IJE Advance Access originally published online on February 14, 2006
International Journal of Epidemiology 2006 35(2):277-279; doi:10.1093/ije/dyl021
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Commentary |
Commentary: Games people play—birthweight
MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: J.Wells{at}ich.ucl.ac.uk
Accepted 25 January 2006
The ubiquitous use of birthweight data in epidemiological analyses owes more to its wide availability than to certainty as to exactly what it provides information about.1 On the other hand, studies have increasingly associated birthweight with both short-term survival2 and the risk of metabolic diseases in later life.3 Monitoring birthweight within and between populations, therefore, remains a highly pertinent epidemiological tool, providing that we bear in mind that it cannot tell us the mechanism linking birthweight variability with outcome.
Our difficulty in understanding the significance of birthweight variability stems from the fact that it is influenced by a large number of major biological processes. Environmental factors may relate to maternal pregnancy physiology, longer-term maternal phenotype, or broader climatic conditions. Genetic factors may relate to ethnicity, body size, or specific polymorphisms, and their influence may be mediated by multigenerational effects counterbalanced by within-lifetime plasticity. Given this complexity, it might be assumed that analyses of birthweight should focus on one factor at a time, while attempting to hold other factors constant. Harding et al.4 have taken a braver and potentially more rewarding option, by investigating birthweight variability not only in two populations in Portugal, one resident and one immigrant, but also secular trends therein over a 7 year period. It is not surprising that the authors conclude with a call for further research to elucidate their findings. Nevertheless, their data highlight the plasticity of birthweight.
The genetic basis of birthweight variability is a notoriously complex issue. Studies of the effect of migration represent a useful approach and, in general, have shown that differences between groups in post-natal size are markedly reduced when a common environment is experienced. One difficulty in researching this issue in relation to birthweight is that it may take several generations for inherited environmental effects to ‘wash out’ completely (for example, small mothers who migrate to better conditions may still, through their reduced body size, constrain the size of their offspring for more than one generation2). As evidence of genetic contributions goes down, so the complementary contribution of plasticity to variability must go up.
In the first decades of the 20th century, the American anthropologist Franz Boas demolished the prevailing argument that differences in children's growth between ethnic groups had a fixed genetic basis. By measuring growth in the children of migrants to the United States, Boas demonstrated major effects of improved nutrition and health.5 In the first decade of the 21st century, with greatly improved measurement technologies and a far more sophisticated understanding of ontogenesis, it could be argued that we are rediscovering the same primacy of early life plasticity.
Migration itself has no consistent effect of early growth. For those leaving a poor environment for a better one, improved circumstances may translate into increased birthweight of their offspring. In contrast, for those encountering discrimination and poor social circumstances in their new environment, migration may generate the opposite effect. In the present study, Harding and colleagues ascribe some birthweight variability to the effect of migration from Africa to Europe, however this interpretation is complicated by evidence of temporal variability within the European population. More broadly, it is worth considering why a trait so closely associated with health and survival should be sensitive to such a broad range of biological factors. Why is birthweight so plastic?
From an evolutionary perspective, parents and offspring are in genetic conflict. Mothers share 50% of their genes with any individual offspring. All other things being equal, selection favours equal maternal investment in each offspring. Offspring share 50% of their genes with each full sibling, and 25% of their genes with each half sibling. Each offspring therefore favours a disproportionate distribution of maternal investment in itself, leading to a conflict of interest between each offspring and its mother in relation to the optimum transfer of resources during the period of parental care. Haig6 has produced an elegant account of the nature of this conflict during pregnancy, describing the physiological battleground where maternal and fetal hormones compete for nutrients in maternal circulation.
Each of the parties in these battles may be considered to be playing a game. Economics has long made use of game theory in order to understand how optimizing the strategy of one individual requires taking into account the strategy of others. Biologists too have used game theory to investigate the dynamics of behavioural interactions, but it may be equally relevant at a physiological level. For the mother, the game consists of allocating resources between different offspring, some of which may already exist and some of which might exist only in the future. All other things never are equal, and maternal investment is tailored to the likely returns on maternal fitness. For example, mothers provide more energy to males than females, demonstrated by increased energy intake during the gestation of a male fetus.7 In general, maternal genes tend to restrict investment in the current fetus in order to preserve resources for other offspring, whereas paternal genes in the fetus favour investment in the current offspring because they cannot be certain of being present in other offspring of the same mother.6
The offspring also plays a game with its energy supply, selectively allocating calories to competing tissues, for example lean vs fat, or muscle vs organ tissues. Males and females adopt different allocation strategies, such that by birth, the average female is not only lighter but also fatter than the average male.8 Within each sex, individual fetuses likewise vary in their allocation strategies.
