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Birth and early life influences on the timing of puberty onset: results from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study

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Early age at puberty onset may predispose an individual to many currently prevalent diseases, including cancer and adiposity. The objective was to investigate whether early life exposures influence the timing of puberty, as defined by both early and late markers, in healthy German girls and boys. Term participants (n = 215; 49.8% female) of the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study, with sufficient repeated anthropometric measurements between 6 and 13 y to allow estimation of age at take-off of the pubertal growth spurt (ATO) and information on a variety of early life exposures, including birth weight, breastfeeding status, velocity of weight gain, and parental characteristics, were studied. Age at peak height velocity (APHV) and menarche were also considered. Children who weighed between 2500 and <3000 g at birth were approximately 7 mo younger at ATO than were the other children (beta +/- SE: -0.56 +/- 0.20 y; P = 0.006). Children who had gained weight rapidly between birth and 24 mo (increase in weight SD score >0.67) experienced ATO 4 mo earlier than those who had gained weight normally (-0.34 +/- 0.15 y; P = 0.02). Rapid weight gain was also associated with an earlier APHV (P = 0.0006) and, in girls, with an earlier menarche (P = 0.002). Adjustment for body mass index SD score or body fat percentage 1, 2, or 3 y before ATO did not account for these effects. In both boys and girls, intrauterine and early postnatal growth factors appear to influence both early and later markers of puberty onset independently of prepubertal body composition.
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Birth and early life influences on the timing of puberty onset: results
from the DONALD (DOrtmund Nutritional and Anthropometric
Longitudinally Designed) Study
1–3
Nadina Karaolis-Danckert, Anette E Buyken, Antje Sonntag, and Anja Kroke
ABSTRACT
Background: Early age at puberty onset may predispose an indi-
vidual to many currently prevalent diseases, including cancer and
adiposity.
Objective: The objective was to investigate whether early life ex-
posures influence the timing of puberty, as defined by both early and
late markers, in healthy German girls and boys.
Design: Term participants (n= 215; 49.8% female) of the DONALD
(DOrtmund Nutritional and Anthropometric Longitudinally De-
signed) Study, with sufficient repeated anthropometric measurements
between 6 and 13 y to allow estimation of age at take-off of the
pubertal growth spurt (ATO) and information on a variety of early
life exposures, including birth weight, breastfeeding status, velocity
of weight gain, and parental characteristics, were studied. Age at
peak height velocity (APHV) and menarche were also considered.
Results: Children who weighed between 2500 and ,3000 g at birth
were 7 mo younger at ATO than were the other children (b6SE:
20.56 60.20 y; P= 0.006). Children who had gained weight
rapidly between birth and 24 mo (increase in weight SD score
.0.67) experienced ATO 4 mo earlier than those who had gained
weight normally (20.34 60.15 y; P= 0.02). Rapid weight gain
was also associated with an earlier APHV (P= 0.0006) and, in girls,
with an earlier menarche (P= 0.002). Adjustment for body mass
index SD score or body fat percentage 1, 2, or 3 y before ATO did
not account for these effects.
Conclusion: In both boys and girls, intrauterine and early postnatal
growth factors appear to influence both early and later markers
of puberty onset independently of prepubertal body composi-
tion. Am J Clin Nutr 2009;90:1559–65.
INTRODUCTION
Early age at puberty onset may be an intermediary factor on the
life-course path to many currently prevalent diseases, including
both breast (1, 2) and testicular (3) cancer, insulin resistance (4),
and adiposity (5). To date, many studies have identified both pre-
and perinatal exposures, such as low birth weight (6) or rapid
growth velocity in infancy (7) as being potential determinants of
pubertal timing. However, many issues remain unresolved.
These studies have mainly focused on girls and, in particular,
on the timing of menarche—a relatively late milestone of re-
productive development that usually takes place after peak height
velocity (PHV) has been achieved and height growth has begun to
slow down. Nevertheless, it has been concluded that an earlier
menarche implies a more rapid progression through puberty (8).
It is, however, possible that early life factors actually influence
when puberty begins and not necessarily the duration. In addition,
influence of a particular early life exposure on both early and late
markers of pubertal timing would support its relevance, but this
has rarely been investigated. Previous studies have also proved
inconclusive about the role of size and body composition in later
childhood. Whereas some have shown no effect of birth size
once childhood growth patterns were accounted for (9, 10), others
have shown additive effects of pre- and postnatal growth (7, 11,
12). Finally, the relevance of early life risk factors for pubertal
timing in boys is unclear, mainly because of the lack of an easily
identifiable puberty marker.
In this study, we used the prospectively collected height
measurements of participants from the DONALD (DOrtmund
Nutritional and Anthropometric Longitudinally Designed) Study
to investigate the association between early life exposures and
both an early marker of puberty onset [ie, age at take-off of the
pubertal growth spurt (ATO)] and 2 later ones [ie, age at PHV
(APHV) and menarche (in girls)]. In addition, we investigated
whether these early life exposures exert their influence on pu-
bertal timing independently of or via a pathway related to pre-
pubertal body composition.
SUBJECTS AND METHODS
Study population
The DONALD Study is an ongoing, open cohort study con-
ducted by the Research Institute of Child Nutrition in Dortmund,
Germany. This study was previously described in detail (13).
Briefly, since recruitment began in 1985, detailed information on
diet, growth, development, and metabolism between infancy and
1
From the Research Institute of Child Nutrition, Rheinische Friedrich-
Wilhelms–Universita
¨t Bonn, Dortmund, Germany (NK-D, AEB, and AS),
and the Department of Nutritional, Food and Consumer Sciences, Fulda
University of Applied Sciences, Fulda, Germany (AK).
2
Supported by a research grant from the World Cancer Research Fund
UK (WCRF UK no.2006/39). The DONALD Study is funded by the Min-
istry of Science and Research of North Rhine Westphalia, Germany.
3
Address correspondence to A Kroke, Department of Nutritional, Food
and Consumer Sciences, Fulda University of Applied Sciences, Marquard-
strasse 35, 36039 Fulda, Germany. E-mail: anja.kroke@he.hs-fulda.de.
Received June 19, 2009. Accepted for publication September 17, 2009.
First published online October 14, 2009; doi: 10.3945/ajcn.2009.28259.
Am J Clin Nutr 2009;90:1559–65. Printed in USA. Ó2009 American Society for Nutrition 1559
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early adulthood has been collected from .1100 children. Every
year, an average of 40 to 50 infants are newly recruited and first
examined at the ages of 3 or 6 mo. Each child returns for 3 more
visits in the first year, 2 in the second and then once annually
until early adulthood (except during adolescence when twice-
yearly visits were offered until 2004). The study was approved
by the Ethics Committee of the University of Bonn, and all
examinations are performed with parental consent.
The ages of the children who were initially recruited into the
DONALD Study when it began in 1985 were quite variable, ie,
information on the first few years of life was not always available.
