Upload
andyk-strapilococus-aureus
View
252
Download
0
Embed Size (px)
Citation preview
7/26/2019 jurnal novi 5.pdf
1/20
D E V E L O P M E N T A L E P I D E M I O L O G Y
Period-specific growth, overweight and modificationby breastfeeding in the GINI and LISA birth cohorts
up to age 6 years
Peter Rzehak
Stefanie Sausenthaler
Sibylle Koletzko
Carl Peter Bauer
Beate Schaaf
Andrea von Berg
Dietrich Berdel
Michael Borte
Olf Herbarth
Ursula Kramer
Nora Fenske
H. -Erich Wichmann
Joachim Heinrich
Received: 22 September 2008 / Accepted: 25 May 2009/ Published online: 12 June 2009
Springer Science+Business Media B.V. 2009
Abstract Childrens weight/growth development is age-
specific and may be influenced by breastfeeding. Wetherefore assessed velocities of weight, length, body-mass-
index and overweight/obesity development from birth up to
age 6 years overall and in relation to breastfeeding. The
method of this study is based on pooled data of the birth-
cohorts GINI-plus and LISA-plus and follows 7,643 heal-
thy full-term neonates in four study-centers in Germany.
Up to nine anthropometric measurements are available.
Overweight/obesity is percentile-defined according to
WHO-Child-Growth-Standards. Fully-breastfed is definedas breastfed for at least 4 months. Piecewise-linear-ran-
dom-coefficient-models were applied to assess growth
trajectories and velocities between 03, 36, 612, 1224
and beyond 24th months. Velocities for weight-, length-
and BMI-development are highest in the first 3 months
after birth and diminish, with differing pace, in the periods
that follow. For overweight and obesity, peak-velocities are
estimated in periods 612 and 36 months. The difference
in the velocity of weight gain for breastfed vs. other chil-
dren is -18 g/month in the first 3 month, -93 g/monthThis study is conducted by the authors for the GINI LISA StudyGroup. The members of the GINI LISA Study Group are given in
Appendix.
P. Rzehak (&) S. Sausenthaler H. -ErichWichmann J. Heinrich
Institute of Epidemiology, Helmholtz Zentrum Munchen,
German Research Center for Environmental Health, Ingolsta dter
Landstrasse 1, 85764 Neuherberg, Germany
e-mail: [email protected]
P. Rzehak H. -ErichWichmannInstitute of Medical Data Management, Biometrics and
Epidemiology, Ludwig-Maximilians University of Munich,
Munich, Germany
S. Koletzko
Dr. von Hauner Childrens Hospital, Ludwig-Maximilians,University of Munich, Munich, Germany
C. P. Bauer
Department of Pediatrics, Technical University of Munich,
Munich, Germany
B. Schaaf
Medical Practice for Pediatrics, Bad Honnef, Germany
A. von Berg D. BerdelDepartment of Pediatrics, Marien-Hospital Wesel, Wesel,
Germany
M. Borte
Municipal Hospital St. Georg, Teaching Hospital of the
University of Leipzig, Childrens Hospital, Leipzig, Germany
M. Borte
Department of Pediatrics, University of Leipzig, Leipzig,
Germany
O. Herbarth
Department of Human Exposure Research and Epidemiology,
UFZ Leipzig-Halle, Leipzig, Germany
O. Herbarth
Faculty of Medicine, Department of Environmental Medicineand Hygiene, University of Leipzig, Leipzig, Germany
U. Kramer
Institut fur Umweltmedizinische Forschung, IUF, University of
Dusseldorf, Dusseldorf, Germany
N. Fenske
Department of Statistics, Ludwig-Maximilians University
Munich, Munich, Germany
1 3
Eur J Epidemiol (2009) 24:449467
DOI 10.1007/s10654-009-9356-5
7/26/2019 jurnal novi 5.pdf
2/20
between month 3 and 6, -14 g/month between month 6
and 12 and -3 g/month beyond the 24th month. Velocities
in length are not different between breastfed and non-
breastfed children. Over time, a slightly lower risk (dif-
ference \ 2%) of being overweight was estimated for
breastfed children, after adjustment for study-center, socio-
economic-status and maternal smoking in pregnancy.
Infants fully-breastfed gain less weight, but grow equally inlength in the first 12 months of life versus mixed or for-
mula-fed children. The protective effect of breastfeeding
on becoming overweight is related to its weight-velocity-
modifying-effect in early infancy.
Keywords Body mass index Breastfeeding GINI and LISA birth cohort studies Length Height Weight Overweight Obesity Period specificgrowth rates Kompetenznetz adipositas
Abbreviations
BMI Body mass index
GINI study German Infant Nutritional Intervention
study
LISA study Influences of Lifestyle related Factors on the
Immune System and the Development of
Allergies in Childhood study
SES Socio economic status
Introduction
Due to the epidemic prevalence of overweight and obesity
in many parts of the world, numerous studies on over-
weight development in children have been published [1].
However, longitudinal data from birth cohorts analyzing
the course of weight, length and overweight development
from birth up to school-age, with more than a few mea-
surements over time, are still scarce [1,2]. Moreover, most
studies report only population averaged estimates, but do
not report the individual variation in growth trajectories
and thus do not allow assessment of subject-specific het-
erogeneity in baseline values and variation in velocity of
growth development. Even more important, only few
papers report different rates of change (velocities of
growth) at several periods in infancy and further childhood
in due detail and with more than one measurement in early
infancy [26]. A protective effect of breastfeeding
regarding later overweight has been shown by several
studies [710]; but, this effect is not consistent [11].
Thus, the aim of this study is to assess growth in length
and weight from birth up to the age of 6 years in large
population-based birth cohorts of healthy full-term neo-
nates living in Germany. This study evaluates whether
velocities of growth in weight and length, body-mass-index
(BMI), overweight and obesity development vary in dif-
ferent life periods of early and later infancy and further
childhood. Moreover, individual variations and the poten-
tial modifying effect of breastfeeding on these velocities of
growth are investigated.
Methods
Study design and population
Data from two ongoing German birth cohorts of healthy
full-term neonates born between 1995 and 1999 in Munich,
Wesel, Bad Honnef and Leipzig were combined for lon-
gitudinal analyses of growth.
The GINI-plus (German Infant Nutritional Intervention)
study is an ongoing birth cohort, initiated to prospectively
investigate the influence of nutrition intervention duringinfancy plus air pollution and genetics on allergy devel-
opment. Between September 1995 and July 1998 a total of
5,991 healthy full-term newborns were recruited in
obstetric clinics in Munich and Wesel. The cohort is
composed of an intervention (n = 2,252) and a non-inter-
vention group (n = 3,739). Group assignment has been
based on family history of allergy. The intervention com-
prised nutritional advice promoting breastfeeding for at
least 4 months and a randomized trial on the effect of
hydrolyzed formula vs. conventional cow-milk formula in
preventing allergies. Details on study design are described
elsewhere [12,13].
The LISA-plus-study is an ongoing population-based
birth cohort study of unselected infants, designed to assess
Influences of Lifestyle related Factors on the Immune
System and the Development of Allergies in Childhood.
Between November 1997 and January 1999, n = 3,097
healthy full-term newborns were recruited from 14
obstetrical clinics in Munich, Leipzig, Wesel, and Bad
Honnef. Details on study design are published elsewhere
[14, 15]. At 6 years follow-up both birth cohort studies
share identical standard operating procedures and before
the 6 years follow-up there were very similar study pro-
tocols. Scheduled timing of follow-ups for questionnaires
were at 0, 6, 12, 24, 36, 48, 60 and 72 months in the GINI-
plus study and at 0, 6, 12, 18, 24, 48, and 72 months in the
LISA-plus study.
For both studies approval by the respective local Ethics
Committees (Bavarian General Medical Council, Univer-
sity of Leipzig, Medical Council of North-Rhine-West-
phalia) and written consent from participants families
were obtained.
450 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
3/20
Measurements
Weight, length, BMI, overweight and obesity
Anthropometric measurements of weight and length were
obtained by the records of the preventive medical check-
ups in the well-baby check-up books (U-Untersuchun-
gen). These are repeated physical examinations of thechild conducted by a pediatrician at birth, at day 310,
week 46, month 34, 67, 1012, 2124, 4348, and at
the 6064th month of life (designated time schedule) to
monitor physical growth and indications of adverse health
outcomes. Due to variation in age at each measurement of
weight and length, data are available for almost every
month in the first 2 years of life and in due detail for further
childhood up to the age of 6 years. BMI is defined as
weight in kilogram divided by squared length in meter.
Overweight and obesity is defined as the 90th and 97th
percentile of the standard deviation score of BMI, respec-
tively, (i.e. C1.28 and 1.88) as derived from the sex andage-specific WHO-Child-Growth-Standards for 05 year
(B1,856 days) old children and according to the Interna-
tional WHO Growth Standards for School-Aged Children
and Adolescents for children older than 1,856 days [16,
17]. Software-macros and documentation of these WHO-
reference-standards can be downloaded from the following
URLs: http://www.who.int/childgrowth/software/en/ and
http://www.who.int/growthref/tools/en/.
Breastfeeding
Breastfeeding was defined as fully breastfeeding for at least
4 months versus other postnatal feeding practices including
formula- or mixed-feeding.
