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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


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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.

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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

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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/


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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]


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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


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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


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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


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



0.25

0.24

0.24

0.24

0.24


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


0.22

0.22

0.22

0.22

0.22


-0.32

-0.32

-0.32

-0.32

-0.32



Changeratepast12by24mon

ths

-0.46

-0.44

-0.44

-0.44

-0.44

a,b,c

SeerespectivefootnotesTable2

d

95%ofthesubject-specificestim

atesarelocatedinthisrange(seeAppen

dix)


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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


1 3


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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


1 3


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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


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.htm


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


1 3


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,


1 3


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


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)


1 3


14/20

Table5

continued

Fixedeffects

BMI(kg/m

2)

ModelAa

ModelBb

ModelCc

SE

z-value

SE

z-value

SE

z-value


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


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


1 3


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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?


1 3


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


1 3


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


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


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


1 3


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).

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