PEDIATRICS Vol. 121 No. 3 March 2008, pp. 570-574 (doi:10.1542/peds.2007-1801)
REVIEW ARTICLE |
Intrauterine Risk Factors for Precocious Atherosclerosis
Human Nutrition Research Centre, Université Claude Bernard, Lyon, France
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ABSTRACT |
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 TOP ABSTRACT MEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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Evidence from noninvasive ultrasound studies of the neonatal aorta and fetal and early childhood postmortem studies indicates that impaired fetal growth, in utero exposure to maternal hypercholesterolemia, and diabetic macrosomia may all be important risk factors for vascular changes consistent with the earliest physical signs of atherosclerosis. Although the exact mechanisms that underlie these associations remain unclear, animal models have suggested that the use of antioxidant, lipid-lowering, and other innovative therapies may counteract the impact of these intrauterine risk factors for cardiovascular disease. This review summarizes the current evidence for intrauterine factors that have a direct impact on atherosclerosis and provides potential treatment and prevention strategies.
Key Words: cardiovascular disease • fetal growth restriction • lipids
Abbreviations: LDL—low-density lipoprotein • IUGR—intrauterine growth-restricted
Clinical cardiovascular events, including myocardial infarction and stroke, are among the leading causes of morbidity and mortality in industrialized nations. These clinical events are the primary clinical sequelae of atherosclerosis. For the most part, atherosclerosis is clinically "silent," with its pathophysiologic origins dating to decades earlier than its associated clinical manifestations. The majority, but not all, of these clinical cardiovascular events are accounted for by recognized risk factors including hypercholesterolemia, smoking, hypertension, obesity, and lack of physical activity.1 Given the long time course for the development of atherosclerosis, some of these unexplained cardiovascular events may result from risk factors that are no longer present at the time of the clinical event. Indeed, they may not even be present in adulthood. For example, an increased risk of a cardiovascular event remains for an undetermined period of time after cessation of smoking,2 and childhood and adolescent obesity are associated with an increased risk of coronary heart disease independent of adult obesity status.3,4 Similarly, impaired fetal growth increases the risk of adult coronary heart disease,5,6 albeit with an extreme duration of more than 4 decades between incidence and cardiovascular event. Indeed, for every 1-kg increase in birth weight, the risk of adult coronary heart disease decreases by 
20%.6 This change in risk of heart disease is comparable to a 5 mmHg difference in diastolic blood pressure7 or a 1 mmol/L (40 mg/dL) decrease in low-density lipoprotein (LDL) cholesterol with statin treatment.8
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MEASURING VASCULAR HEALTH IN NEONATES |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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As with the major cardiovascular risk factors, impaired growth in utero is associated with functional (endothelial dysfunction) and structural (increased wall thickness) changes to the arterial vasculature consistent with early atherosclerosis.9–11 However, these findings are difficult to interpret because of potential confounding by, or interaction with, postnatal influences. It follows that studying the vasculature in neonates or young children may provide strong evidence of whether intrauterine factors per se can influence the vasculature. There are a variety of tests of vascular health that are widely applied in older children and may also be feasible in young children and neonates. These tests have been described in detail by Groner et al12 and perhaps most notably include flow-mediated dilatation (a measure of arterial function) and carotid intima-media thickness (a measure of arterial structure). Both of these techniques use noninvasive, high-resolution ultrasound to image conduit arteries and are readily applicable to studying the early progression of atherosclerosis in children. However, there are few data as to whether these techniques are applicable in very young children (<5 years old) and neonates. Although arterial endothelial function testing is feasible in the femoral artery of young children, technical difficulties (including the small arterial diameter) most likely prohibit it from being used in neonates. Carotid intima-media thickness has been measured in children as young as 2 years of age.13 However, it stands to reason that because the abdominal aorta is the site of the earliest fatty streaks,14 it may present a more useful indicator of early atherosclerosis in children. Indeed, it was demonstrated recently that the noninvasive measurement of aortic wall thickness using high-resolution ultrasound is a better indicator of early atherosclerosis in children than carotid intima-media thickness.15
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IMPAIRED FETAL GROWTH |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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We recently adapted this aortic intima-media thickness technique for use in neonates to examine whether impaired fetal growth is associated with structural changes to the vasculature consistent with the earliest stages of atherosclerosis.16 The single thickest point of the abdominal aortic wall was significantly greater in the intrauterine growth-restricted (IUGR) neonates (<10th percentile of birth weight for gender and gestational age) when compared with neonates born at an appropriate birth weight for gestational age (birth weight between the 50th and 90th percentiles), despite there being no statistically significant difference in the average wall thickness over a 1-cm-long segment of the abdominal aorta. Similar changes in maximum arterial wall thickness, but not mean arterial wall thickness, have been observed in young children with hypercholesterolemia.13 This is consistent with the physical distribution of atherosclerosis, which is characterized (especially during its earliest stages) as a disease that does not overrun the entire arterial wall but, rather, is highly localized to lesion-prone segments.17,18
This association was confirmed recently in a slightly larger study of 80 neonates in Turkey,19 in which neonates with birth weights at the <10th centile had a significantly thicker aortic wall than did neonates with birth weights at between the 50th and 90th centiles. Unlike our study, this difference was apparent for both the mean and maximum aortic wall thickness, perhaps because of the difference in the studied segment of the abdominal aorta (distal versus proximal aorta), or differences in the studied populations. For example, the neonates were 5% smaller in their study, perhaps indicating more extreme fetal undernutrition.
