Nutrition Publication

NNIW61 - The Window of Opportunity: Pre-Pregnancy to 24 Months of Age

Editor(s): D.J.P. Barker, R.L. Bergmann, P.L. Ogra. vol. 61

Related Articles

Subject Index

Author(s): D.J.P. Barker, R.L. Bergmann , P.L. Ogra

Concluding Remarks

Author(s): D.J.P. Barker , R.L. Bergmann, P.L. Ogra

The Biology of Growth

Author(s): N. Cameron

the magnitude and rate of change coincident with the period. In addition, for a radical change in, e.g., height to occur there must also be changes in the anatomical parts that make up total height and these changes are themselves variable. Acceleration, for instance in height velocity, may be the result of different changes in the length of the spine, femur, and/or tibia, each of which may contribute differently to the total process. In addition, not only may the process be variable within a single child, it may also be variable between different children of the same or opposite sexes. The mathematical and statistical problems arising from the seemingly simple process of an increase in height are thus complex. In order to review the biology of human growth this contribution will discuss the principles of growth that are fundamental to our ability to interpret the response of the child to factors that might modify the genetically programmed pattern of growth from conception to maturity. In this way the biology of human growth will be described by a set of phenomena that reflect the actions of biological control mechanisms. These mechanisms are subject to genetic and environmental influences and their expression is characterised by variation in timing, magnitude, and duration.

Human Growth and Cardiovascular Disease

Author(s): D.J.P. Barker

disorders, stroke, hypertension and type 2 diabetes. Associations between low birthweight and later disease have been extensively replicated in studies in different countries. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. CHD and the disorders related to it arise through a series of interactions between environmental influences and the pathways of growth and development that precede them.

The Role of Growth in Heart Development

Author(s): K.L. Thornburg, S. Louey, G.D. Giraud

the mechanisms by which this occurs remain poorly defined. The growing fetus is dependent on the nutrients (including oxygen) it receives from the mother via the placenta. When this supply line is compromised, heart growth patterns are altered. In addition, hormones, other circulating factors, and the hemodynamic environment in which the fetus develops are important in determining outcomes for organ structure and function. Numerous studies in sheep have demonstrated that heart development can be modified in a number of ways, and the nature of the change differs between types and gestational timings of insults. Embolization of the placenta leads to the cessation of proliferation and maturation of cardiomyocytes; this may be due in part to changes in circulating insulin-like growth factor-1 levels. Such insults may be the underlying cause of cardiovascular disease in adults. Insults that modify the maturational timeline, final myocyte number, vascularity and endothelial responsiveness in the heart can have effects that persist long after the insult has been ameliorated.

Growth and Bone Development

Author(s): C. Cooper, N. Harvey, K. Javaid, M. Hanson, E. Dennison

most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual, in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites...

The Role of Genes in Growth and Later Health

Author(s): J.G. Eriksson

Genetic factors are of importance for the development of the metabolic syndrome and type 2 diabetes, but despite extensive research the identification of the underlying genes has not been fruitful. This report focuses on the interactions between intrauterine growth and genes in relation to adult health outcomes based upon findings from the Helsinki Birth Cohort Study. Candidate genes for type 2 diabetes and the metabolic syndrome have been focused upon and we report on interactions between polymorphisms of the peroxisome proliferator-activated receptor (PPAR)-2, plasma cell glycoprotein (PC-1) and the glucocorticoid receptor (GR) genes and - prenatal growth in relation to adult health outcomes. In elderly individuals the effects of the Pro12Pro/Pro12Ala polymorphisms of the PPAR-2 gene depend on their body size at birth. Individuals, who had a small body size at birth and were carriers of the Ala allele, seem to be protected against insulin resistance and type 2 diabetes in later life. Similar gene environment interactions will be described in relation to the PC-1 and the GR genes. We propose that these findings reflect gene–early environment interactions and can be attributed to the phenomenon of developmental plasticity.