Socio-economic status
Socio-economic status (SES) was operationalized as max-
imum completed years of schooling of either parent as
low (\10 years), medium (=10 years) and high SES
([10 years). We defined high SES as more than 10 years
of parental education, due to the different school-systems
between West- and East-Germany 20 years ago.
Statistical analysis
Piecewise-linear-random-coefficient models were applied
to assess subject-specific (individual) and population-
averaged (mean) growth trajectories and period-specific
velocities (rates of change per month) between 03, 36,
612, 1224 months and beyond the 24th month. Such
longitudinal models are described in detail in the books of
Singer et al. and Fitzmaurice et al. [18,19].
Briefly, such longitudinal models do not only account
for the correlated data structure due to repeated measure-
ments, but in addition allow estimation of a separate
average slope for every specified time period by simulta-
neously fitting regression lines to every specified time-
segment. These regression lines are connected at the end of
each period and thus allow the modeling of complicated
nonlinear growth trajectories by the sequence of simplelinear regression lines, which allows an interpretation of
period-specific change. By combining this model with a
multilevel approach, period specific growth curves can be
estimated for each individual and thus allow an assessment
for individual heterogeneity of growth in addition to the
average growth curve. This simplicity of linear approxi-
mation of complex non-linear growth curves and the pos-
sibility to assess individual heterogeneity in trajectories
influenced our choice of piecewise-linear random coeffi-
cient models over alternative ways of longitudinal data
modeling like Coles LMS-method or fractional polyno-
mials [20, 21]. The use of piecewise linear-random-coef-ficient-models were also motivated by the attractive
property of the chosen model, that the theory of critical
time periods for growth can be reflected by specifying such
time periods explicitly [22]. The choice of time-segments
is based on previous literature discussing different time
windows for rapid weight gain [2326]. Within this sta-
tistical approach, a longitudinal form of regression and
logistic regression were applied for the outcomes of
weight, length, BMI and overweight/obesity, respectively.
A detailed description of the statistical models and meth-
ods, their interpretation and the software used is given in
the Appendix.
Results
Characteristics of the study population are listed in
Table1. At birth, boys and girls differ in weight and length
but not substantially in average BMI, percentage of over-
weight or obesity, maternal smoking in pregnancy, gender
fraction within study center and SES. However, the per-
centage of breastfed infants is more than 2% higher in
female than male infants.
Development of weight, length, BMI, overweight
and obesity
Weight
Average birth weight for boys is estimated as 3,465 g and
as 3,262 g for girls (initial status at birth, Table 2, Model
A). Individual birth weights vary considerably as can be
seen graphically from Fig. 1, panel ab and numerically
Period-specific growth rates and breastfeeding 451
1 3
http://www.who.int/childgrowth/software/en/http://www.who.int/growthref/tools/en/http://www.who.int/growthref/tools/en/http://www.who.int/childgrowth/software/en/7/26/2019 jurnal novi 5.pdf
4/20
from the 95%-reference range (initial status at birth,Table3).
In the first 3 months of life an infant adds on average
941.6 g/month, that is a girl or a boy weighs 2,825
(3 9 941.6) g more at the end of the 3rd month than at
birth. In the period 36 months the weight gain velocity
diminishes to 548.9 g/month and to 316, 235 and 188 g/
month in the time periods 612, 1224 months and beyond
the 24th month up to the age of 6 years, respectively. Thus,
the fastest increase in weight gain per month occurs within
the first 3 month of life. The difference in velocities
between the first and the second period is 393 g/month,
between the second and the third period 233 g/month and
81 and 47 g/month between the third and the fourth and the
fourth and fifth period, respectively.
These different weight gain velocities, in absolute terms
of weight development for the average birth weight boy
and girl over time, can be best seen from the darker and
thicker line depicted in Fig. 1, panel ab representing the
average growth trajectory. The thinner, fainter colored
lines are the individual trajectories for each child. Note that
Fig.1, panel ab shows visually that weight gain velocities
in the different periods differ considerably from the aver-age slopes, within each time period, and that the cumula-
tive effect of these individual deviations result in a larger
spread of these individual weight trajectories during
infancy and childhood. The individual rates of weight gain
vary at maximum in the first 3 months of life (571
1,312 g) and range between 414 and 683 g/month for the
period 36 months (see 95%-reference ranges in Table 3).
The velocity in weight gain between months 6 and 12 does
not vary individually and is thus estimated in Table 2 as
316 g/month for all infants (therefore no range is listed
in Table3). The respective 95% ranges for periods
1224 months and beyond the 24th month are 121350 g/
month and 99277 g/month, respectively.
From the correlations in the lower panel of Table 3, high
birth weight (initial status) is only small to moderately
correlated with the individual velocities of weight gain in
the periods 03 months (0.08), 36 months (-0.12) and
612 months (0.25). However, infants who experience a
steeper increase in the first 3 months of life have a much
lower velocity of weight gain between months 3 and 6 and
1224 (-0.93; -0.44), and vice versa. Beyond the 24th
Table 1 Characteristics of study population
Boys Girls Effect sizea
boys vs. girls
Total
n = 3,930 n = 3,713 n = 7,643
Mean or % SD or
CI-95%
Mean or % SD or
CI-95%
Hedges g
or OR
Mean
or %
SD or
CI-95%
Birth weight (g) 3,540.8 464.7 3,401.5 437.6 0.3 3,473.1 457.0
Birth length (cm) 52.3 2.5 51.5 2.4 0.3 51.9 2.5
BMI at birth 12.9 1.2 12.8 1.2 0.1 12.9 1.2
% Overweightb at birth 4 .0 (157/3,930) 3.44.6 4.4 (165/3,713) 3.85.1 0.9 4.2 (322/7,643) 3.84.7
% Obesec
at birth 0.9 (35/3,930) 0.61.2 1.3 (49/3,713) 1.01.7 0.7 1.1 (84/7,643) 0.91.3
% Infants breast-fed
C4 month
51.8 (1,963/3,790) 50.253.4 54.0 (1,921/3,560) 52.355.6 0.9 52.8 (3,884/7,350) 51.754.0
% Maternal smoking
in pregnancy
16.2 (635/3,920) 15.017.4 16.5 (612/3,702) 15.317.7 1.0 16.4 (1,247/7,622) 15.517.2
% Infants from study center
Munich 48.5 (1,905/3,930) 46.950.0 46.9 (1,740/3,713) 45.348.5 1.1 47.7 (3,645/7,643) 46.648.8
Leipzig 11.7 (460/3,930) 10.712.7 12.7 (473/3,713) 11.713.8 0.9 12.2 (933/7,643) 11.512.9
Bad Honnef 3.8 (148/3,930) 3.24.4 4.2 (157/3,713) 3.64.9 0.9 4.0 (305/7,643) 3.64.4
Wesel 36.1 (1,417/3,930) 3 4.637.6 3 6.2 (1,343/3,713) 3 4.637.7 1 .0 36.1 (2,760/7,643) 3 5.037.2
% Parental education
[10th grade 61.4 (2,398/3,907) 59.862.9 61.6 (2,276/3,692) 60.163.2 1.0 61.5 (4,674/7,599) 60.462.6
=10th grade 29.6 (1,158/3,907) 28.231.1 29.9 (1,105/3,692) 28.531.4 1.0 29.8 (2,263/7,599) 28.830.8
\10th grade 9.0 (351/3,907) 8.19.9 8.4 (311/3,692) 7.59.3 1.1 8.7 (662/7,599) 8.19.3
aFor weight, length and BMI at birth Hedges g is calculated, which is the standardized mean difference between boys and girls. For all other
variables effects size is calculated as odds ratio (OR). An overview on these effect sizes and the respective formulas are given by Durlak et al.
[38]b
Defined as C90th percentile of BMI at birth according to age and sex-specific WHO-child-growth standards [16]c Defined as C97th percentile of BMI at birth according to age and sex-specific WHO-child-growth standards [16]
452 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
5/20
Table2
Ratesofchangepermonthforthedevelopmentofweight,lengthandbody-mass-indexfrombirthuptoage6
years
Fixedeffects
Weight(g)
Length(cm)
BMI(kg/m
2)
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
Mode
lCc
ModelAa
ModelBb
ModelCc
All
Breastfed
Other
Breastfed
Other
All
Breastfed
Other
Breas
tfed
Other
All
Breastfed
Other
Breastfed
Other
Initialstatusatbirth
Girls
3,262.0
3,288.6
3,224.0
3,378.4
3,308.0
51.0
51.1
50.9
51.8
51.6
12.52
12.53
12
.44
12.58
12.45
Boys
3,465.1
3,494.4
3,429.8
3,585.8
3,515.4
52.4
52.5
52.3
53.1
52.9
12.83
12.86
12
.77
12.91
12.78
Rateofchangepermonthinperiod
0to\3months
941.6
933.7
951.5
933.5
951.7
3.3
3.3
3.3
3.3
3.3
1.25
1.25
1
.28
1.24
1.27
3to\6months
548.9
504.9
598.3
505.4
598.4
2.2
2.1
2.4
2.1
2.4
0.11
0.08
0
.12
0.09
0.13
6to\12months
316.0
309.5
323.5
309.4
323.5
1.3
1.3
1.3
1.3
1.3
0.01
-0.01
0
.03
-0.01
0.03
12to\24months
235.4
241.6
228.1
241.6
228.1
1.0
1.0
1.0
1.0
1.0
-0.06
-0.05
-0
.07
-0.05
-0.07
24to\72months
188.0
186.6
189.4
186.5
189.5
0.7
0.7
0.7
0.7
0.7
-0.02
-0.02
-0
.02
-0.02
-0.02
a
ModelAistherespectivelongitudinalpiecewiselinearrandomeffectsreg
ressionmodeldescribedindetailintheAppendix;allowingforanestimateofthebaselinevalueandfive
differentchangeratesovertimeand
foramaineffectofsex.Foroutcomesweight,lengthandBMIitisbasedonalongitudinalversionofmultipleregressionandforoutcomesoverweightand
obesityonitslogisticregressionequivalent.Thetableshowsthepopulationaveragedorfixedeffectsestimates.Whichchangeratesvaryindividually(randomslopes
)inadditiontotheinitial
status(randomintercept)isspecifiedinTable3
b
ModelBisbasedontherespectivemodelA,however,supplementedbyth
emaineffectofbreastfeedinganditsinteractionswiththeperiodspecificchangerateslopes
c
ModelCisbasedontherespectiveModelBadjustedformaternalsmokinginpregnancy,studycenterandsocio-economicstatus
Period-specific growth rates and breastfeeding 453
1 3
7/26/2019 jurnal novi 5.pdf
6/20
month, the rate of weight gain is positively correlated
with the rate in the first 3 months of life (0.25). Note
further, the correlations between the change rates in
periods 36, 1224 (0.22) and beyond the 24th month
(-0.32) and between the change rates of periods 1224
and beyond the 24th month (-0.46), indicating a indi-
vidual complex form of tracking weight velocities during
infancy and childhood.
