DOI: https://doi.org/10.21203/rs.3.rs-1668736/v1
Purpose: If children show inadequate infant weight gain, their growth velocity will also decrease, especially £3 years of age. We hypothesized that such children may not only lead to being underweight but also short stature during childhood, and this trend will follow them through adolescence.
Methods: A total of 271 children were enrolled. The Pearson correlation coefficients were calculated to determine the relationships of the increment of weight gain £3 years, from birth to 1.6 years and from 1.6 years to 3 years of age, with height and weight at 3, 7 years and pubertal age, respectively.
Results: The Pearson correlation coefficients between weight gain each of from birth to 1.6 years and from 1.6 years to 3 years of age and weight at pubertal age were 0.34 and 0.37 in boys and 0.47 and 0.48 in girls, and height at pubertal age were 0.34 and 0.24 in boys and 0.65 and 0.40 in girls, respectively.
Conclusions: Insufficient weight gain in children £3 years, especially £1.6 years is not only associated being underweight, but also short stature at 3 and 7 years and at the onset of puberty and it is also suspected that adult height and weight may be affected.
Karlberg developed the infancy-childhood-puberty (ICP) growth model that describes human growth from the latter half of the intrauterine life to adolescence [1]. The components of infancy, childhood and puberty periods depend on nutrition, growth hormone (GH) and synergism between sex steroids and GH, respectively. The periods of infancy and childhood are defined as the latter half of the intrauterine life to approximately 3 years of age and from about 1.5 years of age to the adolescent years, respectively. There are some children who have shown insufficient weight gain at ~1 year of age, just after weaning begins. If such children show inadequate weight gain because of poor dietary intake, their growth velocity will also decrease, especially under the age of 3 years.
It has been reported that stunted growth related to environmental enteric dysfunction (EED) which is commonly defined as an acquired subclinical disorder of the small intestine, is characterized by villous atrophy and crypt hyperplasia, especially among children in developing countries [2]. Nutrient deprivation increases growth hormone and decreases insulin, which promotes lipolysis and depletes white adipose fat stores, thereby reducing adipocyte-derived leptin levels. Hypoleptinemia downregulates the hypothalamic-pituitary-thyroid axis and inhibits conversion of thyroxine to its more active form, triiodothyronine. The fall in triiodothyronine impairs chondrocyte maturation and growth. The stress of acute malnutrition activates the hypothalamic-pituitary-adrenal axis and stimulates a rise in cortisol and IGF binding protein 1, which in combination inhibits IGF-1 action and induces chondrocyte apoptosis. Furthermore, Fibroblast growth factor 21 (FGF21) inhibits bone growth by antagonizing GH effects on chondrocyte proliferation and differentiation. Increased FGF21 during nutrient deprivation may contribute to growth failure by directly inhibiting chondrogenesis in patient with EED [2-4]. Such mechanism explains how nutrient deprivation leads to stunted growth.
We hypothesized that insufficient weight gain in infants and toddlers may not only lead to being underweight but also short stature during childhood, and this trend will follow them through adolescence. To date, this hypothesis has not been validated. Therefore, we performed a preliminary investigation on the relationship of incremental weight gain under 3 years with height and weight in children from the age of 3 years to pubertal age. The data presented below represents initial auxological findings about the relationship between weight gain and stature in children.
A total of 271 healthy children (147 boys and 124 girls) born in Tochigi prefecture in Japan between 1995 and 1996 were enrolled in the study. Length or height and weight were measured at the following ages: birth, 1.6 years, 3 years and 7 years in both boys and girls; 10 years in girls, and 12 years for boys, which coincide with the onset of puberty in girls and boys in Japan, respectively [5]. The Pearson correlation coefficients were calculated to determine the relationships of the increment of weight gain under 3 years with height and weight at 3 years, 7 years, and pubertal age, respectively. We examined the incremental weight gain in two groups by age. One is a group aged from birth to 1.6 years, which corresponds to Karlberg’s infancy period, which is more affected by nutrition. The other group included children from 1.6 to 3 years.
Written informed consent for physical examinations was obtained from parents or guardians. The study was approved by the ethics committee of Dokkyo Medical University (approval number 23020).
The Pearson correlation coefficients between weight gain from birth to 1.6 years of age and weight at 3 years, 7 years and pubertal age were 0.76, 0.51, and 0.34 in boys and 0.76, 0.49, and 0.47 in girls, and height at 3 years, 7 years and pubertal age were 0.58, 0.46, and 0.34 in boys and 0.62, 0.56, and 0.65 in girls, respectively, as shown in Table 1. The Pearson correlation coefficients between weight gain from 1.6 years to 3 years of age and weight at 3 years, 7 years and pubertal age were 0.84, 0.66, and 0.37 in boys and 0.74, 0.50, and 0.48 in girls, and height at 3 years, 7 years and pubertal age were 0.59, 0.48, and 0.24 in boys and 0.49, 0.37, and 0.40 in girls, respectively (Table 1). All correlations except for the relationship between weight gain from 1.6 years to 3 years of age and height at 12 years in boys (p<0.1) were significant (p<0.05).
