Optimizing intrauterine conditions may help prevent chronic diseases in ...
September 28, 2005
Washington DC - Reviews of the developmental origins of adult disease suggest that intrauterine conditions likely influence the risk of developing hypertension and renal disease later in life, according to a number of investigators.
Optimizing intrauterine conditions?especially avoidance of maternal smoking, micronutrient deficiency, and probably alcohol consumption?may in turn help prevent the development of chronic diseases in adulthood. Low-birth-weight children also need to avoid rapid weight gain to offset the tendency to develop a variety of chronic diseases as adults, investigators caution.
"I think it's very important to convey to women that their nutritional status in pregnancy is not going to have an immediate impact [on their child's health] but that they should know their child is perhaps at greater risk for end-stage renal disease if they are born small or premature," Dr Daniel Lackland (Medical University of South Carolina, Charleston, SC) told renalwire .
"So just as if I knew that my parents developed hypertension at a relatively young age, I need to be aware that that if I'm small at birth, I am at greater risk for ESRD and I need to be more careful with my nutrition and my blood pressure and glucose levels as I go through life."
An editorial on the subject by Lackland [ 1 ] was one of a series of articles on the fetal origins of adult disease that were published in the September 2005 issue of the Journal of the American Society of Nephrology.
Cardiovascular disease, diabetes have origins in poor fetal nutrition
In his editorial that examines some of the mechanisms linking conditions in utero with disease in later life, Lackland points out that the hypothesis on fetal origins of adult disease was introduced more than a decade ago by Dr David Barker (University of Southampton, UK). Since then, he writes, "numerous epidemiologic studies have confirmed the associations suggesting fetal programming and mechanisms associated with disease progression. Identification of these mechanisms is essential in the development of interventions to reduce the disease risks."
In a separate article of his own in this issue [ 2 ], Barker and coauthor Dr Susan P Bagby (Oregon Health & Science University, Portland) review the hypothesis and point out that ensuring that mothers have a varied and balanced diet even before conception and prevention of rapid weight gain in low-birth-weight children could have a major impact on the future development of cardiovascular disease (CVD) and type 2 diabetes.
A mother's ability to nourish her fetus depends not only what she eats during pregnancy, but on her body nutrient stores, her metabolic capacity, and, indeed, her lifelong nutritional experience, Barker and Bagby point out. The fetus of a poorly nourished mother?and this doesn't necessarily mean starvation or undernourishment, poor nutrition will do it, too?adapts to the poor nutritional milieu by altering its metabolism and reducing body size, which help it survive.
Thus, "the nutrition of many fetuses and infants remains suboptimal, either because they received unbalanced macronutrients or do not receive essential micronutrients or because the mother's body composition?which also nourishes the fetus and the infant?is suboptimal," they observe.
Low birth weight is not the only pathway through which adults may develop coronary heart disease (CHD) later on. The risk for not just CHD but hypertension and diabetes increases with rapid weight gainin early childhood. This may be partially explained by the fact that rapid weight gain in low-birth-weight children may lead to a disproportionately high fat mass in relation to lean body mass, as infants who are small and thin at birth lack muscle, a deficiency that persists as they mature, they explain.
"The pathway to coronary heart disease and type 2 diabetes may originate either with slow fetal growth as a consequence of undernutrition or with poor infant growth as a consequence of poor living conditions," Barker and Bagby write, "but thereafter the pathway is determined by rates of weight gain in childhood, by socioeconomic conditions, and presumably by other influences as yet undiscovered."
Maximizing "nephrogenic potential"
In a separate overview article [ 3 ], Dr Julie Ingelfinger (Harvard Medical School, Boston, MA) and Dr William Schnaper (Northwestern University, Chicago, IL) point out that the fetus can respond to an unfavorable environment by maturing more rapidly, by conserving nutrients that will restrict or limit its growth, or by aborting. "In terms of the kidney, as the fetus adapts to altered conditions, there may be no renal consequences or the kidney may be affected adversely," they write. Importantly, in utero influences on fetal development interact with other influences once the infant is born.
"Thus, individuals who were relatively small [at birth] but who gain weight fastest after birth are at highest risk [for adverse renal outcomes]," the authors state. They also note that influences other than nutrition, most notably maternal smoking, are associated with fetal growth restriction as well. "Infants who are born early may still be undergoing nephrogenesis," they point out. Both prematurity and the nephrotoxins administered to premature infants to help them survive may negatively affect final nephron formation, they add.
Knowing who is at risk would allow all who care for such people to recommend and prescribe a course of medical care that will maximize renal potential.
The idea that adult disease may have its origin in utero is relevant for nephrologists, Ingelfinger and Schnaper say. "For example, pediatric nephrologists treat many small and premature neonates who have not yet finished nephrogenesis," they observe, "and these small newborns are at particular risk for later renal and cardiovascular disease."
