Early Metabolic Programming - 1 - InfantNutrition - B.Koletzko PDF

Munich, Germany
Topics:
Infant Nutrition and Lifelong Health: z Metabolic Programming of Lifelong
The Power of Metabolic Programming Health: Concept and Examples
z Early Nutrition Programming Project
Berthold Koletzko, MD PhD
Professor of Paediatrics, Dr von Hauner Children‘s Hospital,
University of Munich Medical Centre, Munich, Germany z Infant feeding and later obesity
for the Early Nutrition Programming Project
www.metabolic-programming.org
office.koletzko@med.uni-muenchen.de
Early programming:
Metabolic programming an established concept in biology
Metabolic and nutritional Behavioural programming
factors acting during limited, Hatching geese accept first moving object as „parent“.
sensitive time periods of early Konrad Lorenz 1952
development induce lasting

effects on physiology, function,
health and disease risks
office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de
Early programming: Phenylalanine Ï during pregnancy

an established concept in biology
z Endocrine programming Untreated maternal
Prenatal sex hormone exposure determines phenylketonuria
gender development (e.g. CAH)
⇒ lasting child damage
z Immunological programming
Perinatal exposure may induce tolerance
facial dysmorphia (broad nasal
bridge, small nose), microcephaly,
z Epigenetic programming mental retardation, congenital
Monoallelic expression regulated by differential heart defects
DNA methylation induces Prader-Willi-Syndrome, Dr. Harvey Levy, Children's Hospital, Boston.
Angelman-Syndrome & others (uniparental disomy) http://www.blackwellpublishing.com/korfgenetics/jpg/300_96dpi/Fig11-5.jpg
Prader Willi Syndrome
1
Suboptimal folate during pregnancy Perinatal omega-3 fatty acids
improve verbal IQ @school age
Good folate status
prior to and after
conception prevents
neural tube defects, Ï Seafood intake
and likely orofacial in pregnancy ⇒
clefts and congenital less low verbal IQ
adj. for 28 pot. confounders
heart defects Hibbeln et al, Lancet 2007
⇒ folate fortification of stable foods in

≈40 countries
Koletzko (ed.) Kinder- und Jugendmedizin.
Berlin, Springer, 13th. ed., 2007 office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de
z Undernutrition of animals at early, but not at

later ages, determines adult body size Confusing terminology
Elsie Widdowson & McCance, Cambridge 1970
z Programming Ù Imprinting
z Programming of human adult functions and (metabolic – nutritional - developmental)
diseases by hormones, metabolites and
neuro-transmitters during critical z Developmental / early (fetal) origins
development periods of long-term health /adult disease risk
Günther Dörner, Berlin, Germany 1975
z Developmental plasticity
z Programming by early nutrition in man
Alan Lucas, Cambridge, UK 1991 z Dörner‘s hypothesis
z Fetal Programming of adult disease z Lucas‘ hypothesis
by poor fetal nutrition and low birth weight z Barker‘s hypothesis
Nick Hales, David Barker, Oxford, Southampton, UK 1992
Programming: Prenatal programming

some potential mechanisms
Considerable evidence
z Epigenetic modification z Cell number Particularly from epidemiological
⇒ metabolic differentiation and experimental studies
z Clonal selection
z Chromatin structure
eu-/heterochromatin z Cell size Physiological basis
cause or effect? Very rapid growth/differentiation
z DNA binding proteins 3rd trimester: body weight doubled
z Organ structure in 6 weeks. Depends on substrates
z Apoptosis e.g. cell juxtaposition
z Hepatocyte z Body size & tissue Preventive potential
Somewhat difficult to modify fetal
polyploidization composition substrate supply & growth
z Tissue vascularization z Endocrine regulation
Lucas 1991, Waterland & Garza 1999, Koletzko et al 2009
2
Programming Infant feeding programmes
by Infant Feeding long-term health: evidence
Increasing evidence z Infection & allergy risk
Epidemiologic & experimental z Autoimmune diseases
studies; first controlled e.g. diabetes T1, inflammatory
intervention studies in infants
bowel disease, coeliac disease
Physiological basis
Rapid growth & differentiation z Cardiovascular risk
z Neural & brain function
Neonatal weight doubled in only 21 wks.
Preventive potential
Potential to modulate z Bone health Koletzko et al (ed.) Adv Exp
Med Biol 2005;569:1-237
substrate supply and growth z Obesity & 2009;646:1-196
Birth in „hungry season“ D adult mortality Ï

