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Regular Article |
a Departments of Physiology and
b Obstetrics and Gynaecology, Adelaide University, South Australia 5005, Australia
c Department of Physiology, University of New England, Armidale, New South Wales 2351, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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155% of maintenance requirements (well-fed, n = 8). The fetal fat depots (perirenal and interscapular) were dissected, and the relative proportion of unilocular and multilocular adipocytes in each depot was determined. Maternal plasma glucose and leptin concentrations were significantly increased in well-fed ewes. Fetal plasma glucose concentrations were also higher in the well-fed group (115–139 days gestation: control, 1.65 ± 0.14 mmol/L; well-fed, 2.00 ± 0.14 mmol/L; F = 5.76, P < 0.04). There was no effect of increasing maternal feed intake on total fat mass, the relative mass of unilocular fat, or fetal plasma leptin concentrations (115–139 days gestation: control, 5.2 ± 0.8 ng/ml; well-fed, 4.7 ± 0.7 ng/ml). However, in both the control and well-fed groups fetal plasma leptin concentrations (y) were positively correlated with the relative mass of unilocular fat (x): y = 1.51x + 1.70; (R = 0.76, P < 0.01). Thus, fetal leptin may play a role as a signal of unilocular fat mass in the fetus when maternal nutrient intake is at or above maintenance requirements.
leptin, pregnancy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the human newborn, there is a positive correlation between leptin concentrations in umbilical cord blood at delivery and either birth weight or neonatal adiposity [4–8]. In pregnancies complicated by maternal diabetes, the fetus is hyperglycemic and hyperinsulinemic, and there is an increase in cord blood leptin concentrations that is associated with an increase in infant adiposity [9, 10]. Exposure to maternal diabetes mellitus, gestational diabetes, or mild maternal glucose intolerance during fetal life is also associated with a higher risk of childhood obesity [11]. Although there is considerable interest in the mechanisms whereby exposure to an increase in fetal substrate supply may program postnatal obesity, there have been no studies of the impact of an increase in maternal nutrient intake on adiposity and circulating leptin concentrations before birth. In the adult, leptin is expressed at higher levels in white adipocytes, which characteristically have one dominant lipid locule, than in brown adipocytes, which are multilocular and contain an abundance of mitochondria [12]. In the sheep fetus, fat depots are comprised of both unilocular and multilocular adipocytes [13], although the relative proportion of these cell types in fetal adipose tissue during late gestation is unknown. The aim of the present study was to determine whether a moderate increase in maternal nutrient supply in late gestation would increase fetal leptin concentrations and increase the amount or alter the composition of fetal adipose tissue.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All procedures were approved by the Adelaide University Animal Ethics Committee. Singleton pregnancies were confirmed in 14 adult Merino ewes by ultrasound scanning in early gestation. Surgery was then performed on these ewes between 103 and 113 days gestation (term = 147 ± 3 days) under aseptic conditions. General anesthesia was induced by i.v. injection of sodium thiopentone (1.25 g, Pentothal; Rhone Merieux, Pinkenba, Qld, Australia) and maintained with 2.5–4% halothane (Fluothane; ICI, Melbourne, Vic, Australia) in oxygen. Vascular catheters were implanted in a jugular vein and carotid artery of the ewe and fetus and in the amniotic cavity as previously described [14]. During surgery, i.m. injections of antibiotics (2 ml 250 mg/ml procaine penicillin, 250 mg/ml dihydrostreptomycin, 20 mg/ml procaine hydrochloride; Lyppards, Adelaide, SA, Australia; or 0.1 ml/kg live weight Terramycin 100, 100 mg/ml oxytetracycline hydrochloride; Pfizer, NSW, Australia) were administered to each ewe and fetus. All catheters were filled with heparinized saline, and the fetal catheters were exteriorized through an incision in the ewe's flank.
Before and after surgery, the ewes were housed in individual pens in animal holding rooms with a 12L:12D cycle. Ewes were allowed at least 3 days to recover from surgery prior to experimentation.
