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Adult Sequelae of Intrauterine Growth Restriction

Michael G. Ross, MD, MPH, and Marie H. Beall, MD

Fetal intrauterine growth restriction has been associated with adult disease in both humanepidemiologic studies and in animal models. In some cases, intrauterine deprivationprograms the fetus to develop increased appetite and obesity, hypertension, and diabetesas an adult. Although the mechanisms responsible for fetal programming remain poorlyunderstood, both anatomic and functional (cell signaling) changes have been described inaffected individuals. In some animal models, aspects of fetal programming can be reversedpostnatally; however, at the present time, the best strategy for avoiding the adult conse-quences of fetal growth restriction is prevention.Semin Perinatol 32:213-218 2008 Elsevier Inc. All rights reserved.

KEYWORDS fetal programming, obesity, hypertension, diabetes

Fetal intrauterine growth restriction (IUGR) occurs in hu-mans as a consequence of poor maternal nutrition, pla-cental insufciency, and diminished fetal oxygenation, orexposure to teratogens, among other causes. In animals, andin some cases in humans, IUGR from these causes has beenassociated with the development of adult diseases; this phe-nomenon is called fetal programming. The association of maladaptive programming with adult disease has beentermed the Barker hypothesis. In general, the Barker hy-pothesis1 contends that the malnourished fetus is pro-

grammed to exhibit a thrifty phenotype with increasedfoodintake and fat deposition and possibly decreased energy out-put. Faced with ample available calories, such individualsdevelop obesity and other manifestations of the metabolicsyndrome as adults due to alterations in homeostatic regula-tory mechanisms. 2-4

The issue of fetal programming is not merely of intellectualinterest. Currently, 65% of adults in the United States areoverweight and almost one in three is obese (BMI 30kg/m2), representing a modern health crisis. 5 Obesity and itsrelated diseases are the leading cause of death in Westernsociety, with associated risks of hypertension, coronary heart

disease, stroke, diabetes, and breast, prostate, and colon can-cer. Evidence indicates that a striking 25% to 63% of adultdiabetes, hypertension, and coronary heart disease can beattributed to the effects of low birth weight with acceleratednewborn-to-adolescent weight gain 2; therefore, gestational

programming of low birth weight/IUGR has contributed im-portantly to the population shift toward obesity. In Westernsocieties, the incidence of low-birth-weight infants has in-creased since the mid-20th century. Low-birth-weight in-fants are now being born to women with chronic diseaseswho would previously have had limited survival and repro-ductive capacity, whereas assisted reproductive technologiesand increasing numbers of multiple gestations have resultedin both preterm and low-birth-weight offspring. When com-bined with improved neonatal survival and exposure to

Western diet, this results in an increased number of pro-grammed offspring predisposed to adult obesity. These obesemothers may ultimately give birth to macrosomic newborns,perpetuating obesity in the population.

Evidence forFetal ProgrammingSeveral lines of evidence suggest that human IUGR is associ-ated with adult obesity. Epidemiological studies of individu-als born during the Dutch hunger winter of 1944 to 1945

revealed that maternal starvation was associated with a re-duced infant birth weight and an increased incidence of obe-sity, insulin resistance, hypertension, and coronary arterydisease in adulthood. 6-10 Work by Barker and colleagues on acohort of men and women born in Herfordshire, Englandbetween 1911 and 1930 11 revealed that low weight at birthand 1 year of age are associated with an increased risk of death from cardiovascular disease and stroke. Additionalsupporting evidence came from a study of Swedish malearmy conscripts in which increased diastolic blood pressurewas associated with low birth weight. 12

Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center,Torrance, CA.

Address reprint requests to Michael G. Ross, MD, MPH, Harbor-UCLA Med-ical Center, Department of Ob/Gyn, 1000 W. Carson St., Box 3, Tor-rance, CA 90502. E-mail: [email protected]

2130146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1053/j.semperi.2007.11.005
mailto:[email protected]:[email protected]:[email protected]


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A large number of manipulationshave been used to induceoffspring IUGR in animal models, including maternal calo-rie13 and protein 14 restriction, fetal hypoxia from uterine ar-tery ligation15 and passive maternal smoking, 16 and maternalalcohol administration 17 and hyperthermia. 18 The associa-tion of IUGR with adult disease has been demonstrated inmany animal species. 19 In our laboratory, we have developeda rat model of IUGR caused by 50% maternal food restriction(MFR) during the second half of pregnancy. Newborn pupsfrom MFR mothers have lower body weights with decreasedplasma leptin levels. IUGR offspring nursed by ad libitum feddams demonstrate rapid catch-up growth at 3 weeks andcontinued accelerated growth, resulting in increased weight,percent body fat, and plasma leptin levels as adults. Theseanimals have been used in our studies described below.