In addition, many current participants have not yet reached
adolescence. Therefore, for this analysis, only term (37–42 wk of
gestation) singletons with a birth weight .2500 g who fulfilled
the following minimum requirement were selected (n= 411):
they had already provided height measurements at 6 and 13 y
and 5 measurements between these ages to allow estimation of
ATO by using Preece and Bains model 1 (PB1) (14) (see de-
scription below). The plausibility of each child’s ATO was de-
termined by visual inspection of each individual growth curve
and by using the cutoffs ATO 5 and ,13 y. Reasons for an
implausible ATO included no measurements after age 13 y, too
few measurements between age 13 y and young adulthood, or an
unusually “flat” growth curve. A plausible ATO was achieved
for 376 children. Of these, 215 also had anthropometric meas-
urements at 24 mo (for determination of rapid weight gain be-
tween birth and 24 mo) and complete information on
breastfeeding and on maternal characteristics (BMI and educa-
tional status). Hence, the subcohort analyzed here included 215
term singletons (49.8% female).
Anthropometric measures
DONALD Study participants are measured at each visit by
trained nurses according to standard procedures (15). They are
dressed in underwear only and are barefoot. From the age of 2
onward, standing height is measured to the nearest 0.1 cm with
a digital stadiometer. Weight is measured to the nearest 0.1 kg
with an electronic scale (model 753 E; Seca, Hamburg, Ger-
many). Skinfold thicknesses are measured from the age of 6 mo
onward on the right side of the body to the nearest 0.1 mm with
a Holtain caliper (Holtain Ltd, Crymych, United Kingdom).
On their child’s admission to the study, parents are interviewed
by the study pediatrician, and weighed and measured by the study
nurses using the same equipment as for children from 2 y onward.
Information on birth weight, length and head circumference at
birth, and gestational age are abstracted from a standardized
document given to all pregnant women in Germany.
For this analysis, sex- and age-independent SD scores (SDS)
were calculated by using the German reference curves for weight
and body mass index (BMI; in kg/m
2
) (16). To remove general
deviations of our sample from the reference data, these variables
were internally standardized (mean = 0, SD = 1; by age and sex).
Percentage body fat (BF%) was calculated by using Slaughter
equations for prepubertal children (17).
Puberty outcome variables
Height data were analyzed by using the parametric PB1 (14).
The parameters of each child’s growth curve were estimated by
using a nonlinear regression model (PROC NLIN in SAS; SAS
Institute Inc, Cary, NC). It was previously shown that the lower
limit of the age range offered to the model should not be ,2yof
age and that the fit of the adolescent growth curve is better if the
age range includes data from not more than a few years before
ATO (18). PB1 was therefore fitted on various sex-specific age
ranges of the height-for-age data, beginning with age 2 y, to
determine the optimal range for our data. ATO was defined as the
age at minimal height velocity (zero acceleration) at the onset of
the pubertal growth spurt (19). Goodness of fit was determined as
follows: 1) by graphic inspection of each child’s individual
growth curve, 2) by comparison of the residual SD (random error
had to be smaller than the expected measurement error for
height), 3) by consideration of the plausibility, and 4) on the basis
of the distribution of the pubertal parameters estimated (20).
Consequently, all available measurements from age 5 y onward
for girls and from age 6 y onward for boys were used. The mean
number of measurements per child was 17.7 (range: 9–21) in
girls and 15.7 (range: 8–20) in boys. The PB1 model also pro-
duced estimates of velocity at take-off (VTO), APHV, and PHV.
Two other puberty variables were also considered: age at
Tanner stage 2 for either breast or penis development in girls (n=
75) and boys (n= 66), respectively, and age at menarche in girls
only. Tanner stage is visually assessed by a study pediatrician. In
addition, girls or their parents are asked whether menarche has
occurred since the previous visit, and, if so, in which month and
year. This information was available for 87 of the 107 girls in
this analysis. Of the remaining 20, 2 had incomplete information
on menarche (ie year but not month in which menarche began),
and 18 had not provided any information.
Early life exposures
Birth weight was considered as both a continuous and cate-
gorical variable (ie, 2500 to ,3000 g compared with 3000
g). Birth size-for-gestational-age was defined by using the
German sex-specific birth weight and length-for-gestational-age
curves (21). Small-for-gestational-age (SGA) was defined as
birth weight and length ,10th percentile, and large-for-gesta-
tional-age (LGA) was defined as birth weight and length .90th
percentile. All other infants were classified as appropriate-for-
gestational age (AGA). Other birth variables included year and
season of birth, birth at early (37 or 38 wk) or late (41 or 42 wk)
gestation, first-born status (yes or no), and breastfeeding status,
defined as full breastfeeding for 4 mo. Because rapid early
weight gain has been linked to elevated insulin-like growth
factor I concentrations and insulin resistance, elevated adrenal
androgen concentrations, exaggerated adrenarche, obesity, and
consequently to concentrations of hormones such as leptin, it
has been suggested that these could all promote the activity of
the gonadotropin-releasing hormone pulse generator, thereby
influencing the timing of puberty (22). These effects and the
possible pathway are still unclear. On the basis of this rationale,
the possible pathway between early rapid weight gain, over-
weight in childhood and puberty onset, and sample size con-
siderations, it was decided to follow Monteiro and Victora’s
recommendation in their systematic review (23) and define rapid
early weight gain as an increase in weight SDS .0.67 between
birth and 24 mo. Because a considerable number of siblings
participate in the DONALD Study, we also took the presence of
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siblings in our subcohort (yes or no) into account. Smoking
exposure in the household (yes or no) and the parental charac-
teristics overweight status (BMI 25) and educational status
(12 y of schooling) were also considered.
Statistical analysis
Three ATO groups—early (,25th percentile), middle (25th
percentile and 75th percentile), and late onset (.75th per-
centile)—were created by using the sex-specific distribution of
ATO. Differences between ATO groups were tested by using
analysis of variance or Kruskal-Wallis tests (continuous varia-
bles) and chi-square tests (categorical variables). There was no
interaction between sex and birth weight category (Pfor in-
teraction = 0.5) or sex and rapid weight gain (Pfor interaction =
0.2), so boys and girls were pooled together for all statistical
analyses. Linear mixed-effects regression models (using PROC
MIXED), including both fixed and random effects, were used to
construct longitudinal models of ATO, APHV, or age at men-
arche (in girls only). The random component of these models
accounts for the nested nature of our data (children within
families). Initial models included ATO, APHV, or age at men-
arche (in girls only) as the dependent continuous variable and
the various early life exposures as the independent fixed effects.
All models (except those with age at menarche as the outcome)
included sex, and each early life exposure was initially consid-
ered separately. Variables were only retained in the multivariable
models if they tended to be associated with the outcome (P,
0.1). Next, all multivariable models were adjusted for BMI SDS
or BF% 1, 2, and 3 y before ATO as an indication of whether
early life exposures exert their effect on the respective outcome
via a pathway that involves changes in prepubertal body com-
position (our so-called “pathway model”). In a final step, in-
teractions between variables found to influence the outcomes of
interest were investigated to identify particularly vulnerable
subgroups. A Pvalue ,0.05 was considered statistically sig-
nificant. All statistical analyses were carried out by using SAS
version 8.2 (SAS Institute).
RESULTS
Early life and familial characteristics of the 215 boys and girls
in this analysis are presented in Table 1 according to ATO group.