Food
Each ewe was weighed upon admission to the animal housing facility (103–106 days gestation) and was fed twice daily at 0900 and 1600 h, with water provided ad libitum. Between 103 and 114 days gestation, ewes were fed a diet consisting of lucerne chaff (85% dry matter, metabolizable energy [ME] content = 8.3 MJ/kg) and concentrated pellets containing straw, cereal, hay, clover, barley, oats, lupine, almond shells, oat husks, and limestone (90% dry matter, ME content = 8.0 MJ/kg; Johnsons and Sons, Kapunda, SA, Australia). The diet was calculated to provide 100% of the energy requirements for the maintenance of a pregnant ewe bearing a singleton fetus, as specified by the U.K. Ministry of Agriculture, Fisheries and Food [15].
At 115 days gestation, i.e., prior to the commencement of the rapid fetal growth phase in late gestation [16], ewes were randomly assigned to either a control (n = 6) or well-fed (n = 8) group. Maternal weight at 103–106 days gestation was not different between the control and well-fed groups (control, 52.3 ± 1.6 kg; well-fed, 51.7 ± 2.4 kg). Between 115 and 124 days gestation, control ewes were provided with 19.0 ± 1.1 g of lucerne chaff and 4.7 ± 0.3 g of pelleted concentrate per kilogram of body weight and well-fed ewes were provided with 29.6 ± 2.6 g lucerne chaff and 7.4 ± 0.8 g pelleted concentrate per kilogram of body weight. All food not eaten was weighed daily. The total ME intake for the well-fed group (0.26 ± 0.02 MJ kg-1 day-1) was 55% greater than the total ME intake in the control group (0.17 ± 0.01 MJ kg-1 day-1). The feed allowance of all ewes was proportionately increased by 15% every 10 days to meet the increasing substrate demands of the growing fetus in late gestation [15].
Blood Sampling
Between 116 and 139 days gestation, maternal (5.0 ml) and fetal (3.0 ml) arterial blood samples were collected three times per week prior to morning feeding at 0900 h. Blood samples were centrifuged at 1500 x g for 10 min at 4°C, and plasma was stored at -20°C for subsequent glucose and hormone assays. Fetal arterial blood (0.5 ml) was also collected three times per week for determination of fetal blood gases (PO2, PCO2), oxygen saturation, pH, hematocrit, and hemoglobin using an ABL 520 analyzer (Radiometer, Copenhagen, Denmark).
Postmortem Examination and Tissue Collection
Between 139 and 141 days gestation, all ewes were killed with an overdose of sodium pentobarbitone (Virbac Pty Ltd, Peakhurst, NSW, Australia). All fetuses (control, two females and four males; well-fed, five females and three males) were alive at the postmortem examination. Fetal sheep were delivered by hysterotomy, weighed, and killed by decapitation. All fetal adipose tissue was dissected from the perirenal and interscapular sites and weighed, and a sample from each site was fixed in 4% paraformaldehyde in 0.2 M PBS for subsequent processing and histological analyses. Individual placentomes were also dissected from the placental membranes and weighed. The gross morphology of each placentome was characterized as type A, B, C, or D based on previously defined macroscopic features [17].
Glucose Assay
Maternal and fetal plasma glucose concentrations were determined by enzymatic analysis using the COBAS MIRA automated analysis system (Roche Diagnostica, Basel, Switzerland), which was previously validated for sheep plasma [18]. The intra- and interassay coefficients of variation were both <5%.
Insulin RIA
Insulin concentrations were determined in fetal plasma samples (control, 52 samples; well-fed, 84 samples) using an RIA kit (Phadaseph radioimmunoassay kit; Pharmacia & Upjohn, Uppsala, Sweden) previously validated for sheep plasma [18]. The detection range of the assay was 1.5–240 U insulin/ml. The intra- and interassay coefficients of variation were both <20%.
