Nutrition Publication

NNIW71 - Growth Research: Nutritional, Molecular and Endocrine Perspectives

Editor(s): M. Gillman, P. Gluckman, R. Rosenfeld. 71

Growth and development during the fetal and postnatal periods as well as during the first 2 years of life are important for short and long-term health. There are many growth drivers during this phase of life, among them are nutrition, genetic and epigenetic factors, and hormonal regulation. Prof. M.Gillman, Sir P. Gluckman  and Prof. R. Rosenfeld edited this edition of the workshop book series that covers very prominent questions, e.g. how early infant feeding influences long-term growth and development, and how inadequate nutrition is related to health issues such as obesity and malnutrition.

Related Articles

Early Influences of Nutrition on Fetal Growth

Author(s): M. Makrides, A. Anderson, R. Gibson

During pregnancy, the metabolic requirements of the mother are increased; however, the relationship between maternal intake of key nutrients and optimal fetal growth is not always clear. In this chapter, we have reviewed randomized controlled trials of nutritional interventions during pregnancy, with a particular focus on birthweight and infants who are small for gestational age (SGA). Of the trials that have investigated changing macronutrient and energy intakes during pregnancy, supplements in which <25% of the energy is provided by protein yielded the most promising results, producing a 31–32% reduction in the risk of SGA infants and an increase in birthweight (38–60g) compared with control. Single- nutrient intervention trials using n- 3 long- chain polyunsaturated fatty acid (LCPUFA) supplements demonstrated small increases in birthweight (≈50 g) and birth length (≈0.5 cm), which may be explained by small increases in gestation length (approximately 2.5 days). n- 3 LCPUFA supplementation in pregnancy did not however decrease the proportion of SGA infants. Multiple- micronutrient supplementation trials in developing countries have resulted in increased mean birthweight (22–44 g) and reduced the risk SGA by 9–15%. Further nutritional intervention studies which are rigorously designed and implemented are needed particularly to delineate differential effects in developed and developing countries.

Early Influences of Nutrition on Postnatal Growth

Author(s): B. Koletzko, J. Beyer, B. Brands, H. Demmelmair, V. Grote, G. Haile, D.Gruszfeld, P. Rzehak, P. Socha, M. Weber

Health and nutrition modulate postnatal growth. The availability of amino acids and energy, and insulin and insulin- like growth factor- I (IGF- I) regulates early growth through the mTOR pathway. Amino acids and glucose also stimulate the secretion of IGF- I and insulin. Postnatal growth induces lasting, programming effects on later body size and adiposity in animals and in human observational studies. Rapid weight gain in infancy and the first 2 years was shown to predict increased obesity risk in childhood and adulthood. Breastfeeding leads to lesser high weight gain in infancy and reduces obesity risk in later life by about 20%, presumably partly due to the lower protein supply with human milk than conventional infant formula. In a large randomized clinical trial, we tested the hypothesis that reduced infant formula protein contents lower insulin- releasing amino acid concentrations and thereby decrease circulating insulin and IGF- I levels, resulting in lesser early weight gain and reduced later obesity risk (the ‘Early Protein Hypothesis’). The results demonstrate that lowered protein in infant formula induces similar – but not equal – metabolic and endocrine responses and normalizes weight and BMI relative to breastfed controls at the age of 2 years. The results available should lead to enhanced efforts to actively promote, protect and support breastfeeding. For infants that are not breastfed or not fully breastfed, the use of infant formulas with lower protein contents but high protein quality appears preferable. Cows’ milk as a drink provides high protein intake and should be avoided in infancy.

Genome-Wide Association Studies of Human Growth Traits

Author(s): M. Weedon

Despite the high heritability of human growth traits, until recently little was known about the underlying genes and genetic variants which explain normal variation of growth. In the past few years, genome- wide association studies have successfully identified hundreds of genetic variants that are associated with human growth traits. These variants have implicated many novel genes in the regulation of birthweight and pubertal timing through to final adult height, and are providing new insights into the biology of growth. For example, 180 genetic loci have been robustly shown to influence variation in final adult height. Despite this success, the effect sizes of these variants are small and, even in combination, have left the majority of heritable genetic variation of growth traits unexplained. In this review, I discuss the successes of the genome- wide association approach and some of the novel insights into the biology of growth that have come from these studies. I will also discuss what these studies have not told us and what the future holds for genetic studies of human growth.

