Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets

European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) S40–S49

Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets Reinhard Bauera,*, Bernd Waltera, Peter Brustb, Frank Fu¨chtnerc, Ulrich Zwienera a

Institute for Pathophysiology, Friedrich Schiller University, D-07740 Jena, Germany Institute for Interdisciplinary Isotope Research, University Leipzig, Leipzig, Germany c Institute for Bioinorganic and Radiopharmaceutic Chemistry, Research Center Rossendorf, Rossendorf, Germany b

Abstract Fetal malnutrition may induce asymmetric intrauterine growth restriction (aIUGR) with long-lasting consequences. Understanding the organ-specific structural and functional effects aIUGR may have on the newborn, and understanding the potential impact on the neonatal response to compromising conditions, appears to be essential for adequate treatment. Therefore, a survey is given of some organ-specific alterations in newborns, which have suffered from aIUGR. We studied these effects in a model of asymmetric intrauterine growth restriction based on the spontaneous occurrence of runting in pigs. We wish to demonstrate that experimental studies in animal models are necessary and helpful to elucidate pathogenetic mechanisms. aIUGR seems to have both beneficial and detrimental effects on the newborn. The development of skeletal muscles (conversion to oxidative type I fibers) and of their vascular supply as well as of the brain dopaminergic activity is accelerated. Also, aIUGR apparently improves the ability to withstand critical periods of gradual oxygen deficit as shown by the maintenance of renal blood flow during severe systemic hypoxia, and by improved cerebrovascular autoregulation in hemorrhagic hypotension. On the other hand, aIUGR leads to the reduction of the number of nephrons and to impaired renal excretory functions with arterial hypertension and chronic renal failure. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Asymmetric intrauterine growth restriction; Newborn period; Skeletal muscle development; Renal structure and function; Brain dopamine metabolism; Cerebrovascular autoregulation

1. Introduction 1.1. The problem of aIUGR Asymmetric intrauterine growth restriction (aIUGR; type II) is still an unresolved problem in perinatal medicine. Perinatal mortality is increased (two–eight-fold, [1–3]), as well as the incidence of perinatal asphyxia, because placental insufficiency is the main cause of aIUGR [4] in the developed countries. However, not only is the fetus or newborn acutely endangered by placental insufficiency, but long-term (perhaps lifelong) alterations are also associated with aIUGR. Epidemiological studies have demonstrated recently that there is an increased risk for diseases in adulthood, i.e. arterial hypertension, diabetes mellitus type 2 and the metabolic syndrome (for review see [5–7]). At present, experimental studies extend our understanding of the pathogenesis of placental insufficiency, of intrauterine *

Corresponding author. Tel.: þ49-3641-938956; fax: þ49-3641-938954. E-mail address: [email protected] (R. Bauer).

malnutrition (due to placental insufficiency, maternal protein malnutrition or other causes), of organ-specific responses during ontogenetic development, and of the long-term consequences. This mini review focuses mainly on data from newborn piglets which have suffered as fetuses from spontaneous aIUGR. 1.2. Pathogenesis of aIUGR The most common cause of intrauterine growth restriction (80–90% of all cases) is a compromised supply of nutrients and oxygen to the fetus, which results in the disproportionate growth of the brain (‘‘brain sparing’’) in relation to other fetal organs like liver, kidneys, pancreas, skeletal muscles, and fatty tissues [8–11]. Offspring with the characteristics of aIUGR occur spontaneously in various mammalian species, e.g. humans [12], swine [13,14], rabbits [15], sheep [16], and guinea pigs [17]. The slow-down of fetal growth late in gestation following intrauterine malnutrition can be regarded primarily as a compensatory process, which enables the fetus to survive and which, therefore, improves the reproduction rate [18,19].