Thus, learning how to "maximize nephrogenic potential" and maintain renal functional reserve should be a major research priority, the authors suggest, as "knowing who is at risk would allow all who care for such people to recommend and prescribe a course of medical care that will maximize renal potential."
Another paper in the same issue, by Dr Mandy Keijzer-Veen (Erasmus MC-Sophia, University Medical Center, Rotterdam, the Netherlands) and colleagues, showed that very premature infants who are also small for their gestational age (SGA) are at risk for impaired kidney function in young adulthood, but that kidney function remained normal in those who, despite the same degree of prematurity, were judged appropriate for their gestational age. This paper, a large-scale, prospective follow-up of the Project on Premature and Small for Gestational Age Infants (POPS) cohort, was released online in June and reported by renalwire at that time [ 4 ].
Brain and heart take priority in stressed intrauterine environment
Dr Wendy Hoy (University of Queensland, Brisbane Australia) and multicenter colleagues in turn point out that in a stressed intrauterine environment, "development and growth of the brain and the heart are preserved at the expense of the kidney and other organs and general somatic growth." In humans as well as in animals, "nephron number is strongly correlated with fetal weight and is disproportionately reduced by factors that restrict intrauterine growth, including protein and micronutrient deficiencies." The authors also observe that infants who are small for their gestational age have smaller kidneys, with fewer nephrons and enlarged glomeruli [ 5 ].
Nephron endowment at birth in turn influences blood pressure and renal-disease risk later in life, they suggest. In the UK, for example, researchers found higher rates of microalbuminuria in people of low birth weight or with intrauterine growth retardation, while in Pima Indians with diabetes, birth weights at both the highest and lowest ends of the birth-weight range were associated with increased risk of albuminuria as well.
As Hoy et al state, the implications of low birth weight are "potentially important, given the large cohorts of very low-birth-weight premature infants who are now surviving infancy due to advances in neonatal and perinatal care."
"Prevention depends on optimizing intrauterine conditions," they conclude, "and avoiding the secular trend toward increasing body mass is important...while for those in whom elevated blood pressure or albuminuria has already appeared, multipronged therapy that includes renal-protective drugs promises extension of life by many years."
Support from experimental findings
Finally, as discussed by Dr Matti Vehaskari (Louisiana State University Health Sciences Center, New Orleans) and Dr Lori Woods (Oregon Health & Science University, Portland) [ 6 ], experimental findings in animal models indicate that what happens in utero does influence the development of hypertension in adulthood, although the mechanisms by which intrauterine conditions may do so remain complex and multifactorial. "Because the original human reports linked prenatally programmed hypertension to intrauterine growth restriction, most experimental protocols have aimed at duplicating the fetal growth impairment," they write.
Looking first at global food restriction in experimental animal models, the authors note that even a modest 20% to 30% reduction in maternal food intake during the latter part of pregnancy induces hypertension in offspring in the rat model of fetal growth impairment. In a sheep model of fetal growth impairment, "a 15% reduction in maternal food intake during the first half of gestation causes an increase of approximately 10 mm Hg in mean arterial pressure in the offspring at 80 to 85 days of age," they note, adding that global food restriction for all or part of gestation can lead to increased BP in the offspring.
Reduction in maternal protein intake?though not caloric intake?during pregnancy has also been shown to increase arterial pressure of offspring in adulthood, again in the rat model. Administration of dexamethasone to the mother either throughout or during the last part of gestation causes hypertension in adult offspring, although this may not be a direct effect of the steroid, investigators observe. A "key element" in the hypothesis that adult disease has its origins during fetal development is the fact that the insult?whatever its nature?occurs during a critical period of development.
These critical periods of development differ for different organ systems, "thus permanently changing the structure and function of an organ system," the authors state. For the programming of hypertension, the critical period appears to be earlier in gestation in the sheep than in the rat, a possible reflection of the fact that sheep are more mature at birth than rats. "Thus, the critical periods in the two species may represent comparable stages of development of a specific organ system," investigators observe.
Vehaskari and Woods also emphasize that "once developed, prenatally programmed hypertension seems to persist indefinitely and to get progressively worse with age"?an observation that has been described for low-birth-weight babies as well. On the other hand, at least in the rat model, postnatal administration of an ACE inhibitor and a low sodium diet after weaning?even when given for only a few weeks?appears to have a "pronounced and sustained ameliorating effect" on the later development of hypertension.
Sources
September 28, 2005
Washington DC - Reviews of the developmental origins of adult disease suggest that intrauterine conditions likely influence the risk of developing hypertension and renal disease later in life, according to a number of investigators.
Optimizing intrauterine conditions?especially avoidance of maternal smoking, micronutrient deficiency, and probably alcohol consumption?may in turn help prevent the development of chronic diseases in adulthood. Low-birth-weight children also need to avoid rapid weight gain to offset the tendency to develop a variety of chronic diseases as adults, investigators caution.
