Edition 1/2015

A Summary of the Latest

Scientific News

In this issue:

Protein and
programming

Programming in the womb

Overweight mother
– overweight child?

The significance
of breastfeeding

Metabolomic factors

Protein and allergy

prevention
Nutrition and programming
Editorial
Dear Reader,
It is becoming increasingly clear that the
first 1,000 days from conception to the
end of the 2nd year of life play a signifi-
cant role in long-term development and
human health. At this delicate stage,
the body undergoes programming,
which is clearly of defining importance
not only for childhood. The influence
of epigenetics appears to be just as
significant as genetic disposition. Pre-
and post-natal nutrition is particularly
important among epigenetic factors.
And this, in turn, is where protein in-
take attracts a lot of attention. Not only
in terms of a lack of supply, but also if
there is over-supply. Large amounts of
protein lead to more rapid growth in
infancy and greater weight gain, which
is linked to an increased risk of being
overweight or obese later in life. Inter-
national studies are now presenting the
first pieces of evidence that support
this hypothesis. The latest research is
uncovering answers to questions relat-
ing to the metabolic mechanisms influ-
encing this situation. Research is now
revealing how the mother‘s general and
pre-conception status has an influence
and is also providing answers about
allergic predis­
position. In this edition
we are pleased to offer you a glimpse
at the findings from the latest studies.
We hope you enjoy the articles and find
them informative.
the NNI Team
NNI News 2015
Pre- and post-natal nutrition
and metabolic programming
Insufficient protein intake can lead to
growth and development disorders. The
EU Directive on infant formulae has
therefore set a minimum quantity for
protein and for every essential and semi-
essential amino acid in infant and follow-
on formulas.
Long-term investigations in Gambia – a region
where there is no rainfall for six months
and where there is a lack of fresh food –
reveal some surprising findings: If a child is
born with a normal birth weight, it develops
according to the WHO guideline along the
50th percentile. SGA babies are considerably
below this.
Both groups were fully breastfed for six
months and were not given protein. Pro-
gramming therefore begins in the womb and
depends on the prenatal supply of protein.
(1) Protein – the basis for child development
Brain maturation
Immune system
Muscle develop-
ment & growth
This development not only applies in Gam-
bia, but has also been confirmed in recently
published data from Zimbabwe. If the birth
weight is right and if the baby is breastfed,
children then develop normally – even if they
are given very little protein after birth. This
has been widely overlooked until now.
It is difficult to correct intrauterine malnu-
trition after the birth. The mother needs to
intervene in terms of nutrition. The SGA risk
can be reduced by a third if young women
take appropriate supplements preferably be-
fore pregnancy, as a recent review proves
(Bhutta, Lancet 2013). The message is:
Correct food
for the mother is correct
food for the baby!
Healthy
weight development
Allergy risk
Regulated
digestion
3
(2) Conventional infant formula contributes greatly
to unwanted high levels of protein intake At a glance
3.50
Maternal obesity and rapid
growth in the first months of
3.00
life are an indication of an in-
50. Perc
2.50 creased risk of later obesity.
protein (g/kg/d)
2.00 It leads to incorrect metabolic
50. Perc programming.
1.50
Epigenetic factors appear to
1.00
Infant formula play a greater role, possibly in-
Breast milk
0.50 cluding gut microbiota.
0
Preventing obesity in adult-
3 6
(months) hood should start early: at least
6 months‘ breastfeeding or
Koletzko B et al., 2005 infant formula with a low but
high-quality protein content.
Infant formulae with a high protein content as
Children of overweight mothers
Breastfeeding and protein intake well as cow‘s milk in early childhood lead to
can benefit from this particu-
an increased risk of later obesity.
larly.
There are already very good studies con-
Infants fed on conventional infant formula firming this link, such as the Childhood
absorb significantly more protein than breast- Obesity Project (CHOP). The study inves-
fed children. (Fig.2). tigated whether an infant formula with a
 Protein and life expectancy 5

Infant nutrition
protein content approximately the same as breast milk can lead to a
(3) Differences in 6-year olds:
lower BMI and prevent later obesity.
Infant formula with a high/low protein content

and longevity?
It revealed that those children fed on a conventional infant formu-
16.6 3.0
la had a significantly higher BMI at age 6 compared to those who BMI: Overweight risk:
+ 0.51 2,43 times
had received an infant formula with a lower protein content. The 16.4
2.5

obesity risk was 2.43 times higher; they also demonstrated a 2.0

Overweight risk
Which factors influence health and life

BMI (kg/m2 )
tendency to higher body weight but no difference in height. (Fig.3) 16.2

P=0.009
1.5
P=0.024
expectancy – and which ones can be al-
It can therefore be deduced that infant formula with a lower propor- 16.0
tered?
1.0
tion of protein reduces the BMI and the risk of obesity in children of
15.8 Life expectancyincreased significantly in
school age. That‘s programming! 0.5

the 20th century and the gap between the

15.6 0
low-protein- high-protein- low-protein- high-protein- ages of those living in industrialised coun-
The overweight mother group group group group
tries and those in developing countries be-
Weber M et al., Am J Clin Nutr. 2014 Mar 19 [Epub ahead of print] gan to shrink. (Fig.1)
Fully breastfed babies of overweight mothers put on 1 kilo more
become shorter with that restricting calories does not improve
within the first 12 months of life compared to mothers with a normal (1) Life expectancy:

