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The fetal matrix: evolution, development and disease
  1. A C Breeze

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    Edited by Peter Gluckman and Mark Hanson. Cambridge: Cambridge University Press, 2004, £24.99, pp 256. ISBN 0 521 54235 9

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    The idea that the intrauterine environment has an effect on disease later in life is not new. The “Barker hypothesis” has been around for over 10 years. For those unfamiliar with the hypothesis at its simplest level, it suggests that a low birth weight reflects an adverse intrauterine environment that the fetus has adapted to, in order to survive. This “thrifty phenotype” is the result of altered development in utero to cope with poor supply of nutrients and oxygen from the mother. The consequence of this phenotype, however, is a doubling in the risk of death from heart disease in individuals born with low birth weights (less than 2.5 kg). Gluckman and Hanson develop these ideas, and draw on evidence from zoology and fetal physiology, and suggest that many diseases may, at least in part, result from “predictive adaptive responses”.

    A PAR is a different trajectory of development that the fetus takes as a result of its intrauterine (or perhaps early postnatal) environment, with the aim of maximising chances of survival to reproductive maturity, in a particular expected postnatal environment. For example, in the pregnant snowshoe hare, stress (due to predation, cold, or starvation, for example) may lead to increased maternal cortisol levels. Cortisol may cross the placenta, and the fetus may detect, via signalling from the mother and placenta, that the external environment is a harsh one. The cortisol levels may enhance maturation of fetal organs, such as the lungs, and prepare the fetus for the rigours of postnatal life. However, it appears that exposure to such high cortisol levels in utero may alter the sensitivity of the hypothalamo-pituitary-adrenal axis, making it hyper-responsive after birth. So the offspring of hares that have been stressed during pregnancy, may be hyper-alert—a predictive adaptive response to the expected postnatal environment. One wonders what the effects of an analogous human PAR might be.

    Gluckman and Hanson propose that while we have reached a stage in the 150 000 year history of Homo sapiens where Darwinian evolution is no longer active or has slowed dramatically, the predictive adaptive responses we have evolved now threaten our post-reproductive health, in terms of obesity, type 2 diabetes, atherosclerosis, and hypertension. These responses could be initiated soon after conception, mediated by DNA methylation. What is unclear is the extent to which PARs may play a role in human disease outside the context of birth weight (or rather suboptimal fetal growth) and the metabolic “syndrome X”. Gluckman and Hanson make a case for other diseases such as osteoporosis, cognitive decline, psychosis, and polycystic ovarian syndrome, with varying degrees of persuasiveness.

    The message from the book appears to be twofold: that the evidence for PARs playing a role in human disease is a persuasive one, which should not be overlooked in favour of “sexy” genome research; and secondly, that if these hypotheses are correct then this has significant implications for society, and how we try to reduce the burden of disease in later life. Unfortunately, there appear to be few recommendations we can make for optimising the intrauterine, and postnatal, environment to minimise the potentially harmful effects of inappropriate PARs.

    The fetal matrix concludes with a call for an increased emphasis on the importance of female health before and during pregnancy, with improved female literacy and education (and therefore, hopefully, avoidance of teenage pregnancy), and nutrition. It therefore sends a message to research funding councils of the potential importance of this area of research, and to politicians about priorities. The book should however be of interest (and thought provoking) to anyone with an interest in perinatal care, human nutrition, and fetal physiology.

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