0301-2115/$ – see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0301-2115(03)00171-4

R. Bauer et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) S40–S49

Growth reduction is primarily achieved by altering the endocrine milieu, possibly by reducing the endocrine and paracrine insulin-like growth factor I (IGF-I) activity [20] in response to impaired transplacental nutrient and oxygen transfer [21–23]. Fetal malnutrition initiates a reduction–suspension of anabolic processes by downregulation of growth factors, including the IGF-system, which is a key modulator of fetal growth [24]. Reduced substrate consumption enables—at least at times—the prevention of a life-threatening imbalance between nutritional supply and demand. As shown in a recent study, chronic uteroplacental blood flow reduction (about half of control) in late-term fetal sheep led to a marked reduction in fetal weight, but oxygen and substrate consumption per unit fetal weight remained unaltered [25,26]. An additional restriction in nutritional requirement occurs following reduction/cessation of fetal motor activity including fetal breathing movements [27]. However, reductions in fetal motor activity can be transient, suggesting that brain stem function is normal in compensated hypoxia [28]. In addition, evidence is available that glucocorticoid activity is increased in aIUGR fetuses because maternal glucocorticoids are cleared insufficiently by the placenta [29,30]. Glucocorticoids have been ascribed a pivotal role in the induction of processes during a sensitive period of development with structural and/or functional effects that may persist throughout life [6,31]. 1.3. Natural occurrence of runting in pigs—a useful model of asymmetric intrauterine growth restriction Animal models are of proven value in biomedical research. Development and characterization of animal models were decisive in elaborating different principles of causal pathogenesis of aIUGR. These include: (i) postulate of the hemodynamic theory of placental insufficiency with concomitant occurrence of aIUGR, based on experimentally induced placental (maternal and/or fetal) blood flow reduction during the second part of gestation, initiated by Wigglesworth in rat [32], and then used to provoke aIUGR offspring in different other mammals (guinea pig [33], rabbit [34,35], sheep [26] and rhesus monkey [36,37]); (ii) placental exchange surface reduction (removal of endometrial caruncles [38] or repeated uteroplacental embolization [39]

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in sheep); (iii) alteration in environmental conditions, like maternal malnutrition [40], maternal dietary protein depletion [41], heat stress [42] and overnourishment of adolescent sheep [43]. aIUGR occurs spontaneously in various mammalian species, as mentioned earlier, and exhibits quite similar signs of adaptive/compensatory growth restriction, as shown in human beings. These individuals represent a favorable approach to study functional peculiarities of aIUGR, without the confounding impacts of artificial effects after experimental interventions, which never can be excluded completely. There are several reasons, which suggest that the naturally occurring runted piglet represents a suitable model for newborn aIUGR infants. Besides some developmental similarities between both species (like growth spurt during the perinatal period [44], cardiovascular and central autonomic functions [45,46], energy metabolism [47], and oxidative brain metabolism [48]), there are distinct morphometrical signs in runted piglets, which are pathognomonic for aIUGR (see Table 1). Early sophisticated determinations of body weight distribution [49] and organ size characteristics [13] of newborn piglets have been verified recently in our studies [14]. Based on a statistically reliable random sample (n ¼ 512, 12 h old, obtained from 50 consecutively delivered litters), a classification of aIUGR as those weighing less than the 10th percentile has been achieved. Morphometric data show that naturally occurring growth restriction in swine is asymmetrical with an increase in the mean ratio of brain weight to liver weight as shown in Table 1. The reduction in brain weight was quite small (91 and 83% of NW group). In contrast, the decrease in liver weight (44 and 37% of NW group) was similar to that in body weight (53 and 40% of NW group). All differences in organ weight in relation to normal weight newborn piglets were significant (P < 0:01). In addition, piglets are large enough to be studied with physiological methods from birth and, unlike ruminants, their postnatal nutrient intake can be regulated precisely after weaning [50]. Meanwhile, increasing evidence has appeared that inadequate fetal growth in pigs is obviously caused by alterations associated with placental insufficiency. (i) It has been shown that in pig and other species an association between

Table 1 Morphometric data of newborn piglets following normal growth or intrauterine growth restriction Normal weight piglets (40th–90th percentile; n ¼ 19) Body weight (g) Brain weight (g) Liver weight (g) Brain-to-liver ratio