Mechanisms ofFetal ProgrammingIUGR leads to alterations in numerous fetal organs. Obesity ispotentiated by alterations in appetite regulation and by in-creased adipogenesis. Hypertension is made more likely byalterations in renal and blood vessel development, whereasdiabetes is associated with alterations in cellular insulin sig-naling and decreased beta cell function. These programmedalterations in function, together, induce the full metabolicsyndrome in the adult. Although the specics of fetal pro-gramming are likely to differ depending on the cause of theIUGR, this issue has not been well studied, and the discus-sion below does not attempt to differentiate the various ma-ternal manipulations leading to offspring IUGR.

ObesityThat MFR induces IUGR and subsequent offspring obesity inassociation with an increased appetite is well documented. 20-23Leptin, a primary satiety factor, normally reduces food in-take; it has been shown to be one of the factors inuenced byfetal programming. In growth-restricted fetuses, cord bloodleptin levels are decreased, 24,25 and preterm or low-birth-weight human, rat, or calf newborns have reduced plasmaleptin levels.26-28 These ndings are not surprising, given thereduced fat stores in IUGR offspring. At 2 months of age,however, subcutaneous fat leptin mRNA is negatively corre-lated with birth weight. 29 As adults, leptin and insulin levelsare related to birth weight, independent of adult obesity. 24 Innormal sheep 30-33 and rodents, 34-39 leptin reduces voluntaryfood intake. Adult IUGR offspring, however, exhibit resis-tance to the anorexogenic effects of leptin, 40 suggesting al-tered control of appetite as a source of IUGR-associated obe-sity.

The hypothalamus is an important site for central controlof appetite. Hypothalamic leptin resistance may be due toalterations in leptin transporter, 41-44 hypothalamic leptin re-ceptor (ObRb), 41,45 and/or leptin signaling, 46-48 although it isnot known which of these mechanisms accounts for gesta-

tional programming of leptin resistance and obesity. In ourstudies, MFR-induced IUGR results in offspring with in-

creased ObRb expression and disruption of intracellular lep-tin signaling. In summary, IUGR offspring exhibit reducednewborn leptin levels, although increased leptin levels asadults, and a decreased anorexic response to leptin, possiblydue to abnormalities in intracellular signaling.

In addition to adult leptin resistance, recent studies pro-vide convincing evidence that leptin promotes the develop-ment of hypothalamic neuronal projections, consistent witha role in brain development. Neuronal projections from thearcuate nucleus (ARC) are formed in mice primarily duringthe second week of postnatal life 49 (developmentally similarto human third trimester of pregnancy). In leptin-decient(ob/ob) mice, these projection pathways regulating appetiteare permanently disrupted, demonstrating axonal densitiesone-third to one-fourth that of controls. 50 In the rodent, thecrucial developmental window coincides with a natural post-natal surge in leptin. IUGR in mice is associated with anabnormal leptin surge, 51 and postnatal leptin replacementrescues ARC axonal development. 50 These ndings suggest

that, in addition to signaling alterations, IUGR may be asso-ciated with permanent anatomic changes in the appetite cen-ters of the brain.

IUGR may also affect the development of adipocytes. De-velopment of obesity is associated with increased adipocytedifferentiation, adipocyte hypertrophy, and/or upregulationof lipogenic genes. PPAR 2, an adipogenic transcription fac-tor, promotes both adipocyte differentiation and lipid stor-age.52,53 In our rat model, IUGR offspring showed signi-cantly increased expression (mRNA and protein) of PPAR both as newborns and as adults. Further, the expression of adipogenic transcription factors regulating PPAR was also

upregulated in both groups. Therefore, in addition to centraldisregulation of appetite, IUGR individuals may demonstrateabnormal activation of adipocytes, contributing to the devel-opment of obesity.