Length
Birth length is estimated as 52.4 and 51.0 cm for boys and
girls, respectively (Table2, Model A). Birth length varies
considerably (Fig.1, panel cd; 95%-reference-ranges in
Table3).
Average growth rates are highest in the first 3 months of
life (3.3 cm/month) and decline substantially in the fol-
lowing periods. Individual velocities in length development
vary substantially in the first half year (Table 3). Infants
with high length at birth show lower growth rates in the
first 3 months of life (-0.52), but higher growth rates in
period 36 months (0.53), and vice versa. Moreover, an
almost perfect negative correlation (-0.996) is estimated
between the growth rates in period 03 and 36 months.
BMI
BMI at birth is estimated as 12.8 and 12.5 kg/m2 for boys
and girls, respectively (Table2, Model A). At each of the
first 3 months of life BMI increases on average by 1.25 kg/
m2. For the following two periods the velocity is reduced
substantially and in the periods beyond the 12th and the
24th month the rate is even slightly negative (Fig. 1, panel
ef). From the spread at birth and the parallel trajectories in
the graph it can be seen that infants relative weight varies
only in the initial value of BMI at birth (95% reference-
range 11.114.5 and 10.814.2 kg/m2 for boys and girls,
respectively), but not in their individual slopes.
Overweight and obesity
The percent of overweight and obese infants at birth are
estimated as 3.7 and 1.0% for boys and as 3 and 0.7% for
girls, respectively (Table4, Models A). Note, these and the
following percentages (probabilities) are derived from the
logit coefficients given in Table7 as described in the sta-
tistical section of the Appendix.
The velocity per month for overweight accelerates for
each period up to the 12th month, from 0.36% through
0.570.73% per month. Between months 12 and 24 the rate
slows down somewhat (0.35%). However, beyond month
24 the monthly rate becomes negative (-0.16%) resulting
in a reduction from the peak of 14.3% overweight girls at
month 24 to an estimated percentage of 6.6% at the age of
6 years. The respective percentages for boys are 17.5 and
8.1%.
The velocity for obesity is very small in the first
3 months (0.06% per month). However, during the period
of 36 months, a monthly increase of 0.25% is estimated,
followed by a positive rate of 0.18 and 0.14% in the periods
between month 6 and 12 and 1224, respectively. From the
24th month, the percentage of obese children declines by
-0.04% per month form the peak of 3.7% for girls and
5.2% for boys to 1.6 and 2.3%, respectively.
The development of overweight and obesity over time
are best seen by Fig.2, panel ad depicting the estimated
percentage of being overweight or obese in different
periods after birth for boys and girls. Only population
averaged trajectories are shown as these measures are
dichotomies.
Fig. 1 Subject-specific and population averaged development of
weight, length and BMI by sex from birth up to the age of 6 years
454 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
7/20
Table3
Variationofsubject-specificratesofchangeforthedevelopmentof
weightandlengthfrombirthuptoage6years
Randomeffects
Weight(g)
Length(cm)
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
ModelCc
All
Breastfed
Oth
er
Breastfed
Other
All
Breastfed
Other
Breastfed
Other
95%Referencerangesofinitialstatusandchangeratesd
Initialstatusatbirth
Girls
2,543;3,981
2,553;4,024
2,489;3,959
2,652;4,104
2,582;4,034
46.7;55.3
46.9;55.4
46.7;55.2
47.5;56.0
47.3;55.8
Boys
2,746;4,184
2,759;4,230
2,695;4,165
2,860;4,312
2,789;4,241
48.0;56.6
48.2;56.7
48.0;56.5
48.8;57.3
48.6;57.1
Rateofchangepermonthinpe
riod
0to\3months
571;1,312
567;1,300
585
;1,318
564;1,303
583;1,321
2.0;4.7
2.0;4.7
2.0;4.7
1.8;4.9
1.8;4.9
3to\6months
414;683
375;635
468
;728
375;636
454;743
2.1;2.3
1.9;2.2
2.2;2.5
1.9;2.2
2.2;2.5
6to\12months
12to\24months
121;350
128;355
114
;342
128;355
98;358
24to\72months
99;277
98;275
101
;278
98;275
81;298
Correlationsbetweenchangerates
Initialstatusbycommonrate
0.08
0.08
0.08
0.08
0.08
-0.52
-0.51
-0.51
-0.55
-0.55
Initialstatusbypast3months
-0.12
-0.12
-0.12
-0.12
-0.12
0.53
0.52
0.52
0.55
0.55
Initialstatusbypast6months
Initialstatusbypast12months
0.25
0.24
0.24
0.24
0.24
Initialstatusbypast24months
Commonratebypast3months
-0.93
-0.94
-0.94
-0.94
-0.94
-1.00
-1.00
-1.00
-1.00
-1.00
Commonratebypast6months
Commonratebypast12month
s
-0.44
-0.43
-0.43
-0.42
-0.42
Commonratebypast24month
s
0.25
0.24
0.24
0.24
0.24
Changeratepast3by6months
Changeratepast3by12months
0.22
0.22
0.22
0.22
0.22
Changeratepast3by24months
-0.32
-0.32
-0.32
-0.32
-0.32
Changeratepast6by12months
Changeratepast6by24months
Changeratepast12by24mon
ths
-0.46
-0.44
-0.44
-0.44
-0.44
a,b,c
SeerespectivefootnotesTable2
d
95%ofthesubject-specificestim
atesarelocatedinthisrange(seeAppen
dix)
Period-specific growth rates and breastfeeding 455
1 3
7/26/2019 jurnal novi 5.pdf
8/20
Table 4 Rates of change per month for the development of overweight and obesity from birth up to age 6 years
Fixed effects Overweight (%) Obesity (%)
Model Aa Model Bb Model Cc Model Aa Model Bb Model Cc
All Breastfed Other Breastfed Other All Breastfed Other Breastfed Other
Initial status at birth
Girls 2.99 3.07 2.71 3.58 2.90 0.70 0.68 0.67 1.02 0.86Boys 3.74 3.85 3.40 4.56 3.70 1.01 0.99 0.97 1.53 1.29
Rate of change per month in period
0 to\3 months 0.36 0.34 0.47 0.39 0.50 0.06 0.05 0.09 0.08 0.13
3 to\6 months 0.57 0.42 0.67 0.53 0.76 0.25 0.19 0.31 0.28 0.40
6 to\12 months 0.73 0.49 1.00 0.66 1.20 0.18 0.09 0.29 0.14 0.39
12 to\24 months 0.35 0.41 0.26 0.61 0.42 0.14 0.17 0.11 0.24 0.13
24 to\72 months -0.16 -0.16 -0.16 -0.14 -0.11 -0.04 -0.05 -0.04 -0.07 -0.05
aModel A is based on the respective longitudinal piecewise linear random intercept logistic regression model described in detail in the
Appendix; allowing for an estimate of the baseline value and five different change rates over time and for a main effect of sexb Model B is based on the respective model A, however, supplemented by the main effect of breastfeeding and its interactions with the period
specific change rate slopesc
Model C is based on the respective Model B adjusted for maternal smoking in pregnancy, study center and socio-economic statusNote the percentages listed in Table 4 are derived from the logit coefficients given in Table 7 as described in the statistics section of the
Appendix
Fig. 2 Population averaged
development of overweight and
obesity by sex from birth up to
the age 6 years
456 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
9/20
Modification of velocities of weight, length, BMI,
overweight and obesity development by breastfeeding
Weight
Velocity of monthly weight gain for fully-breastfed infants
is lower for all periods except for the second year of life
when compared to mixed or formula-fed children (Table2,Model B). The largest difference in velocities between
these two groups is estimated for the period 36 months
(-93 g/month) and the smallest for the period beyond 24th
months (-2.8 g/month). Adjustments do not change these
results substantially (Table 2, Model C).