"I think it's very important to convey to women that their nutritional status in pregnancy is not going to have an immediate impact [on their child's health] but that they should know their child is perhaps at greater risk for end-stage renal disease if they are born small or premature," Dr Daniel Lackland (Medical University of South Carolina, Charleston, SC) told renalwire .
"So just as if I knew that my parents developed hypertension at a relatively young age, I need to be aware that that if I'm small at birth, I am at greater risk for ESRD and I need to be more careful with my nutrition and my blood pressure and glucose levels as I go through life."
An editorial on the subject by Lackland [ 1 ] was one of a series of articles on the fetal origins of adult disease that were published in the September 2005 issue of the Journal of the American Society of Nephrology.
Cardiovascular disease, diabetes have origins in poor fetal nutrition
In his editorial that examines some of the mechanisms linking conditions in utero with disease in later life, Lackland points out that the hypothesis on fetal origins of adult disease was introduced more than a decade ago by Dr David Barker (University of Southampton, UK). Since then, he writes, "numerous epidemiologic studies have confirmed the associations suggesting fetal programming and mechanisms associated with disease progression. Identification of these mechanisms is essential in the development of interventions to reduce the disease risks."
In a separate article of his own in this issue [ 2 ], Barker and coauthor Dr Susan P Bagby (Oregon Health & Science University, Portland) review the hypothesis and point out that ensuring that mothers have a varied and balanced diet even before conception and prevention of rapid weight gain in low-birth-weight children could have a major impact on the future development of cardiovascular disease (CVD) and type 2 diabetes.
A mother's ability to nourish her fetus depends not only what she eats during pregnancy, but on her body nutrient stores, her metabolic capacity, and, indeed, her lifelong nutritional experience, Barker and Bagby point out. The fetus of a poorly nourished mother?and this doesn't necessarily mean starvation or undernourishment, poor nutrition will do it, too?adapts to the poor nutritional milieu by altering its metabolism and reducing body size, which help it survive.
Thus, "the nutrition of many fetuses and infants remains suboptimal, either because they received unbalanced macronutrients or do not receive essential micronutrients or because the mother's body composition?which also nourishes the fetus and the infant?is suboptimal," they observe.
Low birth weight is not the only pathway through which adults may develop coronary heart disease (CHD) later on. The risk for not just CHD but hypertension and diabetes increases with rapid weight gainin early childhood. This may be partially explained by the fact that rapid weight gain in low-birth-weight children may lead to a disproportionately high fat mass in relation to lean body mass, as infants who are small and thin at birth lack muscle, a deficiency that persists as they mature, they explain.
"The pathway to coronary heart disease and type 2 diabetes may originate either with slow fetal growth as a consequence of undernutrition or with poor infant growth as a consequence of poor living conditions," Barker and Bagby write, "but thereafter the pathway is determined by rates of weight gain in childhood, by socioeconomic conditions, and presumably by other influences as yet undiscovered."
Maximizing "nephrogenic potential"
In a separate overview article [ 3 ], Dr Julie Ingelfinger (Harvard Medical School, Boston, MA) and Dr William Schnaper (Northwestern University, Chicago, IL) point out that the fetus can respond to an unfavorable environment by maturing more rapidly, by conserving nutrients that will restrict or limit its growth, or by aborting. "In terms of the kidney, as the fetus adapts to altered conditions, there may be no renal consequences or the kidney may be affected adversely," they write. Importantly, in utero influences on fetal development interact with other influences once the infant is born.
"Thus, individuals who were relatively small [at birth] but who gain weight fastest after birth are at highest risk [for adverse renal outcomes]," the authors state. They also note that influences other than nutrition, most notably maternal smoking, are associated with fetal growth restriction as well. "Infants who are born early may still be undergoing nephrogenesis," they point out. Both prematurity and the nephrotoxins administered to premature infants to help them survive may negatively affect final nephron formation, they add.
Knowing who is at risk would allow all who care for such people to recommend and prescribe a course of medical care that will maximize renal potential.
The idea that adult disease may have its origin in utero is relevant for nephrologists, Ingelfinger and Schnaper say. "For example, pediatric nephrologists treat many small and premature neonates who have not yet finished nephrogenesis," they observe, "and these small newborns are at particular risk for later renal and cardiovascular disease."
Thus, learning how to "maximize nephrogenic potential" and maintain renal functional reserve should be a major research priority, the authors suggest, as "knowing who is at risk would allow all who care for such people to recommend and prescribe a course of medical care that will maximize renal potential."