Breastfeeding ⇒ Ð Diabetes
3102 people born 1949-1994. Moore et al, Nature 1997
Birth in the annual hungry season

(July-October) Ä severe
early childhood growth faltering
From the age of 15 years

Ä more severe infections,
3.65fold risk for premature death
November-June
(no hunger)
Birth in the
hungry season
July-October
(hungry season)
office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de Agency f Healthcare Res & Quality 2007
Meta-Analysis: Breastfeeding First gluten introduction during

⇒ Ð inflammatory bowel disease breastfeeding: Ð later coeliac disease
Klement, AJCN 2004
Meta-analysis of 6 case-control-studies
Ulcerative colitis Crohn‘s disease
Celiac disease risk with first
gluten during breast feeding
(compared to gluten after weaning)
Pooled OR 0.48 (95%CI 0.50-0.59)

Î Prudent to introduce small amounts
of gluten whilst still breastfeeding
OR 0.67 OR 0.77
(0.52, 0.86) (0.61, 0.96) Î EU supported RCT is underway
Akobeng, Arch Dis Child 2006
3
Ð Birth weight ⇒ Ï mortality ratios at 20-74 y. Fasting insulin in 426 elderly Finish people:
in 10,141 men born in Hertfordshire 1911-1930 birthweight and PPAR-γ SNPs matter
Coronary Heart All Cardiovascular All Dauses
<3000 g 3000-3500 g >3500 g
Disease Disease of Death
110 110 110
80
Insulin (pmol/L)
100 100 100 P=0.00 P=0.02 n.s.
70 8
90 90 90 60
80 80 80 50
70 70 70 40
60 60 60 30
50 50 50 20
40 40 40 10
<5.5 -6.5 -7.5 -8.5 -9.5 >9.5 <5.5 -6.5 -7.5 -8.5 -9.5 >9.5 <5.5 -6.5 -7.5 -8.5 -9.5 >9.5
0
Birthweight (Brit. Pounds ≅ 454 g) Barker 1994 Pro12Pro Pro12Ala/Ala12Ala Pro12Pro Pro12Ala/Ala12Ala Pro12Pro Pro12Ala/Ala12Ala
office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de Eriksson et al 2002
Low birth weight = Ï later risk Breastfeeding:

for coronary heart disease Meta-analysis on
long term effects
z Systolic RR Ð 1.5 mmHg
Effect of Prenatal Nutrition? z Diastolic RR Ð 0.5 mmHg
z Poor fetal growth z Total cholesterolÐ 7 mg/dL
Ä Fetal Origins of Adult Disease Hypothesis z LDL cholest. Ð 7.7 mg/dL
z Diabetes type 1 Ð 19-27 %
Effect of Postnatal Nutrition?
z Diabetes type 2 Ð 39 %
z Compensatory excessive postnatal growth
z Overweight Ð 7-24 %
Ä Accelerated Postnatal Growth Hypothesis Breastfeeding and Maternal and Infant Health Outcomes in
office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de Developed Countries. AHQR 2007
Early salt intake ⇒ Ï RR later Health economic population

Neonates randomized to higher Na+ (n=245, 2.50+0.95 mmol/day) or lower Na+
impact of reducing diastolic RR
for 6 months. Systolic RR @6 months Ð 2.1 mm Hg
(n=231, 0.89+0.26 mmol/day)
Adj. RR 15 years after Ð Na+ Ð Diast. RR (mmHg) 0.6 1.2 2.5 5 10

