Physiopathology of intrauterine growth retardation ...

1 downloads 0 Views 543KB Size Report
to the hypothesis of the thrifty phenotype of Hales and Barker. [14] according to which exposure during pregnancy to factors such as shortage of nutrients, toxic ...
The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(S5): 13–18 © 2012 Informa UK, Ltd. ISSN 1476-7058 print/ISSN 1476-4954 online DOI: 10.3109/14767058.2012.714639

REVIEW

 hysiopathology of intrauterine growth retardation: from classic P data to metabolomics Angelica Dessì1, Giovanni Ottonello1 & Vassilios Fanos1,2 1Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU Cagliari, Italy and 2Department of Surgery,

Section of Neonatal Intensive Care Unit and Puericulture, University of Cagliari, Cagliari, Italy

such as the reduction in the number of cells, structural alterations of organs and a different regulation of the hormonal axes.

It is well know that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Epidemiological studies In the last decades, it has become increasingly evident that impaired fetal growth may have long-lasting adverse effects on the health outcome of the offspring, not only during the neonatal period, but more importantly throughout its entire lifespan [5]. The first to advance the hypothesis of a fetal origin of some chronic pathologies in the adult were Barker et al. on the basis of epidemiological observation of certain 20th-century English families [6]. In a later study performed on men born in Hertfordshire, the authors found a correlation between low-weight cranial circumference, weight at birth and mortality caused by coronary diseases in adulthood [7]. Subsequently, these associations were observed in other studies and IUGR was correlated with other chronic pathologies in adults such as type 2 diabetes, hypertension, dyslipidemies, obesity and the metabolic syndrome (Table I). It is interesting that this observation, which started from the UK, was subsequently confirmed in other countries such as Holland and recently also in South Africa, India and other developing countries, where obesity is not a great health problem [8]. The suggested explanation for this association was that in the case of impaired intrauterine milieu, such as nutrient restriction, the adverse intrauterine environment drives a reprogramming of the endocrine–metabolic status of the fetus which may be beneficial in the short term for survival.

Keywords:  IUGR, fetal nutrition, perinatal programming, metabolomics, biomarkers

Introduction It is known that low birth weight is in itself closely correlated with infantile morbidity and mortality. Besides premature birth, intrauterine growth retardation (IUGR) is considered one of the most important causes of low birth weight [1]. According to the 2001 classification of the American College of Obstetricians and Gynaecologists, IUGR is defined as a fetus who does not reach his/her growth potential and is characterized at birth by a weight and body mass lower than normal with respect to the number of gestational weeks [2]. The many causes of IUGR are in general subdivided into those intrinsic to the fetus or placenta and those of extrinsic origin, such as maternal factors that act primarily on the fetus, placenta or both [3]. It can thus be stated that the endouterine environment is the main factor conditioning fetal growth and development [4]. Fetal life is a period characterized by phases of rapid cell proliferation and differentiation during which a factor damaging to the environment may impact on prenatal development and determine structural and functional alterations which may continue throughout adult life. This phenomenon, known as “perinatal programming” refers to intrauterine or perinatal events in a critical period of development for different organs and tissues that may negatively influence their proper functioning, with the possibility of making an individual more susceptible to contracting certain diseases in adulthood. This thesis holds that in the precocious stages of life exposure to determined environmental factors may cause permanent effects,

Fetal nutrition Of the factors potentially capable of creating significant variations in fetal programming, one of the best known is surely the supply of nutrients to the fetus. Fetal growth may be influenced by factors such as the maternal diet. In the literature, there are many experimental studies performed on animals in which IUGR was obtained by manipulating the maternal diet. Restriction of protein assumption during gestation determined reduced fetal growth, an increase in blood pressure and intolerance to carbohydrates in the rat [9–11]. A work in 2005 by Bispham et al. on the sheep revealed that the maternal nutrient restriction from the 28th to the 80th day of gestation led to a presence of increased adipose tissue in the offspring [12]. As concerns humans, an epidemiological study on the Dutch population that lived at the end of the second world war in extreme lack of food showed a