A significantly larger proportion of those children whose pu-
berty growth spurt began relatively early were lighter at birth
(between 2500 and ,3000 g) and had gained weight rapidly
between birth and 24 mo compared with those in the middle or
late ATO groups (P= 0.04 and P= 0.006, respectively).
The pubertal characteristics of the study sample, stratified by
both sex and ATO group, are shown in Table 2. In both boys and
girls, those children in the early ATO group displayed an in-
creased velocity at take-off and experienced PHV and menarche
TABLE 1
Early life and familial characteristics of 215 boys and girls from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study,
by sex-specific groups of age at take-off of the pubertal growth spurt (ATO)
ATO group
1
Variable No. of subjects Early (n= 53) Middle (n= 108) Late (n= 54) Pvalue
2
Female sex [n(%)] 215 26 (49.1) 54 (50.0) 27 (50.0) 0.9
Early life characteristics
Birth weight (g) 215 3402 6456
3
3532 6464 3596 6465 0.1
Birth weight ,3000 g [n(%)] 215 11 (20.8) 11 (10.2) 3 (5.6) 0.04
Birth length (cm) 215 52 (50, 53)
4
52 (50, 53) 52 (51, 54) 0.2
Gestational age (wk) 215 40 (39, 41) 40 (39, 41) 40 (39, 41) 0.9
Birth year [n(%)] 215 0.9
,1987 52 11 (20.8) 26 (24.1) 15 (27.8)
1987–1990 96 24 (45.3) 47 (43.5) 25 (46.3)
.1990 67 18 (34.0) 35 (32.4) 14 (25.9)
Winter/spring birth [n(%)] 215 23 (43.4) 54 (50) 22 (40.7) 0.5
Fully breastfed 4mo[n(%)] 215 25 (47.2) 50 (46.3) 32 (59.3) 0.1
Rapid weight gain [n(%)] 215 22 (41.5) 22 (20.4) 10 (18.5) 0.006
Family characteristics [n(%)]
Firstborn 206 31 (63.3) 58 (55.2) 30 (57.7) 0.6
Siblings in data set 215 13 (24.5) 32 (29.6) 14 (25.9) 0.8
Smoking exposure at home 215 18 (34.0) 32 (29.6) 17 (31.5) 0.9
Maternal characteristics [n(%)]
Overweight 215 18 (34.0) 35 (32.4) 11 (20.4) 0.2
12 y of schooling 215 29 (54.7) 58 (53.7) 35 (64.8) 0.4
Paternal characteristics [n(%)]
Overweight 177 22 (51.2) 49 (56.3) 30 (63.8) 0.5
12 y of schooling 214 33 (62.3) 62 (57.9) 35 (64.8) 0.7
1
ATO groups were defined as follows: early (ATO ,25th sex-specific percentile), middle (ATO 25th and 75th sex-specific percentile), and late (ATO
.75th sex-specific percentile).
2
Significant differences between groups were tested by ANOVA for normally distributed continuous variables, Kruskal-Wallis tests for nonnormally
distributed continuous variables, and a chi-square test for categorical variables.
3
Mean 6SD (all such values).
4
Median; quartiles 1 and 3 in parentheses (all such values).
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(girls) at a younger age than the children in the other 2 ATO
groups (P,0.0001 for all 3 variables). In girls only, those in the
early ATO group also reached Tanner stage 2 at a younger age
than did those girls in the other 2 ATO groups (P,0.0001).
To gain an understanding of the clinical relevance of the effect
of those early life exposures, which remained of relevance in the
multivariable models on puberty onset, the association between
ATO, APHV, or age at menarche and these exposures was ex-
amined in linear mixed-model regression analyses, and the results
are presented as the time difference (in y) in ATO, APHV, or age
at menarche between exposed and unexposed children. Table 3
(multivariate model) shows that children who weighed between
2500 and ,3000 g at birth were younger (b6SE: 0.56 60.20
y, ie, 7 mo) at ATO than were those children whose birth
weight was 3000 g (P= 0.006), whereas those children who
had gained weight rapidly between birth and 24 mo experienced
ATO 0.34 60.15 y (ie, 4 mo) earlier than did those who had
gained weight normally in the first 2 y of life (P= 0.02). In
initial models it appeared that children who weighed between
2500 and ,3000 g at birth also experienced both APHV and
menarche earlier than did the other children, but these effects
were attenuated in the multivariable analyses (Tables 4 and 5).
This was also the case for the effect of having been fully
breastfed for 4 mo on APHV (these children tended toward
a delayed APHV by 0.24 60.13 y, or 3 mo in initial models).
Rapid weight gain, however, was associated with both an earlier
APHV (P= 0.0006) and an earlier menarche (P= 0.002). Fi-
nally, the data in Table 5 also suggest that having an overweight
mother resulted in these girls experiencing menarche 0.52 6
0.24 y or 6 mo earlier than those girls without an overweight
mother (P= 0.03).
TABLE 2
Pubertal characteristics of 107 girls and 108 boys from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study,
Dortmund, Germany, by sex-specific groups of age at take-off of the pubertal growth (ATO)
ATO group
1
Variable No. of subjects Early (n= 53) Middle (n= 108) Late (n= 54) Pvalue
2
ATO (y)
Girls 107 7.5 (6.9, 7.8)
3
8.7 (8.3, 9.1) 9.8 (9.4, 10.0) ,0.0001
Boys 108 9.2 (8.9, 9.5) 10.3 (10.0, 10.5) 11.1 (11.0, 11.5) ,0.0001
Velocity at take-off (cm/y)
Girls 107 5.9 60.7
4
5.5 60.5 4.9 60.5 ,0.0001
Boys 108 5.5 60.5 5.1 60.5 4.6 60.5 ,0.0001
Age at peak height velocity (y)
Girls 104 10.3 60.8 11.5 60.6 12.8 60.6 ,0.0001
Boys 104 12.4 60.6 13.4 60.5 14.5 60.6 ,0.0001
Age at Tanner stage 2 (y)
Girls 75 9.5 (9.0, 10.3) 10.5 (9.5, 11.0) 11.5 (11.0, 12.1) ,0.0001
Boys 66 10.5 (10.0, 10.8) 10.6 (10.0, 11.2) 10.5 (10.0, 11.0) 0.4
Age at menarche (y)
Girls 87 11.5 60.8 12.7 60.7 13.9 60.9 ,0.0001
BMI SD score 1 y before ATO
Girls 107 20.05 60.84 0.12 61.00 20.33 61.10 0.2
Boys 108 0.07 61.05 0.05 61.04 20.36 60.90 0.2
Body fat 1 y before ATO (%)
5
Girls 107 18.0 (14.3, 19.7) 16.7 (14.6, 22.6) 16.3 (14.1, 20.5) 0.8
Boys 108 13.7 (12.3, 22.3) 15.7 (13.3, 23.2) 14.8 (12.9, 18.4) 0.4
1
ATO groups were defined as follows: early (ATO ,25th sex-specific percentile), middle (ATO 25th and 75th sex-specific percentile), and late (ATO
.75th sex-specific percentile).
2
Significant differences between groups were tested by ANOVA for normally distributed continuous variables and Kruskal-Wallis tests for nonnormally
distributed continuous variables.