These findings were also supported by a postmortem study of 156 children aged 1 to 13 years20 that showed an inverse association between birth weight and the extent and severity of aortic lesions. Multiple regression models indicated that the only other factors associated with the presence of aortic lesions were age and intrauterine exposure to maternal hypercholesterolemia, which is discussed in more detail later in this review. It is interesting to note that the negative correlation between birth weight and aortic lesions was only apparent in children of normocholesterolemic mothers, perhaps indicating that the influences of birth weight are overpowered at this age by the influences of exposure to maternal hypercholesterolemia.
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DIABETIC MACROSOMIA AND MATERNAL SMOKING |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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In addition to the influence of impaired fetal growth on aortic wall thickness, recent evidence has suggested that both macrosomic neonates of diabetic mothers and maternal smoking may also influence aortic wall thickness in neonates. Koklu et al21 have reported that large-for-gestational-age infants with diabetic mothers had a greater aortic intima-media thickness/birth weight ratio than both healthy large-for-gestational-age neonates and normal-weight neonates. Similarly, infants of mothers who smoked during pregnancy had increased aortic wall thickness, although whether this was independent of the lower birth weights in this group was not tested.22
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PROPOSED MECHANISMS |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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Proposed mechanistic pathways that underlie the increased wall thickness in IUGR neonates may involve increased sympathetic tone, a dyslipidemia that is characterized by raised apolipoprotein B or reduced insulin-like growth factor I.16 Univariate regression analyses from these recent studies by Koklu et al21,23 and Gunes et al22 indicate that postnatal and maternal lipids, specifically LDL cholesterol and triglyceride, postnatal and maternal insulin-like growth factor I and insulin-like growth factor–binding protein 3, and postnatal and maternal leptin levels are all associated with aortic intima-media thickness. Unfortunately, the complete details of the multiple regression analyses, which may have clarified the independence of these associations and provided important information concerning potential mechanisms, were not published.
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MATERNAL HYPERCHOLESTEROLEMIA |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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An etiologic role for lipid levels in the onset of early atherosclerosis is supported by postmortem studies. Maternal hypercholesterolemia is associated with increased fatty-streak formation in fetal aortas, possibly related to the association between fetal cholesterol levels and maternal cholesterol levels during the first 6 months of pregnancy.24 The increase in fatty streaks associated with maternal hypercholesterolemia is most marked in the fetal abdominal aorta and aortic arch, whereas there are negligible differences in the thoracic aorta.24 These fatty streaks may regress to some extent after birth, although this regression is less marked, if at all present, in the abdominal aorta.20 However, in childhood, the extent and severity of lesions in the aorta of those exposed in utero to maternal hypercholesterolemia increases at a markedly faster rate than in those not exposed to this adverse intrauterine environment.20
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EARLY FOUNDATIONS OF ATHEROSCLEROSIS |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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The observed increases in both aortic fatty streaks and aortic wall thickness suggest that these intrauterine factors may contribute to an atherosclerosis "head start" or, perhaps more aptly, a "false start." It is quite plausible that this early, intrauterine increase in the pathologic foundations of atherosclerosis will, all other (postnatal) factors being equal, lead to an increased risk of cardiovascular events decades later. However, there remains no evidence that these changes to the aortic wall in neonates and young children are either the precursors of arterial plaques, although they share the same physical sites,18 or that they are associated with an increased risk of cardiovascular events in adulthood, although evidence from adults shows that arterial wall thickening is associated with an increased risk of subsequent cardiovascular events.25 Furthermore, the fetal postmortem studies discussed above also revealed that fatty streaks from fetal aortas contain both native and oxidized LDL and macrophages, thus sharing a similar morphology to other early atherosclerotic lesions.24
It is also feasible that these intrauterine factors program a predisposition to developing atherosclerosis that is independent of traditional risk factors, as has been suggested for infants exposed in utero to maternal hypercholesterolemia.20 This postnatal predisposition, the increased "background" burden of "atherosclerosis," or, indeed, a combination of the two may form the foundations by which these intrauterine factors could increase the risk of coronary heart disease (see Fig 1).