Length
Breastfeeding does not change velocities of growth in
length for analyzed periods, with the exception of month
36 (-0.3 cm/month), even after adjustment (Table2,
Model B and C).
BMI
For each period, fully-breastfed children have a lower
velocity of monthly BMI change than mixed or formula-
fed children (Table2, Model B). Although these differ-
ences in velocities are rather small it is interesting to note
that the rate of change in BMI becomes negative (i.e. BMI
reduces in absolute terms) in the second half year of life for
breastfed children, whereas for the other children the rate
of change in BMI becomes negative in the second year of
life (see Fig.3, panel ab). Comparison of velocities
between Model B and C reveal that adjustments result in
only minor changes.
Overweight and obesity
Monthly change rates in the percentage of overweight and
obese children are positive for each period up to the 24th
month, and negative thereafter for both breastfed and
otherwise fed children (Table4, Model B). Note, these
percentages (probabilities) are derived from the logit
coefficients given in Table7as described in the statistical
section of the Appendix. However, in the first three
periods up to the 12th month the velocities are lower for
breastfed children by -0.13% (0.340.47%), -0.25% and
-0.51% and -0.4%, -0.12% and -0.20% regarding
overweight and obesity, respectively. That means, the
difference in rates is doubling from period to period within
the first 12 month of life. Between months 12 and 24 fully-
breastfed children have a higher velocity for becoming
overweight or obese versus otherwise fed children. How-
ever, as velocity is negative for the period after the 24th
month, for both groups, a constantly lower percentage of
overweight and obese children is estimated for the breast-
fed group. Adjusted analyses do not result in substantial
differences (Table4, Model C; Fig. 3 panel cf).
Discussion
Overall velocities for weight, length and BMI development
were highest in the first 3 months after birth and decreased
substantially thereafter. However, the monthly change rates
regarding overweight and obesity development are positive
up to the 24th month and are highest between periods 612
and 36 months for overweight and obesity, respectively.
Our results support some previous studies, which have
emphasized that very early infancy weight gain is a critical
period for later weight gain and overweight [2, 3, 24, 27]
and may somewhat question the often recommended period
Fig. 3 Population averaged development of body-mass-index, over-
weight and obesity by breastfeeding and sex adjusted for maternal
smoking in pregnancy, study center, parental education (SES) from
birth up to the age of 6 years. Note the respective darker line
represents the trajectory for breastfed, the fainter line that for the
mixed or formula-fed children
Period-specific growth rates and breastfeeding 457
1 3
7/26/2019 jurnal novi 5.pdf
10/20
of 24 months to define rapid weight gain [23,26]. On the
other hand, the strong negative correlations of individual
rates of change in weight between the velocities at months
13 and 36 (listed in Table3) indicate that high monthly
rates of weight gain in the first 3 month are somewhat
compensated by lower weight gain rates in the following
period.
It was shown that velocity of weight gain, overweightand obesity were reduced in fully-breastfed infants, but not
length. Although differences were only 12% for over-
weight or obese children, these contrasts remain for the
whole study period even after adjustments for maternal
smoking in pregnancy, study center and SES.
Thus, the presented results support previous studies,
which have shown that there is a protective effect of
breastfeeding against later overweight [710] in contrast to
a study, which did not find a difference in fat mass at age of
5 years [11]. These results are also in line with the stated
protein-intake-hypothesis expecting excessive weight
gain in the first months of life due to a higher proteinintake, which may be due to the higher protein content of
formula-milk [28,29]. Moreover, as the reducing effect of
breastfeeding is stronger regarding overweight and obesity
than for BMI, it gives further plausibility for a protective
effect, because it has been already shown that breastfeeding
does not shift the whole BMI-distribution but only the
upper tail [30].
On the other hand, the small overall contrasts of
breastfeeding for BMI, overweight and obesity develop-
ment may raise a question regarding whether the definitions
of breastfeeding and overweight, and adjustments were
sufficient to avoid residual confounding. Moreover, to our
knowledge, no study has examined the reliability and
validity of the German medical checkups (U-Untersuch-
ungen). However, recent publications on this issue
regarding anthropometric measurements within children in
other countries show that measurement deviations within
and between health personnel show acceptable reliability
[31, 32]. Furthermore, as all infants were recruited from
clinical settings, questions regarding sample selection bias
may arise. However, we think it unlikely that the study
results are compromised as home births in Germany were
much less common in the 1990s (and further on) than in
other countries. According to a report from the German
Society of Out of Hospital Midwifery, which used data from
the German Statistical Office, only 2% of all births in
Germany occurred out of hospital (http://www.quag.de/
content/geburtenzahl.htm).
The breastfeeding effect was robust to sensitivity anal-
yses, in which all models were adjusted for parity and for
its period specific interactions with age. However, no
substantial changes were found in respect to the age
specific effects of breastfeeding on any outcome (data not
shown).
The development of underweight over time would cer-
tainly be of additional interest for the present study and
could in principle be performed by using the 10th and 3rd
percentiles of the new WHO-Growth charts for BMI as cut-
points. However, as the study population consists of heal-
thy full-term neonates with an inclusion criteria ofC2,500 g at birth, we failed to include lower birth weight
newborns by design. Consequently, the lower tail of the
relative weight distribution has a restricted generalizability,
which undermines such an endeavor.
In addition, it would be worthwhile to investigate
whether prenatal development, maternal overweight or
lifestyle and genetic disposition are more important for
birth weight and postnatal development [22, 33, 34].
However, a full life-course epidemiological approach is
beyond the scope of this paper [35]. Nevertheless, one
might speculate that our results of an early developing gap
regarding overweight and obesity between breastfed andformula fed children, which does not vanish up to age
6 years, are in line with the Early origins of adult dis-
ease hypothesis and emphasizes the role of nutrition and
potential metabolic programming. Whether this weight
difference tracks into adolescence and adulthood may be
investigated in the next years as GINI and LISA are
ongoing birth cohort studies.
This study has several strengths. The large number of
anthropometric measurements, in particular in the first
2 years of life and the statistical model allowing for several
period-specific growth rates, subject specific growth trajec-
tories and correlations between period specific velocities,
enabling a moreappropriate analysis than those conducted in
most studies. Moreover, the impact of breastfeeding on
period-specific growth velocities has, to our knowledge,
been investigated unspecifically as an overall contrast or
interaction effect with age, but not regarding specific time
windows [7, 8, 10]. Thus, the reported analyses add to a
better understanding of the early developmental process and
the influence of breastfeeding in particular.
Conclusions
Early infancy may be critical for later weight and over-
weight development and longitudinal analyses should
therefore allow for several period-specific slopes to capture
a better approximation of the true trajectories of growth.
Infants fully-breastfed for at least 4 months gain less
weight, but grow equally in length in the first 12 months of
life than mixed or formula-fed children. The protective
effect of breastfeeding regarding weight and overweight
458 P. Rzehak et al.
1 3
http://www.quag.de/content/geburtenzahl.htmhttp://www.quag.de/content/geburtenzahl.htmhttp://www.quag.de/content/geburtenzahl.htmhttp://www.quag.de/content/geburtenzahl.htm7/26/2019 jurnal novi 5.pdf
11/20
development is therefore related to its modifying effect
regarding weight-gain in early infancy. However, prenatal
factors like fetal development have to be incorporated in a
more elaborated model of life course epidemiology to
further strengthen these results. Nevertheless, as the pro-
tective effect of breastfeeding regarding overweight and
obesity lasts at least up to the age of 6 years, breastfeeding
is clearly recommended, whenever possible.
Acknowledgments We thank the families for participation in the
studies; the obstetric units for allowing recruitment, the GINI and
LISA study teams for excellent work and several funding agencies
listed below. Personal and financial support by the Munich Center of
Health Sciences which contributed to this research is gratefully
acknowledged. This work was also supported by the Kompetenznetz
Adipositas (Competence Network for Adipositas) funded by the
Federal Ministry of Education and Research (FKZ: 01GI0826). In
addition, we gratefully acknowledge the editorial work of Elaina
MacIntyre. The GINI Intervention study was funded for 3 years by
grants of the Federal Ministry for Education, Science, Research and
Technology (Grant No. 01 EE 9401-4), the 6 years follow-up of the
GINI-plus study was partly funded by the Federal Ministry of Envi-
ronment (IUF, FKZ 20462296). The LISA-plus study was funded by
grants of the Federal Ministry for Education, Science, Research and
Technology (Grant No. 01 E.G 9705/2 and 01EG9732) and the
6 years follow-up of the LISA-plus study was partly funded by the
Federal Ministry of Environment (IUF, FKS 20462296). Personal and
financial support by the Munich Center of Health Sciences which
contributed to this research is gratefully acknowledged. This work
was also supported by the Kompetenznetz Adipositas (Competence
Network for Adipositas) funded by the Federal Ministry of Educa-
tion and Research (FKZ: 01GI0826).
Appendix
Detailed information on statistical analysis
Piecewise linear random coefficient models were applied to
assess growth trajectories and velocities between 03, 36,
612, 1224 months and beyond the 24th month. These
models allow the longitudinal data structure to be
accounted for by including subject specific random effects
and a nonlinear age effect can be modeled by the piecewise
linear functions (polynomial splines). Such longitudinal
models are described in detail in the books of Singer et al.and Fitzmaurice et al. [18,19]. We used four knots at 3, 6,
12 and 24 months to connect the slopes of the five time
segments. The choice of the knots was based on the liter-
ature, in which different time windows for rapid weight
gain are discussed [2326]. To account for the known sex
specific difference in birth weight and length we included a
main effect for sex in each model.