3
Median; quartiles 1 and 3 in parentheses (all such values).
4
Mean 6SD (all such values).
5
Defined by using Slaughter’s equations for prepubertal children (17).
TABLE 3
Linear mixed models of the association between early life factors and age
at take-off of the pubertal growth spurt (ATO) in a DONALD (DOrtmund
Nutritional and Anthropometric Longitudinally Designed) Study sample
(n= 215)
ATO
1
Pvalue
Multivariate model
Sex (reference category: male) 21.57 60.13 ,0.0001
Birth weight category
(reference category: 3000 g)
20.56 60.20 0.006
Rapid weight gain (reference
category: normal weight gain)
20.34 60.15 0.02
Pathway model
Sex (reference category: male) 21.56 60.12 ,0.0001
Birth weight category
(reference category: 3000 g)
20.63 60.20 0.002
Rapid weight gain (reference
category: normal weight gain)
20.27 60.15 0.07
BMI SD score 1 y before ATO 20.13 60.06 0.03
1
Values are bs6SEs. To account for the clustered nature of our data,
“family” was modeled as a random effect. This set up a common correlation
between all observations and individuals who belonged to the same family.
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The pathway model in Tables 3–5 shows the effect of in-
troducing BMI SDS 1 y before ATO to the multivariable models,
to investigate the role of prepubertal body composition. In the
case of ATO (Table 3), the inclusion of the BMI SDS variable did
not influence the effect of birth weight, but attenuated the effect
of rapid weight gain. In the APHV (Table 4) and menarche (Table
5) models, inclusion of the BMI SDS variable only marginally
influenced the effect of rapid weight gain. However, the effect of
having a lower birth weight reappeared; these children experi-
enced APHV 20.42 60.20 y (ie, 5 mo) earlier (P= 0.04) and,
in girls, menarche 0.68 60.29 y (ie, 8 mo) earlier (P= 0.02)
than did the other children. Similar results were achieved when
BMI SDS 2 or 3 y before ATO or BF% 1, 2, or 3 y before ATO
were used to represent prepubertal body composition. Adjust-
ment for length of gestation did not change the findings de-
scribed above (data not shown).
In a final step, we considered the possible interaction between
birth weight category and weight gain to identify any particularly
susceptible subgroups. As can be seen in Figure 1, those children
with a low birth weight and rapid weight gain in the first 2 y of
life experienced ATO 1.11 60.25 y, APHV 1.14 60.26 y, and
menarche 1.68 60.35 y earlier than did children with a birth
weight 3000 g and normal weight gain between birth and 24
mo (reference group).
DISCUSSION
With the use of prospectively collected growth and puberty
data from 215 boys and girls, we could show that early life
exposures, in particular a relatively low birth weight and rapid
weight gain between birth and 24 mo, were independently as-
sociated not only with an earlier age at PHV or menarche (in
girls), both of which indicate a more advanced stage of pubertal
maturation, but also with an earlier age at take-off of the pubertal
growth spurt—one of the earliest markers of puberty onset. This
was the case in both girls and boys. Furthermore, these associ-
ations were essentially independent of measures of prepubertal
body composition 1, 2, or 3 y before ATO.
The consistent and independent association of both a relatively
low birth weight and rapid weight gain between birth and 24 mo
with an earlier ATO, APHV, and menarche extends the findings of
other studies by showing that these factors are also of relevance
for a very early, relatively unstudied marker of pubertal onset, ie,
ATO. With respect to menarche, our results support the findings
of some, but not all, studies previously reported. Despite their
developing country population, the findings of Adair et al (7) are
the most similar to ours. They showed that those girls who were
long and thin at birth experienced an earlier menarche, and that
this effect of birth size was potentiated by rapid growth in the first
6 mo postnatally (itself an independent determinant of age at
menarche). In our study, investigation of the interaction between
birth weight and weight gain showed that the most vulnerable
group, regardless of the puberty outcome being considered, were
indeed those with a low birth weight who went on to gain weight
rapidly between birth and 24 mo. Two other studies also showed
a possible additive effect of birth weight combined with accel-
erated postnatal growth on age at menarche. The earliest age at
menarche was found in those girls with the lowest birth weight
and highest BMI at age 8 y (11, 12). In contrast, dos Santos Silva
et al (9) initially found opposing effects of prenatal and early
postnatal growth on the timing of menarche, but these effects
disappeared once growth in childhood (2–7 y) was adjusted for.
In this analysis, the effect of the early life exposures remained of
relevance for both early and later markers of puberty, even after
prepubertalBMI SDSor BF%was adjustedfor.The findingsof Adair
et al (7) also remained unmodified by the inclusion of BMI and
skinfold thicknesses at age 8 y. This somewhat contradicts the
suggestion that the timing of menarche, for example, may be set in
TABLE 4
Linear mixed models of the association between early life factors and age
at peak height velocity (APHV) in a DONALD (DOrtmund Nutritional and
Anthropometric Longitudinally Designed) Study sample
(n= 208)
APHV
1
Pvalue
Multivariate model
Sex (reference category: male) 21.85 60.13 ,0.0001
Birth weight category (reference
category: 3000 g)
20.32 60.21 0.1
Breastfed 4 mo (reference
category: no)
0.14 60.13 0.3
Rapid weight gain (reference
category: normal weight gain)
20.54 60.16 0.0006
Maternal BMI 20.03 60.02 0.1
Pathway model
Sex (reference category: male) 21.81 60.13 ,0.0001
Birth weight category
(reference category: 3000 g)
20.42 60.20 0.04
Breastfed 4 mo (reference
category: no)
0.09 60.13 0.5
Rapid weight gain (reference
category: normal weight gain)
20.45 60.15 0.004
Maternal BMI 20.01 60.02 0.5
BMI SD score 1 y before ATO 20.22 60.07 0.002
1
Values are bs6SEs. To account for the clustered nature of our data,
“family” was modeled as a random effect. This set up a common correlation
between all observations and individuals who belonged to the same family.
TABLE 5
Linear mixed models of the association between early life factors and age
at menarche in a DONALD (DOrtmund Nutritional and Anthropometric
Longitudinally Designed) Study subsample (n= 87)
Age at menarche
1
Pvalue
Multivariate model
Birth weight category
(reference category: 3000 g)
20.49 60.29 0.1
Rapid weight gain (reference
category: normal weight gain)
20.82 60.25 0.002
Maternal overweight (reference
category: no)
20.52 60.24 0.03
Pathway model
Birth weight category (reference
category: 3000 g)
20.68 60.29 0.02
Rapid weight gain (reference
category: normal weight gain)
20.60 60.26 0.02
Maternal overweight (reference
category: no)
20.42 60.23 0.07
BMI SD score 1 y before ATO 20.28 60.12 0.02
1
Values are bs6SEs. To account for the clustered nature of our data,
“family” was modeled as a random effect. This set up a common correlation
between all observations and individuals who belonged to the same family.