IGF-I in Human Growth: Lessons from Defects in the GH-IGF-I Axis

Author(s): V. Hwa, P. Fang, M. Derr, E. Fiegerlova, R. Rosenfeld

The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF- I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure. Clinical conditions of IGF- I resistance due to mutations in the IGF- I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation. Postnatal regulation of IGF- I production is predominantly GH dependent. Defects in the GH- IGF- I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH. Other phenotypic features – immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects – are of note. Mutations identified have been predominantly recessive. The identification and assessment of genetic defects in the GH- IGF axis has greatly enhanced our understanding of the critical importance of IGF- I in human linear growth. Continued evaluations will facilitate better diagnosis and management of children presenting with abnormal growth and development.

Non-Imprinted Epigenetics in Fetal and Postnatal Development and Growth

Author(s): K. Godfrey, K. Lillycrop, G. Burdge, P. Gluckman, M. Hanson

Recent evidence demonstrates that the environment in early life can have important effects on fetal and postnatal growth, on development and on risk of developing common non- communicable diseases in later life. In animals, the environment during early life induces altered phenotypes in ways which are influenced or mediated by epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non- coding RNAs. Most is known about DNA methylation changes, which are gene specific, include effects on non- imprinted genes and function at the level of individual CpG dinucleotides to alter gene expression. Preliminary evidence from human studies suggests a similar important role for epigenetic processes. Tuning of phenotype by the developmental environment has adaptive value because it attempts to match an individual’s responses to the environment predicted to be experienced later; hence, such processes have been selected during evolution as conferring fitness advantage. When the phenotype is mismatched, e.g. from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socioeconomic conditions, risk of non- communicable diseases increases. Evidence is accruing that endocrine or nutritional interventions during early postnatal life can reverse epigenetic and phenotypic changes induced, for example, by unbalanced maternal diet during pregnancy. Elucidation of epigenetic processes may enable early intervention strategies to improve early development and growth.

Epigenetic Anomalies in Childhood Growth Disorders

Author(s): I. Netchine, S. Rossigno, S. Azzi, Y. Le Bouc

Fetal growth is a complex process involving environmental, epigenetic and genetic factors. Fetal growth restriction is associated with morbidity among small for gestational age (SGA) neonates as well as in children and adults who were former SGA. Imprinted genes (whose expression is restricted to a single parental allele) have a critical role in controlling mammalian fetal growth. The human chromosome 11p15 encompasses two imprinted domains regulated by their own differentially methylated imprinted control region (ICR1 at the H19/IGF2 domain, and ICR2 at the KCNQ1/CDKN1C domain). Loss of imprinting at these two domains is implicated in two clinically opposite growth disorders. Indeed, our group has identified a loss of DNA methylation (LOM) at ICR1 in over 50% of patients with Russell- Silver syndrome (RSS) characterized by intrauterine and postnatal growth retardation with spared cranial growth, dysmorphic features, frequent body asymmetry and severe feeding difficulties. By contrast, gain of methylation at ICR1 is found in 10% of patients with Beckwith- Wiedemann syndrome (BWS), an overgrowth syndrome with an enhanced childhood tumor risk. We have now identified over 130 RSS patients with 11p15 LOM. This 11p15 epimutation is a frequent and specific cause of RSS as it has not been identified in non syndromic SGA patients. These new findings in the pathophysiology of RSS allow long- term follow- up studies to be performed based on molecular diagnosis. This will help to define appropriate clinical guidelines regarding growth, rapid bone age advance during puberty and feeding difficulties. Remarkably, we have also recently found that ~10% of RSS patients and ~25% of BWS patients showed multilocus LOM at imprinted regions other than ICR1 or ICR2 11p15, respectively. Severalclinical studies demonstrated that assisted reproductive technology significantly increased the risk of human imprinting diseases including BWS and RSS, suggesting that the environment may favor imprinting disorders.

