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The concept that fetal nutrition has an impact on the risk of developing certain diseases in adulthood is often called the Barker hypothesis. The fetus subject to malnutrition is believed to be “reprogrammed” into a “thrifty” phenotype, responsible for higher risk of metabolic disease in the adult years, in the case of post-natal exposure to excess or simply normal food intake (Figure 1). Numerous studies have also shown the inverse relation between birth weight and the different constituents of the metabolic syndrome in young adults (hypertension, insulin resistance, hyper-triglyceridemia).
It has also been shown that rats subject to calorie restrictions during the early neonatal period, showed — in spite of free access to normal food intake after this period of restriction — a weight deficit and anomalies in the body’s composition, extending into adulthood. This was not observed when the calorie restriction occurred at a later time. The prolonged follow-up of premature babies subject to different diets during the neonatal period showed that the programming concept can also be applied to men.
POSTNATAL GROWTH AND HEALTH IN ADULTHOOD
There is a link between type of food and growth dynamics during the first months of life, on the one hand, and long-term health, on the other hand.
Human data mainly come from observational, especially retrospective studies, which make it difficult to show a causal link between early type of diet and long-term health. On the other hand, animal data that proves the relation between these two parameters to be real is abundant. Among young male mice born with low birth weight, the quick recovery of growth retardation (“catch up growth”) with a hyper caloric diet after weaning is accompanied by a decrease of more than 25% in the life expectancy of the animals receiving this diet. In humans, growth rate during the very first months of life seems to have an impact on long-term metabolism. The highest risk of coronary disease, hypertension and type 2 diabetes is observed in subjects born with low birth weight for their terms and showing significant weight gain during early childhood, as part of “recovery” of growth.
There is a highly significant correlation between weight and height gain during the first two years of life and the weight, body mass index and sub scapular skin fold thickness and abdominal perimeter at the age of 14. Recent studies among children born at term receiving a cow’s milk formula have shown that the intensity of weight gain during the first week of life is associated with a higher risk of excess weight in adulthood. An American study has recently confirmed that the risk of being obese at the age of 20 is much higher in case of rapid weight gain during the first months of life.
In a cohort study conducted in Germany on more than 4,000 children, it was observed that weight gain from birth to the age 2 of was correlated to the risk of excess weight at the time of entering elementary school, and constituted the best predicting factor of future weight problems.
Rapid growth during the first months of life is associated with an increased risk of dyslipidemia and a higher prevalence in the presence of the insulin-resistance markers during adulthood.
Statural growth is also involved in adult health. There is a positive association between height and prevalence in the appearance of hormone-dependant cancers (breast, uterus, ovarian, and prostate).
The Barker theory : FETAL MALNUTRITION AND ADULT METABOLIC DISEASES
INFANT DIET AND PREVENTION OF LONG-TERM DISEASES
The preventive effect of diet on the subsequent appearance of diseases is difficult to prove. It is, of course, impossible to perform randomized prospective studies comparing breastfeeding and formula feeding, which induces recruitment bias and variables of confusion: the breastfeeding women are more often from the more privileged socio-cultural backgrounds and more ready to comply with health recommendations. Breastfed infants start community life at a later age than their bottle-fed counterparts, and are as a result protected against contagious and infectious diseases for longer. Retrospective studies meet with the problem of biased memory, especially with respect to how long the infants were breastfed and whether or not this choice was exclusive or partial.
Breastfed children have lower mortality and morbidity than those who are not breastfed.
Breastfeeding helps prevent infectious diseases of young children, in both developing and industrialized countries, on the condition that it is exclusive and in excess of 3 months. Nothing suggests that this protective effect extends into later life.
A meta-analysis including 69,000 children confirmed the existence of a protective effect, of breastfeeding, though minor, against obesity. Certain studies note a dose-effect, with the extent of protection being correlated to the length of breastfeeding. Risk is reduced by 22% during childhood and adolescence by comparison to children fed with infant milk formula made with cow’s milk. It has not been demonstrated that this beneficial effect continues into adulthood.