Table 1.
The Pearson correlation coefficients between weight gain from birth to 1.6 years or 1.6 years to 3 years of age and height or weight at 3 and 7 years in boys and girls and 10 years of age in girls and 12 years of age in boys.
|
|
3 years |
7 years |
10 years |
12years |
|||||
|
|
|
Ht |
Wt |
Ht |
Wt |
Ht |
Wt |
Ht |
Wt |
|
boys |
0~1.6y |
0.58*** |
0.76*** |
0.46*** |
0.51*** |
|
|
0.34* |
0.34* |
|
1.6~3y |
0.59*** |
0.84*** |
0.48*** |
0.66*** |
|
|
0.24(p<0.1) |
0.37* |
|
|
girls |
0~1.6y |
0.62*** |
0.76*** |
0.56*** |
0.49*** |
0.65*** |
0.47** |
|
|
|
1.6~3y |
0.49*** |
0.74*** |
0.37*** |
0.50*** |
0.40* |
0.48** |
|
|
|
P-values: *** <0.0001, ** <0.001, * <0.01
Ht: height, Wt: weight
The correlations between weight gain in both groups and weight at pubertal age were almost same in both of boys and girls. However, there was a stronger correlation between height at pubertal age and weight gain from birth to 1.6 years compared to weight gain from 1.6 years to 3 years in both boys and girls. Furthermore, the correlation was stronger in girls versus in boys at pubertal age. The strongest correlation was between weight gain from birth to 1.6 years and height achieved during puberty in girls (r=0.645).
It has been reported that growth failure starts from early infancy in children with short stature being detected at age 6. These children are reported to be poor bottle-feeders and poor eaters after weaning [6]. It has been also reported that the change in the height standard deviation score from birth to age 3 years showed a strong positive correlation with the change in the weight from birth to age 3 years [7]. Our data shows that insufficient weight gain both of from birth to 1.6 years of age and from 1.6 years to 3 years of age are associated with not only underweight children, but also short stature at 3 years of age. Furthermore, this effect continues to the age of 7 and the onset of puberty. It is also suspected that adult height and weight may be affected. The fact that height had the greatest correlation with weight gain in infancy supports our hypothesis that weight gain during infancy is important in determining adolescent stature. Moreover, it has been reported that protein intake in early life may program body composition and height growth later in life, perhaps mediated by insulin-like growth factor 1 (IGF-1) [8,9]. This relationship provides another mechanism of how insufficient weight gain in infancy influences the height in adolescence. Furthermore, in both boys and girls, there was a stronger correlation between height at pubertal age and weight gain from birth to 1.6 years rather than from 1.6 years to 3 years. This phenomenon supports that the component of infancy period of ICP model depends on nutrition.
It has been reported that most children with constitutional delay of growth and maturation (CDGM) begin to deviate from the normal growth curve before age 2 years, subsequently grow at a relatively normal velocity, and then have a delayed pubertal growth spurt [10]. This growth pattern is similar to that of malnourished children [11], suggesting that CDGM may lie in the spectrum of nutritional dwarfing. Furthermore, Albanese et al. reported that only 0.7% of patients with CDGM attained a final height above mid-parental corrected height [12]. We also show that insufficient weight gain under 3 years is associated with short statute and underweight at adolescence.
There are several limitations to our study. We did not assess the dietary intake throughout the childhood in each subject and we did not confirm the onset of puberty. Additionally, we did not measure levels of growth hormone, IGF-1 and related variables. Further research is needed to determine if insufficient weight gain under 3 years, especially under 1.5 years of age, leads to short stature in adults, and if it correlates with hormonal dysregulation. Overall we show that children with poor weight gain under 3 years of age likely were affected by CDGM and their insufficient weight gain was likely linked to short stature in adolescence and will likely continue into adulthood.
CDGM: constitutional delay of growth and maturation, EED: environmental enteric dysfunction, FGF21: Fibroblast growth factor 21, GH: growth hormone, ICP: infancy-childhood-puberty, IGF-1: insulin-like growth factor 1,
Funding
The authors declare that no funds, grants, or other support were received the preparation of this manuscript.
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
Author Contributions
Dr Koyama conceptualized and designed the study, collected data, and carried out the analysis, and drafted the initial manuscript, and reviewed and revised the manuscript.
Dr Naganuma collected data and carried out the analysis and reviewed and revised the manuscript.
Emeritus Prof Arisaka conceptualized and designed the study, and critically reviewed the manuscript for important intellectual content.
Prof Yoshihara critically reviewed the manuscript for important intellectual content.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Ethics Approval
This is an observational study. The study was approved by the ethics committee of Dokkyo Medical University (approval number 23020).
Consent to participate
Written informed consent for physical examinations was obtained from parents or guardians.
Consent to publish
Our manuscript does not contain any individual person’s data in any form.
Acknowledgements
The authors thank Ms. Yasuyo Kawai for her excellent technical assistance.