Relative risk for CHD 0.97 0.94 0.89 0.79 0.62
Syst. RR Ð 3.6 mm Hg (95%CI: -6.6,-0.5) CHD risk reduction 3% 6% 11% 21% 38%
Relative risk for stroke 0.95 0.90 0.81 0.66 0.44
Diast. RR Ð 2.2 mm Hg (95%CI: -4.5, 0.2) Stroke risk reduction 5% 10% 19% 34% 56%
Hofman et al 1983; Geleijnse at el 1997 HTA 2003;7(31)
4
ADULT HEALTH
CHILD
INFANT
Early nutrition and
FETUS
genes interact Prosp. Observat.
GENES
Lifetime Animal
Î Early nutritional Studies Studies
Follow
programming is up of
rando-
where nature and mised
trials
nurture overlap
DG Research - European Commission

FOOD QUALITY AND SAFETY www.metabolic-programming.org
40 partners Key targets

16 countries z Quantify programming effects (later CVD,
obesity, diabetes, mental, bone health, immune, cancers)
16 countries: z Mechanisms, critical time periods
DE, BE, BR, CH,
CZ, DK, ES, FI, z Important genetic determinants
FR, HU, IT, NL,
z Role of specific nutrients
NO, PL, SE, UK
z Consumer knowledge: health impact 2005-2010
z Economic impact Budget 16.5 Mio€
(≈25.5 Mio US$)
z New technologies
Coordination:
z Training of young researchers Univ. of Munich
office.koletzko@med.uni-muenchen.de www.metabolic-programming.org
Genetics Ï Birthweight Ö Ï adult BMI in

z energy expenditure Current lifestyle Danish conscripts aged 18-26 years
z food intake z diet
z substrate metabolism 25
z physical activity
Adult BMI (kg/sq m)
z endocrine regulation
24
Obesity risk 23
Metabolic programming 22
z intrauterine metabolism <2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5
z postnatal diet/growth Birthweight (kg)
z endocrine regulation Adjusted for gest age, birth length, maternal factors
Sorensen et al., BMJ 1997.
5
Exposure to diabetes in pregnancy ÖÏ later BMI Diabetes in pregnancy and obesity
(58 children from 19 Pima families)
in the offspring: a vicious cycle?
Diabetes Obesity
in pregnancy Ö Diabetes
Dabelea et al 2000
Do postnatal diet and growth Different growth patterns

programme later obesity risk? in breast and bottle fed infants
Rodents: food restriction at early age (but not later) 5,304 Brazilian infants followed prospectively from birth to 12 months.
Growth differs in predominantly breast fed infants (1 mo: 61.3 %, 6 mo. 33.9%)
Î lower adult weight
Undernutrition Undernutrition
from 3 to 6 weeks from 9 to 12 weeks
=> permanently smaller => no permanent effect
Victora et al, J Nutr 1998;128:1134-8

office.koletzko@med.uni-muenchen.de Widdowson & McCance 1963 office.koletzko@med.uni-muenchen.de
Breast feeding: Ð Odds Ratio for obesity Breastfeeding and obesity: Meta-analysis
@school age, adjusted for confounders Covariate adjusted odds ratios, pooled odds ratio
Arenz, Rückerl, Koletzko, von Kries. Int J Obesity 2004
9206 Bavarian children at school entry; Brit Med J 1999,319:147-50
Adj. Odds Ratios Odds Ratio for
Breast fed Overwt. Obesity
Overweight & Obesity
Ever 0.79 0.75

(0.68-0.93) (0.57-0.98)
<2 mon. 0.89 0.90

(n=2084) (0.73-1.07) (0.74-1.02)
3-5 mon. 0.87 0.65 Dose response

(n=2052) (0.72-1.05) (0.44-0.95)
effect of breast
6-12 mon. 0.67 0.57 0.78 feeding duration
(n=863) (0.49-0.91) (0.33-0.99) (0.71, 0.85) in 4/9 studies
>12 mon. 0.43 0.28
(n=121) (0.17-1.07) (0.04-2.04)
<2 m 3-5 m 6-12 m >12 m
office.koletzko@med.uni-muenchen.de Duration of breast feeding office.koletzko@med.uni-muenchen.de
6
Meta-analysis: Ï duration of Probit Study, Belarus: duration of breast
breastfeeding ⇒ Ð later obesity risk feeding not related to obesity @ 6.5 y
OR
AJCN 2007
Proportion of breastfed infants by age No significant differences

in mean BMI (cluster-
adjusted mean difference:
0.1; 95% CI: 20.2, 0.3)
and prevalence of obesity
<1 mon 1-3 mon 4-6 mon 7-9 mon >9 mon (OR: 1.2; 95% CI: 0.8,1.6)
Risk Ð 4 % per month breast feeding

office.koletzko@med.uni-muenchen.de Harder et al, Am J Epidemiol 2005;162:397-403 office.koletzko@med.uni-muenchen.de
Breastfeeding does not shift the entire

