice Maternal suppletion with methyl donors (choline, folic acid, vitamin B12) Increased DNA methylation of Agouti gene Reduction of offspring with yellow coat (corresponds to risk of obesity and diabetes)

8 Relation of (early) nutrition with later health From empiric observation to epidemiologic study Granny s tales Fish oil and health Cod liver oil (n-3 and n-6 PUFA s, Vitamin D) Overall health and CZS development Folic acid and spina bifida (patho)physiologic mechanisms Experimental (animal) studies Subsequent intervention studies If/when feasible.

9 Early nutrition and later cardiovascular disease Epidemiologic (human) studies Hertfordshere, UK Dutch famine (+ 6 months) Helsinki birth cohort Confirmation (in experimental animal) studies IUGR rats Results from clinical human studies SGA children

10 Epidemiological studies CVD related mortality and birth weight in individuals in Hertfortshere. Birth weight kg Death ratio Death numbers < > Total Barker & Osmond 1986

11 Epidemiological studies Cardiovascular disease in Dutch famine study Coronary heart disease Sex adjusted OR 3.0 for individuals with early gestational famine exposure No increased prevalence in mid and late gestational famine exposure Blood pressure Relation birth weight adult blood pressure Most important determinant of high blood pressure is lower protein-carbohydrate ratio in last trimester of gestation. Fetal environment is a risk factor of coronary heart disease Roseboom, 2000 en Painter, 2006

12 Epidemiological studies Helsinki birth cohort study 7086 individuals born Detailed birth and growth data (6-16yr) OR type 2 diabetes 1.38 ( ) per kg lower birth weight OR type 2 diabetes 1.39 ( ) per 1 SDS weight gain during 6-16 yr of age Frosen et al, Ann Int Med 2000

13 Experimental animal studies Fetal growth redardation increases blood pressure and heart rate in aging rats. Schreuder, 2006

14 Experimental animal studies Fetal growth retardation vs adult heart rate and blood pressure Baseline and stressed conditions in (male) rats IUGR CTRL IUGR CTRL (Δ 8 mm Hg) R = 0.70 Schreuder, 2007

15 Clinical studies Mean carotid IMT at age 9 according to thirds of the distribution of current weight and maternal energy intake in late pregnancy Indicates fetal malnutrition Indicates accelerated post natal growth Gale CR, 2006

16 Clinical studies SGA AGA Controls SGA vs AGA AGA vs Controls N=21 N=29 N=30 Mean SD Mean SD Mean SD value P value Baseline SBP (mmhg) <0.001* Baseline DBP (mmhg) h blood pressure SBP (mmhg) * DBP (mmhg) Daytime blood pressure SBP (mmhg) * DBP (mmhg) Nighttime blood pressure SBP (mmhg) DBP (mmhg) Data expressed by mean [standard deviation (SD)] and regression P value adjusted for gender SGA small for gestational age prematurely bom individuals, AGA appropriate for gestational age prematurely bom individuals, controls appropriate for gestational age term-bom individuals, SBP systolic blood pressure, DBP diastolic blood pressure * P<0.05 Mean 24-h, daytime and night time blood pressure values in young adults, born as SGA and AGA preterms and controls Keizer-Veen MG, 2010

17 Developmental Origin of Health and Disease Percieved affluent optimal fetal environment Percieved sparse fetal environment Long(er) life expectancy Short(er) life expectancy Adaptation toward longevity - Aiming for regeneration and recovery - Building natural reserve : e.g. more neurons, nephrons - Big(ger) adults: bonemass, muscular mass Adaptation toward fetal survival - Intra-uterine growth retardation - Preterm birth Adapted reproduction - Early puberty and early offspring* Defense mechanisms (RR, HR) - Insulin resistence (type 2 diabetes) - Fat storage (dyslipidemia) - CNS adaptation - HPA-axis (stress response) - ADHD - Depression, Ψ disorders

18 Role of antenatal nutrition in the offspring Maternal malnutrition Fetal malnutrition Other maternal or placental abnormalities Other organ malfunction e.g. liver Decreased β cell mass Altered insulin sensitivity Abnormal vascular development Hyperlipidemia Non insulin-dependent diabetes Hypertension CVD and Metabolic syndrome Barker

19 Post-natal growth as determinant of adult disease Accelerated (catch-up) growth hypothesis Fast growth: Traditionally required for survival of (low birth weight) newborns Preterm (< 37 wks) SGA (< -2SD) Beneficial for cognitive development Increased survival discloses latent adult diseases Hypertension, CVD Type 2 diabetes Metabolic syndrome Singhal A, Lancet 2004

20 Early life and later cardiovascular disease Fetal growth retardation (+10%, steady) Preterm birth (9-12%, max 18%, increasing due to ART) Accelerated (catch up) postnatal growth Centile crossing

21 Contribution of fetal and (early) post natal growth in the development and prevention of CVD Good body of evidence Large effect size Long term scope Prevention cost-effective Mechanism revealing studies (Potential) effect in Different populations and Different environment Adult Adolescent periconceptional Child Environmental (vs genetic factors) factors in the transgenerational perspective of CVD fetus Infant

22 ABCD study Amsterdam Born Children and their Development study Birth cohort, including data of >5000 children from 1st trimester pregnancy until age 5 (2010), and will continue every 5 yrs until 20. Early determinants of cardiovascular function, stress (HPA axis), behaviour and cognition Particular attention for ethnic differences Collaboration of Municipal Health Service Amsterdam Academic Medical Center Amsterdam VU University Medical Center, Amsterdam Find us at:

23 The people who do the work Manon van Eijsden, Municipal Health Service, Amsterdam Tanja Vrijkotte, Academic Medical Center, Amsterdam Reinoud Gemke, VU University Medical Center, Amsterdam Marieke de Beer Aimee van Dijk Marieke de Hoog PhD students Eva Loman Gerrit van der Berg

24

25 New model Any neonate No acceleration in weight gain Accelerated weight gain (especially in the first 3 month of life) Fat accumulation during infancy and childhood Insulin sensitivity Unfavourable body composition Unfavourable lipid profile Blood pressure No higher risk Development of adult disease

26 Fetal growth and birth weight Determinants for adult health and disease Cardiovascular disease Hypertension Diabetes type 2 Dyslipidaemia Metabolic syndrome Osteoporosis Sub/infertility CZS disorders Depression ADHD Psychiatric disorders Increased mortality

27 Is birth weight related to insuline sensitivity? Variables Birth weight SDS Adult weight SDS Fat mass (kg) Lean body mass (kg) Insuline sensitivity Insuline sensitivity Insuline sensitivity B P-value B P-value B P-value 0,146 0,049 0,115 0,098 0,083 0,210-0,199 <0,001-0,044 <0,001-0,002 0,840 Adjusted for age, gender, SES, birth lenght SDS, adult height SDS * Log transformed Leunissen R. 2008

28 Early life: Predictive adaptive response Gluckman 2004

29 Gluckman 2004

30 Life course approach Chronic disease risk Developmental Plasticity Response to new challenge

31 IUGR and control rats Significant differences in cytosine methylation Yellow: DNA hypomethylation Red: DNA hypermethylation Thompson RF, 2010

32 Versnelde ( inhaal )groei en etniciteit Brinkkemper & Vrijkotte, 2007

33 Developmental programming of cardiovascular disease Short cohort description Aim of the study

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