Formally, the basic piecewise linear random coefficient
model at hand (Model A) can be expressed as follows:
Yij; b0i b1iAgeij b2iAgeij 3 b3iAgeij 6
b4iAgeij 12 b5iAgeij 24 b6boyi
eij gijA eij 1
whereYij is the respective continuous outcome (i.e. length,
weight or BMI) for child i at measurement j and Ageij is
age since birth, coded in months, for each child i at mea-
surement j (calculated from the exact age in days). The
term (Ageij - c)?with knots c [ {3, 6, 12, 24} is equal to
(Ageij - c) if Ageij[ c and equal to 0 if Ageij\ c. The
effects bki for k= 0,,5 consist each of a population
averaged fixed effect bk and a subject specific random
effectuki, as given by:b0i b0 u0i;b1i b1 u1i;b2i
b2 u2i;b3i b3 u3i;b4i b4 u4i and b5i b5 u5i.Hence, a subject specific interceptu0ias well as five subject
specific slopes u1i,, u5i are estimated. The subject spe-
cific random effects vectors ui = (u0i,,u5i)T are assumed
to be mutually independent for all i and normally distrib-
uted with zero mean and a covariance matrix R
,i.e. ui * N(0, R). The diagonal ofR contains the coeffi-
cient specific variancesrk2 for k= 0,,5. The error terms
eijare also assumed to be normally distributed and identical
and mutually independent for all i, j, i.e. e ij * N(0, re2)
i.i.d. In addition, they are considered as independent from
the random effects. The short notationgijAin [1] stands for
the predictor of Model A and is introduced by reason of
comparability between the different models.
As for interpretation for the regression coefficients, 1can be regarded as the population baseline velocity of
change for the respective outcome and hence, u1i is the
subject specific deviation from this population baseline. Theterm (Ageij - 3)? represents the time since the age of
3 months until measurement j of child i, consequently 2represents the population based deviation from the slope 1in the following time period andu2istands for the associated
individual deviation. For all other knots the coding and
interpretation is analog. Thus, each child can have his own
baseline value at birth and a child specific slope or linear
trajectory in each time period, which yields to a subject
specific non-linear growth pattern by the cumulative com-
bination of the several linear growth estimates. The growth
rate GR at the age period k [ {03, 36, 612, 1224, 24
72} months is thus the cumulative period specific sum of theestimated regression coefficients, for the first three periods
it can be expressed as follows: GR(0 3 3 b1;GR(0 6 6 b1 3 b2; GR(6 12 12 b1 9
b2 6 b3:To ease interpretation and to spare the reader the trouble
of calculation we do not report the single slope coefficients
in the result section but we do report the calculated abso-
lute growth rates (velocities) of the outcome per month in
the respective time period (Tables2, 4). The subject
Period-specific growth rates and breastfeeding 459
1 3
7/26/2019 jurnal novi 5.pdf
12/20
specific variation of the intercept terms (initial status at
birth) and of the period specific growth rates (rate of
change per month in period) are expressed as 95%-refer-
ence rangesand listed in Table 3. A reference range is the
range in which 95% of the estimated subject-specific
intercepts or slopes (here for the calculated growth rates)
are located, formally: bk 1.96 9 estimated standard
deviation of the subject specific estimates uik(square rootof the estimated random effect variance r2k). Note that if the
growth rate is a combination of several slopes (e.g. for
period 36 months, which is calculated as the sum of the
slopes in period 03 and 36), then the standard deviation
is calculated as the square root of the sum of the respective
variances of the slopes and the sum of two times the
respective covariances of these random effects.
To what extent individual initial status of the outcome at
birth and individual change rates co-vary between the
different time windows is expressed as correlations
(derived from the estimated random effects covariance
matrix R) and is listed in the lower part of Table 3. Wereport these subject specific variations of growth rates only
for weight and length because for the models regarding
BMI, overweight and obesity development no reliable
random variation in growth rates (beyond the intercept
term) could be estimated.
For the dichotomous outcomes of overweight and
obesity generalized random coefficient models with logit-
link function were applied. Therefore the outcome Yij was
assumed to follow a binomial distribution with probability
pij, i.e. Yij * B (1, pij). Hence, the model (Model A) can
be expressed as follows:
pij EYij=gijA 1
1 expgijA 2
where Yij is a dichotomous outcome (i.e. overweight or
obesity) and gijA is the predictor as in [1]. Since they are
easier to interpret, we report probabilities in Table4of the
result section (instead of using logarithmic odds).
In Tables2 and 3 of the result section there are three
models for each outcome presented. The respective Model
A has already been introduced in [1] and [2], depending on
the outcome. It gives estimates for the baseline value
(initial status) of the outcome and the time period specific
velocities (absolute change of the outcome per month in the
respective period) for the five time segments with sex as
the only covariate. Model B aims at investigating the
influence of breast feeding on the rates of change for the
five time periods by including a main effect for breast-
feeding (BF) as well as interaction effects with the piece-
wise linear terms. Formally, Model B can be obtained by
replacing the predictor gijA of Model A in Eqs.1and 2 by
gijB, as given by:
gijB gijA b7iAgeij BFi b8iAgeij 3 BFi
b9iAgeij 6 BFi b10iAgeij 12
BFi b11iAgeij 24 BFi b12BFi: 3
In the result section we do not show the single
interaction estimates but report the absolute growth rates
for the breastfed and for the other children in two differentcolumns. These interaction effects allow an evaluation as
to whether breastfeeding influences the velocities of
growth in the different time windows.
Model Caccounts for the potential confounding effects
of maternal smoking in pregnancy (Smoke), study center
(Center) and socio-economic status (SES) in addition to the
breastfeeding Model B by adjusting for the respective
number of dummy coded categorical variables. Hence, the
predictor for Model C can be expressed as follows:
gijC gijB Smokei SESi Centeri: 4
Descriptive analyses were conducted by the statisticalsoftware SAS, version 9.1.3 [36]. All longitudinal analyses
were performed with the special purpose software for
multilevel modeling MLwiN, version 2.02 [37]. (Tables5,
6,7and8).
GINI-plus study group
Institute of Epidemiology, Helmholtz Zentrum Muenchen-
German Research Center for Environmental Health, Neu-
herberg (Wichmann HE, Heinrich J, Schoetzau A, Popescu
M, Mosetter M, Schindler J, Franke K, Laubereau B,Sausenthaler S, Thaqi A, Zirngibl A, Zutavern A, Filipiak
B, Gehring U); Department of Pediatrics, Marien-Hospital,
Wesel (Berdel D, von Berg A, Albrecht B, Baumgart A,
Bollrath C, Buttner S, Diekamp S, Gro I, Jakob T, Klemke
K, Kurpiun S, Mollemann M, Neususs J, Varhelyi A, Zorn
C); Ludwig Maximilians University of Munich, Dr. von
Hauner Childrens Hospital (Koletzko S, Reinhard D,
Weigand H, Antonie I, Baumler-Merl B, Tasch C, Gohlert
R, Sonnichsen C); Clinic and Polyclinic for Child and
Adolescent Medicine, University Hospital rechts der Isar of
the Technical University Munich (Bauer CP, Grubl A,
Bartels P, Brockow I, Hoffmann U, Lotzbeyer F, Mayrl R,Negele K, Schill E-M, Wolf B); IUF-Environmental Health
Research Institute, Dusseldorf (Kramer U, Link E, Sugiri
D, Ranft U).
LISA-plus study group
Institute of Epidemiology, Helmholtz Zentrum Muenchen-
German Research Center for Environmental Health,
460 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
13/20
Table5
Detailedlistingofregress
ioncoefficients(fixedeffects)fromwhich
changeratesofTable2werederived
Fixedeffects
Weight(g)
Length(cm)
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
ModelCc
SE
z-value
SE
z-value
SE
z-value
SE
z-value
SE
z-value
SE
z-value
Initialstatusatbirth
Intercept
3,262.0
7.3
446.60
3,224.0
9.3
344.92
3,308.0
19.7
168.09
51.04
0.04
1,412.68
50.93
0.04
1,139.37
51.55
0.09
580.13
Genderofinfant
Boyvs.Girl
203.1
10.0
20.39
205.8
10.1
20.38
207.4
10.1
20.64
1.32
0.05
28.97
1.33
0.05
29.04
1.30
0.04
29.11
Ageinmonths
Age
941.6
3.1
307.81
951.5
4.4
214.30
951.7
4.5
212.91
3.35
0.01
291.98
3.35
0.01
296.11
3.34
0.01
276.74
Age3?
-392.7
4.8
-81.91
-353.2
7.0
-50.56
-353.3
7.0
-50.33
-1.15
0.02
-62.95
-0.99
0.02
-48.57
-0.98
0.02
-47.17
Age6?
-232.9
3.5
-67.04
-274.8
5.1
-54.16
-274.9
5.1
-54.01
-0.90
0.01
-68.83
-1.06
0.02
-57.95
-1.06
0.02
-58.03
Age12?
-80.6
1.9
-42.79
-95.4
2.7
-35.00
-95.4
2.7
-34.88
-0.27
0.01
-43.48
-0.29
0.01
-31.85
-0.29
0.01
-31.71
Age24?