Correspondence: Vassilios Fanos, Department of Surgery, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU and University of Cagliari, Italy. E-mail: [email protected]

13

14   A. Dessì et al. Table I.  Epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed. No of Associated Study Year patients Date of birth Place of birth pathology Author results Barker et al. [7] 1989 5654 (M) 1911–30 Hertfordshire Death from Men with the lowest weights at birth and at one (England) ischemic heart year had the highest death rates from ischemic disease heart disease Hales et al. [14] 1991 468 (M) 1920–30 Hertfordshire Diabetes 2, Reduced growth in early life is strongly linked with (England) hypertension impaired glucose tolerance, non-insulin dependent diabetes and hypertension Barker et al. [51] 1993 1586 (M) 1907–24 Sheffield (England) Death from Standardized mortality ratios for cardiovascular cardiovascular disease fell from 119 in men who weighed 5.5 disease pounds (2495 g) or less at birth to 74 in men who weighed more than 8.5 pounds (3856 g) Phipps et al. [52] 1993 140 (M); 1935–43 Preston (England) Diabetes 2 Those subjects found to have impaired glucose 126(F) tolerance or non-insulin-dependent diabetes mellitus had lower birth weight, a smaller head circumference and were thinner at birth Osmond et al. [53] 1993 10141 (M); 1911–30 Hertfordshire Cardiovascular Among women and men death rates from cardio5585 (F) (England) disease vascular disease fell progressively between the low and high birth weight groups McCance et al. [54] 1994 1179 (M) 1940–72 Arizona (USA) Diabetes 2 The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes Martyn et al. [55] 1995 337 (M&F) 1939–40 Sheffield (England) Hypertension Both systolic and diastolic blood pressures were higher in people whose birth weight was low, who were short or who had small abdominal or head circumferences at birth Curhan et al. [56] 1996 22846 (M) 1911–46 USA Diabetes 2, Low birth weight was associated with an increased hypertension risk of hypertension and diabetes Frankel et al. [57] 1996 1258 (M) Between 45 South Wales Coronary heart There is an important interaction between birth and 59 years (England) disease weight and BMI such that the increased risk of coronary heart disease associated with low birth weight is restricted to people who have high BMI in adulthood Lithell et al. [58] 1996 2322 (M) 1920–24 Sweden Diabetes 2 Prevalence of diabetes at age 60 years was 8% in men whose birth weight was less than 3250 g compared with 5% in men with birth weight 3250 g or more Stein et al. [59] 1996 517 (M&F) 1934–54 South India Coronary heart The highest prevalence of coronary heart disease disease was in people who weighed 2.5 kg or less at birth and whose mothers weighed less than 45 kg during pregnancy Rich-Edwards et al. 1997 121700 (F) 1921–46 USA Non fatal These data provide strong evidence of an associa[60] cardiovascular tion between birth weight and adult coronary disease heart disease and stroke Leon et al. [61] 1998 14611 (M&F)1915–29 Sweden Ischemic heart Cardiovascular disease showed an inverse associadisease tion with birth weight for both men and women Ravelli et al. [13] 1998 702 (M&F) 1943–47 Amsterdam Glucose intolerance, Prenatal exposure to famine, especially during late (Holland) obesity gestation, is linked to decreased glucose tolerance in adults Levitt et al. [62] 2000 137 (M&F) 1975–76 South Africa Glucose intolerance, The link between low birth weight and adult hypertension glucose intolerance and blood pressure elevation occurs in young adults in a high-risk, disadvantaged population despite a lack of full catch-up growth Xiao et al. [63] 2010 2019 (M&F) 1921–54 Beijing (China) Metabolic Subjects who had birth weights of less than 2500 g syndrome were 66% more likely to develop a greater number of metabolic syndrome components in adulthood Meas et al. [64] 2010 45(M); 55(F) 1971–85 France Glucose intolerance, Individuals born SGA were more insulin-resistant metabolic syndrome and showed a significantly higher prevalence of metabolic syndrome

major reduced tolerance to glucides and metabolic alterations in adults born in that period and in particular in those who were at the final third of pregnancy during the period of the greatest food shortage [13]. Results obtained in experimental studies on animal models and epidemiological observations in humans led to the hypothesis of the thrifty phenotype of Hales and Barker