EARLY LIFE EXPOSURES AND PUBERTY ONSET 1563
by guest on June 22, 2013ajcn.nutrition.orgDownloaded from
utero but modified by changes in body size and composition in
childhood (9) and, instead, suggests that early life factors could
influence the timing of puberty via a pathway other than the one that
leads via increased fat mass (24). We should point out, however, that
we used BMI and BF% estimated from skinfold-thickness meas-
urements to represent prepubertal body composition. We cannot
thereforeexclude the possibility thatthese crude markers of fat mass
concealed a true role of prepubertal body composition.
It has been suggested that lower birth weight results in an
earlier, more rapid progression through puberty because those
with the lowest birth weights reached menarche, which com-
monly occurs after PHV, earlier (8). However, by considering the
effect of early life exposures on both early and late pubertal
markers, we showed that one of the earliest indicators of pubertal
onset, ATO, occurs earlier too. This suggests that these children
do not necessarily experience a more rapid progression through
puberty, but rather a general shift to the left of pubertal de-
velopment as a whole, so that everything occurs at a younger age.
Lazar et al (25) showed a similar phenomenon but used the
association between Tanner stage, as a marker of puberty onset,
and menarche.
A significant degree (50–80%) of variability in pubertal timing
has been attributed to genetic differences between individuals
(26). Not being able to directly adjust for such factors (eg,
mother’s age at menarche) may therefore be seen as a limitation
of this analysis. However, the secular trend that has been observed
over the past 200 y, ie, a decrease in the age at menarche both in
the United States (27) and in Europe (28), suggests that factors
other than genetics must also have a role to play because the gene
pool alone has not really had a sufficient time to respond (24).
The strengths of this study include the availability of detailed,
prospectively collected height measurements from birth until
early adulthood in a sample of both boys and girls. Consequently,
both early and later markers of puberty could be estimated on the
basis of the pubertal growth curve, and we were not reliant on
either recall of pubertal events or more subjective markers of
puberty such as Tanner stage (29). Also, the consistency in the
results shown between the different pubertal variables clearly
supports their accuracy. The fact that we included birth variables,
as well as growth in infancy and prepubertal body composition,
meant that we could more closely investigate the role of each of
these components in pubertal timing. Finally, we could also
adjust for many potential confounders related to parental char-
acteristics and socioeconomic status.
The public health relevance of a difference in age at pubertal
onset of 4 to 7 mo remains to be addressed. Early age at puberty is
an established risk factor for many hormone-related cancers,
including breast (1, 2) and testicular cancer (30, 31), and has also
been linked to insulin resistance (4), higher insulin-like growth
factor I concentrations, and other hormonal changes associated
with cancer risk, obesity (32), and, more recently, mortality (33).
If one takes the example of breast cancer, the most common
cancer in women, a meta-analysis of 26 epidemiologic studies
showed a risk reduction of 9% for every additional year at
menarche (34). Breast cancer was diagnosed in more than
a million women worldwide in 2002 (35), so a difference in age at
menarche of 6 mo could result in a risk reduction of 4.5% or
40,000 fewer cases, provided steps were taken to prevent low
birth weight or to monitor growth in infancy.
In this study we have identified early life factors that increase
a child’s risk of beginning puberty early. Furthermore, we have
shown that these factors act independently of prepubertal body
composition. These findings have important implications,
FIGURE 1. Least-squares mean (6SE) differences in age at take-off of
the pubertal growth spurt (A; n= 215), age at peak height velocity (B; n=
208), and age at menarche in girls only (C; n= 87) between subgroups of
growth velocity and birth weight. Differences are between the reference
group (normal weight gain, birth weight 3000 g; NN) and the other
subgroups: normal weight gain, birth weight between 2500 and ,3000 g
(NL); rapid weight gain, birth weight 3000 g (RN); and rapid weight gain,
birth weight between 2500 and ,3000 g (RL). See Tables 3–5 for
information on the multivariate models used for prediction. Pfor
interaction = 0.1 (A), 0.04 (B), and 0.01 (C). *Significantly different from
the reference group, P,0.05.
1564 KARAOLIS-DANCKERT ET AL
by guest on June 22, 2013ajcn.nutrition.orgDownloaded from
especially in view of the secular trend in pubertal onset. More
studies are needed to identify the mechanisms by which these
factors might operate.
The participation of all children and their families in the DONALD Study is
gratefully acknowledged. We also thank the staff of the Research Institute of
Child Nutrition for carrying out the anthropometric measurements and med-
ical examinations.
The authors’ responsibilities were as follows—NK-D and AK: conceived
the research project and acquired the funding; NK-D and AS: performed the
initial statistical analyses; NK-D: performed further analyses and drafted the
manuscript; and AEB and AK: supervised the project. All authors contributed
to the interpretation of the results and to critical revision of the manuscript.
None of the authors had any personal or financial conflicts of interest.
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... Information on parental smoking status and maternal social capital was from the first survey. These variables were included regarding previous research (27,28). Rapid weight gain during the first two years of life is linked to earlier pubertal timing (28). ...
... These variables were included regarding previous research (27,28). Rapid weight gain during the first two years of life is linked to earlier pubertal timing (28). Children from father-absent households are more likely to be bottle-fed during infancy, which is associated with rapid weight gain in the first year of life (29). ...
... Overweight at age 4.5 was determined as BMI z score of 1SD or more according to WHO criteria (26). Rapid weight gain was determined as gaining more than 0.67 SD of weight from birth to age 1.5 years old (28). ...
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Introduction Previous studies have shown that paternal absence leads to earlier pubertal timing among girls in high-income countries. Despite the low divorce rate in Japan, paternal separation is commonly seen due to a unique corporation system, tanshin funin , where employees relocate with their spouses and children. We examined paternal separation, including paternal absence (due to divorce or paternal death) and paternal tanshin funin , during early childhood as a predictor of earlier girl’s pubertal development, assessed as age at peak height velocity (PHV). Methods This study examined 15 214 girls from a longitudinal survey conducted in Japan from 2001 to 2016 by the Ministry of Health, Labor and Welfare. Paternal separation was determined by the occurrence through annual surveys conducted at ages 0.5 to 4.5 years. Outcome was defined as age at PHV between ages 6 to 15 years. We conducted linear regression, adjusted for potential confounders and other covariates. Results Continuous father cohabitation was seen in 88.7% of households, while paternal separation was experienced 1-2, 3-4 and 5 times (always) among 7.4%, 2.8% and 1.1% of households, respectively. Girls who confronted continuous paternal separation (5 times) experienced 0.42 years earlier [95% confidence interval (CI): -0.75, -0.10] age at PHV compared to their peers who always lived with their fathers. Conclusion Girls who experienced paternal separation throughout ages 0.5 to 4.5 years experienced PHV earlier.
... Previous studies have reported that infant catchup growth is associated with earlier puberty [8][9][10][11][12][13]. However, these studies have several methodological limitations. ...
... Several previous studies have demonstrated that girls with catch-up growth from birth to about age 2 years experienced earlier pubertal timing [8,9,12,51]. In a longitudinal study of 215 German children, those with catchup growth between birth and 24 months experienced earlier puberty (measured as pubertal growth spurt, age at peak height velocity, and menarche), all independent of pre-pubertal BMI [9]. ...