HypertensionReduced numbers of nephrons are associated with elevationsin arterial blood pressure and changes in postnatal renalfunction. A reduction of nephron number of as little as 11%in sheep 54 and 13% in the rat 55 can result in adult hyperten-sion. In the human, there was a strong correlation betweenlow nephron number and hypertension among individualsinvolved in fatal accidents. 56 Studies indicate that IUGR cor-relates with decreased nephron numbers. 57-61 Work in ourlaboratory demonstrates a 19% reduction in glomerularnumber in male rat IUGR offspring at 3 weeks of age, with thedevelopment of adult hypertension. 62 Many factors are likelyto be involved in determining nephron endowment, includ-ing all of those responsible for the complex process of nephrogenesis. In our rat model, fetal kidneys demonstratedaltered expression of genes in pathways regulating events of nephrogenesis, including ureteric bud branching (UBB) andmesenchymal to epithelial transformation (unpublisheddata). All of this suggests that permanent changes in renal

anatomy result from IUGR, with an increased propensity toadult hypertension. Investigation of renal growth in utero

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suggests that 26-34 weeks of gestation in humans could bethe period during which altered renal development may leadto hypertension. 58

Thevascularendotheliumis another target for programming.Several studieshaveshown that endothelial-dependantand -in-dependent vasodilation is impaired and ow-mediated dila-tion is decreased in low-birth-weight individuals at 3 monthsof age, in later childhood and in early adult life. 63-65 In ratsthat were undernourished during the rst 18 days of gesta-tion, increased blood pressure at 60 days after birth wasnoted, and the maximal vasoconstriction response to phen-ylephrine and norepinephrine was reduced in isolated fem-oral arteries, 66 although other maternal nutrient restricteddiets67,68 showed no effect on vasoconstrictor responses.

A major determinant of blood pressure is arterial compli-ance, which is a function of the extracellular matrix (ECM). 69The ECM, made of collagen, elastin, and smooth muscle, 69can be altered by diet even in the adult state. Adult rats fed ahigh-salt diet over a course of 8 weeks showed structural

changes in the aorta with an increase in wall thickness, adecrease in collagen, and an increase in elastin/collagen ra-tio.70 Studies in our laboratory demonstrate marked changesin the ECM composition of vessel wall as a result of MFR. 71

In summary, IUGR is associated with hypertension, par-ticularly in male offspring. Programmed offspring exhibitchanges in renal structure, as well as in vascular structureandfunction that precede and are probably contributory to thedevelopment of hypertension. The relative importance of these changes remains to be determined.

DiabetesLow newborn weight has been associated with an increasedrisk for type 2 diabetes in human epidemiologic studies 72 andwith abnormal insulin secretion and glucose intolerance inrats and sheep. 73,74 Several factors may contribute to thisphenomenon. First, the IUGR offspring may have a reducedability to secrete insulin due to reduced numbers of pancre-atic islets. Adult humans born IUGR have impaired insulinresponses to glucose. 7 In rats, adult IUGR offspring have alower beta cell mass andpancreatic insulin content, as well asa reduced insulin response to glucose. 75 A reduction in thecapacity to excrete insulin may be associated in IUGR indi-viduals with an increase in insulin requirement. When theinsulin requirement exceeds the capacity of the pancreas,diabetes results.

One reason for an increased insulin requirement in IUGR offsring is increased gluconeogenesis. Hepatic gluconeogen-esis is increased in adult IUGR rats, 15 and this increase pre-cedes the development of hyperglycemia and is relativelyresistant to the effects of insulin compared with controls.Expression of PPAR coactivator-1, a regulator of mRNAexpression of glucose-6-phosphatase and other gluconeo-genesis enzymes, is increased in the livers of IUGR rat off-spring,76 suggesting that thealteration in hepatic glucose pro-duction may be the result of changes in intracellular

signaling.The development of glucose intolerance in IUGR individ-

uals may also be associated with other alterations in insulinsignaling. For example, glucose entry into skeletal muscleoccurs via the glucose transporter GLUT4; the process isstimulated by insulin. In the rat, fetal skeletal muscle GLUT4expression is decreased, but the amount of GLUT4 presenton the plasma membrane is increased, with diminished in-tracellular stores, suggesting a compensatory adaptation tolow glucose availability.13 In theadult IUGR rat, skeletal mus-cle GLUT4 continues to be increased on the plasma mem-brane, but there is diminished translocation of additionalGLUT4 to the plasma membrane in response to insulin.

Adult IUGR human subjects with insulin resistancealso dem-onstrated a failure to upregulate muscle GLUT4 after insulinstimulation. 77 As skeletal muscle is a primary site for insulin-induced glucose utilization, this unresponsiveness may beassociated with glucose intolerance.