[14] according to which exposure during pregnancy to factors such as shortage of nutrients, toxic substances and reduction of the placental blood flow may have permanent effects on fetal programming. In such conditions the fetus appears to bring into play a series of adaptive mechanisms to increase the immediate possibilities of survival, such as the saving of glucose to ensure

The Journal of Maternal-Fetal and Neonatal Medicine

Physiopathology of intrauterine growth retardation  15 nutrition to the most important organs (brain and heart) with a consequent reduction in insulin secretion, an increase in hepatic glucogenesis and alteration of the β-pancreatic function. These mechanisms appear to be irreversible and continue during the postnatal period, thus increasing the risk of developing diseases such as type 2 diabetes in adulthood [15]. Thus in response to stress factors the developing fetus is capable of adapting to such conditions to ensure survival by altering its size and the structure and function of tissues. These adaptations, although useful in the short term, contrast with environmental conditions of extrauterine life, where there is a sufficient supply of nutrients. In the postnatal period the altered insulin function is associated with accelerated and excessive growth: newborns with low birth weight and rapid postnatal growth are those most exposed to the risk of contracting diabetes, obesity and coronary heart disease in adulthood [16–18]. This hypothesis was later reviewed by Gluckman and Hanson [19] according to whom fetal growth is determined by the interaction between the environment and the fetal genome. The fetal environment, in turn, is determined by the maternal environment and by maternal and placental physiology. There is evidence that the interaction between the fetal environment and genome can determine the risk of postnatal disease, as well as the individual’s capacity to cope with the postnatal environment. In addition to immediate homeostatic responses, the developing organism may make predictive adaptive responses of no immediate advantage but with long-term consequences. The “developmental origins of disease” paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those in which they evolved. The developmental origins of health and disease can be understood by reference to the fundamentals of developmental plasticity. It is essential to distinguish between those environmental effects acting during development that are disruptive from those that have adaptive value. It is suggested that greater disease risk is created by a mismatch between the environment predicted during the plastic phase of development and the actual environment experienced in the postplastic phase [20,21].

Genotype, phenotype and epigenetics It is surely possible that the fetal genotype may play an important role in the development of diseases in adulthood. However, many studies conducted on monozygotic twins of different birth weight have shown a major probability of the presence of type II diabetes in adulthood in the twin with lower birth weight compared to the one with acceptable gestational weight [22,23], thus underlining the importance of the phenotype over the genotype. During embryogenesis the DNA undergoes epigenetic processes of demethylation, chromatin remodeling and histone acetylation [24]. Such mechanisms are fundamental for the development of an individual since they are inheritable modifications of the genome function that take place without changing the DNA sequence but may modify the phenotype of the individual or his/ her progeny. Epigenetics thus offers an explanation of how genetic material adapts to environmental changes. Studies on animals demonstrate that modifications of DNA methylation in the fetus are conditioned by the maternal diet [25]. It is now known that a folic acid supplement in the maternal diet starting from the preconception period prevents the development of defects in the fetus neural tube [26]. Folic acid is a donor of methylic groups and protects the DNA by regulating methylation, synthesis and repairs [27]. Moreover, some works on animals and humans have

© 2012 Informa UK, Ltd.

