The Society for Social Medicine John Pemberton Lecture 2011. Developmental overnutrition-an old hypothesis with new importance?*

This paper is concerned with whether mothers who are more adipose or have higher glucose levels during pregnancy may overfeed their developing infants in utero and in doing so may set them on a pathway to greater adiposity throughout their lives. If this is the case, then the more adipose daughters of these mothers may also subsequently overfeed their infants in utero, thereby perpetuating the risk of greater adiposity across generations. I begin with the historical context of how gestational diabetes was first recognized and early evidence that diabetes in pregnancy results in increased birth size and adiposity. I then consider four questions, which are the main focus of the paper. Each of the four questions involves an exposure during pregnancy and evidence concerned with whether the exposure is causally related to offspring adiposity via intra-uterine mechanisms. The four related exposures are: (i) pregnancy diabetes; (ii) extreme maternal pregnancy obesity (> 40 kg/m(2) or meeting criteria for bariatric surgery); (iii) incrementally greater pre-/early pregnancy adiposity across the whole distribution seen in pregnant women; and (iv) gestational weight gain. Since randomized controlled trial evidence is not available I focus on methods that can provide the best causal evidence from observational data such as negative control studies, family comparisons and using genetic variants as instrumental variables (i.e. Mendelian randomization studies). Having addressed these four questions I go on to briefly discuss the possible role of epigenetic modification mediating any effects of maternal exposures on offspring outcomes. I conclude with a discussion about the future research and policy implications of evidence to date in this field.