Probit Study: BMI distribution but only the upper parts
lack of power Data on 9,368 preschool children, collected @school-entry examinations 1999 & 2002 in Bavaria, Germany
Point estimates (95%CI) for Δ BMI

This cluster-randomized BMI Distribution between breast-and formula-feeding
for 0.1–0.9 deciles and 0.03 and 0.97
trial on the promotion of percentile in the multivariable
breastfeeding, the largest Breastfed
quantile regression model
Formula fed
such trial thus far, was
underpowered to assess
the association between
breastfeeding and
childhood obesity
office.koletzko@med.uni-muenchen.de Rückinger et al 2008 office.koletzko@med.uni-muenchen.de Beyerlein et al 2008
Breastfeeding: modest but consistent

protection against later obesity Early Protein Hypothesis
Ö Promote, Protect, Support Breastfeeding
Why does breastfeeding protect? Lower protein supply
z Residual confounding
with breast feeding
z Effects on behaviour, taste, food choice
z Dietary lipid quality reduces high early weight

z Modulating effects of gut bacteria gain and later obesity risk
z Early growth less rapid
Koletzko B. Adv Exp Med Biol 2005;569
z Lower protein supply European Childhood
Obesity Project
z Several other hypotheses
7
Growth of breast- High weight gain
% Overweight at 5/6 years

40
birth to 2 yrs
and bottle fed infants Î high risk of 30
overweight at
z 19 growth studies in infants from
affluent populations (Australia, Canada,
school age 20
Denmark, Finland, Italy, Japan, South Africa, Sweden, USA) Height and weight in 4,235 children
at birth, 6, 12 & 24 mon. (preventive
z Lower weight gain in the 1st. year health checks by paediatricians/ 10
GPs) & at 5-6 years (school entry)
of life in breastfed infants
if 9 / 12 mon. breastfed, @1 yr. Ð 400 / 600 g 0
10 20 30 40 50 60 70 80 90 100
Dewey, Biol Neonate 1998;74:94-105 Arch Pediatr Adolesc Med 2004;158:449-452 Centile weight gain 0 – 2 yrs
Early protein intake: a causal factor?

Protein intakes (g/kg&d) of breast and formula fed infants
3 Meta-analyses, >20 studies German DONALD study, FKE 1999
3,5
g protein/kg&d
Formula Protein
90th Perc.
3
Insulin rel. amino acids

High early weight gain: 2,5 Breast 50th perc.
90th perc.
10th perc. Insulin, IGF1
2-3fold risk of obesity in
2
50th perc.
1,5
10th perc. Growth Adipogenic

school age and adulthood 1 0-2 yrs.
Karlberg 1995
Activity
Wabitsch 1995
0,5
Baird 2005, Monteiro 2005, Ong 2006
3 mon. 6 mon.
European Childhood
0 Obesity Project
Can infant feeding European Childhood Obesity Project

reduce later obesity? www.metabolic-programming.org
Berthold Koletzko*, Veit Grote, Rüdiger 1757 healthy newborns enrolled