shown that an inadequate maternal diet (both under- and overnutrition) in the prenatal period may lead to epigenetic alterations of the genes that regulate the metabolism and predispose towards the development of the metabolic syndrome in the offspring [28,29]. Recently, a review was published concerning evaluation of the role of epigenetics in the onset of type II diabetes in adulthood [30]. According to the authors, epigenetic programming allows the development of different phenotypes from a single genotype for the purpose of allowing each organism to respond to its environment. In the case of an IUGR fetus, when in extrauterine life the environmental conditions change, the organism is incapable of dealing with the new situation and this may predispose towards the development of pathologies in adulthood, such as type 2 diabetes. The experimental studies on animals by Chen et al. [31] show that fetal undernutrition, especially when caused by maternal protein restriction, may cause permanent alteration of the podocytes, which can be observed under the electron microscope. These may be the main reason for the triggering of a cascade leading to proteinuria, hypertension, stroke and all the characteristics of the metabolic syndrome. Since the number of nephrons is one of the factors determining kidney mass, these observations, in a community in which weight in most cases is attributable to IUGR, suggest that renal damage is a consequence of intrauterine malnutrition and its negative effects on nephrogenesis, the final result of which is a reduction in the number of nephrons. In a recent review by Fanos et al. [32] it emerged that an epigenetic modification may be transmitted to successive generations. Furthermore, what is important is not only the kind of nutrition at birth, but rather its adequacy or unsuitability or its mismatching with the new metabolic requirements created by an unfavorable intrauterine environment to which a genetically predetermined organism had to adapt by changing its developmental trajectory (perinatal programming). In IUGRs, besides renal involvement, many other organs will never reach their full development potential if insufficient growth takes place in a specific critical period of development. In another recent work by Cottrell et al. [33], different studies on animals were analysed in which, besides the different harmful factors, the administration of glucocorticoids during pregnancy was associated with reduced fetal growth. In humans, glucocorticoids are administered in pregnancy for the prevention of the neonatal Respiratory Distress Syndrome (RDS) in the case of preterm births and for the treatment of maternal chronic diseases. The glucocorticoids most studied for their effects on the fetus are β-methasone and dexamethasone, given their capacity to rapidly cross the placental barrier and reach the fetus in their active form. Some authors have observed that the exogenous administration of glucocorticoids reduces placental activity of 11betahydroxysteroid dehydrogenase-2 (11β-HSD2). This enzyme acts as a ‘barrier’ to prevent premature or inappropriate action on glucocorticoid-responsive tissues during fetal development. Thus the inactivation of 11β-HSD2 decreases this barrier to excess glucocorticoids and reduces fetal growth [34].

Biomarkers & IUGR: from classic data to metabolomics In the literature there are several works that associate IUGR with biomarkers, both in pregnancy and the neonatal period. Nezar et al. [35] correlated the increase in Endothelin-1 and Leptine in maternal blood with the degree of fetal growth restriction caused by deterioration of the placental function. A study by Florio et al. [36] revealed high values of the protein S100B in

16   A. Dessì et al. Table II.  Metabolomic studies that have revealed an altered metabolism in IUGR patients compared to controls. Sample Metabolomics Author Year Type of patient N° Patients analysed analysis Nissen 2011 Newborn piglet 12 IUGR vs 12 Plasma Nuclear magnetic et al. [42] controls resonance (NMR) based Alexandre2011 Newborn rat 8 IUGR vs 8 Plasma Liquid chromaGouabau controls tography highet al. [50] resolution mass spectrometry (LC-HRMS) Dessì 2011 Human neonate 26 IUGR vs 30 Urine Proton nuclear et al. [45] controls magnetic resonance spectroscopy (1H-NMR) Favretto et al. [49]