Another paper in the same issue, by Dr Mandy Keijzer-Veen (Erasmus MC-Sophia, University Medical Center, Rotterdam, the Netherlands) and colleagues, showed that very premature infants who are also small for their gestational age (SGA) are at risk for impaired kidney function in young adulthood, but that kidney function remained normal in those who, despite the same degree of prematurity, were judged appropriate for their gestational age. This paper, a large-scale, prospective follow-up of the Project on Premature and Small for Gestational Age Infants (POPS) cohort, was released online in June and reported by renalwire at that time [ 4 ].
Brain and heart take priority in stressed intrauterine environment
Dr Wendy Hoy (University of Queensland, Brisbane Australia) and multicenter colleagues in turn point out that in a stressed intrauterine environment, "development and growth of the brain and the heart are preserved at the expense of the kidney and other organs and general somatic growth." In humans as well as in animals, "nephron number is strongly correlated with fetal weight and is disproportionately reduced by factors that restrict intrauterine growth, including protein and micronutrient deficiencies." The authors also observe that infants who are small for their gestational age have smaller kidneys, with fewer nephrons and enlarged glomeruli [ 5 ].
Nephron endowment at birth in turn influences blood pressure and renal-disease risk later in life, they suggest. In the UK, for example, researchers found higher rates of microalbuminuria in people of low birth weight or with intrauterine growth retardation, while in Pima Indians with diabetes, birth weights at both the highest and lowest ends of the birth-weight range were associated with increased risk of albuminuria as well.
As Hoy et al state, the implications of low birth weight are "potentially important, given the large cohorts of very low-birth-weight premature infants who are now surviving infancy due to advances in neonatal and perinatal care."
"Prevention depends on optimizing intrauterine conditions," they conclude, "and avoiding the secular trend toward increasing body mass is important...while for those in whom elevated blood pressure or albuminuria has already appeared, multipronged therapy that includes renal-protective drugs promises extension of life by many years."
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Support from experimental findings
Finally, as discussed by Dr Matti Vehaskari (Louisiana State University Health Sciences Center, New Orleans) and Dr Lori Woods (Oregon Health & Science University, Portland) [ 6 ], experimental findings in animal models indicate that what happens in utero does influence the development of hypertension in adulthood, although the mechanisms by which intrauterine conditions may do so remain complex and multifactorial. "Because the original human reports linked prenatally programmed hypertension to intrauterine growth restriction, most experimental protocols have aimed at duplicating the fetal growth impairment," they write.
Looking first at global food restriction in experimental animal models, the authors note that even a modest 20% to 30% reduction in maternal food intake during the latter part of pregnancy induces hypertension in offspring in the rat model of fetal growth impairment. In a sheep model of fetal growth impairment, "a 15% reduction in maternal food intake during the first half of gestation causes an increase of approximately 10 mm Hg in mean arterial pressure in the offspring at 80 to 85 days of age," they note, adding that global food restriction for all or part of gestation can lead to increased BP in the offspring.
Reduction in maternal protein intake?though not caloric intake?during pregnancy has also been shown to increase arterial pressure of offspring in adulthood, again in the rat model. Administration of dexamethasone to the mother either throughout or during the last part of gestation causes hypertension in adult offspring, although this may not be a direct effect of the steroid, investigators observe. A "key element" in the hypothesis that adult disease has its origins during fetal development is the fact that the insult?whatever its nature?occurs during a critical period of development.
These critical periods of development differ for different organ systems, "thus permanently changing the structure and function of an organ system," the authors state. For the programming of hypertension, the critical period appears to be earlier in gestation in the sheep than in the rat, a possible reflection of the fact that sheep are more mature at birth than rats. "Thus, the critical periods in the two species may represent comparable stages of development of a specific organ system," investigators observe.
Vehaskari and Woods also emphasize that "once developed, prenatally programmed hypertension seems to persist indefinitely and to get progressively worse with age"?an observation that has been described for low-birth-weight babies as well. On the other hand, at least in the rat model, postnatal administration of an ACE inhibitor and a low sodium diet after weaning?even when given for only a few weeks?appears to have a "pronounced and sustained ameliorating effect" on the later development of hypertension.
Sources
Lackland D. Mechanisms and fetal origins of kidney disease. J Am Soc Nephrol 2005; 16:2531-2532.
Barker D, Bagby S. Developmental antecedents of cardiovascular disease: A historical perspective. J Am Soc Nephrol 2005; 16:2537-2544.
Ingelfinger J, Schnaper HW. Renal endowment: Developmental origins of adult disease. J Am Soc Nephrol 2005; 6:2533-2536.
Keijzer-Veen MG, Schrevel M, Finken MJJ, et al. Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol 2005; 16:2762-2768.
Hoy W, Hughson M, Bertram J, et al. Nephron number, hypertension, renal disease, and renal failure. J Am Soc Nephrol 2005; 16:2557-2564.
Vehaskari VM, Woods L. Prenatal programming of hypertension: Lessons from experimental models. J Am Soc Nephrol 2005; 16:2545-2556.
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