The gap is closing each division. Metabolic the genetic potential, but unlimited protein
weight. Whereas the protein contents were within the normal pre- (4) Protein concentration in breast milk,
disorders and inflammation obviously speed intake does erode that potential. The time
scribed range in the CHOP study, a recent study investigated the ef- formula with high/low protein content 90
up this process. A series of risk factors is factor is also important: protein reduction
fect of nutrition with a protein content below this guideline in children 80
Industrialised countries
3.50 Developing countries associated with this. And influences in early before birth shortens the telomeres, re-
of overweight mothers. (Fig.4)
3.00
70
childhood clearly determine the length of stricting protein after birth lengthens them.
In this study children of overweight mothers in Chile received an

Age
2.50
60 the telomeres. The length at birth and the A healthy lifestyle is of course always im-
infant formula with the lowest permitted protein content (1.8 g/
g protein/100 kcal

50 level of degradation determine telomere portant but particular importance should be

2.00
100 kcal) in the first 3 months and then an infant formulawith 1.65 g/ 40 length at any time, with the process also placed on the basics: before conception,
100 kcal or 2.7 g/100 kcal until the end of the 12th month. At age 3–6 1.50
slowing down over time. Longevity can be during pregnancy and lactation, and in early

2000
1940

1960

1980

1990
1930

1950
1920

months when the children were fed exclusively with the relevant infant
formula, the weight gain (g/day) of the children who were fed with low
protein nutrition was significantly lower compared to the control group.
Weight and BMI up to the age of 2 years remained lower than in the
control group but similar to the breastfed children. At 24 months the
difference was over 500 g (Inostroza et al. 2012; Inostroza et al. 2014).
In a study in the USA, the safety of a low protein milk such as this
from the 4thmonth of life until the end of the first year was inves-
tigated in children of unselected mothers. The protein content was
1.61 g/100 kcal compared to 2.15 g/100 kcal in the comparison group;
breastfed children were the reference group. Growth and metabolic
levels proved its safety. Growth in the low protein group correspond-
ed to that of the breastfed children, with no differences in body
composition. This means that infant formula with a low protein con-
tent is safe for all infants and can be used for babies of overweight
mothers to prevent rapid weight gain compared to breastfed children.
Protein quality
Improved protein quality is critical for a low protein content. This is
achieved by removing the CGMP (casein glycomacropeptide) from
the whey, which leads to a reduction in the proportion of threonine
and an increase in the proportion of tryptophane. (Fig.5)
The amino acid profile therefore closely resembles that of breast
milk. Other advantages cannot be so easily copied, but its amino acid
pattern can be largely replicated – for the benefit of children who
cannot be breastfed.
1970
1.00 Control (high-protein) formula
low-protein formula
0.50
Breast Milk (BF)
0 set before birth. Harmful influences in the
0 3 6 9 12
Age/Months Improved living conditions in the first
months of life are often underestimated as
Inostroza, 2014
the crucial contributing factor.
Infant development still plays an important
(5) Improvement of protein composition role in differing life expectancy. But at the
in formula with low protein content beginning of the 21stcentury new health
problems are emerging: an increasing num-
Removal of the CGMP (Caseino-Glyco- ber of allergies and especially childhood
Makropetide) from whey results in essential obesity with the associated complications
amino acis composition to breast milk in later life lead to the paradoxical situation
in which life expectancy for future genera-
tions will diminish, despite all the advances
that have been made.
– 25 % + 35 % So what significance does infant nutrition
have? Firstly it is important to realise that
Threonine-Concentration Tryptophan-Concentration cell division limits longevity and that the
cells themselves are not able to continue
Patents Haschke et al. 2000; 2007; 2009; 2012 dividing as often as they like. This is known
as the Hayflick limit and it varies depending
on the species: in mice it is approximately
14–28 cell divisions, in Galapagos tortoises
Summary of a presentation by Prof.Ferdinand Haschke, 2014
90–125 and in humans 40–60. Telomeres
EAPS Biennial Congress of European Academy of Pediatric
are responsible for this. They are the single-
Societies, Barcelona
stranded ends of chromosomes, which
predicted from the length of the telomeres childhood.
in infancy. The biological clock is already
Summary of a presentation by Prof.
Susan Prescott, 2014 at the 4th NNI
womb and a low birth weight (LBW) present
Regional Symposium Adelaide, Australia,
shortened telomeres. Early intervention
October 2014
therefore makes sense.
The lives of modern people bear all the hall-
marks of captive animals: abundant food,
At a glance
even temperatures, no hunters, ”hygiene“,
living in rooms with artificial lighting, no
physical exertion, and with the concomitant Depending on the species, only a
effects of overnutrition, susceptibility to dis- certain number of cell divisions
eases and increased inflammatory risk. are possible and these divisions
determine life expectancy.
The increase in allergic diseases is another
characteristic. Research also reveals that
The length of the telomeres,
all this begins in the womb. A higher pre- which decides cell division, is de-
conception BMI is an indicator for obesity, termined significantly by the life
cardiovascular diseases, diabetes, asthma circumstances of the pregnant
and pulmonary diseases. Can obesity also woman and the newborn.
be a signal for an increased allergy risk?
Following a generally healthy life-
There is also the question whether restrict- style is important, but especially
ing calories can help. The animal model has so during the pre-conception
shown for a hundred years already that a phase and in the first 1,000 days
smaller proportion of protein coupled with after conception.
an adequate intake of all essential nutri-
ents, vitamins and minerals can extend life.
Viewed from a different angle, it is the case