Early Growth and Development of Later Life Metabolic Disorders

Author(s): J. Foo, C. Mantzoros

Growth is effected via a complex interaction of genetic, nutritional, environmental and growth factors. Hormonal factors such as the growth hormone (GH) and insulin-like growth factor (IGF) signaling system, the human placental lactogen, and insulin play an integral role in early growth. Genetic factors affecting the GH-IGF system and insulin secretion and actions, and epigenetic mechanisms including DNA methylation have been further implicated as contributory factors. These hormonal systems, on a background of genetic susceptibility, together with other factors including maternal nutrition, placental and environmental factors, regulate not only early growth but also development. These interactions may impact on later health consequences in adult life. Accumulating data in the last few decades on developmental programming and later life metabolic disorders has provided a novel perspective on the possible pathogenesis of metabolic dysregulation. Despite postulations put forward to elucidate the mechanism underlying the association between early growth and later life metabolic disorders, it remains unclear what the dominant factor(s) would be, how any underlying mechanisms interact, or whether these mechanisms are truly causal.

Human Growth: Evolutionary and Life History Perspectives

Author(s): P. Gluckman,A. Beedle, M. Hanson, F. Low

Evolutionary and life history perspectives allow a fuller understanding of both patterns of growth and development and variations in disease risk. Evolutionary processes act to ensure successful reproduction and not the preservation of health and longevity, and this entails trade- offs both between traits and across the life course. Developmental plasticity adjusts the developmental trajectory so that the phenotype in childhood and through peak reproduction will suit predicted environmental conditions – a capacity that may become maladaptive should early- life predictions be inaccurate. Bipedalism and consequent pelvic narrowing in humans have led to the evolution of secondary altricialism. Shorter inter- birth intervals enabled by appropriate social support structures have allowed increased fecundity/fitness. The age at puberty has fallen over the past two centuries, perhaps resulting from changes in maternal and infant health and nutrition. The timing of puberty is also advanced by conditions of high extrinsic mortality in hunter- gatherers and is reflected in developed countries where a poor or disadvantaged start to life may also accelerate maturation. The postpubertal individual is physically and psychosexually mature, but neural executive function only reaches full maturity in the third decade of life; this mismatch may account for increased adolescent morbidity and mortality in those with earlier pubertal onset.

Secular Trends in Birthweight

Author(s): E. Oken

From the mid- to late 20th century, average birthweight increased in many countries, including the United States. However, more recent data now suggest that mean birthweight has begun to decline. The most recent US data indicate that in 2008, compared with 1990, about half as many babies were macrosomic at birth (≥5,000 g), whereas there was a 17% increase in low birthweight (<2,500 g). Part of the observed decline in birthweight likely relates to decreases in gestation length and corresponding increases in rates of preterm and early term birth over the past several decades. However, available data suggest that fetal growth has also declined independent of gestational age at birth. Since 2000, rates of small for gestational age have increased, whereas rates of large for gestational age have decreased. Declines in birthweight and macrosomia are most likely largely explained by decreases in gestation length, itself caused by obstetric interventions, especially induction of labor and to a lesser extent elective cesarean delivery. However, it appears that fetal growth is also declining, at least in some settings, independent of gestation length. Reasons for this decline are as of yet unexplained and merit further investigation.

Secular Changes in Childhood, Adolescent and Adult Stature

Author(s): B. Bogin

This essay provides a brief history of the etymology and usage of the phrase ‘secular change’ followed by a description of secular changes in height and relative leg length in childhood, adolescence, and adulthood. Both positive and negative changes are described. Possible causes are reviewed, with an emphasis on nutrition, infection and social- economic- political (SEP) environments. The case of the Maya people living in Mexico, Guatemala, and the United States is given, which shows that intergenerational changes in stature and its components – leg length and upper body length – may occur in different directions and at different rates. The deleterious consequences of rapid catch- up growth after birth have been proposed as a hypothesis to explain the 150 years of positive secular change in height of populations in the richer nations. That hypothesis is found to be an incomplete explanation. Growth changes better track the rate of change in SEP factors. Epigenetic assimilation is a new hypothesis, which focuses on those epigenetic processes regulating gene expression, metabolic function, physiology, and behavior. Epigenetic assimilation shows promise to account for plasticity and intergenerational changes in human growth and development phenotypes.