von Kries, Ricardo Closa Monasterolo, maternal
choice
Joaquín Escribano Subías, Silvia Excl. breast Study formula
Scaglioni, Marcello Giovannini, Jeannette
Early Nutrition
fed >3 mon. from <8 weeks
Programming Project (n=619) (n=1138)
Beyer, Hans Demmelmair, Dariusz
double blind, randomised
Gruszfeld, Anna Dobrzanska, Anne
Sengier,Jean-Paul Langhendries, Ð Prot.: 1.77 (IF) Ï Prot.: 2.9 (IF)
Marie-Francoise Rolland Cachera, & 2.2 (FOF) & 4.4 (FOF)
for the European Childhood g/100kcal g/100kcal
Obesity Project. Munich, Germany; European Childhood
Tarragona, Spain; Milano, Italy; Warsaw, Obesity Project Standardised follow-up intensive until 2 yrs, 6monthly
Poland; Brussels & Liege, Belgium up to 8 yrs: growth, markers of obesity risk, feeding, Koletzko et al,
behaviour, health, biochemical markers, DNA Am J Clin Nutr
2009;89:1836-45.
8
Randomisation
Not allocated n= 24 Not allocated n= 24
Randomized groups not different for: parental refusal n= 10

medication/illness n= 9
other reasons n= 5
Low protein
n = 564
High protein
n =574
parental refusal n= 13
other reasons n= 7
Allocation
z Gender Lost to follow-up: n= 47

parental refusal
other reasons/
n= 37
Low protein
n = 540
High protein
n = 550
Lost to follow-up: n= 42
parental refusal
other reasons/
n= 30
unknown n= 10 unknown n= 12
Parental age, education

Follow-up 6
Exclusion n= 65 Exclusion n= 85
z lack of compliance n= 65
months lack of compliance n= 82
Low protein High protein
Lost to follow-up: n= 31 Lost to follow-up: n= 30
n = 428 n = 423
Single mothers
parental refusal n= 20 parental refusal n= 23
z other reasons/
unknown
Exclusion
n= 11
n= 13
Follow-up 12
months
other reasons/
unknown
Exclusion
n= 7
n= 10
lack of compliance n= 12 lack of compliance n= 10
Smoking
z Lost to follow-up: n= 45
n = 384 n = 383 Lost to follow-up: n= 34
other reasons/ other reasons/
unknown n= 25 Follow-up 24 unknown n= 13
Birth order
Exclusion n= 1 months Exclusion n= 0
z medication/illness n= 1
n = 338 n = 349
Anthropometry at birth/study entry

Weight or Length
z
measured
n = 313 n = 322
office.koletzko@med.uni-muenchen.de Koletzko et al, Am J Clin Nutr 2009 office.koletzko@med.uni-muenchen.de Koletzko et al, Am J Clin Nutr 2009
higher protein
lower protein
Protein Intake higher protein
Intervention period
Energy Intake 1200
4 Ï protein (kcal/day)
Energy intake (kcal/day)

g/kg&d 1000
3 Ð protein
800
2
FAO/WHO/UNU **
Reference Intakes 2008
1 600
0 400
3 6 12 24 months
3 6 12 24
office.koletzko@med.uni-muenchen.de Koletzko et al, Am J Clin Nutr 2009 Koletzko et al, Am J Clin Nutr 2009 office.koletzko@med.uni-muenchen.de Age in months
SDS length for age not different SDS weight for length: Ï @high protein
z-scores, mean, 95 % CI, relative to WHO growth charts. z-scores, mean, 95 % CI, relative to WHO growth charts. p-values from Anova adjusted
for baseline value comparing higher and lower protein group: * <0.05, **<0.01, ***<0.001
0.4 ***
0.5 **
0.2 **
z -s c o re
0.0
z-score
0.0
-0.5
-0.2
lower protein higher protein breastfed

lower protein higher protein breastfed lower protein higher protein breastfed
-0.4 -1.0
1 3 6 12 24 Age (months) 1
1 3
3 6
6 12
12 24
24 Age (months)
office.koletzko@med.uni-muenchen.de Koletzko et al, Am J Clin Nutr 2009 office.koletzko@med.uni-muenchen.de Koletzko et al, Am J Clin Nutr 2009
9
BMI Ï @high protein Predicted effect on later overweight
z-scores, mean, 95 % CI, relative to WHO growth charts. p-values from Anova adjusted
for baseline value comparing higher and lower protein group: * <0.05, **<0.01, ***<0.001
z Δ 1 SD in weight-for-length gain birth
*** BMI at 2 years to 2 yrs = OR 1.87 (95%CI 1.10-3.18) for
0.5 ** p < 0.01*
obesity @14-16 yrs (Monteiro et al 2003; Ong & Loos
2006)
0.40 ± 0.95
0.4
z -s c o re
Lower protein formula
z score ± SD
z
**
⇒ 13 % reduction
0.3
0.0
0.25 ± 0.95
0.2 0.19 ± 0.89