NNI News 2015

Intrauterine programming 7

Pre-conception BMI Maternal obesity and weight gain lead to

and the overweight child obesity in the offspring
Overweight and obesity in women of childbearing age affects The EPOCH study includes children who
(1) Maternal obesity has become one of the major challenges of modern obstetrics
not only industrialised nations but is increasingly becoming a were born between 1992 and 2002 in a
and is increasingly associated with growing complications for mother and child.
serious health problem in China. However, until now we have single hospital in Colorado and whose
lacked a meta-analysis to measure the extent to which the mothers were entered in the Kaiser Per- 32 95
pre-conception Body Mass Index (BMI) affects the birth weight manente of Colorado Health Plan (KPCO). Excessive GWG 90 Excessive GWG
Adequate GWG Adequate GWG
85

Child BMI (kg/m2 )

and obesity of the offspring. 27

For this investigation, bibliographic compilations of data from MED-
LINE, EMBASE and CINAHL between 1970 and 2012 were recorded
and 45 studies of best to average significance in this regard were
selected.
The most significant findings:
Pre-conception underweight increases the risk of
an SGA baby (Small for Gestational Age)
and low birth weight (< 2.500 g)
Pre-conception overweight/obesity increases the risk of
an LGA baby (Large for Gestational Age)
high birth weight (> 4.000 g)
a macrosomic baby (≥ 4.500 g)
and subsequent overweight/obesity
Despite the variety in the design and scope of the studies selected,
the mother‘s pre-conception BMI has a significant influence on the
Child WC (cm)
313 mother-child pairs took part. All children 80
of mothers with an excessive gestational 22
75
weight gain (GWG) were included and those 70
65
without GWG influences as a random sam- 17 60
ple. Children were thoroughly re-examined 55
on average at 10.5 years. 12 50
16 21 26 31 36 41 46 51 56 61 16 21 26 31 36 41 46 51 56 61
Increased pre-conception BMI was associ- Maternal pre-pregnancy BMI Maternal pre-pregnancy BMI
ated with a poorer child outcome, particularly
in mothers with excessive weight gain. Chil-
dren whose mothers showed a pre-concep-
tion BMI > 30 were more likely to be over- The findings suggest that measures for mon- Kaar JL et al.: Maternal Obesity, Gestation-
weight at 2.3 and 4 years. Similarly the fat itoring weight development in pregnancy are al Weight Gain, and Offspring Adiposity:
birth weight and later overweight/obesity risk. The role played by
mass increased for boys by 0.26 and for girls needed to prevent childhood obesity. The Exploring Perinatal Outcomes among
other factors such as blood pressure, gestational diabetes, smoking
by 0.42 at 9 years for each BMI unit more of Children Study. J Pediatr 2014;165:509–15
or weight gain during pregnancy need to be verified in other investi-
the mother. (Fig.1)
gations
Yu Z et al.: Pre-Pregnancy Body Mass Index in Relation to Infant
Birth Weight and Offspring Overweight/Obesity: A Systematic
Review and Meta-Analysis. PLoS ONE 8(4): (2013) e61627.
Gestational At a glance

Maternal obesity has a long-term influence weight gain? Pre-conception underweight or

overweight already has an effect
in terms of programming the

on the child‘s insulin level
The development of approximately
1,000 children from all categories of
population born between November
2000 and November 2001 at Ulm‘s Uni-
versitätsfrauenklinik was followed up
and investigated as part of the Ulm chil-
dren‘s study to determine which factors
influence weight gain over this period.
Parents were also included in the study.
The insulin concentration in the blood in
422 of the children now aged 8 was also
determined. It revealed that although the
breastfeeding duration, educational level
and social status of the families have a cer-
tain influence on weight development, the
weight of the mother before pregnancy
appears to be a significant factor. Mothers
who had developed gestational diabetes
were excluded from the study.
The insulin level of children from overweight
pre-conception mothers was 40 to 50 per
cent higher than that of children whose
mothers had a normal weight. This is to
be seen as an indicator for an increased
obesity risk. The BMI of these children at
birth and at 8 years was above that of children
from mothers without an increased insulin
level. This study therefore provides a strong
indication of prenatal programming.
Lehman LJ: Zusammenhänge zwischen
dem elterlichen Gewichtsstatus, aus-
gewählten Verhaltensfaktoren und der
Entwicklung von Übergewicht und ab-
dominaler Adipositas des Kindes. Ergeb-
nisse der Ulmer Geburtskohortenstudie.
Ulm, 2012
Maternal obesity has become one of the
major challenges of modern obstetrics
and is increasingly associated with
growing complications for mother and
child.
There is growing interest in gestational
weight gain (GWG) with an emphasis on the
link between excessive GWG and increased
foetal growth.
The most recent recommendations of the
Institute of Medicine in the USA have re-
vised down their recommendations for
weight gain for overweight pregnant wom-
en. It seems appropriate to review the ad-
vice on GWG and lifestyle before, during
and after pregnancy. The evidence is slim
that intervention studies reduce excessive
child‘s speed of growth and
weight gain.
GWG or improve intrauterine foetal growth.
Maternal overweight can lead to
There is actually a potential risk that inappro- increased birth weight, more rap-
priate interventions during pregnancy lead id weight gain and increased risk
to foetal malnutrition and both short and of obesity in the offspring.
long-term negative clinical consequences. It
would be more appropriate to concentrate The findings should not lead to
on physical activity and improved nutrition a heavy reduction in the recom-
mended amounts of protein.
rather than focussing on the weight of the
mother. Advice, improved nutrition and
more activity are what‘s called
O’Higgins AC et al.: The relationship be-
tween gestational weight gain and fetal for.
growth: time to take stock? J. Perinat.
Med. 2014; 42(4): 409–415