2012

Human neonate

22 IUGR vs 21 controls

Cord blood

the urine of neonates affected by IUGR; these were found to be a useful parameter in identifying cases of underdevelopment and the possible risks of neurological sequels in the prenatal period, whether or not associated with other biomarkers. Instead, according to Malamitsi-Puchner et al. [37], pathological conditions in pregnancy associated with IUGR may be responsible for high levels of visfatin in the maternal blood. According to the authors, the increase of the same in neonatal blood with growth retardation may be useful as an early predictive marker of the later development of insulin resistance or type 2 diabetes in adulthood. Other studies conducted both on animals and humans have shown a reduction in plasmatic levels of insulin-like growth factor (IGF)-1, an essential marker for fetal and postnatal growth, in fetuses exposed to unfavorable uterine conditions and with growth retardation [38]. It is interesting to note that in some cases the reduction in IGF-1 was attributed to a gene mutation, thus emphasizing the possibility that alterations of the IGF axis may also be caused by altered epigenetic regulation [39]. Thus if it is true that the literature contains several works that correlate the behavior of the single metabolites with IUGR, suggesting their possible role as markers in such a pathology, in any case up to now knowledge on the overall metabolic state of low-weight neonates is still scanty. In clinical practice, only a limited number of metabolites are commonly measured in the biological liquids of neonates by means of conventional analytical methods. However, in recent years the new holistic metabolomic approach (about 2400 metabolites) has assumed an important clinical role in the identification of “disorders” in a patient’s metabolic profile. In fact, the qualitative and quantitative evaluation at the same time and as a function of time of a consistent number of metabolites, such as those that can be determined through NMR or mass spectrometry (MS) in biological fluids, is capable of providing, with acceptable probability, the description of the present biochemical state of an organism, providing information on the interrelations between the different metabolic processes that define the state [40]. In this way, rather than taking into consideration one or a few metabolites with the relative metabolic processes, it is possible to examine the entire metabolic profile determined by the interconnection of the different processes [41]. Recently, some studies of metabolomics have been published. They reveal an altered metabolism in IUGR patients compared to controls (Table II). Nissen et al. (2011) performed a study based on a metabolomic investigation conducted on piglets with

Liquid chromatography highresolution mass spectrometry (LC-HRMS)

Conclusions IUGR is related to impaired glucose metabolism during fetal development, which may cause type 2 diabetes in adulthood The long-term deregulation in feeding behavior and fatty acid metabolism in IUGR rats depends on postnatal growth velocity The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences The identification of significant differences in relative abundances of essential amino acids between IUGR and AGA fetuses, emerges as a promising tool for studying metabolic alterations

IUGR which revealed different glucose and myo-inositol levels in samples of plasma of piglets of low birth weight compared to those of high weight [42]. A significantly higher concentration of myo-inositol and d-chiro-inositol was observed in IUGR piglet plasma compared to that of their larger siblings. The authors of this study conclude that since myo-inositol and d-chiro-inositol have been associated with glucose intolerance and insulin resistance in adults [43,44], the altered glucide metabolism during fetal development in IUGRs, shown by the increase in plasma myo-inositol, may predispose towards type II diabetes in adulthood. These results are in agreement with a quite recent work on humans [45] where the metabolomic analysis succeeded in showing different urinary metabolic profiles between IUGR neonates and controls. In this study, metabolomics identified certain molecules responsible for the differences in the different metabolic profiles, among which myo-inositol, creatine, creatinine and sarcosine, whose urine content had increased in the IUGRs compared to controls. An increase in these metabolites in the urine is observed in states of hypercatabolism, as in the case of fasting [46]. It is also known that insulin plays a role in favoring lipid and protide synthesis as well as cell growth [47]. We can thus hypothesize that a reduced supply of glucide to the fetus may cause reduced insulin secretion. The decrease in insulin may thus cause a decrease in protein synthesis and an increase in its catabolism, a decrease in lipid synthesis and reduced cell proliferation. These events would explain low birth weight and the presence of the altered metabolic pattern observed in IUGR patients. Recent experimental studies on animals [48] suggest that fetal growth restriction due to a low placental substrate supply results in increased abundance of the insulin receptor in skeletal muscle which persists into postnatal life and can then, in the presence of the higher levels of nutrition present in postnatal life, result in the accelerated growth of the IUGR infant. Following birth, in fact, the increase in the abundance of the insulin receptor in the skeletal muscle persists and, together with the transition to the higher level of nutrition present in postnatal life, this results in an increase in the abundance of the insulin signaling molecules, phosphatidylinositol 3 kinase (PI3K) and insulin-dependent glucose transporter (GLUT4), and with accelerated postnatal growth [17]. A very recent work by Favretto et al. [49] used nontargeted metabolomic profiling to study the alterations in fetal and/or placental metabolism in IUGR fetuses by means of liquid chromatography high-resolution mass

The Journal of Maternal-Fetal and Neonatal Medicine

Physiopathology of intrauterine growth retardation  17 spectrometry (LC-HRMS) of cord blood collected immediately after birth. This metabolomic analysis led to the revealing of significant differences in abundance of essential amino acids (such as phenylalanine and tryptophan) between IUGRs and fetuses of proper weight for their gestational age, emerging as a promising instrument for the study of metabolic alterations. Finally, another recent study of metabolomics performed on rats shows that IUGRs with rapid postnatal growth are characterized by an altered metabolism of fatty acids in the long term [50].

