Commentary: The impact of fetal and infant exposures along the life course

Mary Beth Terrya and Ezra Sussera,b

a Division of Epidemiology, Joseph L Mailman School of Public Health at Columbia University, New York, NY 10032, USA.
b New York State Psychiatric Institute, New York, NY 10032, USA.

What happens in the womb sets the stage for development of the child and influences the health of offspring throughout their life course. Until recently, however, most epidemiologists focusing on adult diseases paid little attention to fetal origins of health. Due in part to tantalizing reports that birthweight is associated with health outcomes in both children and adults, that has changed. In this recent surge of interest, the best documented finding for adults is that lower birthweight predicts higher risk of cardiovascular disease.1,2 A smaller but growing literature reports intriguing findings for numerous other domains of child and adult health, for example, higher birthweight has been related to an increased risk of breast and other cancers.1 Especially relevant to the papers in this issue of the Journal are recent findings suggesting that the relation of neurocognitive development to birthweight goes beyond low birthweight and well into the normal birthweight range. The few available reports on birthweight and health in developing countries, including two in this issue, find similar relationships.

The accumulating evidence for associations between birthweight and health posed three central challenges from the start: refining the measure of early experience, tracing the causal pathway that connects early experience with later health, and ruling out confounding by social class. As yet, none has been fully met. Nonetheless, progress has been made, and the studies in this issue are noteworthy for pursuing these lines of questioning.

Refining the measure of early experience

In early reports, maternal nutrition was sometimes assumed to be the operative factor. A common view was that poor maternal nutrition led to low birthweight as well as to intrauterine ‘programming’, i.e. a long-term alteration in genetically programmed development induced by in utero experience. This hypothesis was a useful starting point but could not explain the complex findings from human studies. Studies of the Dutch Hunger Winter, for example, reported that severe maternal undernutrition in late gestation led to reduced weight, length and head size at birth.3 With respect to later health outcomes, however, early gestation undernutrition was related to increased obesity,4 and increased risk of schizophrenia. Neither early nor late gestation undernutrition was related to IQ at age 18.3,5 More refined hypotheses are needed to explain these results along with the associations noted earlier for birthweight and health.

As underscored in the accompanying review paper in this issue,6 many investigators have taken up this challenge and now advance refined ‘nutritional’ hypotheses that differentiate fetal from maternal nutrition and specify the relevant dimension and timing of fetal nutrition.6 In addition, intriguing ‘non-nutritional’ hypotheses focus on other factors in the intrauterine environment, such as growth hormones and glucocorticoids, that may play a role in intrauterine programming.6 Studies based on birthweight alone cannot make the distinctions required to test these refined hypotheses. We will need epidemiological studies with measures of underlying biological processes as well as complementary animal studies. We can continue to learn much from birthweight, however, particularly when it is combined with other measures of growth. The reports in this issue contribute to this process, by exploring the different predictive powers of birthweight and other measures available at birth. For example, Cheung et al. report that birth length is more influential in predicting childhood motor development than birthweight7 and Law et al. find inverse associations for birthweight, birth length, and head circumference with childhood systolic blood pressure.8 We hope these efforts will be followed by additional research on how best to combine these and other measurements to define meaningful groups in terms of intrauterine nutrition and growth.

Tracing the causal pathway

The studies in this issue illustrate the importance of the childhood period in tracing underlying pathways linking birthweight to adult health. Studies of early life exposures and childhood health are important to children, but crucial too for interpreting studies of the fetus and newborn as related to adult health. Childhood data enable us to identify intermediate markers; to follow growth patterns; and to test whether fetal and newborn associations with subsequent health effects can be modified by childhood environment.

Three studies in this issue examine potential intermediate markers for adult health. Law et al.8 find low birthweight associated with blood pressure as early as age 3; Kelly et al.9 report associations between low birthweight and childhood behaviour; and Nilsson et al. find low birthweight associated with a measure of stress in young men.10 The association of an early antecedent with the marker may differ from its association with the endpoint, however, if an antecedent (e.g. birthweight) has multiple effects across the causal chain, or if pathways to disease are multiple, or if an intermediate marker is much more common than the endpoint.11 An obvious next step is to track these effects over time.