Economic Drivers and Consequences of Stunting

Author(s): H. Alderman

This paper reviews evidence addressing four questions pertinent to the understanding of the economic returns to investing in nutrition: (a) Where are the promising areas of interface between economics and nutrition? (b) What is the contribution of income growth to improving nutrition? (c) Is adult chronic disease being given too little consideration in nutrition programs? (d) More generally, are we using the right outcome measures to assess nutrition interventions?

Pharmacological Interventions for Short Stature: Pros and Cons

Author(s): R. Rosenfeld

Although growth hormone (GH) therapy is virtually always effective in accelerating growth and restoring height potential to children with GH deficiency (GHD), the expansion of its use to a wide variety of other clinical disorders associated with short stature has resulted in considerable ethical and cost- benefit issues. Logic would demand that therapy should either be restricted to true ‘replacement’, thereby limiting its use to cases of unequivocal GHD, or treatment should be considered as a legitimate ‘enhancement’, and be available to all children with significant short stature. Consideration of the latter option requires a careful look at issues surrounding efficacy (both in terms of stature and any perceived disability resulting therefrom), cost and potential adverse effects. Similar concerns involve treatment with insulin- like growth factor- I and any related growth- augmenting therapy. To date, safety issues have been addressed through pharmaceutical- sponsored postmarketing surveillance studies. While of definite use, such investigations also have significant limitations, especially in addressing long- term concerns. The possibility of lifespan cohort studies, with surveillance of all GH recipients throughout life and comparison with data from appropriate controls, should be considered.

Epidemiologic Transitions: Migration and Development of Obesity and Cardiometabolic Disease in the Developing World

Author(s): T. Forrester

For centuries, the challenge has been the maintenance of bodyweight in the face of marginal food availability. Since the industrial revolution, energy expenditure related to economic activity and domestic life has fallen progressively as technological innovation has replaced muscular power with labor- saving devices. This fall in activity energy expenditure however has not been associated over this entire period with population weight gain. In the 1970s and the 1980s, there was an abrupt uptick in the rate of rise of relative weight in industrialized countries followed rapidly by developing countries. This has led to high and increasing rates of overweight and obesity in high- income countries worldwide, but also an alarming inclusion of low- and middle- income populations in this obesity epidemic. The precise drivers of these concurrent epidemics are not agreed, but probably include on the one hand an increase in dietary energy intake resulting from the impact of industrialization and globalization on food availability and price. On the other, there is the facilitating underlying status of a steadily falling activity energy expenditure as muscle power as an input into economic production as well as household and leisure activities has been supplanted. The rise in population weight without accompanying linear growth manifests as obesity. The accretion of fat as well as the response to other environmental exposures during progressive industrialization and modernization has evoked an accompanying epidemic of cardiometabolic pathology that has significant impact on health as well as macroeconomics. Given the power and presumed irreversibility of industrialization and globalization, our ability to reverse these obesity epidemics is heavily dependent on new knowledge being developed which gives insight with prevention and therapeutic implications on the proximal and distal drivers of this progressive positive energy balance.

State of the Art of Growth Standards

Author(s): L. Weaver

Growth charts have become widely used, if not universal, tools for the assessment of the growth and health of children. In 2006, the WHO published a set of charts designed to represent standards to which all the world’s children should aspire. They were produced in response to the apparent variability in the patterns of child growth documented worldwide, and with the aim of creating a prescriptive standard based on best feeding advice. Our modern understanding and use of growth references arose out of the application of technology, mathematics and charting to the biology of growth in the 19th century. As means of summarizing normal development, modern growth standards have replaced Renaissance conceptions of human form based on idealized proportions in harmony with the cosmos, and the simple reference to key developmental milestones first noted by the ancients. The WHO growth standards are the culmination of a search for a human ideal based on 20th century biology. However, while they may be the ‘best’ standards based on contemporary feeding advice, they are ‘provisional’ because all developmental processes in biology, including body growth, are plastic and permit a flexibility of life course trajectories in response to epigenetic, nutritional and other environmental conditions.