NNI News 2015

 Breast milk and protein 9

Protein and (1) Prevalence (in %) of obesity in children

and adolescents in the USA Breastfeeding duration
breastfeeding Age in years
2–5
1976–1980
5.0
1999–2000
10.3
2003–2004
13.9
2007–2008
10.4
and adiposity risk
6–11 6.5 15.1 18.8 19.6
Breastfeeding is the ideal form of nutrition in the first months be- 12–19 5.0 14.8 17.4 18.1
Systematic investigations suggest that a between birth and the first year. Introducing a milk other than breast milk
cause it fulfils the baby‘s needs and has proven benefits: longer breastfeeding duration is associa- before the 6th month created a risk factor
Total 5.5 13.9 17.1 16.9 At 3 years and after a breastfeeding du-
ted with a reduction in the risk of later of being overweight or obese at 20 com-
It promotes healthy growth and development, ration of < 4 months children showed an
overweight and obesity. pared to weaning after the 6th month.
it effectively protects against infections and diseases, Ogden, 2010 increased risk of early rapid growth.
The study objective was to investigate the The basic biological mechanisms are based
it bonds mother and child.
ion of breast milk long-term effect of early nutrition on adipo- From the 1st to 8thyear the children who
were breastfed ≤ 4 months were signi-
on the unique composition and the metabo-
International experts and organisations therefore promote breast- (2) Speed of growth and protein intake sity risk in childhood, adolescence and early lic and physiological reactions to breast milk.
feeding exclusively for the first six months of life (IOM 2011, WHO in breastfed children adulthood based on new and already publis- ficantly more likely to exceed the 95th Breastfeeding should be encouraged and
milk composition is not constant, but weight percentile compared to those
2013, ESPGHAN 2009). (Fig.1) Breast milk intake in the first 12 months hed data. Data from the Western Australian recommended until the 6th month and bey-
esponse to the changing nutritional 2.25 1200 breastfed ≥ 12 months.
Growth rate Pregnancy Cohort (Raine) Study in Perth ond to protect against increasing adiposity.
Research
macronutrient conducted
in breast in recent
milk evolves in years has shown that the composi- 1.4
1100
Protein intake was used to examine associations between
tion the
ith perhaps of most
breaststriking
milk over days and months adjusts perfectly to the
changes 2.00 1000
The period when breastfeeding was re- Oddy WH et al.: Early infant feeding and
Breast milk intake ( kg/d)

1.2
breastfeeding and adiposity at 1, 2, 3, 6, 8,
g/kg Kbody weight/day

900
hese variations
changing are needs
believedoftothe
respond
baby. There is increasing evidence too that 1.0 Lower growth rate = placed with another milk played a signifi- adiposity risk: from infancy to adulthood.
1.75 800 10, 14, 17 and 20 years.
l effectsthe
on benefits
growth and development continue into adulthood. The particular Lower protein needs

g/month
of breastfeeding 0.8 700
cant role in BMI development from birth Ann Nutr Metab 2014; 64(3-4):262–70
composition of breast milk appears to have a positive effect on early 1.50 600
The most significant findings: to 14 years. Weaning at 4 months was
0.6
metabolic programming. 0.4
500 Breastfeeding for longer was associated uniformly associated with a higher BMI
Higher growth rate =
1.25 400
Higher protein needs with a reduction in the weight z-score development.
d breastWhat
milkisconsumption
essential to bear in mind is that the infant‘s protein require- 0.2
300

creasesment
very does
rapidly,
notdoubling duringbut reduces with age in relation to body
remain static 0
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12
200
0–1 1–2 2–3 3–4 4–5 5–6 6–7 9–12
mirrors the infants’
weight, increasing
where energy is particularly steep in the first months
the reduction Age (month)
Age/months

Excessive weight gain with exclusive breastfeeding?

lthy growth andThe
of life. development.
protein intake of the breastfed child reduces with age in
Ref: Adapted from
Van’t da Costa et al. 2010
Hof, 2000
line with the child‘s requirements, mainly because the protein con-
tent of breast milk reduces from approximately 14.0 g/L (1.85 g/100
ion of breast milk
he first year of life Important changes in energy density in breast milk also take place during the
kcal) in the first month to 8.6 g/L (1.35 g/100 kcal) in the fourth-
lactation period. It is generally accepted that the energy content of breast milk is Breastfeeding is regarded as the optimal Since this pattern suggested full breastfeed-
month. The breastfed infant therefore gets just the right amount of (3) Breast milkseveral
intakestudies
in thehave
firstdemonstrated
12 months that caloric density
67 kcal/100mL; however, nutrition for healthy infant growth and ing to be the cause, the composition of the At a glance
protein. (Fig.2/3)
milk composition is not constant, but varies during breast-feeding and that it is below this standard value (Lucas et al. development. Studies show the link breast milk was compared with correspond-
esponse to the changing nutritional Breast milk intake in the first 12 months
1987; de Bruin1.4et al. 1998; Reilly et al. 2005). Some studies have even estimated
The situation is different for bottle-fed infants. The protein content between breastfeeding and a reduced ing published guidance levels. Lactose, fat,
macronutrient in breast milk evolves in the caloric density of breast milk at 57 kcal/100mL (Lucas et al. 1987), questioning Breastfeeding is the ideal form of
of infant formula is designed to meet the protein requirements at the 1.4
1.2 risk of being overweight later in life. fatty acids, polar lipids, carnitine and insulin
ith perhaps the most striking changes the widely used standards. nutrition in the first months be-
Breast milk intake (kg/Tag)
Breast milk intake ( kg/d)