... Several previous studies have demonstrated that girls with catch-up growth from birth to about age 2 years experienced earlier pubertal timing [8,9,12,51]. In a longitudinal study of 215 German children, those with catchup growth between birth and 24 months experienced earlier puberty (measured as pubertal growth spurt, age at peak height velocity, and menarche), all independent of pre-pubertal BMI [9]. A more recent population-based cohort study in Denmark also found that an increase in weight z-score from 0 to 12 months was associated with earlier pubertal development (self-reported SMR and other hallmarks) [8]. ...
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Background: Early puberty increases risk of adverse health conditions throughout the life course. US girls are experiencing earlier puberty without clear reasons. Studies suggest early life factors, such as infant growth, may influence pubertal timing. We assessed the associations between infant growth and onset of breast development (thelarche), pubic hair development (pubarche), and menarche in girls. Methods: A prospective cohort of girls born at a Kaiser Permanente Northern California medical facility in 2005-11 was used. Weight-for-age z-scores were calculated at birth and 24 months. Difference in z-scores greater than 0.67 represent rapid "catch-up" growth, less than -0.67 represent delayed "catch-down" growth, and between -0.67 and 0.67 represent "normal" growth. Pubertal onset was measured using clinician-assessed sexual maturity ratings (SMRs) and defined as the age at transition from SMR 1 to SMR 2 + for both thelarche and pubarche. SMR data was collected through June 2020. Menarche was analyzed as a secondary outcome. Weibull and modified Poisson regression models were used. Models were adjusted for potential confounders. Results: There were 15,196 girls included in the study. Approximately 30.2% experienced catch-up growth, 25.8% experienced catch-down growth, and 44% had normal growth. Girls with catch-up growth had increased risk of earlier thelarche (hazard ratio = 1.26, 95% confidence interval (CI): 1.18, 1.35), pubarche (1.38, 95% CI: 1.28, 1.48), and menarche (< 12y, relative risk = 1.52, 95% CI: 1.36, 1.69) compared to those with normal growth, after adjusting for covariates. These associations were partially mediated by childhood body mass index. Catch-down growth was associated with later pubertal onset. Conclusions: Girls who experience infant catch-up growth have higher risk of earlier pubertal development compared to girls with normal growth and the associations are partially explained by childhood obesity. This information may help clinicians to monitor girls who are at high risk of developing earlier.
... We selected these covariates based on previous publications that found an association between child growth and pubertal onset. [34][35][36][37][38][39][40] ...
... 34 Similar results have been reported in other studies with longer age intervals, including from birth to 12 months in the Danish National Birth Cohort 35 and the Birth to Twenty cohort, 39 from birth to 20 months in the Avon Longitudinal Study of Parents and Children, 38 and from birth to 24 months in the Dortmund Nutritional and Anthropometric Longitudinally Designed study. 36 Findings from the North Carolina Infant Feeding study also showed that greater weight gains during infancy and early childhood were associated with earlier menarche and more advanced pubic hair development. 40 The clinical implications of earlier menarche are well known; it has been shown to increase the risks of breast cancer and coronary heart disease in adulthood. ...
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Importance: Earlier pubertal onset may be associated with an increased risk of chronic diseases. However, the extent to which growth in the first 5 years of life-an important developmental life stage that lays the foundation for later health outcomes-is associated with pubertal onset remains understudied. Objective: To assess whether changes in weight, length or height, and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) during the first 5 years of life are associated with earlier pubertal onset. Design, setting, and participants: This cohort study used data from 36 cohorts participating in the Environmental Influences on Child Health Outcomes program from January 1, 1986, to December 31, 2015. Participant inclusion required at least 1 anthropometric measure in the first 5 years of life and at least 1 measure of pubertal onset. Data were analyzed from January 1 to June 30, 2021. Exposures: Standardized velocities of weight, length or height, and BMI gain in early infancy (0-0.5 years), late infancy (0.5-2 years), and early childhood (2-5 years). Main outcomes and measures: Markers of pubertal onset for boys and girls, including age at peak height velocity (APHV), time to puberty score greater than 1, time to Tanner pubic hair stage greater than 1, and time to menarche. Multivariable regression models were used to estimate mean differences in APHV by growth periods. Results: Of 7495 children included in the study, 3772 (50.3%) were girls, 4505 (60.1%) were White individuals, and 6307 (84.1%) were born during or after the year 2000. Girls had a younger APHV (10.8 vs 12.9 years) than boys. In boys, faster weight gain (per 1-SD increase) in early infancy (β, -0.08 years; 95% CI, -0.10 to -0.06), late infancy (β, -0.10 years; 95% CI, -0.12 to -0.08), and early childhood (β, -0.07 years; 95% CI, -0.08 to -0.05) was associated with younger APHV after adjusting for the child's birth year, race, and Hispanic ethnicity as well as maternal age at delivery; educational level during pregnancy; annual household income during pregnancy; prenatal cigarette smoking; whether the mother was nulliparous; whether the mother had gestational diabetes, hypertension, or preeclampsia; mode of delivery; prepregnancy BMI; gestational weight gain; and gestational age at delivery. Similar associations were observed for length or height and BMI gains during the same age periods. In girls, faster gains (per 1-SD increase) in weight (β, -0.03 years; 95% CI, -0.05 to -0.01) and height (β, -0.02 years; 95% CI, -0.04 to 0.00) in early childhood were associated with younger APHV. Faster BMI gain in late infancy was associated with earlier time to menarche, whereas faster BMI gain in early childhood was associated with earlier time to Tanner pubic hair stage greater than 1. Conclusions and relevance: This cohort study found that faster gains in weight, length or height, or BMI in early life were associated with earlier pubertal onset. The results suggest that children who experience faster early growth should be monitored closely for earlier onset of puberty and referred as appropriate for supportive services.
... Studies indicate that a larger gain in BMI during childhood whether in the first 20 months [8], in the first 5 years [9] or between the ages of two and eight years [10] is related to an earlier onset of puberty. There also appears to be a relationship between age of pubertal onset and weight at birth [9,11]. ...
... This result could be indicative of a further contribution of weight gain after entering puberty in determining the age of onset of menarche and in regulating the end of pubertal growth. We ascertained a statistically valid relationship between the tempo of puberty and the Z-score change between BW and BMI at B2 (R: 0.20; p < 0.0001) (Fig. 2b) (Table 2) suggesting that weight gain in the first years of life has a significant effect on the timing of puberty (11)(12)(13). ...
Article
Objective: over the last few decades there has been a progressive decline in the average age of onset of pubertal development stages in both sexes. The increase in the prevalence of childhood obesity seems to play an important role in this phenomenon. Design: we undertook a retrospective, longitudinal evaluation of the average age of thelarche and menarche to evaluate the relationship between BMI and weight change during the first years of life and the timing and tempo of puberty. Methods: we evaluated data for 577 Italian girls born between 1995 and 2003. We collected the main auxological and clinical parameters, including age at B2 and at menarche, BMI SDS at B2 and menarche, gestational age and birth weight and Z-score change from birth weight (BW) to BMI at B2 and menarche. Results: the mean age of B2 was 10.06 ± 1.03 years and the mean age of menarche was 12.08 ± 1.02 years. Age at B2 and menarche were inversely correlated with BMI SDS (p < 0.0001). Both age at menarche and at thelarche have an inverse relationship with the Z-score change from birth weight and BMI at menarche and thelarche respectively (p < 0.0001). Conclusions: our data confirm a significant relationship between BMI and age of B2 and menarche. We observed a clear relationship among weight change during the first years of life, age at thelarche and menarche and the duration of puberty, demonstrating the importance of weight and weight gain in determining the timing and tempo of pubertal changes and growth.
