Long-term consequences of early nutrition
Introduction
“Metabolic programming” and “developmental origins of adult diseases” have become important key words in medical research [1]. Researchers from different areas have significantly contributed to advance and refine the concept. Programming has been defined as “either the induction, deletion, or impaired development of a permanent somatic structure or the “setting” of a physiological system by an early stimulus or insult operating at a “sensitive” period, resulting in long-term consequences for function” [2]. The term programming has been introduced into scientific literature to describe the finding that hormones, metabolites and neurotransmitters during critical early periods of development are capable of pre-programming brain development and up to human adulthood functional disturbances, diseases as well as syndromes of reproduction and metabolism [3].
The concept has gained wide popularity following epidemiological studies documenting an inverse relationship between body weight at birth and at age 1 year, respectively, and the risks of hypertension, diabetes and coronary heart disease in adulthood [4]. These observations have led to the hypothesis that maternal malnutrition during pregnancy would induce both foetal growth restriction and increased later disease risk, the foetal origins of adult disease hypothesis. It was later recognized that not the weight at birth or at any other specific age is the strongest predictor for later health, but rather a low initial weight and an accelerated weight gain after birth might be a risk factor for later disease [5].
The potential impact of programming on public health can be exemplified by considering the observation that 13 to 16 year old teenagers, who were breast fed showed an arterial blood pressure of 81.9 ± 7.8 mm Hg (M ± SD), while those who had received infant formula showed a significantly higher blood pressure of 86.1 ± 6.5 mm Hg [6]. The authors point out that this difference is greater than the effects of other blood pressure lowering measures, such as weight loss, salt restriction and physical exercise. A 2 mm reduction of blood pressure has been estimated to correspond to 17% and 6% reductions in the prevalence of hypertension and coronary heart disease, respectively. Early growth pattern has been shown to be related to insulin resistance, increased blood pressure, high plasma triacylglycerols, unfavourable LDL/HDL cholesterol ratio and central obesity, which are major components of the metabolic syndrome [4], [7], [8]. This further highlights the importance of investigating the relationship between early diet and later health, because metabolic syndrome and obesity show dramatically increasing prevalence in developed and developing countries and represent major health risks [9].
The association between low birth weight and increased risk of impaired health in later life may be explained partly/mainly by an influence of early nutrition, but it is worth to consider the possibility that there is a common underlying genetic influence. In a study of 64 years old monozygotic twins with different glucose tolerance, birth weights were lower in the twins with abnormal glucose tolerance: In the non insulin dependent diabetics + impaired glucose tolerance subjects (n = 106) birth weight was 2622 ± 45 g (M ± SE), and in subjects with impaired glucose tolerance (n = 62) it was 2613 ± 55 g, both significantly lower than in twins with normal glucose tolerance (n = 112, 2800 ± 51 g, p = 0.01 and p = 0.03, respectively) [10]. Since twins are genetically identical, this finding indicates that the association between birth weight and non insulin dependent diabetes mellitus is at least partly independent from the genotype and may result from an influence of intrauterine nutrition and early postnatal diet.
Huxley and colleagues criticized that the inverse association between birth weight and later blood pressure had erroneously been overestimated due to inappropriate adjustment for potential confounders, mainly current weight [11]. Using simulations, it was demonstrated that this might occur due to co-linearity between birth weight and current weight, which both influence blood pressure [12]. This possibility should be considered and proper statistical models should be applied, which enable the confirmation of associations detected in the unadjusted data after considering confounding factors in multivariate analysis.
Physiology, epidemiology and clinical science contribute to the progress in the field of programming, which has been summarized in recent reviews [13], [14], [15] and not all aspects studied can be discussed here. Rather some results which seem important for paediatric nutrition are discussed here.
Section snippets
Can adverse foetal programming outcome be reduced by postnatal dietary intervention?
In rat experiments excess glucocorticoid exposure in utero causes hyperleptinemia and hypertension in the offspring [16], [17]. Wyrwoll et al. exposed pregnant Wistar rats to a synthetic glucocorticoid (dexamethson) and compared this to a control group [18]. Within 24 h after birth pups were cross-fostered to dams either fed with standard rat chow without detectable n − 3 long chain polyunsaturated fatty acids (LCPUFA), which have been shown to positively affect cardiovascular disease risk and
Can the risk of later obesity be significantly influenced by early postnatal diet?
Childhood obesity is considered a global epidemic in view of the alarming increase of its prevalence and severity, not only in affluent but also in less privileged childhood populations worldwide [21]. Serious short and long term consequences of childhood obesity arise in terms of damage to quality of life, performance, health and life expectancy. In addition, the size of the obesity epidemic is estimated to create huge costs for society due to loss of productivity and ensuing costs for health
Early growth and later obesity risk
Already in the 1950s, McCance and Widdowson showed that alteration of early growth by manipulation of feeding conditions during sensitive pre- and postnatal periods predetermined the weight of rats in adulthood [24]. In humans high birth weight has been proposed as a risk factor for later overweight [25], which could reflect both the roles of genetics and of early priming by intrauterine environment. Recent studies also pointed to further priming of childhood overweight in the first months and
Protective effects of breast feeding against later obesity
It has long been known that infants fed breast milk differ in their growth kinetics from formula fed infants who show higher weight and length gains [29]. Based on a systematic review of 19 studies in affluent populations, Dewey concluded that by the age of 12 months, the cumulative difference in body weight amounts to approximately 400 g in infants breast fed for 9 months and as much as 600–650 g in infants that are breast fed for 12 months [30]. Given this very large effect of the mode of
Potential causes for the protective effects of breast feeding on later obesity
A number of hypotheses can be raised on potential causes for a protective effect of breast feeding. Since one cannot randomise healthy babies to feeding breast milk or formula for ethical and practical reasons, undisputable proof for a protective effect of breast feeding can hardly be obtained. Nevertheless, the establishment of a biological plausibility and the elucidation of mechanisms, which might mediate the protective effect of breast feeding, would further support the concept.
Differences
Early diet and neurodevelopment and the immune system
Besides the investigation of programming effects in relation to later obesity risk, cardiovascular disease and the metabolic syndrome several other long term outcomes of early nutrition have received considerable attention during the last years, amongst them the long term effects of the availability of LCPUFA during the perinatal period and early influences on the immune system.
Human milk contains n − 3 and n − 6 LCPUFA, which have been absent from many infant formulae until recently [57]. The
Testing the potential of metabolic programming by early nutrition: EARly Nutrition programming–long term follow up of Efficacy and Safety Trials and integrated epidemiological, genetic, animal, consumer and economic research (EARNEST)
Clinical science, epidemiology and animal/in vitro experimentation, which are all important for the investigation of programming by early diet are combined in the EU supported Early Nutrition Programming Project (www.metabolic-programming.org). In addition, socioeconomic and technological research is performed (Fig. 3).
The clinical trials in theme 1 all are follow up studies of already performed randomised intervention trials, which offers the advantage that the time period which can be covered
Acknowledgments
The authors thank the participating families and all project partners for their enthusiastic support of the project work. The studies reported herein have been carried out with partial financial support from the Commission of the European Communities, specific RTD Programme “Quality of Life and Management of Living Resources”, within the 5th Framework Programme, research grants no. QLRT-2001-00389 and QLK1-CT-2002-30582, and the 6th Framework Programme, contract no. 007036. This manuscript does
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