highest point, i.e. in the first month of life. The protein content of 1.2
1.0 in the milk corresponded to the guidance lev-
hese variations are believed to respond The composition of breast milk varies with ma- cause it fulfils the baby‘s needs
infant formulas is between 1.85 and 2.10 g/100 kcal so that it covers 1.0 els, but the adiponectin content was elevat-
l effects on growth and development 0.8
ternal nutrition, lifestyle, genetic determinants best.
the protein requirement in the first month. 0.8
Evolution in energy content of breast milk ed. The most significant change was a high
0.6 and breastfeeding duration. However, little
0.6 milk protein content (1.25 g/dl compared Exclusive breastfeeding is recom-
Not only does the quantity of breast milk change, so does the prote- 0.4 85 is known whether interindividual differences
0.4 to 0.8 g/dl). It has been shown that a high mended during the first 6 months
6-7 in profile.
7-8 8-9 The 10-11
9-10 ratio 11-12
between the two main constituents, whey and 80 in breast milk have relevant effects on child
dmonth)
breast milk consumption 0.2
0.2
75 supply of protein during infancy increases of life.
Calorie (kcal/100ml)

casein, vary during lactation, as do lipids and carbohydrates. growth and health. There are indications that
creases very rapidly, doubling during 00 70 plasma concentrations of the growth factor
0
65
0
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9 10
9
11
10
12
11 12 certain differences in the polyunsaturated ami- The composition of breast milk
mirrors the infants’
Breast increasing
fed babies and energy
those fed with infant formulas show different Age (month) insulin and of IGF-1, as well as the later obe-
60 Age/months
no acids of breast milk brought about through
lthy growth and development.
patterns of weight gain. The difference in the protein concentration 55 sity risk. perfectly matches the baby‘s chan-
Ref: Adapted frometda
da Costa al.,Costa
2010 et al. 2010 nutrition and genetic variants influence cogni-
could lead to increased weight gain in non-breastfed children, or 50 ging needs.
o support growth and physical activity 45 tive development and asthma risk. It may be assumed that individual variants of
what is known as the“early protein hypothesis“.
nhebreast milk
first year consumption. A recent
of life Important changes0 in energy density in breast milk4 also take place 6during the adiponectin and protein in breast milk influ- The benefits of breastfeeding ap-
Babies of overweight 1 mothers
2 have
3 a greater risk 5 of becoming A macrosomic baby (4.56 kg) was observed
The data seems to imply
an isotope tracer in infants aged 0-24 that increased weight gain in the early
lactation period. It is generally accepted that the
Months energy content of breast milk is ence the growth of breastfed children and pear to continue into adult life.
overweight themselves later on. A randomised double-blind who during full breastfeeding showed exces-
by infantsdevelopment phasethe
increases during has consequences
first 4 that extend onto adult67life.
kcal/100mL; however, several studies have demonstrated that caloric density in this case led to excessive weight gain.
study
Ref: Adapted fromtested
Lucas etthe extent
al. 1987; toetwhich
Hosoi al. 2005;growth could
Saarela et beNielsen
al. 2005; normalised in
et al. 2008; sive weight gain significantly in excess of the
The particular composition of
). ”Metabolic programming“ takes place. varies
Thakkarduring breast-feeding and that it is below this standard value (Lucas et al.
et al. 2013 This hypothesis needs to be tested in future
non-breastfed babies of overweight mothers (BMI > 25) if given 97th percentile. At 4 months the baby‘s weight breast milk appears to have a posi-
1987; de Bruin et al. 1998; Reilly et al. 2005). Some studies have even estimated cohort studies.
was already over 11 kg. The clinical diagnosis
The potentially negative effects of an infant formula with a highthe pro-caloricandensity
infant offormula withata57
breast milk lower protein(Lucas
kcal/100mL content (1.65
et al. g/100
1987), kcal).
questioning tive effect on early metabolic pro-
tein content have led scientists to research the effect of nutrition Compared
the widely used standards. to the weight gain with a standard formula, nutrition showed no pathological causes. After intro- Grunewald M, Hellmuth C, Demmelmair gramming.
with a low protein content. A European project (Koletzko et. al 2009) with a low protein content led to a slow-down in weight gain in ducing complementary feeding and reduced H, Koletzko B: Excessive Weight Gain dur-
5
confirmed the positive effect of nutrition of this kind compared to the first year of life and biomarkers approximated those of breastfed breast milk, the weight gain was curtailed and ing Full Breast-Feeding. Ann Nutr Metab
Evolution in energy content of breast milk
conventional infant formula on weight gain and later overweight risk. children (Inostroza et al. 2014). progressed in parallel to the upper percentiles. 2014; 64: 271–275
85
6-7 7-8 8-9 9-10 10-11 11-12 80
month) 75
lorie (kcal/100ml)