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PREVENTION AND TREATMENT: EVIDENCE FROM ANIMAL MODELS |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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Considering that these factors influence the progression of atherosclerosis and may be associated with adult cardiovascular events independently of traditional risk factors, they present attractive targets for prevention or treatment strategies. Data from studies that used animal models of impaired fetal growth have provided some indication of the nature and extent of the potential benefits from such strategies. Animal studies have indicated that both cholestyramine-induced lipid lowering and vitamin E (an antioxidant) supplementation reduce the extent of atherosclerosis at birth in the offspring of hypercholesterolemic mothers.26 In rats, blockage of maternal glucocorticoid synthesis and both maternal dietary glycine and folate supplementation reverse the increase in blood pressure associated with intrauterine exposure to a maternal low-protein diet without altering birth weight.27–29 Furthermore, folate supplementation partially reverses the endothelial dysfunction that is seen in this model.27
These findings suggest that novel treatment strategies can improve vascular health in the offspring without altering birth weight. However, additional research is needed to demonstrate whether these benefits translate to humans.
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PREVENTION AND TREATMENT: POTENTIAL THERAPIES IN HUMANS |
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TOPABSTRACTMEASURING VASCULAR HEALTH IN...IMPAIRED FETAL GROWTHDIABETIC MACROSOMIA AND MATERNAL...PROPOSED MECHANISMSMATERNAL HYPERCHOLESTEROLEMIAEARLY FOUNDATIONS OF...PREVENTION AND TREATMENT:...PREVENTION AND TREATMENT:...REFERENCES |
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Lifestyle treatment strategies that focus on healthy diet and exercise are frequently used in subjects with a strong family history of cardiovascular disease or familial hypercholesterolemia and could similarly be used to treat people who were exposed to intrauterine risk factors for adult cardiovascular disease. Lifestyle treatment strategies have been demonstrated to be effective in the prevention of diabetes,30,31 have beneficial effects on cardiovascular risk factors, and reduce the incidence of cardiovascular events.32,33 Regular monitoring of the progression of atherosclerosis by using noninvasive techniques, such as measuring carotid intima-media thickness using high-resolution ultrasound, may inform us of the effectiveness and required intensity of such long-term treatment.
However, lifelong treatments can be an intimidating option for those concerned, which perhaps contributes to reduced compliance. For this reason, and given the potential short time course necessary for prevention strategies (ie, during and around pregnancy), prevention may be more effective and easier to implement than treatment. Maternal hypercholesterolemia presents perhaps the most promising target for prevention. Although the safety of the statin class of lipid-lowering drugs has not been demonstrated during pregnancy, nutritional interventions during pregnancy can cause modest lipid reductions relative to a control diet34 and, thus, are a strong candidate for prevention strategies. Furthermore, the potential exists for these nutritional recommendations to be tailored to the particular lipid profile; for example, 
-3 polyunsaturated fatty acids reduce serum triglyceride levels35 and, thus, may be of particular benefit to mothers with hypertriglyceridemia.
Given the results of animal studies, the use of antioxidants may be relevant for a broad spectrum of "at-risk" groups. This may be particularly pertinent for the IUGR fetus, given that strategies to improve growth in the IUGR fetus are generally unsuccessful, and promising therapies, including amniotic insulin-like growth factor I administration, are still in development.36
Additional data regarding the nutrition-related determinants of intrauterine growth restriction–associated early atherosclerosis may assist in identifying at-risk subjects and in developing prevention strategies. Data from animal studies have suggested that different forms of dietary undernutrition, such as reduced protein or caloric restriction, may have differing effects on the vasculature.37,38 These vascular effects of maternal dietary undernutrition may also differ from those of fetal undernutrition resulting from placental insufficiency, which is perhaps a more common cause of intrauterine growth restriction in industrialized nations.
The use of noninvasive measurement of aortic wall thickness presents an attractive modality by which to further explore and define the intrauterine factors, beyond intrauterine growth and maternal hypercholesterolemia, that are associated with increased atherosclerosis and to assess the physical impact on the arterial wall of potential prevention strategies.
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ACKNOWLEDGMENTS |
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Dr Skilton was supported by a fellowship from the Fondation pour la Recherche Médicale.
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FOOTNOTES |
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Accepted Aug 13, 2007.
Address correspondence to Michael R. Skilton, PhD, Baker Heart Research Institute, PO Box, 6492 St Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail: michael.skilton{at}baker.edu.au
The author has indicated he has no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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