Maternal Nutrition Before and During Pregnancy

Author(s): Theresa O. Scholl

In humans, the link between the maternal diet and the outcome of pregnancy is best illustrated by the classic study of wartime famine in Holland. During the famine it is likely that a low food intake reduced the glucose stream from the mother to fetus and gave rise to smaller size at birth. Maternal glucose production is also influenced by the type of carbohydrate in the diet. Even when famine and starvation are not issues, a low dietary glycemic index can alter maternal blood glucose production and the area under the glucose curve, and give rise to reductions in fetal growth and infant weight at birth. Reduced food intake in famine areas would also reduce the concentration of micronutrients in the maternal diet. Two micronutrients (iron and folate) have effects on pregnancy outcome that have been shown with some consistency in pregnant women. Emerging evidence now suggests that use of micronutrient- containing prenatal vitamins before and during pregnancy is associated with reductions in the risk of congenital defects, preterm delivery, low infant birthweight, and preeclampsia.

The Diabetic Pregnancy, Macrosomia, and Perinatal Nutritional Programming

Author(s): A. Plagemann, T. Harder, J.W. Dudenhausen

Health and diseases are generally perceived to be caused genetically. It is meanwhile accepted, however, that alterations in the intrauterine and early postnatal nutritional, metabolic, and hormonal environment may also predispose to disorders and diseases throughout later life. Studies in the offspring of diabetic mothers (ODM) have decisively contributed to this perception and our understanding of causal mechanisms. It has long been known that hormones are environment-dependent organizers of the developing neuroendocrine-immune network, which regulates all fundamental processes of life. When present in non-physiological concentrations during critical periods of development, induced by altered intrauterine and/or neonatal environment, hormones can therefore also act as endogenous functional teratogens. Fetal and neonatal hyperinsulinism is the pathognomic feature in ODM. Epidemiological, clinical, as well as experimental data obtained by our group indicate that insulin itself, when occurring in elevated concentrations during perinatal life, may program the development of obesity and diabetes. Similar situations may occur due to maternal overweight accompanied by increased fetal food supply, and neonatal overfeeding. From a clinical point of view, general screening and therapy of all types of diabetes during pregnancy as well as avoidance of early postnatal overfeeding are therefore recommended. These measures might serve as causal approaches to a genuine primary prevention.

Undernutrition and Growth Restriction in Pregnancy

Author(s): R.L. Bergmann, K.E. Bergmann, J.W. Dudenhausen

Newborn size is the result of intrauterine growth. Premature, low birthweight of 2,500 g, small for gestational age (SGA, 10th percentile), or intrauterine growthrestricted (IUGR) newborns may have similar weights. Serial fetal biometry (ultrasound), required for the diagnosis, timing and severity of intrauterine growth restriction in the individual infant, is still not common in epidemiological studies. SGA newborns have less lean body mass, but they particularly lack fat mass. The most important etiological determinants of intrauterine growth restriction in developed countries is cigarette smoking, while in developing countries it is usually longstanding food deprivation. Follow-up studies of SGA newborns consistently showed a positive association between birthweight and later lean body mass, whereas associations with adiposity were more variable. Most SGA infants had catch-up in length/height. Signs of the metabolic syndrome accompanied the catch-up in bodyweight and central adiposity. So far, no overarching model is available to explain how the epigenetic and hormonal tunings, which accompany intrauterine malnutrition from preconception through pregnancy, can program the regulatory systems of fundamental life processes. The theoretical concepts of a thrifty phenotype (Hales and Barker) and of a predictive adaptive response (Gluckman and Hanson) offer a comprehensive approach to understanding the empirical and experimental findings.

Growth and Nutrition:The First Six Months

Author(s): L.Å. Hanson, S. Zaman, B. Werner, L. Håversen, C. Motas, M. Moisei, I. Mattsby-Baltzer, S. Lange, M. Banasaz, T. Midtvedt, E. Norin, S-A. Silfverdal

Today the WHO Growth Chart Standards, based on the growth of breastfed infants, are used. These growth curves solve the problem of the deviating observations for breastfed compared to non-breastfed infants using previous growth charts. Presently it is not clear how the mother’s diet, especially the fat intake, influences the growth of the offspring. Animal experiments indicate that a low intake of n-3 polyunsaturated fatty acids via the milk may have short- and long-term negative consequences. There is limited information in man. It has been suggested that the mammary glands may have phylogenetically originated from glands providing innate immunity, later developing capacities for providing nutrition. This would agree with the fact that human milk contains so many major components which do not primarily function as nutrients, but seem to protect nutrition and growth. Lactoferrin, oligosaccharides, glycoproteins, secretory IgA antibodies, -lactalbumin and the antisecretory factor have such functions.