Several factors could be involved in the protective role of breastfeeding: slower statural and ponderal growth in breastfed children, lower protein intake, with variations in flavor, odor and composition of breast milk possibly influencing behavioral development regarding food…
Breastfed populations have on average lower blood pressure in adulthood. The content of polyunsaturated fatty acids (PUFA) could also be involved due to its effect on vascular endothelium. Indeed, a randomized study has shown that infant milk formulas enriched with long-chain polyunsaturated acids (LCPUFAs) were associated with figures significantly lower than TA measured at the age of 6. The low sodium content of breast milk could play a modulating role on TA in the long term. Milk type could also promote subsequent dietary preferences, which in turn could be responsible for differences in the intake of certain key foods in the course of childhood, thus impacting or modulating the TA.
The higher plasma concentrations of total cholesterol and LDL-cholesterol observed in breastfed infants are probably linked to the high cholesterol concentration in breast milk. Differences depending on the initial feeding mode no longer exist during childhood and adolescence, while cholesterolemia is lower in adults who were breastfed. Everything happens as if high intake of cholesterol during the initial period of life constituted a nutritional stimulus activating a programmed regulation of the activity of HMG-CoA reductase or LDL-cholesterol receptors, which persists in the long term.
The protective effect of breastfeeding in the prevention of type 1 diabetes is controversial. In animals, studies conducted on an experimental diabetes model show that a diet with hydrolyzed cow’s milk proteins should not be associated with a higher risk of diabetes. Immunization against cow’s milk proteins (ß-lactoglobulin, ß-casein, serumalbumin and others) could trigger an auto-immune reaction against the Langerhans islet cells, which could result in a similar structure between one or more cow’s milk proteins and the autoantigens located on the islets.
The role of breastfeeding in allergy prevention is also much debated by comparison to a formula diet based on cow’s milk. However, exclusive breastfeeding for 3 months is associated with a 42% reduction in the risk of atopic dermatitis in the case of family allergy background, a 30% reduction in the risk of asthma among the general population and 48% reduction in the case of family atopia. Many factors found in breast milk seem to be responsible for the protective effect against allergies (secretory IgA, TGF (transforming growth factor-ß), certain type n-3 polyunsaturated fatty acids, some interleukins, especially interleukine 10).
A meta-analysis has confirmed a benefit of 3.2 intellectual quotient points in favor of healthy children, after adjustment for confusion factors (age, the mother’s and father’s cultural and educational level, socio-economic status, mother’s smoking, etc.). It is very difficult to assess the real biological significance of this difference on an individual level, which continues into childhood and adolescence. It tends to increase with the length of breastfeeding and is smaller in children born prematurely (5.2 points against 2.7 points among children born at term).
Among the factors likely to explain this advantage, some could have to do with the high content in breast milk of certain AGPI-LC, particularly docosahexaenoic acid (DHA), which has a demonstrated role in the maturation of the retina and the cerebral cortex.
The preventive effect of diet on the subsequent appearance of diseases is difficult to prove. It is, of course, impossible to perform randomized prospective studies comparing breastfeeding and formula feeding, which induces recruitment bias and variables of confusion: the breastfeeding women are more often from the more privileged socio-cultural backgrounds and more ready to comply with health recommendations. Breastfed infants start community life at a later age than their bottle-fed counterparts, and are as a result protected against contagious and infectious diseases for longer. Retrospective studies meet with the problem of biased memory, especially with respect to how long the infants were breastfed and whether or not this choice was exclusive or partial.
Breastfed children have lower mortality and morbidity than those who are not breastfed.
Breastfeeding helps prevent infectious diseases of young children, in both developing and industrialized countries, on the condition that it is exclusive and in excess of 3 months. Nothing suggests that this protective effect extends into later life.
A meta-analysis including 69,000 children confirmed the existence of a protective effect, of breastfeeding, though minor, against obesity. Certain studies note a dose-effect, with the extent of protection being correlated to the length of breastfeeding. Risk is reduced by 22% during childhood and adolescence by comparison to children fed with infant milk formula made with cow’s milk. It has not been demonstrated that this beneficial effect continues into adulthood.