In summary, IUGR is associated with both anatomicchanges in the pancreatic islets and with changes in intracel-lular insulin signaling pathways. The end result of these al-

terations is to decrease the individuals capacity to secreteinsulin, while increasing thedemandfor insulin leading to anincreased liklihood of frank glucose intolerance.

Manipulation ofFetal ProgrammingThe many deleterious effects of a programmed thrifty phe-notype in a setting of postnatal calorie abundance lead to thequestion as to whether fetal programming can be reversed orameliorated. Although no treatments are currently available,there are several promising lines of inquiry.

Immediate postnatal nutrition can affect long-term healthin IUGR offspring. Although adults born during the Dutchhunger winter developed hypertension and diabetes asadults, those exposed in utero to starvation in the siege of Leningrad were not diabetic or hypertensive at a rate greaterthan controls. 78 One explanation for this is that the siege of Leningrad was of greater duration, and those starved in uterowere also likely to have been starved as newborns. Similarly,in our laboratory 79 and others, 13 rats born IUGR who contin-ued to be nutritionally deprived during lactation did notbecome obese as adults. However, in our studies, these post-natally deprived rats did exhibit elevated serum total andLDL cholesterol, and insulin insufciency. 79

Treatment of rats with peripheral leptin, either to the damduring pregnancy and to the pup during lactation 80 or to thepup alone during early lactation, 81 resulted in adults whowere neither obese nor diabetic. These observations suggestthat supplementation of leptin to assure a normal plasmaleptin surge at rat postnatal day 10 to 12, may facilitate thedevelopment of arcuate axonal projections. 82,83 In contrast torats, there is no evidence of a human postnatal leptin surge. 84Consequently, it is speculative as to whether leptin adminis-tration would be effective in human IUGR.

The interventions above are empiric and unlikely to be

completely effective due to the wide range of effects of IUGR on adult health. Truly reversing the effects of maladaptive

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fetal programming will likely require an ability to reprogramthe changes in gene expression, probably by epigeneticchanges to the chromatin.

Epigenetics

There is growing evidence that maternal nutritional statuscan alter the state of the fetal genome and imprint gene ex-pression. Epigenetic alterations (stable alterations of gene ex-pression through covalent modications of DNA and corehistones) in early embryos may be carried forward to subse-quent developmental stages. 85 Two mechanisms mediatingepigenetic effects are DNA methylation and histone modi-cation (acetylation and methylation). 86 Either of these mech-anisms can alter gene expression gene expression. 86 Epigen-etic changes in IUGR individuals have been demonstrated inrelevant genes, including those involved in hepatic insulinsignaling,87 and beta cell development. 88 Interestingly, folic

acid, a methyl donor, has been shown to reverse at least someepigenetic changes associated with IUGR in a rat model, al-though the folic acid dose used (1 mg/kg) far exceeds thatused in human clinical practice. 89

Epigenetic changes may also explain the transgenerationaleffect of the thrifty phenotype. In support of this hypothesis,offspring of IUGR rat dams demonstrated altered insulin sig-naling and glucose metabolism, even when gestated by con-trol rats. 90 Offspring of IUGR dams also had persistence of altered methylation of the promoters for PPAR and glu-cocorticoid receptor despite being gestated by dams beingfed a regular diet. 91

ConclusionGrowth restriction in utero is associated with the develop-ment of obesity, hypertension, anddiabetes in animal modelsandin humanswhen ample calories areprovided postnatally,as occurs in most Western societies. The resultant adultobesity has become a signicant health risk. The currentunderstanding is that intrauterine deprivation programs theindividual for a deprived environment, and that such pro-gramming is maladaptive in a nondeprived environment.

Programming causes both anatomic changes, such as a de-crease in the number of glomeruli, and functional changes,such as a decrease in GLUT4 induction after insulin treat-ment. The sum of these changes is an increase in appetite andin adipocyteactivity, leading to obesity, a decrease in glomer-uli and in vascular compliance, contributing to hypertension,and a reduction in beta cells and insulin signaling, contrib-uting to diabetes. Data suggest that at least some of theseprogrammed effects are subject to postnatal alteration, al-though there are currently no accepted human manipula-tions. At present, the best treatment is prevention. AvoidingsevereIUGR is thereforeof importance not only in improving

fetal and neonatal outcomes, but in improving adult healthboth for the index individual and for their children.

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