Growth in the First Two Years of Life

Author(s): D.M. Bier

Compared to other periods of life, infancy is a period of rapid growth, but the relative relationships among rates of linear growth, weight accretion and brain growth vary greatly during the first years of life. Additionally, while the energy requirements for body tissue deposition as a fraction of daily energy needs decrease dramatically during infancy, brain energy demands, measured as the cerebral rate of glucose utilization, increase markedly during the same period. There is now substantial evidence that postnatal growth in infancy is associated with various consequences detrimental to health in adult life, particularly hypertension, cardiovascular disease, obesity and type 2 diabetes, but the relationships vary depending on whether one takes growth to mean statural growth or ponderal growth, as well as on the specific period of infant growth. Recently, several mechanisms have surfaced that might account for the relationships observed. These include epigenetic effects on gene expression, alterations in neuronal signaling because of inappropriate dendritic pruning, and gut microbiota effects on fat storage.

Effects of Early Environment on Mucosal Immunologic Homeostasis, Subsequent Immune Responses and Disease Outcome

Author(s): Y.A. Maldonado

It is estimated that there are 4million neonatal deaths and an equal number of stillbirths annually, the majority in the developing world. Neonatal deaths account for one third of deaths in children less than 5 years of age, and at least one third of neonatal deaths are related to infections. Infections also account for 80% of deaths in the postneonatal period through 5 years of age. There are several viral and parasitic infections which produce fetal and neonatal morbidity and mortality. Neonatal infections occur during one or more perinatal periods: in utero (congenital), intrapartum (during labor and delivery), and early or late postpartum. Here the term perinatal refers to all of these stages of fetal or neonatal infections. The mechanisms of perinatal viral and parasitic infections vary depending on the specific pathogen, however, all begin with maternal infection. Following maternal infection, organisms may produce indirect placental infection with or without fetal infection, direct fetal or neonatal infection, or primary maternal infection and subsequent perinatal sequelae without either placental or fetal infection. Some pathogens may produce infections by more than one mechanism. This brief report will provide an overview of the pathogenesis, general outcomes, and known pathogens associated with perinatal viral and parasitic infections.

Induction of Antigen-Specific Immunity in Human Neonates and Infants

Author(s): C.B. Wilson, T.R. Kollmann

The first months of life represent a period of heightened susceptibility to infection, but the immunological differences involved are as yet incompletely understood. T cellindependent B cell (antibody) responses are markedly compromised in the first year of life. T cell-dependent antibody responses mature much earlier, but neonates and infants may require multiple immunizations to achieve or sustain titers comparable to those in older individuals. Neonates can mount effective antigen-specific T cell responses, but CD4 T cell responses are often slower to develop, less readily sustained, and in general more easily biased towards a Th2 type response. The last observation likely reflects in part the less efficient capacity of neonatal dendritic cells to establish a milieu that favors a Th1 CD4 T cell response, but this limitation can be overcome given appropriate stimuli, as occurs in neonates immunized with bacillus Calmette-Guérin. We currently lack a clear mechanistic understanding of the molecular basis for these immunological differences between adults and neonates. The goal of ongoing and future studies is to generate the mechanistic insights needed to enable the rational design of vaccines and adjuvants for use in neonates and young infants, and thereby reduce the morbidity and mortality of infections early in life.

Growth and Host–Pathogen Interactions

Author(s): A.M. Prentice, M.K. Darboe

Differing trajectories of infant and child growth are associated with different patterns of disease and mortality in adulthood. Since postnatal growth patterns are partially modifiable by diet, these associations raise fresh questions about what constitutes an optimal growth rate. We use data from contemporary societies that still suffer poor nutrition and high burdens of infectious disease to illustrate early growth patterns that have likely been typical of our evolutionary past. Pathogenic assault is a major suppressor of growth; populations frequently average 1.0 to 1.5 z scores (standard deviations relative to standard growth curves) for height, and 2.0 to 2.5 z scores for weight, body mass index and head circumference. Many infections are symptomatic (e.g. diarrhea, malaria, pneumonia, HIV), but others are subclinical (e.g. hepatitis B, cytomegalovirus, Epstein-Barr virus, herpes, Helicobacter pylori). The great majority of young children become infected by multiple pathogens which initiate a downward cycle of infection→suppressed appetite and malabsorption→reduced growth→lowered immunity→repeated infection. Examination of the evolutionary ‘norm’ for early growth, and the external environmental factors that influenced it, may provide clues towards identifying the current day optimum for growth.