-47.4
1.1
-44.95
-38.6
1.6
-24.88
-38.6
1.6
-24.77
-0.37
0.00
-140.64
-0.36
0.00
-93.92
-0.36
0.00
-94.14
Breastfeeding
d
C4vs\4months
64.6
10.6
6.12
70.4
11.0
6.39
0.21
0.05
4.43
0.24
0.05
4.89
Breastfeeding9
Age
BF9
Age
-17.9
6.1
-2.92
-18.2
6.1
-2.96
BF9
Age3?
-75.6
9.6
-7.87
-74.8
9.6
-7.76
-0.31
0.02
-18.13
-0.31
0.02
-17.93
BF9
Age6?
79.4
7.0
11.40
78.9
7.0
11.30
0.29
0.02
12.30
0.30
0.02
12.30
BF9
Age12?
27.6
3.7
7.40
27.6
3.7
7.39
0.03
0.01
2.66
0.03
0.01
2.49
BF9
Age24?
-16.4
2.1
-7.77
-16.5
2.1
-7.81
-0.01
0.01
-2.56
-0.01
0.01
-2.43
Maternalsmokinginpregnancy
Yesvs.No
-59.5
14.2
-4.20
-0.33
0.06
-5.26
Studycenter
Munich
-124.7
11.5
-10.82
-0.62
0.05
-12.15
Leipzig
-37.2
17.4
-2.13
-1.46
0.08
-18.83
BadHonnef
2.1
26.7
0.08
-0.13
0.12
-1.10
Wesel(ref)
Parentaleducation
[
10thgrade
-7.9
19.4
-0.41
-0.06
0.09
-0.72
=10thgrade
-32.2
20.0
-1.61
-0.20
0.09
-2.20
\10thgrade(ref)
Period-specific growth rates and breastfeeding 461
1 3
7/26/2019 jurnal novi 5.pdf
14/20
Table5
continued
Fixedeffects
BMI(kg/m
2)
ModelAa
ModelBb
ModelCc
SE
z-value
SE
z-value
SE
z-value
Initialstatusatbirth
Intercept
12.52
0.02
719.13
12.44
0.02
561.37
12.45
0.04
283
.99
Genderofinfant
Boyvs.Girl
0.31
0.02
14.34
0.33
0.02
14.66
0.33
0.02
15
.10
Ageinmonths
Age
1.25
0.01
198.50
1.28
0.01
197.23
1.27
0.01
196
.66
Age3?
-1.14
0.01
-88.97
-1.17
0.01
-90.38
-1.15
0.01
-89
.38
Age6?
-0.10
0.01
-10.01
-0.09
0.01
-8.33
-0.10
0.01
-9
.75
Age12?
-0.07
0.00
-13.64
-0.10
0.01
-17.97
-0.10
0.01
-17
.41
Age24?
0.04
0.00
18.90
0.05
0.00
18.32
0.05
0.00
18
.18
Breastfeeding
d
C4vs\4months
0.09
0.02
3.71
0.13
0.03
5
.05
Breastfeeding9
Age
BF9
Age
-0.03
0.00
-13.11
-0.03
0.00
-12
.92
BF9
Age3?
BF9
Age6?
BF9
Age12?
0.06
0.01
11.54
0.06
0.01
11
.33
BF9
Age24?
-0.03
0.00
-7.08
-0.03
0.00
-6
.96
Maternalsmokinginpregnancy
Yesvs.No
0.12
0.03
3
.94
Studycenter
Munich
-0.15
0.03
-6
.05
Leipzig
0.31
0.04
8
.08
BadHonnef
0.04
0.06
0
.76
Wesel(ref)
Parentaleducation
[10thgrade
-0.01
0.04
-0
.18
=10thgrade
-0.01
0.04
-0
.29
\10thgrade(ref)
aModelAistherespectivelongitudinal
piecewiselinearrandomeffectsregressionmodeldescribedindetailintheAppendix
bModelBisbasedontherespectiveModelA,however,supplementedbythemaineffe
ctofbreastfeedinganditsinteractionswiththeperiodspecificslopes
cModelCisbasedontherespectiveModelBadjustedformaternalsmokinginpregnan
cy,studycenterandsocio-economicstatus
dBreastfeedingwasdefinedasfullybreastfeedingforatleast4monthsversusotherpos
tnatalfeedingpracticesincludingformula-ormixed-feeding
462 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
15/20
Table6
RandomeffectsofmodelslistedinTable5
Randomeffects
Weight(g)
Leng
th(cm)
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
ModelCc
Estimate
SE
z-value
Estimate
SE
z-value
Estimate
SE
z-value
Estim
ate
SE
z-value
Estimate
SE
z-value
Estimate
SE
z-value
Withinchildren(level1variance)b
134,476
1,171
114.88
133,730
1,16
6
114.65
133,719
1,170
114.31
1.9
5
0.01
139.36
4.75
0.09
51.14
1.90
0.01
135.86
Betweenchildren(level2(co)variances)c
Intercept/intercept
141,200
3,367
41.94
140,700
3,39
1
41.49
137,200
3,342
41.05
4.8
3
0.09
51.79
4.75
0.09
51.14
4.72
0.09
50.12
Age/age
35,770
983
36.40
35,010
96
6
36.25
35,470
986
35.99
0.5
0
0.01
43.20
0.47
0.01
42.94
0.60
0.01
40.52
Age3?/age3?
31,160
1,209
25.77
30,950
1,19
7
25.86
31,520
1,221
25.81
0.5
0
0.01
42.07
0.46
0.01
41.76
0.60
0.02
39.70
Age6?/age6?
Age12?/age12?
5,172
266
19.47
4,502
25
4
17.72
4,503
255
17.67
Age24?/age24?
3,918
127
30.90
3,825
12
5
30.55
3,833
126
30.49
Intercept/age
5,350
1,305
4.10
5,913
1,29
8
4.56
5,443
1,299
4.19
-0.8
0
0.03
-30.14
-0.75
0.03
-29.37
-0.92
0.03
-30.04
Intercept/age3?
-8,065
1,435
-5.62
-7,967
1,43
3
-5.56
-7,766
1,434
-5.42
0.8
1
0.03
30.23
0.76
0.03
29.45
0.93
0.03
30.09
Intercept/age6?
Intercept/age12?
6,608
522
12.65
5,922
51
2
11.56
6,024
510
11.82
Intercept/age24?
Age/age3?
-31,110
1,054
-29.52
-30,780
1,04
0
-29.60
-31,290
1,063
-29.44
-0.5
0
0.01
-42.53
-0.46
0.01
-42.27
-0.60
0.01
-40.03
Age/age6?
Age/age12?
-5,997
357
-16.82
-5,416
34
7
-15.62
-5,353
350
-15.28
Age/age24?
2,952
248
11.92
2,765
24
5
11.29
2,765
247
11.20
Age3?/age6?
Age3?/age12?
2,762
418
6.60
2,644
40
9
6.46
2,576
413
6.23
Age3?/age24?
-3,527
273
-12.93
-3,516
27
1
-13.00
-3,513
273
-12.87
Age6?/age12?
Age6?/age24?
Age12?/age24?
-2,065
153
-13.49
-1,819
14
8
-12.27
-1,822
149
-12.25
Randomeffects
BMI(kg/m
2)
ModelAa
ModelBb
ModelCc
Estimate
SE
z-value
Estimate
SE
z-value
Estimate
SE
z-value
Withinchildren(level1variance)b
1.21
0.01
163.52
1.21
0.01
172.71
1.21
0.01
162.46
Betweenchildren(level2(co)variances)c
Intercept/intercept
0.75
0.01
50.75
0.75
0.01
50.44
0.73
0.01
50.05
Age/age
Age3?/age3?
Age6?/age6?
Age12?/age12?
Period-specific growth rates and breastfeeding 463
1 3
7/26/2019 jurnal novi 5.pdf
16/20
Table6
continued
Randomeffects
BMI(kg/m
2)
ModelAa
ModelBb
ModelCc
Estimate
SE
z-value
Estimate
SE
z-value
Estimate
SE
z-value
Age24?/age24?
Intercept/age
Intercept/age3?
Intercept/age6?
Intercept/age12?
Intercept/age24?
Age/age3?
Age/age6?
Age/age12?
Age/age24?
Age3?/age6?
Age3?/age12?
Age3?/age24?
Age6?/age12?
Age6?/age24?
Age12?/age24?
a,
b,
cSeerespectivefootnotesTable5
464 P. Rzehak et al.
1 3
7/26/2019 jurnal novi 5.pdf
17/20
Table7
Detailedlistingoflogisticregressioncoefficients(fixedeffects)from
whichchangeratesofTable4werederived
Fixedeffects
Overweight
Obesity
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
ModelCc
Logit
SE
z-value
Logit
SE
z-value
Logit
SE
z-value
Logit
SE
z-value
Logit
SE
z-value
Logit
SE
z-value
Initialstatusatbirth
Intercept
-3.479
0.054
-64.28
-3.582
0.070
-50.86
-3.512
0.110
-31.84
-4.955
0.09
9
-50.09
-5.005
0.127
-39.47
-4.747
0.177
-26.79
Genderofinfant
Boyvs.Girl
0.232
0.050
4.68
0.236
0.050
4.72
0.252
0.050
4.99
0.371
0.07
7
4.81
0.381
0.078
4.90
0.408
0.079
5.18
Ageinmonths
Age
0.105
0.028
3.75
0.145
0.029
5.01
0.144
0.029
4.97
0.072
0.05
6
1.29
0.116
0.057
2.03
0.124
0.057
2.15
Age3?