Conclusions The literature suggests that IUGR represents a situation of fetal compensation aimed at saving glucose in the case of intrauterine hypoglycemia. Postnatal attempts to cancel the consequences of fetal programming, for example recovery of body weight, may impact on the risk of developing diseases in adulthood. Scientific advances made in medical research in the last few years have laid the foundations for future development of personalized treatments aimed at remedying pathological conditions on the basis of subjective characteristics. The reaching of this objective calls for the application of diagnostic systems capable of providing detailed and as complete as possible information concerning the metabolic state of an individual. In the cases of SGA or IUGR, integration of breast feeding as well as the formulas should be specifically adapted to individual needs, taking into account the long-term consequences, such as the accumulation of inappropriate fat. Metabolomics has the potential to lead to an overall vision of metabolic conditions and the biochemical events associated with the state of health or disease of an individual. As such, the unconditioned and impartial approach of metabolomics can provide a complete picture both of physiological conditions in the stationary state and the dynamic responses of a given organism to genetic and environmental conditions. In future, specific neonatalogical studies will be able to suggest the possible role of metabolomics in identifying subgroups of IUGR neonates to whom to administer a diversified diet as well as evaluating the single metabolites for the purpose of monitoring these patients over a period of time and preventing the onset of diseases in the adult age from the viewpoint of personalized, predictive and preventive medicine at the same time. Declaration of Interest: The authors report no conflicts of interest

References 1. Diderholm B. Perinatal energy metabolism with reference to IUGR & SGA: studies in pregnant women & newborn infants. Indian J Med Res 2009;130:612–617. 2. Committee on Practice Bulletins Gynecology, American College of Obstetricians and Gynecologists, Washington, DC 20090-6920, USA. Intrauterine growth restriction. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 2001;72:85–96. 3. McCowan LM, Roberts CT, Dekker GA, Taylor RS, Chan EH, Kenny LC, Baker PN, et al.; SCOPE consortium. Risk factors for small-forgestational-age infants by customised birthweight centiles: data from an international prospective cohort study. BJOG 2010;117:1599–1607. 4. King JC. Physiology of pregnancy and nutrient metabolism. Am J Clin Nutr 2000;7:1218–1225. 5. Nicoletto SF, Rinaldi A. In the womb’s shadow. The theory of prenatal programming as the fetal origin of various adult diseases is increasingly supported by a wealth of evidence. EMBO Rep 2011;12:30–34. 6. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077–1081. 7. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577–580. 8. Kanaka-Gantenbein C. Fetal origins of adult diabetes. Ann N Y Acad Sci 2010;1205:99–105.

© 2012 Informa UK, Ltd.

9. Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr Res 1996;40:438–443. 10. Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav 2006;88:234–243. 11. Desai M, Babu J, Ross MG. Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition. Am J Physiol Regul Integr Comp Physiol 2007;293:R2306–R2314. 12. Bispham J, Gardner DS, Gnanalingham MG, Stephenson T, Symonds ME, Budge H. Maternal nutritional programming of fetal adipose tissue development: differential effects on messenger ribonucleic acid abundance for uncoupling proteins and peroxisome proliferatoractivated and prolactin receptors. Endocrinology 2005;146:3943–3949. 13. Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998;351:173–177. 14. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019–1022. 15. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20. 16. Eriksson JG, Forsén T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999;318:427–431. 17. Morrison JL, Duffield JA, Muhlhausler BS, Gentili S, McMillen IC. Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity. Pediatr Nephrol 2010;25:669–677. 18. Claris O, Beltrand J, Levy-Marchal C. Consequences of intrauterine growth and early neonatal catch-up growth. Semin Perinatol 2010;34:207–210. 19. Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res 2004;56:311–317. 20. Gluckman PD, Hanson MA, Morton SM, Pinal CS. Life-long echoes–a critical analysis of the developmental origins of adult disease model. Biol Neonate 2005;87:127–139. 21. Gluckman PD, Cutfield W, Hofman P, Hanson MA. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early Hum Dev 2005;81:51–59. 22. Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance–a population-based twin study. Diabetologia 1999;42:139–145. 23. Bo S, Cavallo-Perin P, Scaglione L, Ciccone G, Pagano G. Low birthweight and metabolic abnormalities in twins with increased susceptibility to Type 2 diabetes mellitus. Diabet Med 2000;17:365–370. 24. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001;293:1089–1093. 25. Sebert S, Sharkey D, Budge H, Symonds ME. The early programming of metabolic health: is epigenetic setting the missing link? Am J Clin Nutr 2011;94:1953S–1958S. 26. Fuller NJ, Bates CJ, Cole TJ, Lucas A. Plasma folate levels in preterm infants, with and without a 1 mg daily folate supplement. Eur J Pediatr 1992;151:48–50. 27. Liotto N, Miozzo M, Giannì ML, Taroni F, Morlacchi L, Piemontese P, Roggero P, Mosca F. Early nutrition: the role of genetics and epigenetics. Pediatr Med Chir 2009;31:65–71. 28. Hulsey TC, Neal D, Bondo SC, Hulsey T, Newman R. Maternal prepregnant body mass index and weight gain related to low birth weight in South Carolina. South Med J 2005;98:411–415. 29. Smith GC, Konycheva G, Dziadek MA, Ravelich SR, Patel S, Reddy S, Breier BH, et al. Pre- and postnatal methyl deficiency in the rat differentially alters glucose homeostasis. J Nutrigenet Nutrigenomics 2011;4:175–191. 30. Liguori A, Puglianiello A, Germani D, Deodati A, Peschiaroli E, Cianfarani S. Epigenetic changes predisposing to type 2 diabetes in intrauterine growth retardation. Front Endocrinol (Lausanne) 2010;1:5. 31. Chen J, Xu H, Shen Q, Guo W, Sun L. Effect of postnatal high-protein diet on kidney function of rats exposed to intrauterine protein restriction. Pediatr Res 2010;68:100–104. 32. Fanos V, Puddu M, Reali A, Atzei A, Zaffanello M. Perinatal nutrient restriction reduces nephron endowment increasing renal morbidity in adulthood: a review. Early Hum Dev 2010;86 Suppl 1:37–42. 33. Cottrell EC, Seckl JR. Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci 2009;3:19. 34. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 2004;151 Suppl 3:U49–U62.