of later obesity risk
0.1
z Similar to estimated breast-
lower protein higher protein breastfed
-0.5 lower protein higher protein breastfed feeding effect ⇒ might be
0.0
1 33 6
6 12
12 24
24 Age (months)
Breast-
fed
Lower
protein
Higher
protein
due to lower protein supply
Koletzko et al, Am J Clin Nutr 2009 *ANOVA adjusted for baseline value
Ð Protein supply during 1st. year: z Nutrition and health during

z No change of length gain/length @2 yrs pregnancy, lactation and
z Ð Branched chain amino acids/IGF1 infancy has a major impact
on long-term child health
z Normalized weight f. length & BMI @2 yrs
similar to breast fed babies/WHO growth standards z Disease prevention in adults
z Effect induced in 1st.
year tends to persist and old age: new tasks for
nd.
in 2 year Ö programming obstetrics and paediatrics
z May reduce risk of later obesity by ≈13 % z Major public health importance
z Review policy, recommendations, justifies large investments into
practice and research
product design office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de
Sincere thanks 6-8 May 2010

Munich, Germany
z For your kind attention
z To study families
z To wonderful collaborators
z To EU and further funding bodies
Information, abstract submission, registration

Munich Collaborators EARNEST/NUTRIMENTHE Collaborators
10

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Munich, Germany

sensitive time periods of early Konrad Lorenz 1952

development induce lasting

Early programming: Phenylalanine Ï during pregnancy

⇒ folate fortification of stable foods in

z Undernutrition of animals at early, but not at

Programming: Prenatal programming

Birth in „hungry season“ D adult mortality Ï

Birth in the annual hungry season

From the age of 15 years

office.koletzko@med.uni-muenchen.de office.koletzko@med.uni-muenchen.de Agency f Healthcare Res & Quality 2007

Meta-Analysis: Breastfeeding First gluten introduction during

Pooled OR 0.48 (95%CI 0.50-0.59)

Low birth weight = Ï later risk Breastfeeding:

Early salt intake ⇒ Ï RR later Health economic population

Adj. RR 15 years after Ð Na+ Ð Diast. RR (mmHg) 0.6 1.2 2.5 5 10

Î Early nutritional Studies Studies

DG Research - European Commission

40 partners Key targets

Genetics Ï Birthweight Ö Ï adult BMI in

Do postnatal diet and growth Different growth patterns

Victora et al, J Nutr 1998;128:1134-8

Ever 0.79 0.75

<2 mon. 0.89 0.90

3-5 mon. 0.87 0.65 Dose response

Proportion of breastfed infants by age No significant differences

Risk Ð 4 % per month breast feeding

Breastfeeding does not shift the entire

Point estimates (95%CI) for Δ BMI

office.koletzko@med.uni-muenchen.de Rückinger et al 2008 office.koletzko@med.uni-muenchen.de Beyerlein et al 2008

Breastfeeding: modest but consistent

z Dietary lipid quality reduces high early weight

% Overweight at 5/6 years

Early protein intake: a causal factor?

3 Meta-analyses, >20 studies German DONALD study, FKE 1999

Insulin rel. amino acids

10th perc. Growth Adipogenic

Can infant feeding European Childhood Obesity Project

Berthold Koletzko*, Veit Grote, Rüdiger 1757 healthy newborns enrolled

Randomized groups not different for: parental refusal n= 10

z Gender Lost to follow-up: n= 47

Parental age, education

Anthropometry at birth/study entry

Energy intake (kcal/day)

lower protein higher protein breastfed

Lower protein formula

0.2 0.19 ± 0.89

Ð Protein supply during 1st. year: z Nutrition and health during

Sincere thanks 6-8 May 2010

z To EU and further funding bodies

Information, abstract submission, registration

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