Several factors could be involved in the protective role of breastfeeding: slower statural and ponderal growth in breastfed children, lower protein intake, with variations in flavor, odor and composition of breast milk possibly influencing behavioral development regarding food…
Breastfed populations have on average lower blood pressure in adulthood. The content of polyunsaturated fatty acids (PUFA) could also be involved due to its effect on vascular endothelium. Indeed, a randomized study has shown that infant milk formulas enriched with long-chain polyunsaturated acids (LCPUFAs) were associated with figures significantly lower than TA measured at the age of 6. The low sodium content of breast milk could play a modulating role on TA in the long term. Milk type could also promote subsequent dietary preferences, which in turn could be responsible for differences in the intake of certain key foods in the course of childhood, thus impacting or modulating the TA.
The higher plasma concentrations of total cholesterol and LDL-cholesterol observed in breastfed infants are probably linked to the high cholesterol concentration in breast milk. Differences depending on the initial feeding mode no longer exist during childhood and adolescence, while cholesterolemia is lower in adults who were breastfed. Everything happens as if high intake of cholesterol during the initial period of life constituted a nutritional stimulus activating a programmed regulation of the activity of HMG-CoA reductase or LDL-cholesterol receptors, which persists in the long term.
The protective effect of breastfeeding in the prevention of type 1 diabetes is controversial. In animals, studies conducted on an experimental diabetes model show that a diet with hydrolyzed cow’s milk proteins should not be associated with a higher risk of diabetes. Immunization against cow’s milk proteins (ß-lactoglobulin, ß-casein, serumalbumin and others) could trigger an auto-immune reaction against the Langerhans islet cells, which could result in a similar structure between one or more cow’s milk proteins and the autoantigens located on the islets.
The role of breastfeeding in allergy prevention is also much debated by comparison to a formula diet based on cow’s milk. However, exclusive breastfeeding for 3 months is associated with a 42% reduction in the risk of atopic dermatitis in the case of family allergy background, a 30% reduction in the risk of asthma among the general population and 48% reduction in the case of family atopia. Many factors found in breast milk seem to be responsible for the protective effect against allergies (secretory IgA, TGF (transforming growth factor-ß), certain type n-3 polyunsaturated fatty acids, some interleukins, especially interleukine 10).
A meta-analysis has confirmed a benefit of 3.2 intellectual quotient points in favor of healthy children, after adjustment for confusion factors (age, the mother’s and father’s cultural and educational level, socio-economic status, mother’s smoking, etc.). It is very difficult to assess the real biological significance of this difference on an individual level, which continues into childhood and adolescence. It tends to increase with the length of breastfeeding and is smaller in children born prematurely (5.2 points against 2.7 points among children born at term).
Among the factors likely to explain this advantage, some could have to do with the high content in breast milk of certain AGPI-LC, particularly docosahexaenoic acid (DHA), which has a demonstrated role in the maturation of the retina and the cerebral cortex.
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Conclusion
MAJOR PUBLIC HEALTH ISSUES
“Nutritional programming” induces a specific vulnerability to certain environmental factors. Indeed, intra-uterine growth retardation and rapid statural and ponderal growth during the first months of life represent risk factors that must be better understood for proper nutritional management of children. In populations with a high rate of low birth weight, the predisposition to metabolic diseases will be expressed in the future through sedentariness and the growing prevalence of obesity. The risk of intra-uterine growth retardation at birth mainly affects developing countries: 30 million children throughout the world are born every year with a growth deficit, of whom 75% in Asia and 20% in Africa. It is necessary to improve the detection and early treatment of intra-uterine growth disorders, and to pursue research on the relationships between the growth profile during the first months of life and metabolic disease in adulthood. The long-term health benefits of breastfeeding represent an additional argument in its favor, in line with mothers’ individual beliefs.
References
- Eriksson JG. The fetal origins hypothesis – 10 years on. BMJ 2005; 330 : 1096.
- Junien C, Gallou-Kabani C, Vigé A, Gross MS. Epigénomique nutritionnelle
du syndrome métabolique. Médecine/Sciences 2005; 21: 396–404. - Ministère des Solidarités, de la Santé et de la Famille, et Société française de pédiatrie. Allaitement maternel. Les bénéfices pour la santé de l’enfant et de sa mère. Fascicule Programme National Nutrition Santé, 2005, 72 pages (http://www.sante.gouv.fr.)
- Ong KKL, Ahmed ML, Emmett PM, Preece MA, Dunger DB, and the Avon Longitudinal Study of Pregnancy and Childhood Study Team. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000; 320: 967–71.
- Singhal A, Lucas A. Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 2004; 363:1642–5.
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