18   A. Dessì et al. 35. Nezar MA, el-Baky AM, Soliman OA, Abdel-Hady HA, Hammad AM, Al-Haggar MS. Endothelin-1 and leptin as markers of intrauterine growth restriction. Indian J Pediatr 2009;76:485–488. 36. Florio P, Marinoni E, Di Iorio R, Bashir M, Ciotti S, Sacchi R, Bruschettini M, et al. Urinary S100B protein concentrations are increased in intrauterine growth-retarded newborns. Pediatrics 2006;118:e747–e754. 37. Malamitsi-Puchner A, Briana DD, Boutsikou M, Kouskouni E, Hassiakos D, Gourgiotis D. Perinatal circulating visfatin levels in intrauterine growth restriction. Pediatrics 2007;119:e1314–e1318. 38. Randhawa R, Cohen P. The role of the insulin-like growth factor system in prenatal growth. Mol Genet Metab 2005;86:84–90. 39. Holness MJ, Sugden MC. Epigenetic regulation of metabolism in children born small for gestational age. Curr Opin Clin Nutr Metab Care 2006;9:482–488. 40. Coen M, Holmes E, Lindon JC, Nicholson JK. NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. Chem Res Toxicol 2008;21:9–27. 41. Nicholson JK, Connelly J, Lindon JC, Holmes E. Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Discov 2002;1:153–161. 42. Nissen PM, Nebel C, Oksbjerg N, Bertram HC. Metabolomics reveals relationship between plasma inositols and birth weight: possible markers for fetal programming of type 2 diabetes. J Biomed Biotechnol 2011;2011:378268. 43. Kennington AS, Hill CR, Craig J, Bogardus C, Raz I, Ortmeyer HK, Hansen BC, et al. Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus. N Engl J Med 1990;323:373–378. 44. Ostlund RE Jr, McGill JB, Herskowitz I, Kipnis DM, Santiago JV, Sherman WR. D-chiro-inositol metabolism in diabetes mellitus. Proc Natl Acad Sci USA 1993;90:9988–9992. 45. Dessì A, Atzori L, Noto A, Visser GH, Gazzolo D, Zanardo V, Barberini L, et al. Metabolomics in newborns with intrauterine growth retardation (IUGR): urine reveals markers of metabolic syndrome. J Matern Fetal Neonatal Med 2011;24 Suppl 2:35–39. 46. Sugita O, Uchiyama K, Yamada T, Sato T, Okada M, Takeuchi K. Reference values of serum and urine creatinine, and of creatinine clearance by a new enzymatic method. Ann Clin Biochem 1992;29 (Pt 5):523–528. 47. Lam YY, Hatzinikolas G, Weir JM, Janovská A, McAinch AJ, Game P, Meikle PJ, Wittert GA. Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: the effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids. Biochim Biophys Acta 2011;1811:468–475. 48. Muhlhausler BS, Duffield JA, Ozanne SE, Pilgrim C, Turner N, Morrison JL, McMillen IC. The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signalling in skeletal muscle. J Physiol (Lond) 2009;587:4199–4211. 49. Favretto D, Cosmi E, Ragazzi E, Visentin S, Tucci M, Fais P, Cecchetto G, et al. Cord blood metabolomic profiling in intrauterine growth restriction. Anal Bioanal Chem 2012;402:1109–1121.

50. Alexandre-Gouabau MC, Courant F, Le Gall G, Moyon T, Darmaun D, Parnet P, Coupé B, Antignac JP. Offspring metabolomic response to maternal protein restriction in a rat model of intrauterine growth restriction (IUGR). J Proteome Res 2011;10:3292–3302. 51. Barker DJ, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 1993;306:422–426. 52. Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993;36:225–228. 53. Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ. Early growth and death from cardiovascular disease in women. BMJ 1993;307:1519–1524. 54. McCance DR, Pettitt DJ, Hanson RL, Jacobsson LT, Knowler WC, Bennett PH. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 1994;308:942–945. 55. Martyn CN, Barker DJ, Jespersen S, Greenwald S, Osmond C, Berry C. Growth in utero, adult blood pressure, and arterial compliance. Br Heart J 1995;73:116–121. 56. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 1996;94:3246–3250. 57. Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD. Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet 1996;348:1478–1480. 58. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. BMJ 1996;312:406–410. 59. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ. Fetal growth and coronary heart disease in south India. Lancet 1996;348:1269–1273. 60. Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997;315:396–400. 61. Leon DA, Lithell HO, Vâgerö D, Koupilová I, Mohsen R, Berglund L, Lithell UB, McKeigue PM. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29. BMJ 1998;317:241–245. 62. Levitt NS, Lambert EV, Woods D, Hales CN, Andrew R, Seckl JR. Impaired glucose tolerance and elevated blood pressure in low birth weight, nonobese, young south African adults: early programming of cortisol axis. J Clin Endocrinol Metab 2000;85:4611–4618. 63. Xiao X, Zhang ZX, Li WH, Feng K, Sun Q, Cohen HJ, Xu T, et al. Low birth weight is associated with components of the metabolic syndrome. Metab Clin Exp 2010;59:1282–1286. 64. Meas T, Deghmoun S, Alberti C, Carreira E, Armoogum P, Chevenne D, Lévy-Marchal C. Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age. Diabetologia 2010;53:907–913.

The Journal of Maternal-Fetal and Neonatal Medicine

Copyright of Journal of Maternal-Fetal & Neonatal Medicine is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.