... In terms of pubertal onset, an important link between nutrition and puberty lies in the relation between overfeeding and the consequent weight gain and obesity development [107]. Indeed, a low birth weight, followed by rapid weight gain and high body weight in infancy and childhood, has been correlated with an early onset of puberty and early menarche [2,102,[118][119][120]. It is important to underline that nutrition can influence pubertal timing independently of weight gain, for instance, acting on infant-parent attachment [121][122][123]. ...
... Different studies have attempted to evaluate the influence of breastfeeding on the process of pubertal development, but the results are not always coherent. Two European cohort studies examining the relationship between breastfeeding and early puberty onset did not find an association between breastfeeding and menarche age [119,127]. Breastfeeding was not associated with pubertal age in non-Western settings either, suggesting that the correlation may vary by context [128]. In a recent population-based cohort study in 13,511 boys and girls, a shorter duration of breastfeeding was associated with earlier pubertal development in boys but not in girls. ...
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Puberty is a critical phase of growth and development characterized by a complex process regulated by the neuroendocrine system. Precocious puberty (PP) is defined as the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal. The timing of puberty has important public health, clinical, and social implications. In fact, it is crucial in psychological and physical development and can impact future health. Nutritional status is considered as one of the most important factors modulating pubertal development. This narrative review presents an overview on the role of nutritional factors as determinants of the timing of sexual maturation, focusing on early-life and childhood nutrition. As reported, breast milk seems to have an important protective role against early puberty onset, mainly due to its positive influence on infant growth rate and childhood overweight prevention. The energy imbalance, macro/micronutrient food content, and dietary patterns may modulate the premature activation of the hypothalamic–pituitary–gonadal axis, inducing precocious activation of puberty. An increase in knowledge on the mechanism whereby nutrients may influence puberty will be useful in providing adequate nutritional recommendations to prevent PP and related complications.
... There also appears to be a relationship between age of pubertal onset and weight at birth. [9,11] Insulin resistance and excess hepato-visceral fat may play an important role in determining the appearance of the rst signs of pubertal development. The early appearance of pubertal development signs could be an escape mechanism to minimise increases in central ectopic fat [12] in which the organism anticipates sexual development and the growth spurt to avoid the further accumulation of fat. ...
... This result could be indicative of a further contribution of weight gain after entering puberty in determining the age of onset of menarche and in regulating the end of pubertal growth. We ascertained a statistically valid relationship between the tempo of puberty and the Zscore change between BW and BMI at B2 (R: 0.20; p < 0.0001) suggesting that weight gain in the rst years of life has a signi cant effect on the timing of puberty (11)(12)(13) (Fig. 2b). ...
Preprint
Full-text available
Objective over the last few decades there has been a progressive decline in the average age of onset of pubertal development stages in both sexes. The increase in the prevalence of childhood obesity seems to play an important role in this phenomenon. Design we undertook a retrospective, longitudinal evaluation of the average age of thelarche and menarche to evaluate the relationship between BMI and weight change during the first years of life and the timing and tempo of puberty. Methods we evaluated data for 577 Italian girls born between 1995 and 2003. We collected the main auxological and clinical parameters, including age at B2 and at menarche, BMI SDS at B2 and menarche, gestational age and birth weight and Z-score change from birth weight (BW) to BMI at B2 and menarche. Results the mean age of B2 was 10.06 ± 1.03 years and the mean age of menarche was 12.08 ± 1.02 years. Age at B2 and menarche were inversely correlated with BMI SDS (p < 0.0001). Both age at menarche and at thelarche have an inverse relationship with the Z-score change from birth weight and BMI at menarche and thelarche respectively (p < 0.0001). Conclusions our data confirm a significant relationship between BMI and age of B2 and menarche. We observed a clear relationship among weight change during the first years of life, age at thelarche and menarche and the duration of puberty, demonstrating the importance of weight and weight gain in determining the timing and tempo of pubertal changes and growth.
... Pre-and postnatal growth patterns (birth weight and early catch up growth) have been associated with timing of puberty(4) , (5), but some of the epidemiological studies are conflicting. Some studies have shown associations between low birth weight and earlier menarche (6,7), i.e. a large study of more than 90,000 UK women showed that menarche occurred earlier in those born with low birth weight (8). ...
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Context Controversy exists regarding associations between early life growth patterns and timing of puberty. Objective To investigate associations between birth anthropometry, early growth patterns and onset/progression of pubertal milestones in boys and girls. Design and Participants Among children examined at birth (1997-2003) and at 36 months of age in a mother child cohort, pubertal Tanner stages (B1-5, PH1-5, G1-5) and testicular volume were examined by trained physicians at 1-5 follow-up examinations during childhood and adolescence (672 girls and 846 boys, 2006-2013). Main Outcome Measures With parametric survival models we analyzed associations between birth weight, changes in standard deviation scores (SDS) from birth to 36 months (Δ SDS 0-36 >0.67 SD defining catch up growth), and age at pubertal onset/attainment of late pubertal stages /menarche. Results A 1 kg higher birth weight was associated with earlier onset of B2+ (thelarche): -3.9 months (CI: -6.7; -1.1), G2+ (gonadarche): -2.7 months (-5.3;-0.1), Tvol3+ (testis size > 3ml):-2.8 months (-4.9; -0.7), but with later G4+ and PH4+ in boys, and a slower progression from B2 to menarche (5.3 months (1.2; 9.4)) in girls. Catch up growth was associated with earlier PH2+ (pubarche) in girls (-4.1 months (-7.6;-0.6)), earlier PH2+ in boys (-3.4 months (-6.6;-0.2)), faster progression from B2 to menarche in girls (-9.1 months (14.6; 3.5)) and earlier G4+ and PH4+ in boys. Conclusions Associations between birthweight and infancy catch up growth differed for gonadarche and pubarche, and for early and late pubertal markers, with similar patterns in both sexes.
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We outline an operationalization and extension of the thrifty phenotype and fetal overnutrition hypotheses, two developmental hypotheses stemming from the developmental origins of health and disease (DOHaD) perspective, for developmental pathways from preconception and prenatal risk through child growth to early puberty. The available evidence suggests that both the thrifty phenotype and fetal overnutrition pathways have direct and indirect effects on child growth and pubertal timing, with potential moderating effects of sex and race. Further investigating the hypothesized pathways will be helpful toward identifying youth who are at high risk of earlier pubertal timing, who may be on trajectories leading to poor health in adolescence and adulthood. Future studies should investigate the role of the pathways in predicting mental and physical health outcomes which may lead to a better understanding of health trajectories across the life course.