Likewise, childhood growth measures are important to understanding causal processes because it may not be low birthweight per se but rather a pattern of growth—for instance, restricted fetal growth followed by very rapid postnatal ‘catch-up’ growth—that is important to underlying disease pathways. In this issue, Cheung et al.7 collected multiple growth measures in infancy. They found that the effect of birthweight on motor development was not fully mediated by infant growth measures.

Moreover, the impact of fetal and infant exposures may be modified by the childhood environment. For example, Kelly et al.9 investigate potential effect modification of the association between birthweight and childhood behaviour by social class. Although their study is inconclusive, this line of investigation should be applied in other studies of birthweight and health. Estimating the presence and extent of modification is important not only to understanding the underlying causal processes but also in designing public health and social policy interventions.

Whereas most of the studies in this issue concern the period after birth, Shaw et al.12 and Raum et al.13 focused on the period before it. For insight into underlying processes which can illuminate the direction as well as the components of causal relationships, it is vitally important to collect information about the prenatal period.

Confounding by social class

Those sceptical of the fetal origins hypothesis can still make a plausible argument that confounding by social environment may explain the observed associations. Social class, for example, is strongly related to birthweight as well as child and adult health. Most of the studies presented in this issue adjust for social class through proxies such as maternal education but none of the measures are entirely satisfactory. Given the strength of social class effects and the more modest associations between birthweight and health, residual confounding due to measurement error is entirely possible. Twin studies might refute this challenge,14 but these are few and the results are sometimes inconsistent. Novel study designs may be needed before the controversy can be put to rest. One such approach may be to compare health outcomes in a large number of same sex siblings who are discordant on measures of early experience such as birthweight.

In sum, the collection of studies in this issue are revealing both of how far the field of fetal origin research has come and of how far it still has to go. As we continue to improve the measures of early experience, to formulate better the causal pathways we want to test, and to implement new approaches to control for social class confounding, further advance will undoubtedly result.

References

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2 Barker DJP. Fetal and Infant Origins of Adult Diseases. London: British Medical Journal, 1992, p.341.

3 Stein Z, Susser M, Saenger G, Marolla F. Famine and Human Development: The Dutch Hunger Winter of 1944–45. New York: Oxford University Press, 1975.

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6 Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol 2001;30:15–23.[Free Full Text]

7 Cheung YB, Yip PSF, Karlberg JPE. Fetal growth, early postnatal growth and motor development in Pakistani infants. Int J Epidemiol 2001;30:66–72.[Abstract/Free Full Text]

8 Law CM, Egger P, Dada O et al. Body size at birth and blood pressure among children in developing countries. Int J Epidemiol 2001;30:52–59.[Abstract/Free Full Text]

9 Kelly YJ, Nazroo JY, McMunn A, Boreham R, Marmot M. Birthweight and behavioural problems in children: a modifiable effect? Int J Epidemiol 2001;30:88–94.[Abstract/Free Full Text]

10 Nilsson PM, Nyberg P, Östergren P-O. Increased susceptibility to a psychological stress test in young males is associated with low birthweight. Int J Epidemiol 2001;30:75–80.[Abstract/Free Full Text]

11 Terry MB, Neugut A, Schwartz S, Susser E. Risk factors for a causal intermediate and an endpoint: reconciling differences. Am J Epidemiol 2000;151:1–7.

12 Shaw GM, Todoroff K, Carmichael SL, Schaffer DM, Selvin S. Lowered weight gain during pregnancy and risk of neural tube defects among offspring. Int J Epidemiol 2001;30:60–65.[Abstract/Free Full Text]

13 Raum E, Arabin B, Schlaud M, Walter U, Schwartz FW. The impact of maternal education on intrauterine growth: a comparison of former West and East Germany. Int J Epidemiol 2001;30:81–87.[Abstract/Free Full Text]

14 Leon DA. Twins and fetal programming of blood pressure. Questioning the role of genes and maternal nutrition. BMJ 1999; 319:1313–14.[Free Full Text]