1496 33.3 41.9 0.79

   

179 1.8 9.4 0.26

aIUGR piglets (5th–10th percentile; n ¼ 10)

aIUGR piglets (<5th percentile; n ¼ 10)

798  47a 30.2  3.6a 18.5  2.3a 1.63  0.22a

592 27.9 15.4 1.90

Classification according to affiliations of birth weight classes, published in [14].Values are presented as means  S.D. a Comparison between newborn normal weight piglets and asymmetric intrauterine growth restricted (aIUGR) piglets. b P < 0:05, comparison between both groups of aIUGR piglets. c P < 0:01.

   

92a,c 2.1a 3.3a,b 0.50a

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placental amino acid transport and fetal growth exists. Indeed, placentae supplying inadequately grown pig fetuses showed a reduced capacity to transport the essential amino acid, leucine [51,52]. (ii) A disturbance of the placental barrier to maternal glucocorticoids apparently occurs in pigs. An inverse relationship between fetal weight and plasma cortisol concentration in mid gestation (day 65) and late in gestation (day 100) of fetal pig was reported recently [52]. Furthermore, it has been shown that there is a significant association between fetal pig size and placental 11b-hydroxysteroid dehydrogenase (11b-HSD) net dehydrogenase activity [53], which is responsible for rapid conversion of maternal glucocorticoids to inactive products (in order to prevent them reaching the fetus) [54]. Recent findings have shown that elevated cortisol levels in the smallest fetuses of each litter at day 100 of gestation were not caused by elevated plasma ACTH and, therefore, may reflect reduced placental 11b-HSD or increased adrenal activity in these small fetuses [55]. Limited uterine space is obviously not a primary determinant of fetal growth. It has been shown that inadequately grown pig fetuses can be identified statistically as early as day 30 of the 114 days of gestation [52]. The suitability of the naturally occurring runted piglet as useful model of aIUGR has been emphasized additionally by a recent report, which verified that arterial blood pressure in 3-month-old pigs is positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations [50].

2. Effects of aIUGR on the neonate We would like to emphasize that aIUGR does not only provoke complications during intrauterine and perinatal life, but may cause adaptational and permanent changes in the neonate. These changes will be discussed with regard to organs which are essentially involved in diseases associated with aIUGR. Most studies were done using the newborn aIUGR piglet model of naturally occurring runted piglets.

2.1. Effects of aIUGR on renal structure and function It has been proposed that cardiovascular alterations causal for adult hypertension can be initiated during fetal life [56]. As the kidneys are involved in long-term arterial blood pressure regulation, the question arose whether aIUGR has a typical influence on renal structure and function in the newborn. It is known that fetal growth restriction is associated with impaired excretory renal function which is manifest early after birth [57,58]. There is no indication for a hemodynamic cause of reduced glomerular filtration rate (GFR), because renal blood flow is unaltered (Fig. 1). Several experimental studies have shown that, independent of its etiology and in different species, aIUGR is associated with a marked reduction in nephron number [59–63]. We found a nearly proportional reduction in nephron number (normalized to the kidney weight) by 27% and in GFR (reduced by 31%) in piglets 11–25 h after birth. These results showed also that despite glomerular hyperperfusion (which follows from maintained renal blood flow) the filtration rate per nephron remained nearly unaltered (single nephron glomerular filtration rate of normal weight piglets, 15:85  4:09 nl min1; aIUGR piglets, 14:81  3:40 nl min1). Therefore, in this species at birth a response to compensate the nephron deficit does not exist [63]. In growing rats, which were born following aIUGR caused by maternal undernutrition, hypertrophy of the depleted glomeruli occurred (shown in 2-week-old rats) [59]. This adaptation normalized renal excretory function throughout a 11-month observation period [60,64]. Longterm consequences of aIUGR offspring after maternal low protein diet during pregnancy are a progressive increase of systolic pressure, increased plasma aldosterone values, sodium retention and expanded extracellular volume, mild proteinuria, nephrosclerosis and a shortened life span [62,64,65]. Thus, low renal size persisted and blood pressure was elevated early in adulthood, which supports the hypothesis that aIUGR may program the renal nephron number and is related to the development of hypertension at an adult age [60,62]. However, the mechanism by which prenatal events