These games are not conducted in a vacuum, for accommodating environmental conditions is their function. Furthermore, resolution of each game requires long-term maternal offspring dynamics to be taken into account.9 A large baby represents a large burden on the maternal energy budget for the next decade or more. Some have argued that the offspring's ontogenetic strategy is based on prediction of its likely adult environment.10 Such a view fails to address the continuing tension between mother and offspring after birth, or indeed the fitness value of playing such games in the first place. The reason that migration studies illustrate the plasticity of birthweight is no accident. Human evolution might be considered one long process of dispersal, migration and colonization. Adults pioneer entry into new environments and leave their offspring to cope with the consequences. The plasticity of birthweight and early growth is a critical component of how this adaptation is achieved—birthweight is the ultimate trade-off, the consequence of multiple strategic decisions and negotiations in unpredictable conditions. As we rediscover the importance of early life plasticity for human health, we are really rediscovering our evolutionary heritage.
Appreciation of the plasticity of birthweight leaves us with a difficult question—what is optimum birthweight in any population? From an evolutionary perspective, there is no optimum, except in an abstract mathematical sense, quantified in terms of genetic fitness. From a medical perspective, the optimum birthweight might be considered that at which offspring morbidity and mortality is minimized.11 Such an optimum might not, however, be that at which maternal morbidity and mortality are minimized. Finally, given the sensitivity of physiological systems to physical factors such as temperature or altitude, optima are likely to vary between geographical locations, as suggested by a recent analysis of population variability in birthweight.12
We can only make things more complicated, but more realistic, if we take into account the composition of birthweight. The optimal ratio of fat and lean, and organs to muscles, may likewise vary according to circumstances. In the context of the metabolic syndrome, fat may represent a toxin, but in the context of early survival, fat represents an insurance policy.8 The fetal ontogeny of body composition is closely related to the derivation of different metabolic settings. The game played by babies in utero is little different to that played by team engineers on the Formula One circuit. At each Grand Prix, cars undergo subtle adjustments in relation to the local temperature, weather, and track topography. In each race the ‘metabolic settings’ and ‘anatomical structure’ of the car are altered to maximize output. For engine design, read cardiovascular structure. For engine setting, read the profile of insulin and related hormones. By birth, babies have already selected a ‘race strategy’, and while they can revise it after birth in the remaining window of plasticity, they cannot negate it entirely.
Birthweight thus represents the endpoint of the game of pregnancy, though not of the game of development. The endpoint matters because, as Barker and colleagues have noted, a large proportion of organogenesis is already achieved by birth. In order to understand the health consequences of different fetal strategies, it is necessary to go beyond birthweight and undertake prospective studies of the relationship between birth body composition and subsequent health outcomes. Until recently, this research area was relatively unexplored, owing to a lack of appropriate methodologies. Anthropometry is by no means redundant and can reveal important effects.13 In the last decade, four more sophisticated techniques have also emerged—isotope dilution, dual energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI) and a form of densitometry based on whole-body plethysmography designed especially for neonates, known as the Peapod.
Of these four techniques, DXA is likely to suffer from the greatest error, owing to soft-tissue measurements being confounded by the presence of bone. It may also present practical difficulties and involves exposure to radiation. Isotope dilution has been used extensively from early infancy onwards,14 and presents few practical difficulties. The main limitation of this technique is the need for accurate data on the hydration of lean tissue. Plethysmography likewise requires data on the composition of lean mass, but appears well tolerated by infants.15 The composition of lean mass can be measured by combining isotope dilution and plethysmography, an approach that provides the three component model of body composition. MRI is also increasingly conducted in neonates and infants.16 From a theoretical perspective, MRI is the most sophisticated technique, distinguishing bone, lean, and fat, and also assessing regional body composition. However unlike the other techniques it measures adipose tissue rather than fat, and there are some concerns as to how constant the fat content of adipose tissue is in infants.17 Bearing in mind that the gold standard for body composition assessment remains cadaver dissection, the limitations of in vivo techniques described above should not discourage their application. The suite of available techniques now enables measurements in individual neonates for both whole-body and regional body fat with acceptable accuracy for many research questions.
If growth, as Boas argued, offers a mirror of the human condition, then studies of birthweight remind us that humans continue to come and go between environments of varying quality, as they always have done. There is no doubt that migration can have major effects on health, in current or future generations, as Boas showed. Measurement of body composition at birth is likely to make a major contribution to understanding how these effects develop.
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