Book of the Month: The Fetal Matrix: Evolution, Development and Disease
Authors: David Sharp
Journal: Journal of the Royal Society of Medicine (2005)

The test of a good hypothesis, curiously, is not that it should be true. Philosophers of science say that proof is impossible, the highest accolade being a long-running failure to refute. We can also look at the amount of research and debate that it generates, and on this basis David Barker's fetal origins hypothesis is a cracker. For our hunter–gatherer ancestors there were advantages in having the unborn programmed physiologically for a nutritionally deprived environment, but such preparation works less well when babies grow up in a world with fast-food outlets on every corner. Readers seeking something more formal by way of description of the Barker hypothesis could try the 1995 wording: 'fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease'.1 Barker's new way of thinking has the added merit of acting as a counterweight to the argument that bad lifestyle choices are almost entirely to blame for cardiovascular disease, diabetes and so on. However, at least something can be done about such choices—smoking, unhealthy diets, lack of exercise. It is far less clear what we can do about the adult ills that stem from the fetus's receipt of misleading signals about what extrauterine life would really be like.

The story of Barker's hypothesis and its exploration so far is set out by Peter Gluckman and Mark Hanson in The Fetal Matrix: Evolution, Development and Disease.2 The authors have their sights on lay people as well as the scientifically and medically trained—a sometimes overworked ambition but a sensible one here, given the practical consequences of acting on the hypothesis. But also a difficult target, as suggested by the clutter of 145 explanatory footnotes and the complexity of some sections, such as the one on osteoporosis, and of occasional terms (e.g. 'teleological[ly]', a word to be treated with care).

Professor Barker offered no biological explanation for the early and unexpected observation that maps of the distribution of coronary heart disease did not fit the received wisdom that this was somehow an affliction of the better-off and the later finding, from records found in Hertfordshire to give just one example,3 that low birthweight was associated with increased cardiovascular problems later in life. Gluckman and Hanson fill in the gaps and provide much more, with well-linked chapters on evolution, on environmentally driven developmental changes in animals in their natural habitats, and on fetal biology to supplement excellent accounts of the epidemiological, clinical and laboratory animal evidence. Excellent with one irritating exception. 'Further reading' can certainly be a useful device in books aimed at the non-specialist but here the original papers listed are never linked exactly with statements in the text, and occasionally this matters. The Lancet is accused (by comparison with the BMJ anyway) of neglecting the Barker hypothesis and of discouraging correspondence on it. (Your reviewer was on the editorial staff of that journal for many years and his possibly biased recollection is rather different.) The authors go on to criticize a paper without identifying the target—which is, presumably, Huxley, Neil and Collins.4 These workers noted that the link between low birthweight and later high blood pressure was very weak, being of the order of 1 mmHg per kg. This was a meta-analysis of human data, not a review article, yet Gluckman and Hanson criticize it for failing to refer to the evolutionary perspective and the experimental evidence. They also argue that blood pressure is a poor proxy for hypertension, just as birthweight is for fetal growth. Maybe, but elsewhere sphygmomanometry seems to be serving the salt/hypertension debate pretty well. Incidentally, that 2002 paper kept The Lancet's correspondence editor busy for the last issue of the year, and 19865 and 19893 papers in the same neglectful journal surely helped the hypothesis on its way.

The published work does not all point in the same direction—indeed we should be surprised if it did. In 2004, though too late for this book, Huxley and Neil6 reported a follow-up of a 60-year-old study of nutrition in wartime pregnancies. They found 'no evidence to support the hypothesis that birth weight or maternal nutrition in pregnancy are associated with [coronary heart disease] risk factors in adult life'. A cholesterol meta-analysis7 has reached a conclusion similar to the one on blood pressure. On the surface, data on twins do not support the hypothesis either,8 though Gluckman and Hanson challenge that interpretation. In this Journal Wilkin and Voss have lately argued that, for more recent birth cohorts, some other explanation for the rise in metabolic syndrome may have to be sought.9 5 years earlier Lucas and colleagues10 were noting flaws in some of the evidence cited for the fetal origins hypothesis. The vigour and rigour with which the hypothesis has been challenged is both a compliment to the idea and a reflection of healthy and necessary scepticism.

Southampton, where the MRC Environmental Epidemiology Unit was the base for much of the pioneering work, now hosts a Centre for Developmental Origins of Health and Disease (director, Mark Hanson). There is also an International Council for Research into the Fetal Origins of Adult Disease, and the Third International Congress on Developmental Origins of Health and Disease will be held in Toronto in November, 2005. There is a specialty in the making here, which some are tempted to call 'evolutionary medicine',11 covering responses on a time scale quicker than the sluggish pace of classical darwinian progress but slower than physiological homoeostasis. The Fetal Matrix argues that the questions to be answered will require a multidisciplinary approach and commitment as great as that for unravelling the human genome or sorting out particle physics. Two questions at a practical level seem especially pressing. Barker himself has never said that disease causation lies solely in experiences in utero. He seeks 'a new strategy for the prevention of Western disease, which will focus on the nutrition of young women and their babies as well as the lifestyles of men and women in middle age'.12 But how is the blame to be divided? Work from Finland (once again the reader is not directed to the relevant article) confirms the importance of inappropriate signals received by the fetus but does not quite say that they explain X%, leaving the rest to be ascribed to lifestyle, defective DNA or as yet unknown mechanisms. Gluckman and Hanson use the term predictive adaptive response (PAR) to describe the mechanism whereby species under acute threat, which might otherwise become extinct if darwinian evolution had to be relied upon, do survive to reproduce. To epidemiologists, however, PAR means something very different—population attributable risk. The INTERHEART case–control study13 reckons to have 90% of that risk for acute myocardial infarction accounted for by nine factors. Some of them (e.g. hypertension, diabetes, obesity) crop up in the fetal origins type of PAR, so unhealthy living as a cause of disease in adulthood will be confounded by inappropriate signalling in utero and vice versa. This minefield of confounding will make X (and 100 minus X)—the big unknowns, at least from the practical perspective of public health—very hard to calculate.

Physicians, health ministers and advisers would not wish to be remembered for recommending a policy of relative starvation for young children, which a simplistic reading of the hypothesis might seem to ask for. Fortunately for them, matters are nothing like that straightforward. In addition to attention to maternal nutrition during pregnancy, individually tailored early-life nutrition plans may be the answer, Gluckman and Hanson suggest. To use their examples, that means something different for a baby born at 3800 g and 52 cm long than for one a bit lighter and longer at 3300 g and 58 cm. This is asking a lot, and not just of mothers and fathers. The modern emphasis on developmental rather than simply 'fetal' origins of adult disease reflects the opportunities for intervention both during gestation and postnatally, but the second tricky practical question is how to ensure that the right balance is struck between the two.

Those seeking an alternative to the current preventive approaches focused on healthy choices by adults should certainly read Gluckman and Hanson's book, which argues that adulthood will often be too late. If these and other readers come away from The Fetal Matrix somewhat depressed, that response should be blamed on the continuing uncertainty about when, let alone how, the fetal origins argument can be applied to clinical medicine. The book itself provides a clear description of the origin and development of a provocative and truly original idea.