Healthy Infant Growth: What Are the Trade- Offs in the Developed World?

Author(s): M. Belfort, M. Gillman

More rapid infant weight gain is associated with long- term benefits, such as better neurodevelopmental outcomes for some infants, but also with harms, such as an increased risk of later obesity and higher blood pressure. Determining the optimal rate of infant weight gain requires balancing these benefits and risks, the magnitude of which appears to differ for specific populations of infants. Among healthy full- term infants, gain in weight- forlength is associated with obesity and adverse cardiometabolic outcomes, with no substantial benefit to neurodevelopment. Preterm infants derive substantial neurodevelopmental benefit from gain in weight- for- length during the neonatal intensive care unit stay, and possibly from linear growth thereafter; excess weight- for- length gain may predict adverse cardiometabolic outcomes. Among full- term SGA infants, evidence is limited; excess weight- for- length gain in infancy may predict later cardiometabolic risk, but does not appear to modify neurodevelopmental outcomes. Future research should consider not just the magnitude but also the value of the various outcomes in each population. More work is also needed to identify shared determinants of rapid early weight gain, cardiometabolic risk, and neurodevelopment, and to differentiate effects of weight gain that is proportional to linear growth from weight gain that is excessive.

Relationship between Childhood Growth and Later Outcomes

Author(s): A. Archanjo Ferraro, M. Bechere Fernandes

Many studies in different settings and times provided us with enough evidence of the association between environmental exposures (mainly nutrition) during pregnancy/infancy and later health outcomes, such as adult non- communicable diseases (NCDs). An individual with a given susceptibility will continue to experience new environmental challenges (e.g. growth), and these later experiences will modulate the early ones. Children that are thin in infancy and then become larger are at greater risk for later NCD. Studies demonstrated that rapid weight gain is a strong predictor of later NCD, independently of the birthweight. But which periods imply a greater risk for developing NCD? Two periods in the first years of life have been linked to the early obesity onset: the first 6 months and between 2 and 5 years of age. And when do these later health outcomes appear? The literature suggests that they start long before adulthood. Children with rapid weight gain have greater risk for hypertension and cardiovascular disease in the first years of life. These lines of evidence suggest that future research should be committed with educational programs and preventive actions focusing on better life behavior in childhood, adolescence and pregnancy.

Public Policy Implications of Promoting Growth

Author(s): P. Wise

Translating the new science of growth into constructive policy will not happen naturally. Rather, the emerging science will need to be reframed to address certain core policy requirements. First, the complexity of early genetic and environmental interactions should be respected as their impact may vary in different, real- world settings. Second, the scale of impact is important to gauge as early- life interactions, while real, may not account for a large portion of later outcomes. Third, judgments regarding critical periods and the amenability of early- life influences to later intervention should be made cautiously as the etiologic nature or timing of early- life interactions do not, per se, determine if their life course effects are amenable to later interventions. Fourth, there is a need for incremental efficacy, such that the new science significantly enhances the impact of extant policybased interventions. Finally, the translation of the new developmental science into policy should be viewed in a historical context and responsive to social and cultural needs. This provides a basis for reframing the new science of growth in a manner that best ensures that the science receives the constructive policy response it so urgently demands.

Discussion on Economic Drivers and Consequences of Stunting

Author(s): L. Adair

Discussion on Migration and Development of Obesity and Cardiometabolic Disease in the Developing World

Author(s): L. Adair

Discussion on Growth Standards and Trade- Offs in Healthy Infant Growth

Author(s): C. Law

Discussion on Childhood Growth and Later Outcomes, Policy Implications and Treatment of Short Stature

Author(s): A. Stein