Fig. 1. Effect of aIUGR on renal blood flow and glomerular filtration rate of spontaneously growth restricted newborn piglets (aIUGR: n ¼ 7, 1-day-old) [14,116] (normal weight, NW: n ¼ 8, 1-day-old) (modified from [58], with permission); b.wt., body weight. Bars and whiskers are mean þ S:D. (*) indicates P < 0:05 for differences between NW and aIUGR piglets.

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program future hypertension remained unclear. Vehaskari et al. [62] reported neonatal aIUGR after prenatal maternal protein deprivation in a genetically normotensive rat strain, with a reduced number of nephrons, alterations in renin– angiotensin–aldosterone axis, hypertension, accelerated nephrosclerosis, and shortened life span. However, they did not find a consistent relationship between hypertension and relative number of nephrons and suggested that it seemed unlikely that reduced filtration surface area relative to body size is the sole pathophysiological factor in the development of hypertension. It appears more likely that early reduction in filtration initiates a cascade of events which include, for instance, inappropriate tubuloglomerular balance and sodium reabsorption, that ultimately is responsible for the generation of hypertension [62]. Indeed, prenatal programming of hypertension involves transcriptional up-regulation of Naþ transport in thick ascending limb and distal convoluted tubule [65]. Glucocorticoids may contribute to impair renal development [66,67] and there is evidence that they are causally involved in reduced nephrogenesis during aIUGR. Celsi et al. [67] induced aIUGR in rats by administration of

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dexamethasone to the mother. They found a reduced number of glomeruli and of cells undergoing mitosis in the cortical nephrogenic zone [67]. Exposure of fetal tissues to dexamethasone affects several paracrine growth factor activities mainly by modulation of their receptor availability due to an increase of their binding proteins [68], proliferation of undifferentiated mesenchymal cells essential for nephrogenesis may be reduced. Surprisingly, severe O2 deprivation does not further aggravate impaired renal functions in newborns after aIUGR. We have recently shown that in newborn IUGR piglets, reduction in renal blood flow during severe normocapnic hypoxemia is less pronounced than in controls. This indicates an improved capacity to withstand periods of severely disturbed oxygenation [69]. 2.2. Effect of aIUGR on skeletal muscle fibers Skeletal muscle fibers are genetically determined at the embryonic stage, because muscle fiber heterogeneity stems from distinct populations of myoblasts that are committed to form myotubes within a given range of phenotypic options

Fig. 2. Skeletal muscle blood flow (measured with colored microspheres [117]), muscle vascular resistance (MVR), muscle O2 delivery, and muscle tissue pO2 in normal weight (NW; n ¼ 9) and asymmetrically intrauterine growth restricted (aIUGR; n ¼ 9) newborn piglets. Plasma thyroid hormone concentration in newborn NW (n ¼ 14) and aIUGR (n ¼ 8) piglets (modified from [75], with permission). (*) indicates P < 0:05 for differences between NW and IUGR piglets.