70
65

NNI News 2015 60

55
Proteins and postnatal nutrition 11

Regulating Composition of infant formula

early growth
Growth and development are significant
characteristics of childhood. Deviations from
normal growth can be an indication of serious
health problems.
The harmful influence of growth disorders and malnutrition on
later health has been known about for a long time. But it is also
being increasingly proven that nutrition during infancy and ear-
ly childhood and rapid growth lead to an increased risk of later
obesity and associated diseases. The link has been confirmed
in a large randomised controlled study in which the early protein
hypothesis was tested. The findings point to the necessity of
analysing growth patterns and their nutrition-related regulation
and of describing the basic metabolic and epigenetic mecha-
nisms. A better understanding of these processes could have
a very positive effect on promoting public health, consumer-
related dietary recommendations and the development of
improved foods for special target groups.
Early obesity – later consequences
Infant nutrition has a significant effect Here nutrition during pregnancy and in
on the direct outcome and long-term infancy plays a particular role.
health and later disease risks, a phe-
According to the latest prospective ob-
nomenon described as ”metabolic
servational studies from birth to 2 years,
programming“.
there are primarily three factors linked to
Obesity has increased dramatically in re- childhood obesity.
cent years. This also increasingly the case
Overweight mother
in emerging countries where the socio-
economic transition is leading to over- High birth weight
nutrition.
Rapid growth in the first 12 months
Koletzko B et al.: Regulation of early human growth: impact on
long-term health. Ann Nutr Metab. 2014; 65(2–3):101–9
At a glance
The relationship between nutri-
tion and growth in the first two
years of life with the risk of later
obesity and associated diseases
is still unclear.
It is accepted that the milk protein
influences IGF1 concentrations
affects growth
Can proteins, other macronutrients and
LC-PUFA in infant formula influence child
growth? The BeMIM study considered
the effect of a duly modified formula on
growth.
In a double-blind, randomised study 213
healthy babies born at full term received
either a protein reduced, isoenergetic inter-
vention formula (IF) or a conventional control
formula (CF). IF with 1.89 g protein/100 kcal
contained alpha-lactalbumin (ALAB) and LC-
PUFA while CF delivered (2.30 g protein/
100 kcal) standard whey and no LC-PUFA.
The anthropometric data and nutrition intake
were regularly recorded, after 120 days a
venous blood sample was taken.
Despite the lower protein and calorie intake,
the IF did not lead to a lower average weight
gain than the CF group. Compared with the
group of breastfed children, the IF children
showed a significantly higher weight gain
(g/day) (Fig.1) and a greater increase of the
weight-for-age z-score between the 30th
and 120th day.
The most significant findings:
No definitive statement can be drawn
from this study about the effect of the re-
duced protein content in this formula milk
(1) Significantly higher average daily weight gain
with low protein nutrition
31
because other factors were additionally and rapid weight gain. The differences in pro-
modified in the composition. tein quality between the two infant formulas
evidently had a stronger influence on growth
A reduced protein content is not the
than the reduction in protein quantity.
only factor that influences child growth.
Protein quality plays a crucial role as well. Fleddermann M et al.: Infant formula com-
position affects energetic efficiency for
Both the CF and IF group had a signifi-
growth: The BeMIM study, a randomized
cantly higher plasma urea level at 120
controlled trial. Clinical Nutrition 33 (2014)
days than the group of breastfed children.
588e595
What could the reason be for these un­
expected study findings?
IF and CF had different protein qualities. IF
was enriched with alpha-lactalbumin and
free tryptophan. This was necessary in order
to achieve the legal minimum content of tryp-
tophan based on that of breast milk despite
At a glance
Growth depends
The results of existing studies
not only on protein quantity
but on protein quality.
allow inferences to be drawn for
paediatric practice.
Breastfeeding is the best choice
the reduced protein content. This supple- for infant nutrition and should be
ment could be the reason for the significant- actively encouraged, supported
ly higher plasma tryptophan level compared
and safeguarded.
to that of the breastfed children and which
leads to an elevated IGF-1, a driver for growth For infants who are not breastfed
or not entirely breastfed, infant
formula and follow-on formula
with low protein content should
be chosen. Good protein quality
in food is important.

The present publication discusses the hy- in childhood and triggers such a For healthy children, a very rapid
There is agreement that the pre- and 30
potheses and mechanisms investigated in programming effect while other increase in weight in the first
post-natal phases are the most important
weight gain (g/day)

the Early Nutrition Project. epigenetic factors play a lesser 29

two years of life is not desirable.
period for programming later obesity.
role. 28 Where the percentiles intersect,
Rapid growth in the first two years of life,
Brands B, Demmelmair H, Koletzko B:
particularly with milk protein, influences Further investigations are neces- 27
specific advice should be sought.
How growth due to infant nutrition in-
the metabolic setting of the IGF. Epi­ sary to unlock the precise mech-
fluences obesity and later disease risk. 26 Normal cow‘s milk with high pro-
genetic processes appear to play a role anistic paths and to offer solid
Acta Pædiatrica 2014 103, pp. 578–585 tein content should not be given
here. evidence for practical recommen- 25

dations. Intervention – IF Control – CF Breastfed as a drink in the first year of life.

The evidence is growing that being over-
weight or obese at 5 means a later obe-
sity risk with the associated diseases.

NNI News 2015

Influencing factors 13

Protein intake influences amino acid Influencing factors on the microbiota

and acylcarnitine metabolism
The protective effect of breastfeeding
against later obesity can be explained by
the lower protein content compared to
formula milk. But the metabolic mecha-
nisms remain unknown.
of neonates
(1) Distribution of the ratio of acylcarnitines C14, C16, C18 The shift from a relatively simple micro- significantly later in C-section children and of microbiota also applies to healthy neo-
to free carnitine across the study groups biota in neonates to a more mature an- those born after a shorter gestation period. nates. The composition of early microbiota is
aerobic microbiota in later months is in- linked with long-terms effects on health and
Independently of these factors, the children
p<0.001 p=0.01 p<0.001
fluenced by environmental factors. This disease.
with high levels of bifidobacterium and col-
p<0.001 p<0.001 p<0.001
is the finding from a long-term study

0.003 0.004
0.006 0.008
p<0.001 p<0.001 p<0.001
linsella showed lower obesity at 18 months. Dogra S et al.: Dynamics of Infant Gut
with 75 children.
0.003

As part of the large-scale CHOP study The composition of microbiota is a marker for Microbiota Are Influenced by Delivery

C16 / free Carnitine

C18 / free Carnitine

C14 / free Carnitine

(Childhood Obesity Project) – a multicentre Most at the age of 6 months had acquired a obesity at 18 months and for potential obe- Mode and Gestational Duration and Are
0.002

randomised intervention study – children microbiotic profile high in bifidobacterium and sity risk in later years. The marked influence Associated with Subsequent Adiposity.