0.018
0.054
0.34
-0.005
0.054
-0.09
0.004
0.054
0.08
0.139
0.10
6
1.32
0.116
0.105
1.10
0.105
0.105
0.99
Age6?
-0.021
0.038
-0.56
-0.015
0.038
-0.39
-0.013
0.039
-0.34
-0.122
0.07
2
-1.71
-0.120
0.071
-1.68
-0.113
0.071
-1.58
Age12?
-0.070
0.015
-4.59
-0.103
0.017
-6.03
-0.104
0.017
-6.03
-0.048
0.02
7
-1.77
-0.086
0.029
-2.91
-0.090
0.029
-3.06
Age24?
-0.050
0.006
-9.16
-0.039
0.008
-5.15
-0.039
0.008
-5.10
-0.055
0.00
9
-5.95
-0.037
0.012
-3.04
-0.036
0.012
-2.93
Breastfeeding
d
C4vs\4months
0.128
0.079
1.63
0.219
0.081
2.71
0.018
0.144
0.13
0.174
0.147
1.18
Breastfeeding9
Age
BF9
Age
-0.046
0.010
-4.80
-0.046
0.010
-4.80
-0.054
0.018
-3.02
-0.056
0.018
-3.13
BF9
Age3?
BF9
Age6?
BF9
Age12?
0.067
0.016
4.09
0.067
0.017
4.07
0.088
0.030
2.96
0.090
0.030
3.01
BF9
Age24?
-0.024
0.011
-2.29
-0.024
0.011
-2.28
-0.042
0.018
-2.33
-0.042
0.018
-2.33
Maternalsmokinginpregnancy
Yesvs.No
0.264
0.069
3.83
0.318
0.104
3.06
Studycenter
Munich
-0.299
0.058
-5.17
-0.409
0.090
-4.56
Leipzig
0.359
0.083
4.32
0.256
0.127
2.02
BadHonnef
-0.007
0.133
-0.05
0.086
0.200
0.43
Wesel(ref)
Parentaleducation
[10thgrade
-0.098
0.096
-1.02
-0.331
0.141
-2.35
=10thgrade
-0.098
0.098
-1.00
-0.289
0.144
-2.01
\10thgrade(ref)
aModelAisbasedontherespectivelongitudinalpiecewiselinearrandominterceptlogisticregressionmodeldescribedintheAppendix
bModelBisbasedontherespectiveM
odelA,however,supplementedbythemaineffectofbreastfeedinganditsinteractionswiththe
periodspecificslopes
cModelCisbasedontherespectiveModelBadjustedformaternalsmokinginpregnancy,studycenterandsocio-economicstatus
dBreastfeedingwasdefinedasfullybre
astfeedingforatleast4monthsversusotherpostnatalfeedingpracticesincludingformula-ormixed-feeding
Period-specific growth rates and breastfeeding 465
1 3
7/26/2019 jurnal novi 5.pdf
18/20
Neuherberg (Wichmann HE, Heinrich J, Bolte G, Belcredi
P, Jacob B, Schoetzau A, Mosetter M, Schindler J, Hohnke
A, Franke K, Laubereau B, Sausenthaler S, Thaqi A,
Zirngibl A, Zutavern A); Department of Pediatrics, Uni-
versity of Leipzig (Borte M, Schulz R, Sierig G, Mirow K,
Gebauer C, Schulze B, Hainich J); Institute for Clinical
Immunology and Transfusion Medicine (Sack U, Emmrich
F); Department of Pediatrics, Marien-Hospital, Wesel (vonBerg A, Schaaf B, Scholten C, Bollrath C, Gro I, Mo l-
lemann M); Department of Human Exposure-Research and
Epidemiology, UFZ-Center for Environmental Research
Leipzig-Halle (Herbarth O, Diez U, Rehwagen M, Schlink
U, Franck U, Jorks A, Roder S); Department of Environ-
mental Immunology, UFZ-center for Environmental
Research Leipzig-Halle (Lehmann I, Herberth G, Daegel-
mann C); Ludwig Maximilians University Munich, Dr. von
Hauner Childrens Hospital, Department of Infectious
Diseases and Immunology (Weiss M, Albert M); Friedrich-
Schiller-University Jena, Institute for Clinical Immunology
(Fahlbusch B), Institute for Social, Occupational andEnvironmental Medicine (Bischof W, Koch A); IUF-
Environmental Health Research Institute, Dusseldorf
(Kramer U, Link E, Ranft U, Schins R); Clinic and Poly-
clinic for Child and Adolescent Medicine, University
Hospital Rechts der Isar of the Technical University
Munich (Bauer CP, Brockow I, Grubl A); Department of
Dermatology and Allergy Biederstein, Technical Univer-
sity Munich (Ring J, Grosch J, Weidinger S).
References
1. Lobstein T, Baur L, Uauy R. Obesity in children and young
people: a crisis in public health. Obes Rev. 2004;5(Suppl 1):4
104. doi:10.1111/j.1467-789X.2004.00133.x .
2. Sachdev HS, Fall CH, Osmond C, Lakshmy R, Dey Biswas SK,
Leary SD, et al. Anthropometric indicators of body composition
in young adults: relation to size at birth and serial measurements
of body mass index in childhood in the New Delhi birth cohort.
Am J Clin Nutr. 2005;82(2):45666.
3. Lindsay RS, Cook V, Hanson RL, Salbe AD, Tataranni A,
Knowler WC. Early excess weight gain of children in the Pima
Indian population. Pediatrics. 2002;109(2):E33. doi:10.1542/peds.
109.2.e33.
4. McCarthy A, Hughes R, Tilling K, Davies D, Smith GD, Ben
Shlomo Y. Birth weight; postnatal, infant, and childhood growth;
and obesity in young adulthood: evidence from the Barry Caer-
philly Growth Study. Am J Clin Nutr. 2007;86(4):90713.
5. Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB.
Association between postnatal catch-up growth and obesity in
childhood: prospective cohort study. BMJ. 2000;320(7240):967
71. doi:10.1136/bmj.320.7240.967 .
6. Stettler N, Zemel BS, Kumanyika S, Stallings VA. Infant weight
gainand childhood overweight status in a multicenter,cohort study.
Pediatrics. 2002;109(2):1949. doi:10.1542/peds.109.2.194 .
7. Arenz S, von Kries R. Protective effect of breastfeeding against
obesity in childhood. Can a meta-analysis of observationalTable8
RandomeffectsofmodelslistedinTable7
Randomeffects
Overweight
Obesity
ModelAa
ModelBb
ModelCc
ModelAa
ModelBb
ModelCc
EstimateSE
z-valueEstimateSE
z-valueEstimateSE
z-valueEstimateSE
z-valueEstimateSE
z-value
EstimateSE
z-value
Withinchildren(level1variance)1
1
1
1
1
1
Betweenchildren(level2(co)variances)
Intercept/intercept
2.65
0.0735.78
2.68
0.08
35.70
2.663
0.07635.23
5.12
0.1829.02
5.10
0.1828.72
5.05
0.1828.25
a,b,c
SeerespectivefootnotesTable
7
466 P. Rzehak et al.
1 3
http://dx.doi.org/10.1111/j.1467-789X.2004.00133.xhttp://dx.doi.org/10.1542/peds.109.2.e33http://dx.doi.org/10.1542/peds.109.2.e33http://dx.doi.org/10.1136/bmj.320.7240.967http://dx.doi.org/10.1542/peds.109.2.194http://dx.doi.org/10.1542/peds.109.2.194http://dx.doi.org/10.1136/bmj.320.7240.967http://dx.doi.org/10.1542/peds.109.2.e33http://dx.doi.org/10.1542/peds.109.2.e33http://dx.doi.org/10.1111/j.1467-789X.2004.00133.x7/26/2019 jurnal novi 5.pdf
19/20
studies help to validate the hypothesis? Adv Exp Med Biol.
2005;569:408. doi:10.1007/1-4020-3535-7_7.
8. Bergmann KE, Bergmann RL, von Kries R, Bohm O, Richter R,
Dudenhausen JW, et al. Early determinants of childhood over-
weight and adiposity in a birth cohort study: role of breast-
feeding. Int J Obes Relat Metab Disord. 2003;27(2):16272. doi:
10.1038/sj.ijo.802200 .
9. Fewtrell MS, Morgan JB, Duggan C, Gunnlaugsson G, Hibberd
PL, Lucas A, et al. Optimal duration of exclusive breastfeeding:
what is the evidence to support current recommendations? Am J
Clin Nutr. 2007;85(2):635S8S.
10. Scholtens S, Gehring U, Brunekreef B, Smit HA, de Jongste JC,
Kerkhof M, et al. Breastfeeding, weight gain in infancy, and
overweight at seven years of age: the prevention and incidence of
asthma and mite allergy birth cohort study. Am J Epidemiol.
2007;165(8):91926. doi:10.1093/aje/kwk083 .
11. Burdette HL, Whitaker RC, Hall WC, Daniels SR. Breastfeeding,
introduction of complementary foods, and adiposity at 5 y of age.
Am J Clin Nutr. 2006;83(3):5508.