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[70]. Furthermore, both humoral and neuronal factors are known to influence physiological, morphological and histochemical properties of muscle fibers [71]. aIUGR has a distinct impact on fetal skeletal muscle development and differentiation. For example, weight reduction of skeletal muscles is disproportionally larger than reduction of total body weight [14]. It was recently shown also that the mitochondrial function of rat skeletal muscle cells is postnatally altered following intrauterine growth restriction [72]. Furthermore, insulin resistance and a delay in activation of glycolysis/glycogenolysis in exercising skeletal muscle were found in prepubertal children and adult women born with aIUGR. This is a potential marker for the early identification and intervention in the development of adult-onset non-insulin dependent diabetes mellitus [73,74]. aIUGR affects in addition the conversion of fiber types (from type II to type I) and the contractility of skeletal muscle cells [75,76]. Contractility is mainly determined by fiber type and blood supply. In normal neonates, skeletal muscle cells of type IIB (fast-twitch) prevail, whereas type I cells (slow oxidative) develop with increasing age [77]. Evidence exists that these changes [78] as well as the development of the muscular vascular bed [79], depend on thyroid hormones. Myogenesis in the pig as well as in many other mammalian species is a biphasic process with the formation of two generations of muscle fibers. Fibers of the second generation undergo a process of maturation from late gestation through the first postnatal weeks [80,81]. We have shown that an increased proportion of mature type I fibers in flexor digitalis superficialis and gastrocnemius medialis appears in newborn piglets after aIUGR [76]. Although the molecular controls that govern muscle fiber differentiation and contractile function development remain unclear [82], aIUGR seems to accelerate the maturation of fiber type conversion. It is well known that thyroid hormones influence muscle maturity [78]. As plasma thyroxine levels are increased in newborn aIUGR piglets (Fig. 2), the accelerated maturation of skeletal muscles may result from this hormonal alteration. Previous studies have demonstrated that, in thyroid hormone deficient porcine fetuses, the development of blood vessels in muscle tissue was retarded both quantitatively and qualitatively [79]. We studied in piglets following aIUGR the capillary bed of hindlimb calf muscles and the muscle fiber type distribution by immunohistochemical techniques and found an increased capillary density in combination with an increase of mature type I fibers (unpublished observations). In recent studies, we found a distinct increase of muscle blood flow (P < 0:05) caused by reduction of vascular resistance (Fig. 2). Also, force development per square centimeter cross-sectional area was increased (P < 0:05), and the reduction of force with repeated isometric contractions was distinctly less (P < 0:05) than in normal weight controls (Fig. 3). These differences in contractile force and in fatigue tolerance normally reflect maturational changes as reported in fetal sheep [83]. It appears, therefore, that

muscular development is accelerated in newborn piglets due to aIUGR [75,76]. These data indicate that aIUGR induces a structural and functional acceleration of the development of skeletal muscles. We suggest that the improved tolerance to fatigue during repeated isometric contractions indicates an improved oxidative capacity. 2.3. Effect of aIUGR on cerebrovascular autoregulation and brain dopaminergic activity The perinatal morbidity and mortality of neonates after aIUGR is mainly caused by post-asphyxial encephalopathy [4]. The most dangerous complication is brain injury

Fig. 3. Upper panel: force development during repeated isometric contractions of hindlimb plantar flexors: force development of the first (closed columns) and last (open columns) isometric contractions of a series of 21 nerve stimulations in newborn NW (n ¼ 9) and aIUGR (n ¼ 9) piglets anesthetized with thiopental. Middle panel: percentage of force reduction between the first and last isometric contractions (as an indicator of muscle fatigue). Lower panel: specific muscle tension (N cm2) in NW and aIUGR piglets. Bars and whiskers are mean þ S:D. (*) indicates P < 0:05 for differences between NW and aIUGR piglets (modified from [75], with permission).

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secondary to hypoxic–ischemic disease, which is the predominant form of all brain injuries encountered in the perinatal period [84]. Periods of arterial hypotension are frequently involved in the initial period of acute perinatal asphyxia [85]. Cerebrovascular autoregulation protects against brain hypoperfusion provided arterial pressure does not fall below the lower limit of the autoregulatory range. The efficiency of autoregulation to prevent hypoperfusion generally improves with increasing fetal age and maturity of the brain [86–88]. This implies that the immature brain is susceptible to ischemia during hypotension [89], or more accurately, during reduced cerebral perfusion pressure (CPP, difference between arterial blood pressure and intracranial pressure). Therefore, poor autoregulation may place the immature brain at risk for injury [90,91]. We studied the effects of stepwise decrease of the cerebral perfusion pressure by hemorrhagic hypotension while the pressure of the sagittal sinus remained unchanged (methodological details are given in [92,93]). During hemorrhagic hypotension different responses of cerebrovascular autoregulation in various brain regions became evident. Whereas in the brainstem cerebral blood flow (CBF) remained unaltered in NW piglets, and even increased in aIUGR animals, a marked decrease of CBF in the cortex occurred with moderate and severe CPP reduction in NW piglets (Table 2). However, aIUGR piglets were able to withstand a moderate CPP reduction (about 58% of baseline) and autoregulation failed only when CPP was severely reduced (about 46% of baseline). Therefore, autoregulation in the brain cortex has a lower threshold in aIUGR piglets than in NW animals. A similar response was shown for forebrain oxygen uptake. Causal mechanisms for these differences are unknown. It seems that aIUGR newborns are more capable of protecting some brain regions against hypoperfusion during hypotensive periods than NW neonates. The importance of the intrauterine environment for fetal brain development has been demonstrated by earlier

