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Birth Weight is Forever

Basso, Olga

doi: 10.1097/EDE.0b013e31816379d9

Birth weight is associated not just with infant morbidity and mortality, but with outcomes occurring much later in life, including adult mortality, as reported by a paper by Baker and colleagues in this issue of Epidemiology. While these associations are tantalizing per se, the truly interesting question concerns the mechanisms that underlie these links. The prevailing hypothesis suggests a “fetal origin” of diseases resulting from alterations in fetal nutrition that permanently program organ function. The most commonly proposed alternative is that factors, mainly genetic, that affect both fetal growth and disease risk are responsible for the observed associations. Although both mechanisms are intellectually attractive—and may well coexist—we should be cautious to not focus excessively on fetal growth. Doing this may lead us in the wrong direction, as has likely happened in the case of birth weight in relation to infant survival.

From the Epidemiology Branch, NIEHS, NIH, HHS, Research Triangle Park, North Carolina.

Supported by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences.

Editors' note: A related article appears on page 206.

Correspondence: Olga Basso, Epidemiology Branch, MD A3-05, NIEHS, NIH, HHS, PO Box 12233, 111 TW Alexander Drive, Research Triangle Park, NC 27709. E-mail:

Although we only experience it for the shortest time, our weight at birth follows us, quite literally, from the cradle to the grave. Beyond its well-known correlation with infant mortality and morbidity, birth weight is predictive of several conditions that manifest later in life, such as hypertension, obesity, and insulin resistance.1–3 Mortality in adult life is also associated with birth weight, and Baker and colleagues4 present in this issue of Epidemiology results from a large Danish cohort of individuals born between 1936 and 1973 whose mortality was ascertained until 2004.

The authors note that an increased hazard of death is present not only among individuals who were light at birth, but also among the heaviest ones. Cancer mortality rises monotonically with birth weight, which is in agreement with a recent study reporting an increase in the incidence of most cancers with birth weight.5 The patterns for cardiovascular mortality and for mortality from all other causes are both U-shaped, similar to the well-known pattern for infant death, although much weaker.

Birth weight results from a complex network of influences, and the fact that it correlates so consistently with adult health is one of its many tantalizing features. The truly interesting question, however, concerns the mechanisms behind this correlation. The prevailing hypothesis postulates that undernutrition in utero results in permanent organ programming that influences susceptibility to disease throughout life.1,6 Others propose that factors that simultaneously affect birth weight and predispose to later disease are at the root of this association, as may be the case for maternal and fetal genotypes that are associated with both fetal growth and susceptibility to diabetes.7,8

As a reproductive epidemiologist, I should probably favor the former hypothesis, which—if proven true—would significantly bolster my main area of research. Yet, I surprise myself by being more inclined towards the latter explanation, probably because having struggled with the relation between birth weight and infant mortality has colored my vision on this issue. For many years, the strategy to improve infant survival has been aimed at efforts to prevent low birth weight, despite questionable evidence of it having a causal effect on mortality.9 This may not only have misled us for decades but, on occasions, may even have caused harm.10 Even the World health Organization has recently shifted its focus away from birth weight.11 As someone who is skeptical of any major role of birth weight on early mortality,12 I am thus reluctant to interpret the weaker associations between birth weight and adult disease as a direct consequence of disrupted fetal growth.

Coming at this problem as a somewhat prejudiced outsider, I tend to be overwhelmed by the amount of evidence favoring, in turn, the fetal programming or the genetic hypothesis, although the 2 mechanisms may well coexist.13 Animal studies consistently suggest that manipulation of prenatal conditions leads to permanent alterations of various organ systems—for example, through programming of the fetal hypothalamus2 and epigenetic effects.14 Studies in humans cannot, however, provide such direct evidence. Additionally, many have not been fully controlled for social status or other environmental factors. This is the case for the study in this issue,4 although it is now generally accepted that confounding is not driving these associations.2 Twin studies, which have much to recommend as far as confounder control is concerned, also yield ambiguous evidence.15–17 Virtually all twins are undernourished in utero, yet, they have a similar overall mortality pattern compared with singletons and no excess of cardiovascular deaths.18 It has also been argued that findings in twins may not apply to singletons.18,19

Baker and colleagues do not take a strong position in this debate, although they speculate that the current increase in the proportion of babies weighing over 4000 g may result in elevated mortality in the future.4 The implications of this trend are not clear. If we could manipulate birth weight, independently of what caused it to be excessively low or excessively high, could we then modify the burden of adult diseases? The answer to this question may have a tremendous public health impact, but the answer is distant still.

As Baker et al4 point out, the advice of increasing birth weight as a method to improve health may have been too simplistic. In fact, any attempt to influence birth weight in either direction, before having fully understood the complex mechanisms that underlie fetal growth as well as disease etiology, is potentially an act of hubris, and proponents of the developmental origin of disease hypothesis recognize this complexity.2,14 In 1995, Paneth and Susser20 invited scientists examining this hypothesis to subject it to “true ordeals,” so that it would have the opportunity to be refuted. Several researchers appear to have taken this exhortation to heart, and such healthy skepticism may prevent us from focusing on the wrong entity, as has likely happened with the role of birth weight in infant health.

Birth weight may be forever. We can hope that it will not take that long to understand why.

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OLGA BASSO worked at the Danish Epidemiology Science Centre (Denmark) prior to coming to the National Institute of Environmental Health Sciences (USA). Her main area of research is in reproductive epidemiology, with a special interest in birth weight and its relation with early mortality.

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