0.004

0.002
received either an infant formula with a collinsella, but the time point of this shift was of environmental factors on the development mBio 6(1):e02419–1
high (HP - 2.05 g/100 ml) or low (LP - 1.25
0.001

0.002

0.001
g/100 ml) protein content or were breast-
fed. Plasma samples of 691 children who

Current information on nutrition

0

had received the HP/LP infant formula were
collected. Changes in the plasma amino
acid and acylcarnitine concentrations of the
6-month old babies were determined by LC-
MS/MS analysis according to the different
protein intake. (Fig.1)
29 metabolites differed significantly between
the HP and LP group. Branched-chain amino
acids (BCAA) were the most discriminant
metabolites. Their by-products, the short-
chain acylcarnitines C3, C4 and C5 were also
elevated in the HP group. A breakpoint analy-
sis confirmed that with increasing BCAAs
the ratio between acylcarnitine and BCAAs
BF LP
decreases. Long-chain acylcarnitine were
reduced among children in the HP group.
BCAAs appear to play a central role in nutri-
tion with a high protein proportion in terms
of their effect on beta oxidation and fat stor-
age. This is renewed proof of a potential sat-
uration of the BCAA degradation pathway,
which represents the mechanism by which
a high protein intake influences metabolic
regulation. It also appears to inhibit the first
0
HP BF LP HP
step in beta oxidation, which leads to high-
early weight gain and fat storage.
Kirchberg FF et al.: Dietary protein intake
affects amino acid and acylcarnitine me-
tabolism in infants aged 6 months. J Clin
Endocrinol Metab. 2014 Nov 4: jc20143157.
BF LP HP
Nestlé is investing in epigenetic re-
search: the science of how nutritional
habits and other environmental influenc-
es impact genes, health and the well-
being of the offspring.
The company has announced an investment
of 22 million Swiss francs in a 6-year re-
search partnership with EpiGen Consortium,
an international community of researchers in
Southampton, Auckland and Singapore. This
public-private partnership is one of the
largest of its kind.
The partnership aims to improve nutrition
and reduce the risk factors of pregnancy-re-
lated situations such as gestational diabetes,
a growing problem and one which affects
around 20 percent of pregnancies in south-
east Asia. Gestational diabetes is known to
have a negative impact on child growth and
development and on the future health of the
mother.
”The wide-ranging expertise of the Epi-
Gen researchers in conjunction with the
scientists at Nestlé enables us to progress
towards better health for future generations.
A strength of EpiGen is the possibility to
study mothers and children in three very
different populations and to gain further in-
sight into the relationship between genetic
background and nutritional influences on the
health concerns of mother and child,“ em-
phasises Keith Godfrey, Head of the EpiGen
Science Management Group at the Univer-
sity of Southampton.
EpiGen is a global consortium of leading re-
searchers and aims to achieve a better un-
derstanding of the developmental and envi-
ronmentally-related processes that influence
health throughout life.

Metabolic factors for obesity

Despite increasing interest in the hy-
pothesis of an early origin of later diseas-
es, little is known about the metabolic
underpinnings linking infant weight gain
and obesity in later childhood.
The objective of this investigation was to
identify biomarkers with a metabolomic ap-
proach that indicate the link between weight
change in the first 6 months of life and
overweight/obesity at 6 years. The analysis
comprised 726 children from a European
multicentre study CHOP (Childhood Obesity
Programme) from whom blood samples at
6 months and anthropometric data at 6 years phatidylcholine LPCaC14: 0 remained signifi-
were available. Rapid growth was defined as cantly associated with rapid weight gain and
a positive difference to WHO standards in the obesity at 6 years.
first 6 months, weight change was regressed
This suggests that the LPCaC14:0 levels
on each of 168 metabolites (acylcarnitines,
have a metabolically programmed effect on
lysophosphatidylcholines, sphingomyelins
later obesity risk.
and amino acids). Following Bonferroni‘s cor-
rection, significant metabolites were tested Rzehak P et al.: Rapid Growth and Child-
as predictors for later overweight/obesity. hood Obesity Are Strongly Associated
Among the overall 19 significant metabolites, with LysoPC(14:0). Ann Nutr Metab 2014;
4 were associated with rapid growth and 15 64: 294–303
with less than ideal weight change. After
adjusting for the nutrition group (high, low
protein intake, breastfed) only the lysophos-