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animal studies which showed persistent behavioral abnormalities when the fetuses were subjected to maternal environmental perturbances, such as maternal noise and light stress [94,95]. In humans, aIUGR is associated with an increased incidence of mild to moderate behavioral disturbances [96–98]. Dopamine as a major neurotransmitter in the mammalian central nervous system (CNS) plays a pivotal role in its maturation and differentiation [99,100]. Various perinatal disorders, such as germinal matrix hemorrhage, asphyxia and aIUGR appear to modify the levels of monoamines including dopamine in various brain regions, and postnatal behavioral abnormalities thus may be related to alterations in the central dopaminergic activity of the fetus [97,101]. Recently, it has been shown that aIUGR induces a marked increase in metabolic activity of the mesostriatal and telencephalic dopaminergic systems [102]. An up-regulation of brain aromatic amino acid decarboxylase activity (AADC, a key enzyme of dopamine metabolism) in newborn aIUGR piglets, measured by positron-emission tomography and 18 FDOPA, indicates an increased functional activity in target regions of the dopaminergic network (Fig. 4). This is equivalent to an accelerated/premature maturation of the dopaminergic system owing to aIUGR [103,104]. The cause of AADC up-regulation is unknown, but evidence is available that maternal glucocorticoids may influence brain dopaminergic activity in aIUGR offsprings. As the concentration of circulating corticosteroids is several fold higher in the mother than in the fetus [105–107], protection of the fetus against maternal corticosteroids is normally achieved by an appropriate placental 11b-HSD activity, which rapidly converts active glucocorticoids to inactive metabolites [29,54,108]. For example, in pregnant swine it has been shown that maternal plasma cortisol did not differ (P ¼ 0:48) between 50 (70:2  7:4 ng ml1) and 100 days (62:4  5:8 ng ml1) of gestation (full gestational period: 114 days). Conversely, fetal cortisol increased (P ¼ 0:048) between 50 (8:5  2:5 ng ml1) and 100 days

Table 2 Effect of gradual cerebral perfusion pressure (CPP) decrease on regional cerebral blood flow (CBF) and forebrain oxygen uptake (CMRO2) in normal weight (NW) and asymmetrically intrauterine growth restricted (aIUGR) newborn piglets (n ¼ 7) Baseline

CPP-50

CPP-40

CPP-30

CBF brainstem (ml min1 100 g1)

NW aIUGR

67  19 50  16

68  16 85  32

72  13 94  31a

66  24 69  23a

CBF brain cortex (ml min1 100 g1)

NW aIUGR

40  11 40  14

50  11a 56  26

27  5a,b 40  12

20  10a 21  13a

CMRO2 (ml O2 min1 100 g1)

NW aIUGR

2.9  0.9 2.9  1.2

3.4  0.9 3.4  1.1

1.8  0.7a 2.7  1.2

1.7  1.2a 1.3  0.6a

Animals were anesthetized and ventilated. CPP was altered (for 30 min at each CPP level) by stepwise controlled hemorrhagic decrease of the arterial blood pressure (ABP (mm Hg) (NW/aIUGR): baseline, 70  10=66  7; CPP-50, 51  4=47  3; CPP-40, 40  3=38  3; CPP-30, 31  4=28  3) while the intracranial pressure remained unchanged (methodological details in [92]). CBF was estimated by colored microspheres [117]. CMRO2 was calculated for the cerebral cortex, the cerebral white matter, the basal ganglia, the thalamus, and the hippocampus [118] as the product of forebrain CBF times arterial-venous (sagittal sinus) difference of oxygen content). Values are mean  S.D. a Differences compared with baseline (t-test, ANOVA for repeated measures). P < 0:05. b Differences between NW and aIUGR animals. P < 0:05.

