Department of Social Medicine, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK. E-mail: y.ben-shlomo{at}bristol.ac.uk
The paper by Mogren and colleagues1 provides further evidence for an association between low birthweight (LBW) and various measures of cardiovascular risk. In addition, they suggest potential interactions between LBW and a positive family history of premature cardiovascular disease and maternal pre-eclampsia or hypertension during pregnancy in increasing offspring blood pressure. They conclude that from a public health perspective, heredity was more important than low birthweight (LBW) for elevated systolic blood pressure.
The observation that birthweight is inversely associated with blood pressure is one of the most consistent and convincing features of the fetal origins hypothesis.2 However, similar associations with other features of the insulin resistance syndrome (glucose intolerance, elevated triglycerides, central adiposity) remain more controversial. McKeigue has argued that small baby syndrome, the association of birthweight with high blood pressure, hyperinsulinaemia and glucose intolerance, does not generally include lipid abnormalities.3 In the study by Mogren and colleagues,1 raised triglycerides and cholesterol levels were seen for LBW but were inconsistent by gender. Low birthweight was paradoxically associated with reduced obesity. Measures of central adiposity, such as waist-hip ratio were not available but do correlate moderately with body mass index.
The novel findings that a positive family history of cardiovascular disease and pre-eclampsia or pregnancy hypertension may interact with LBW in increasing risk of hypertension require replication. The markedly wide confidence intervals around both synergy indices indicate that there is no statistically significant interaction. Despite this, it is important to consider what these results tell us, assuming they are not merely chance occurrences. Foetal programming argues that undernutrition in utero permanently changes the body's structure, physiology and metabolism and leads to a variety of chronic diseases in adult life.2 However, another possibility is the role of a common genetic mechanism that determines both intrauterine growth and later adult disease.3,4 In this case, a small baby with a positive family history or maternal hypertension may be a better marker for genetic factors contrary to the fetal programming hypothesis. Alternatively, genetic influences on blood pressure may influence intrauterine growth through the intermediary phenotype of maternal pre-eclampsia and hypertension. Higher maternal blood pressure, but not paternal blood pressure, has been shown to be associated with birthweight, but both maternal and paternal blood pressure were associated with offspring blood pressure with relatively similar effect estimates.5 Similarly, birthweight of offspring is inversely associated with both maternal and paternal risk of cardiovascular mortality, although the maternal association appears to be stronger.6
Previous studies have tried to differentiate inappropriately small babies by examining whether the effect of birth dimensions on adult outcomes is greater for small babies who are tall as compared to short in adulthood. The assumption is that such babies have experienced some form of uterine growth restraint which has resulted in worse growth in relation to their genetic potential. Post-natally, however, subsequent catch-up growth has enabled them to reach their appropriate growth trajectory. Mogren and colleagues1 claim to find further evidence in support of this observation,7 but in fact they cannot compare the risk of systolic hypertension (160 mmHg) for LBW subjects with and without short stature as there were no subjects in the latter category. Their data for diastolic hypertension (
95 mmHg), however, (provided by authors in response to reviewers) show almost identical odds ratios of around 2.5 for LBW for subjects both below and above the median height. Studies that have direct measures of catch-up growth fail to find evidence that increased weight gain in infancy, as would be expected for inappropriately small babies, has any relationship with adult blood pressure.8,9 These results, if confirmed, can only be consistent with either a genetic model or environmental factors that cause a permanent resetting of an infant's growth trajectory, hence preventing any observed effect of catch-up growth.
The authors attempt to estimate the population attributable proportion due to LBW as compared to heredity to provide some context to the public health importance of the fetal programming hypothesis. By unusually dichotomizing birthweight into a low and normal birthweight group they artefactually underestimate the potential benefits of shifting the whole birthweight distribution to the right by increasing birthweight. Furthermore, a positive family history does not merely indicate genetic influences but will also include shared environmental features such as socioeconomic conditions. More realistic estimates of the preventable fractions associated with birthweight, assuming that such associations are causal and reversible, have been made and conclude that such benefits would be modest and smaller than conventional adult risk factor modification.10 More importantly, whilst such birthweight associations with adult disease may provide novel aetiological clues as to underlying pathophysiological mechanisms, one cannot consider single disease end points in isolation. Using the seminal data from the Hertfordshire cohort for both men and women,11,12 regrouped to be comparable to that from the Uppsala cohort,13 one can see that the association between birthweight and all-cause mortality for both men and women (Uppsala data taken for deaths 65 years) is relatively weak or flat (Figure 1
). There are clearly a range of other outcomes that are positively associated with increased birthweight, such as breast, ovarian, and prostate cancer, type 1 diabetes and atopy.10 As the range of morbidity contributing to all-cause mortality will differ by country and time period, one must be cautious in extrapolating these results. Birthweight may also have differential associations with infant and childhood mortality as compared to adult mortality. However for developed countries, with the continuing decline in cardiovascular disease and increases in cancer, it remains uncertain as to whether a shift in increasing the birthweight distribution will have any mortality benefits for future generations.
|
References
1 Mogren I, Högberg U, Stegmayr B, Lindhal B, Stenlund H. Fetal exposure, heredity and risk indicators for cardiovascular disease in a Swedish welfare cohort. Int J Epidemiol 2001;30:85362.
2 Barker DJP. Mothers, Babies and Health in Later Life. 2nd Edn. London: BMJ Publishing Group, 1994.
3 McKeigue P. Diabetes and insulin action. In: Kuh D, Ben-Shlomo Y (eds). A Life Course Approach to Chronic Disease Epidemiology. Oxford: Oxford Medical Publications, 1997, pp.78100.
4 Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999;353:178992.[ISI][Medline]
5 Walker BR, McConnachie A, Noon JP, Webb DJ, Watt GCM. Contribution of parental blood pressures to association between low birth weight and adult high blood pressure: cross sectional study. Br Med J 1998;316:83437.
6 Sterne JAC, Davey Smith G, Leon DA, Tynelius P, Rasmussen F. Fetal growth is associated with parents' cardiovascular mortality: record linkage study. Pediatr Res 2001 (in press);Supplement, Abstract FC9/4.
7 Leon DA, Koupilova I, Lithell HO et al. Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men. Br Med J 1996;312:40106.
8 Law CM, Shiell AW, Syddall HE (on behalf of the Brompton Adult Blood Pressure Steering Group). Growth in utero, infancy and childhood: which influences adult blood pressure? Pediatr Res 2001 (in press); Supplement, Abstract FC4/2.
9 McCarthy A, Ben-Shlomo Y, Elwood P, Davies D, Davey Smith G. The relationship between birth weight, catch up growth in infancy and blood pressure in young adulthood. Pediatr Res 2001 (in press); Supplement, Abstract POS12/11.
10 Joseph KS, Kramer M. Should we intervene to improve fetal growth? In: Kuh D, Ben-Shlomo Y (eds). A Life Course Approach to Chronic Disease Epidemiology. Oxford: Oxford Medical Publications, 1997, pp.27796.
11 Barker DJP, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;ii: 57780.
12 Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds SJ. Early growth and death from cardiovascular disease in women. Br Med J 1993;307:151924.[ISI][Medline]
13 Leon DA, Lithell HO, Vågerö D et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15000 Swedish men and women born 19151929. Br Med J 1998;317:24145.