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Background : Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown. Methods : A retrospective review was performed of patients age >8 years with PIF managed at an intestinal rehabilitation program. Outcomes of interest were peak height velocity (PHV), age at PHV, and age at pubertal onset (Tanner stage 2). Outcomes were stratified by sex and compared to established norms. Results : Of 110 patients with PIF, 54.5% were male. Compared to the CDC 50th percentile, PHV in PIF patients was similar for females (8.09±2.36 vs. 7.37cm/yr;p=0.23) but significantly higher for males (9.27±2.56 vs. 7.91cm/yr;p=0.038). Age at PHV in PIF patients was significantly younger for both males (12.31±2.14 vs. 13.38 years;p=0.049) and females (10.70±1.06 vs. 11.71 years;p=0.001). PIF patients reached pubertal onset earlier than published norms; this was significant for males (12.41±1.80 vs. 13.44 years;p=0.014), but not for females (10.45±1.81 vs. -11.15 years;p=0.13). The mean height-for-age Z-score was -1.2, with 20% of patients having a Z-score less than -2. Conclusions : Pubertal onset and growth are neither delayed nor diminished in patients with PIF. The high incidence of short stature, however, highlights the importance of optimizing prepubertal linear growth to attain full height potential.
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Background Heavier body mass index (BMI) is the most established predictor of earlier age at puberty. However, it is unknown whether the timing of the childhood switch to heavier BMI (age at BMI rebound) also matters for puberty. Methods In the LEGACY Girls Study (n = 1040), a longitudinal cohort enriched with girls with a family history of breast cancer, we collected paediatric growth chart data from 852 girls and assessed pubertal development every 6 months. Using constrained splines, we interpolated individual growth curves and then predicted BMI at ages 2, 4, 6, 8 and 9 years for 591 girls. We defined age at BMI rebound as the age at the lowest BMI between ages 2 and 8 years and assessed its association with onset of thelarche, pubarche and menarche using Weibull survival models. Results The median age at BMI rebound was 5.3 years (interquartile range: 3.6–6.7 years). A 1-year increase in age at BMI rebound was associated with delayed thelarche (HR = 0.90; 95% CI = 0.83–0.97) and menarche (HR = 0.86; 95% CI = 0.79–0.94). The magnitude of these associations remained after adjusting for weight between birth and 2 years, was stronger after adjusting for BMI at age 9, and was stronger in a subset of girls with clinically assessed breast development. Conclusions Earlier BMI rebound is associated with earlier pubertal timing. Our observation that BMI rebound may be a driver of pubertal timing in girls with and without a family history of breast cancer provides insight into how growth and pubertal timing are associated with breast cancer risk.
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Background In recent studies a larger birth size has been shown to delay the timing of menarche. The mechanisms underlying this association are not clear, however, as birthweight is a predictor of body size in childhood, and a large body size is known to be associated with an early onset of menarche. Methods Data from a representative British cohort of 2547 girls born in 1946 who were followed prospectively throughout childhood were used. Information was available on prenatal characteristics, birthweight, height, weight and social circumstances during childhood, and on age at menarche. Random coefficients models were used to estimate the individual trajectories in height and body mass index (BMI) up to age 7 years. The parameters identified by these models were then included in Weibull survival models for the timing of menarche together with birthweight. Results Birthweight was found to positively influence height and BMI values at age 2 years, but not to affect their rates of change from age 2 to 7 years. Initial analyses showed low birthweight to be associated with an early onset of menarche, but after controlling for growth in infancy this effect was reversed, with girls who were heavy at birth reaching menarche earlier than others with similar infant growth. Rapid growth in infancy was also related to early pubertal maturation. The effects of birthweight and infant growth disappeared, however, when further controlled for growth from age 2 to 7 years. Conclusions The effects of birthweight and growth in infancy on the timing of menarche seem to be mediated through growth in early childhood. These findings are consistent with the possibility that timing of menarche may be set in utero or early in life, although it may be modified by changes in body size and composition in childhood.
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BACKGROUND Breast carcinoma risk may be modified by early life factors, including physical growth and development, diet, and life-style factors of preadolescence and adolescence, as well as genetic factors.METHODS The authors tested their hypothesis that adolescent growth and development are related to breast carcinoma incidence by evaluating 65,140 women who participated in the Nurses' Health Study. During 16 years of follow-up, 806 women were diagnosed with breast carcinoma prior to menopause, and another 1485 were diagnosed after menopause. Because adolescent growth was not directly observed in this cohort, the peak height growth velocity for each participant was estimated by using a model from another longitudinal study. Finally, Cox proportional hazards regression models were used to study associations between breast carcinoma incidence and adolescent factors in the Nurses' Health Study.RESULTSLater menarche (relative risk [RR] = 0.52 for ≥15 vs. ≤11 years) and more body fatness at age 10 years (RR = 0.60 for fattest vs. leanest) were associated with a decreased risk of premenopausal breast carcinoma. The risk of postmenopausal breast carcinoma was lower for girls with later menarche (RR = 0.80), more body fat at age 10 years (RR = 0.72), and shorter adult height (RR = 1.29 for ≥67 vs. ≤62 inches). Higher peak height growth velocity, derived from these 3 variables, was associated with increased risk of both premenopausal (RR = 1.31 for highest vs. lowest quintile) and postmenopausal (RR = 1.40) breast carcinoma. These analyses controlled for birth cohort, other possible risk factors from the adolescent period, and family history. These associations persisted after controlling for age at the birth of a first child, parity, adult adiposity, and age at menopause. Post-hoc analyses suggested that, although childhood body fatness was associated with lower risk, increasing body fatness between ages 10 and 20 years was not protective against either premenopausal or postmenopausal breast carcinoma.CONCLUSIONS Earlier menarche, extremely lean body mass at age 10 years, and taller adult height were predictive of elevated breast carcinoma risk. The same three factors were also predictive of higher peak growth velocities during adolescence, lending credence to the hypothesis that more rapid adolescent growth may increase the risk of breast carcinoma development. Cancer 1999;85:2400–9. © 1999 American Cancer Society.
Article
Objective To study the influence of birthweight, and weight and height at age seven years, on menarcheal age in a national sample of 1471 girls in England, Scotland and Wales. Methods We studied 1471 girls included in the MRC National Survey of Health and Development. During medical examinations carried out by school doctors in this cohort, born in the first week of March 1946, the mothers of girls were asked whether their daughters had started to menstruate, and if so, the month and year when this happened. Anthropometric measurements at birth and at age seven years were also obtained. Results Girls who were heavier at age seven years had menarche at an earlier age. The average age at menarche of those in the highest fifth of the distribution of weight at seven years was 7.3 months less than that of those in the lowest fifth of the distribution. In contrast, girls who were heavier at birth had menarche at a later age. The average age at menarche of those in the highest fifth of the birthweight distribution was 2.2 months more than those in the lowest fifth. These opposing trends of birthweight and weight at seven years on age at menarche were observed across the distribution of each variable, and exerted statistically significant (P < 0.001) independent effects in a multivariate model. Conclusions These observations are consistent with the hypothesis that menarcheal age is linked to programmed patterns of gonadotrophin release established in utero, when the fetal hypothalamus is imprinted, and is subsequently modified by weight gain in childhood.