12. Filipiak B, Zutavern A, Koletzko S, von Berg A, Brockow I,
Grubl A, et al. Solid food introduction in relation to eczema:
results from a four-year prospective birth cohort study. J Pediatr.
2007;151(4):3528. doi:10.1016/j.jpeds.2007.05.018 .
13. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grubl
A, Wichmann HE, et al. Certain hydrolyzed formulas reduce the
incidence of atopic dermatitis but not that of asthma: three-year
results of the German Infant Nutritional Intervention Study.
J Allergy Clin Immunol. 2007;119(3):71825. doi:10.1016/j.jaci.
2006.11.017.
14. Chen CM, Rzehak P, Zutavern A, Fahlbusch B, Bischof W,
Herbarth O, et al. Longitudinal study on cat allergen exposure
and the development of allergy in young children. J Allergy
Clin Immunol. 2007;119(5):114855. doi:10.1016/j.jaci.2007.
02.017.
15. Zutavern A, Rzehak P, Brockow I, Schaaf B, Bollrath C, von
Berg A, et al. Day care in relation to respiratory-tract and gas-
trointestinal infections in a German birth cohort study. Acta
Paediatr. 2007;96(10):14949.
16. de Onis M, Garza C, Onyango AW, Borghi E. Comparison of the
WHO child growth standards and the CDC 2000 growth charts.
J Nutr. 2007;137(1):1448.
17. Butte NF, Garza C, de Onis M. Evaluation of the feasibility of
international growth standards for school-aged children and
adolescents. J Nutr. 2007;137(1):1537.
18. Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal
analysis. Hoboken: Wiley; 2004.
19. Singer JD, Willett JB. Applied longitudinal data analysis. Mod-
eling change and event occurrence. Oxford: Oxford University
Press; 2003.
20. Cole TJ, Freeman JV, Preece MA. British 1990 growth reference
centiles for weight, height, body mass index and head circum-
ference fitted by maximum penalized likelihood. Stat Med.
1998;17(4):40729. doi:10.1002/(SICI)1097-0258(19980228)17:
4\
407::AID-SIM742[
3.0.CO;2-L.21. Sauerbrei W, Royston P, Binder H. Selection of important vari-
ables and determination of functional form for continuous pre-
dictors in multivariable model building. Stat Med. 2007;26(30):
551228. doi:10.1002/sim.3148.
22. Dietz WH. Periods of risk in childhood for the development of
adult obesitywhat do we need to learn? J Nutr. 1997;127(9):
1884S6S.
23. Monteiro PO, Victora CG. Rapid growth in infancy and child-
hood and obesity in later lifea systematic review. Obes Rev.
2005;6(2):14354. doi:10.1111/j.1467-789X.2005.00183.x .
24. Stettler N, Stallings VA, Troxel AB, Zhao J, Schinnar R, Nelson
SE, et al. Weight gain in the first week of life and overweight in
adulthood: a cohort study of EuropeanAmerican subjectsfed infant
formula. Circulation. 2005;111(15):1897903. doi:10.1161/
01.CIR.0000161797.67671.A7 .
25. Stettler N. Nature and strength of epidemiological evidence for
origins of childhood and adulthood obesity in the first year of life.
Int J Obes Lond. 2007;31(7):103543. doi:10.1038/sj.ijo.0803659 .
26. Toschke AM, Grote V, Koletzko B, von Kries R. Identifying
children at high risk for overweight at school entry by weight
gain during the first 2 years. Arch Pediatr Adolesc Med.
2004;158(5):44952. doi:10.1001/archpedi.158.5.449 .
27. Mei Z, Grummer-Strawn LM, Thompson D, Dietz WH. Shifts in
percentiles of growth during early childhood: analysis of longi-
tudinal data from the California Child Health and Development
Study. Pediatrics. 2004;113(6):e61727. doi:10.1542/peds.113.6.
e617.
28. Koletzko B, Broekaert I, Demmelmair H, Franke J, Hannibal I,
Oberle D, et al. Protein intake in the first year of life: a risk factor
for later obesity? The E.U. childhood obesity project. Adv Exp
Med Biol. 2005;569:6979. doi:10.1007/1-4020-3535-7_12.
29. Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs
E, et al. Randomized trial of nutrient-enriched formula versus
standard formula for postdischarge preterm infants. Pediatrics.
2001;108(3):70311. doi:10.1542/peds.108.3.703 .
30. Koletzko B, von Kries R. Are there long term protective effects
of breast feeding against later obesity? Nutr Health. 2001;15(3
4):22536.
31. Onis M, WHO Multicentre Growth Reference Study Group. Reli-
ability of anthropometric measurements in the WHO Multicentre
Growth Reference Study. Acta Paediatr Suppl. 2006;450:3846.
32. Johnson W, Cameron N, Dickson P, Emsley S, Raynor P, Sey-
mour C, et al. The reliability of routine anthropometric data
collected by health workers: a cross-sectional study. Int J Nurs
Stud. 2009;46(3):3106. doi:10.1016/j.ijnurstu.2008.10.003 .
33. Barker DJ. Obesity and early life. Obes Rev. 2007;8(Suppl 1):
459. doi:10.1111/j.1467-789X.2007.00317.x .
34. Eisenmann JC. Insight into the causes of the recent secular trend in
pediatric obesity: common sense does not always prevail for
complex, multi-factorial phenotypes. Prev Med. 2006;42(5):329
35. doi:10.1016/j.ypmed.2006.02.002 .
35. Ben Shlomo Y, Kuh D. A life course approach to chronic disease
epidemiology: conceptual models, empirical challenges and
interdisciplinary perspectives. Int J Epidemiol. 2002;31(2):285
93. doi:10.1093/ije/31.2.285 .
36. SAS Institute Inc. SAS/STAT 9.1 users guide. Cary: SAS
Institute Inc.; 2004.
37. Rasbash J, Steele F, Browne W, Prosser BA. Userss guide toMLwiN. Version 2.0. Center for multilevel modelling. London:
Institute of Eductaion, University of London; 2004.
38. Durlak JA. How to select, calculate, and interpret effect sizes.
J Pediatr Psychol. 2009. doi:10.1093/jpepsy/jsp004 .
Period-specific growth rates and breastfeeding 467
1 3
http://dx.doi.org/10.1007/1-4020-3535-7_7http://dx.doi.org/10.1038/sj.ijo.802200http://dx.doi.org/10.1093/aje/kwk083http://dx.doi.org/10.1016/j.jpeds.2007.05.018http://dx.doi.org/10.1016/j.jaci.2006.11.017http://dx.doi.org/10.1016/j.jaci.2006.11.017http://dx.doi.org/10.1016/j.jaci.2007.02.017http://dx.doi.org/10.1016/j.jaci.2007.02.017http://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/sim.3148http://dx.doi.org/10.1111/j.1467-789X.2005.00183.xhttp://dx.doi.org/10.1161/01.CIR.0000161797.67671.A7http://dx.doi.org/10.1161/01.CIR.0000161797.67671.A7http://dx.doi.org/10.1038/sj.ijo.0803659http://dx.doi.org/10.1001/archpedi.158.5.449http://dx.doi.org/10.1542/peds.113.6.e617http://dx.doi.org/10.1542/peds.113.6.e617http://dx.doi.org/10.1007/1-4020-3535-7_12http://dx.doi.org/10.1542/peds.108.3.703http://dx.doi.org/10.1016/j.ijnurstu.2008.10.003http://dx.doi.org/10.1111/j.1467-789X.2007.00317.xhttp://dx.doi.org/10.1016/j.ypmed.2006.02.002http://dx.doi.org/10.1093/ije/31.2.285http://dx.doi.org/10.1093/jpepsy/jsp004http://dx.doi.org/10.1093/jpepsy/jsp004http://dx.doi.org/10.1093/ije/31.2.285http://dx.doi.org/10.1016/j.ypmed.2006.02.002http://dx.doi.org/10.1111/j.1467-789X.2007.00317.xhttp://dx.doi.org/10.1016/j.ijnurstu.2008.10.003http://dx.doi.org/10.1542/peds.108.3.703http://dx.doi.org/10.1007/1-4020-3535-7_12http://dx.doi.org/10.1542/peds.113.6.e617http://dx.doi.org/10.1542/peds.113.6.e617http://dx.doi.org/10.1001/archpedi.158.5.449http://dx.doi.org/10.1038/sj.ijo.0803659http://dx.doi.org/10.1161/01.CIR.0000161797.67671.A7http://dx.doi.org/10.1161/01.CIR.0000161797.67671.A7http://dx.doi.org/10.1111/j.1467-789X.2005.00183.xhttp://dx.doi.org/10.1002/sim.3148http://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1002/(SICI)1097-0258(19980228)17:4%3c407::AID-SIM742%3e3.0.CO;2-Lhttp://dx.doi.org/10.1016/j.jaci.2007.02.017http://dx.doi.org/10.1016/j.jaci.2007.02.017http://dx.doi.org/10.1016/j.jaci.2006.11.017http://dx.doi.org/10.1016/j.jaci.2006.11.017http://dx.doi.org/10.1016/j.jpeds.2007.05.018http://dx.doi.org/10.1093/aje/kwk083http://dx.doi.org/10.1038/sj.ijo.802200http://dx.doi.org/10.1007/1-4020-3535-7_77/26/2019 jurnal novi 5.pdf
20/20
Reproducedwithpermissionof thecopyrightowner. Further reproductionprohibitedwithoutpermission.