Neonatal Microbial Flora and Disease Outcome

Author(s): M.F. Vassallo, W. Allan Walker

The now outdated perception of microorganisms of the gastrointestinal tract as pathogens or at best commensals continues to undergo remodeling. It is now clear that the microbiome of the gut participates in many activities including: digestion, ecologic protection from pathogens, and an increasingly appreciated immunoregulatory role in vertebrates. Studies of the complex interactions of microbes and hosts point to a convergence of two well-supported (though imperfect) hypotheses: the ‘hygiene hypothesis’ and the ‘fetal programming hypothesis’ proposed by Strachan and Barker, respectively. Our current understanding is one in which factors that exist before conception, during gestation, or occur perinatally in the infant milieu, in addition to exposures to nutrients and microbes, have the potential for long-term effects in the development of healthy offsprings and adults. Epidemiology, basic science and clinical research in such previously diverse areas of study such as microbiology, allergy, gastroenterology, endocrinology, immunology, rheumatology, infectious disease, perinatology, and nutrition are providing evidence that appropriate development and tendency towards the development of certain diseases are directly affected by intestinal microbe–host interactions. It appears likely that perinatal colonization of the gastrointestinal tract is a particularly pivotal process in which microbe-host programming occurs. Intestinal microbes and hosts have co-evolved that, when in appropriate balance, they produce and propagate a life-long mutualism.

Impact of Fetal and Neonatal Viral (and Parasitic) Infections on Later Development and Disease Outcome

Author(s): Y.A. Maldonado

It is estimated that there are 4million neonatal deaths and an equal number of stillbirths annually, the majority in the developing world. Neonatal deaths account for one third of deaths in children less than 5 years of age, and at least one third of neonatal deaths are related to infections. Infections also account for 80% of deaths in the postneonatal period through 5 years of age. There are several viral and parasitic infections which produce fetal and neonatal morbidity and mortality. Neonatal infections occur during one or more perinatal periods: in utero (congenital), intrapartum (during labor and delivery), and early or late postpartum. Here the term perinatal refers to all of these stages of fetal or neonatal infections. The mechanisms of perinatal viral and parasitic infections vary depending on the specific pathogen, however, all begin with maternal infection. Following maternal infection, organisms may produce indirect placental infection with or without fetal infection, direct fetal or neonatal infection, or primary maternal infection and subsequent perinatal sequelae without either placental or fetal infection. Some pathogens may produce infections by more than one mechanism. This brief report will provide an overview of the pathogenesis, general outcomes, and known pathogens associated with perinatal viral and parasitic infections.

Environmental Influences on the Development of the Immune System:Consequences for Disease Outcome

Author(s): B. Björkstén

Early T cell responses to external antigens and autoantigens are subject to a variety of regulatory mechanisms. A unifying link between the increase in both Th1-dependent autoimmune disease and Th2-linked atopic allergy would be a disturbed immune regulation involving T regulatory cells. There is a strong global correlation between childhood wheezing and diabetes. It is increasingly recognized that microbial colonization of the gastrointestinal tract, linked with lifestyle and/or geographic factors, may be important determinants of the heterogeneity in disease prevalence throughout the world. These suggestions are supported by observations that germ-free mice do not develop tolerance in the absence of a gut flora. The potential effects of environmental stimuli on immune function is greatest in early life including fetal life when systems and responses are developing, and the maternal influences during fetal life could be particularly important for the development of immune regulation and tolerance induction. In recent years, focus has switched from searching for environmental risk factors towards an interest in factors that could induce and maintain immune regulation and tolerance to allergens and autoantigens. Currently evaluated strategies include the use of immunomodulatory factors, such as probiotics, prebiotics, and dietary nutrients, although data are still insufficient to make specific recommendations.