NNI News 2015

Protein and allergies
Strategies for preventing
food allergies
The occurrence of food allergies in the
first years of life has increased dramati-
cally across the world. In Australia, pre-
school children experience a fivefold in-
crease of food-related anaphylaxis, over
10 percent of one-year olds have a clini-
cal food allergy. Late or even early aller-
gen exposure has proven to be a poten-
tial strategy to prevent food allergies.
In 2000 it was recommended that children
with an increased familial risk of allergies
should not be introduced to allergy-triggering
foods until later, including the avoidance of
eggs until the second year and nuts until
the third year of life. By contrast, studies in
the last ten years have shown that later ex-
posure to some foods after the 6th to 10th
month is associated with an increased risk.
A large cohort study in particular proved that
introducing eggs in the 10th to 12th month
is associated with an increased risk of an egg
allergy compared to introducing them in the
4th – 6th month.
This has led to a fundamental rethink in
terms of the recommendations. However it
became clear that further efficiency from ad-
ditional RCT studies is needed. Such a study
has now been published in which parents
(1) Time point for introducing egg into food
for children with increased eczema risk
Intervention from 4 to 8 months of age:
daily egg (pasteurised raw whole egg) or
rice powder mixed with infant solid foods
4 Months
Allergic reaction to egg powder
Egg group: 15/49 (31 %)
Caution needs to be taken when infants
with eczema first ingest egg in solid foods
NNI News 2015
included a spoonful of egg powder (n=49) or
ricepowder (n=37) every day in the food for
children with an increased allergy risk from
the 4th – 8th month. Both groups received
eggs at 8 months and at 12 months were in-
vestigated to determine whether an egg al-
lergy had developed. A total of 33 percent of
the children who had already come into con-
tact with egg powder at 4 months showed
an allergic reaction compared to 51 percent
of the children who did not receive eggs until
after the 8th month. (Fig.1)
All infants were introduced
to cooked egg in their diet
8 Months
Allergic reaction to cooked egg
Egg group: 6/40 (15 %)
Rice group: 6/35 (17 %)
(p=0.80; RR 0.88; 95 % CI 0.31–2.47)
Unfortunately, this study is of no statistical
significance because of the low number of
subjects. There are currently at least 7 RCT
studies in progress across the world to clarify
to what extent food allergies can be prevent-
ed with early allergy exposure.
Palmer DJ: Nutrition Strategies to Prevent
Food Allergy. The Nest 36 (2014) 4–5
Egg
challenge
12 Months
Allergic reaction to raw egg
Egg group: 14/42 (33 %)
Rice group: 18/35 (51 %)
(p=0.11; RR 0.65; 95 % CI 0.38–1.11)
Health and economic impacts
of early allergy prevention
The prevalence of allergies in infants and
children has increased continuously in
the last 50 years, with atopic dermatitis
(AD) being one of the commonest aller-
gic diseases.
Atopic dermatitis is a heavy burden for the
affected families, healthcare systems and
society at large. Effective allergy prevention
also means benefits in terms of health and
quality of life for the affected families and for
healthcare systems.
Atopic eczema prevention
by nutritional intervention
Neurodermatitis affects one child in
three with a family history of the condi-
tion, about half of them develop skin
lesions in infancy. The eczema risk can be
significantly reduced with a hydrolysed
infant formula in the first four months if
full breastfeeding is not possible.
Atopic eczema is the most common aller-
gic manifestation in the first 10 years of life
and with a worldwide increasing incidence.
Moderate and severe forms have an enor-
mous impact on the quality of life of children
and their families. The eczema risk is twice
as great if allergies have already occurred in
the family. This applies just as much to babies
breastfed in the first four months as it does
to those who received an infant formula.
Ever since it became recognised that early
contact with food allergies plays an impor-
tant role in the development of tolerance
and sensitisation, corresponding intervention
strategies have been proposed for primary
allergy prevention.
The majority of these intervention studies
focussed on children with increased heredi-
tary risk. The GINI study, by far the largest
Exclusively breastfeeding in the first 3
months of life has a positive effect. The GINI
study has shown that a hydrolysed infant
formula has a similar effect if breastfeeding
is not possible.
Apart from the relief for the affected fami-
lies, the economic factor of this prevention is
also notable. The GINI study also noted the
savings when using a partially hydrolysed in-
fant formula. The result shows a saving for
German families of up to 14 million over the
of these studies, comprised 5,991 children,
a non-intervention arm followed up children
with and without a known family predisposi-
tion (n=3,991).
Breastfeeding was promoted, but if this was
not possible, the children at risk of allergy re-
ceived in a randomised double-blind trial one
of four identically packaged study formulas:
either one of the two ”normal“ tasting – a
conventional (=CMF) and a partially hydro-
lysed infant formula (=pHF-W whey-based)
or one of two bitter tasting extensively hy-
drolysed formulas (=eHF-W whey-based or
eHF-C casein-based).
15
first six years of life because the effect
continues even after the use phase.
This cost efficiency can be transferred to
other countries as well. The proven preven-
tive effect of a partially hydrolysed infant
formula should also be recommended in
economic terms.
Spieldenner J: The Health and Economic
Impacts of Early Prevention of Atopic
Dermatitis. The Nest 36 (2014) 6–7
At a glance
The most significant
recommendations:
No special diet during pregnancy
or when breastfeeding.
Exclusive breastfeeding for 4–6
months.
If breastfeeding is insufficient
or not possible, a hypoallergenic
infant formula with a proven
clinical preventive effect is
recommended.
It is not necessary to avoid intro-
ducing complementary feeding
after the 4thmonth and to then
hold back potentially allergic food
or to support their exposure.
The protective effect of the hydrolysed for-
mulas as opposed to the CMF was also evi-
dent in the 10-year follow-up, as well as in
the per-protocol-analysis and in the intention-
to-treat-analysis, even significantly so for
pHF-W and eHF-C.
Koletzko S: Prevention of Atopic Eczema
by Nutritional Intervention during Infancy.
The Nest 36 (2014) 2–3