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network comes from [18 F]FDOPA-PET studies on children with ADHD. Ernst et al. found recently an abnormally high accumulation of [18 F]FDOPA in the right midbrain, caudate, and putamen which indicates an unilateral increase in AADC activity of these brain regions [115]. These findings and our results from IUGR piglets suggest that cerebral regions which are dependent on midbrain dopamine input (striatum, prefrontal cortex, limbic structures) may be affected during their development in utero and could be involved in the development of ADHD [97].

3. Conclusions

Fig. 4. Increase of the rate constants for FDA production derived from conversion of 18 FDOPA to 18 Fdopamine by brain aromatic amino acid decarboxylase (AADC activity). AIUGR, growth restricted piglets (n ¼ 10); NW, normal weight piglets (n ¼ 10). Bars and whiskers are mean þ S:D. (*) indicates P < 0:05 for differences between NW and aIUGR piglets (modified from [102], with permission).

(24:2  4:2 ng ml1). Maternal cortisol accounted for 22:8  2:0% of fetal cortisol at 50 days of gestation, and this contribution decreased (P < 0:001) to 5:87  0:8% at 100 days. This marked fetal protection against maternal glucocorticoid administration may be different in IUGR pregnancies. For example, placental 11b-HSD activity is reduced in rats which are growth restricted by low-protein maternal diet [109], and a significant association was found between placental 11b-HSD activity and aIUGR in different species including man [53,107,110]. In addition, IUGR rats exhibited elevated activities of specific glucocorticoid-inducible marker enzymes in liver and brain [111], which suggests an increased glucocorticoid action in brain and liver. Long-term consequences of an increased prenatal glucocorticoid administration include an enhanced dopamine metabolism with concomitant short- and long-term neuronal and behavioral alterations [100,112]. There is some evidence that the attention deficit hyperactivity disorder (ADHD) syndrome, a common neurodevelopmental disorder, is also associated with abnormalities in the prefrontal [113] and striatonigral [114,115] dopaminergic systems. Direct evidence for the involvement of the dopamine

Asymmetric IUGR is associated with typical structural and functional changes in organs of the neonate. In skeletal muscles, development appears to be advanced (from type II to type I conversion, force development and fatigue tolerance are increased) and this applies also to the dopaminergic system in the brain (increased activity of AADC). In kidney, the number of nephrons is reduced and excretory function (GFR) is impaired. These changes provide the basis for disturbances which may emerge later in the adolescent and adult periods like arterial hypertension, chronic renal failure and ADHD. Somewhat surprisingly, aIUGR also induces in kidneys and the brain of newborns an improved ability to endure periods of oxygen deficit with maintenance of renal blood flow during severe systemic hypoxia and of cerebral blood flow during hemorrhagic hypotension.

Acknowledgements The authors thank Drs. E. Will and H. Linemann for their help during the PET studies and Mrs. U. Ja¨ ger, Mrs. R.-M. Zimmer, Mrs. R. Scholz, Mrs. R. Herrlich and Mr. L. Wunder for skillful technical assistance. The studies were supported by the Bundesministerium fu¨ r Bildung und Forschung, Bonn, Federal Government, Germany, Grants BMBF 01ZZ9104 (to R. Bauer), Thuringian State Ministry of Science, Research, and Arts, Grant 3/95-13 (to R. Bauer) and the Saxon Ministry of Science and Art, Grant 7541.82FZR/309 (to P. Brust).

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