Leptin Assay
A competitive ELISA previously validated for sheep plasma [19] was used to determine plasma leptin concentrations in maternal (control, 56 samples; well-fed, 77 samples) and fetal (control, 49 samples; well-fed, 84 samples) plasma samples. An ELISA plate was preincubated with recombinant bovine leptin in 50 µl 0.1 M bicarbonate buffer and blocked with 200 µl 5% skim milk in ELISA buffer. Biotinylated chicken anti-recombinant bovine leptin antiserum (50 µl) was added to the wells, followed by the addition of samples (100 µl) in duplicate. Following an overnight incubation at 37°C, the plate was washed, and alkaline phosphatase-strepavidin conjugate (Amrad Biotech, Boronia, Vic, Australia) was added. The plate was incubated for 1 h, and the result was developed with p-nitrophenylphosphate disodium salt hexahydrate. The sensitivity of the assay was 0.5 ng/ml, and the inter- and intraassay coefficients of variation were 10.9% and 8.8%, respectively.
Adipose Tissue Histology
Samples of perirenal and interscapular adipose tissue were immersion fixed in 4% paraformaldehyde in 0.2 M PBS at 4°C for a minimum of 3 days. Tissues were then washed in 0.01 M PBS and immersed in 70% ethanol for 24 h before being processed and embedded in paraffin. Sections were cut (4 µm), stained with hematoxylin and eosin and examined using an Olympus BH2 microscope (20x objective). Standard point counting techniques, as first described by Weibel [20], were used with Video Image Analysis using Video Pro software (Leading Edge, Adelaide, SA, Australia) to determine the volume density of unilocular and multilocular cells in the perirenal and interscapular depots for each animal. A Merz grid was used to determine the adipose tissue component (unilocular adipose cell or multilocular adipose cell) falling below each of the 36 grid points. For each adipose tissue site, one section was randomly selected for each animal, and the adipose tissue component falling below each of the 36 points in each of 10 fields 1 mm apart (a total of 360 points/animal) was determined. The volume density (Vd) of unilocular and multilocular cells in the adipose tissue depots was calculated as described previously [21]: Vd = N/T, where N is the number of points falling on unilocular or multilocular cells, and T is the total number of points counted. The mass of the unilocular and multilocular component for each fat depot was calculated by multiplying the mass of each fat depot by the volume density of unilocular or multilocular cells within that depot. Total unilocular fat mass was then calculated as the sum of unilocular fat mass of the interscapular and perirenal depots. The relative unilocular fat mass (g/kg) was calculated by dividing the total unilocular fat mass by fetal weight.
Statistical Analysis
Data are presented as the mean ± SEM. The effect of nutritional treatment on fetal arterial blood gases, measures of placental and fetal growth, and fat mass were determined using a one-way ANOVA. The effects of increasing maternal nutrient intake on maternal plasma glucose and leptin concentrations were analyzed by multifactorial ANOVA with repeated measures using the Statistical Package for Social Sciences (SPSSX) on a VAX mainframe computer. Specified variables for the ANOVA were nutritional treatment, fetal gestational age (in 5-day blocks), and animal. The effect of nutritional treatment on mean placentome weight was also determined using a multifactorial ANOVA with placentome type (A, B, C, or D), nutritional treatment, and animal as the specified variables. Effects of nutritional treatment and gestation on fetal plasma glucose, insulin, and leptin concentrations were similarly determined. Where required, data were log transformed to reduce heterogeneity of variance. In the instance where a fetal plasma sample was not available at a particular sampling time point, such as 139 days gestation, because of catheter blockages, etc., fetuses were not included in correlation analyses. Correlations between mean maternal plasma leptin and glucose concentrations were determined using linear regression analyses. Correlations between fetal plasma leptin and glucose or insulin concentrations and between fetal plasma leptin and relative total fat mass or unilocular fat mass were also determined using linear regression analyses. A probability of 5% (P < 0.05) was taken as the level of significance in all analyses.
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RESULTS |
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Plasma concentrations of glucose were higher in the well-fed ewes than in the control ewes between 115 and 141 days gestation (control, n =5; well-fed, n = 7; F = 7.80, P < 0.05), and there was no change in maternal glucose with increasing gestational age in either treatment group (Fig. 1A). There was no difference between the well-fed and control groups in maternal plasma leptin concentrations between 115 and 120 days gestation (i.e., during the first 5 days after the start of the feeding regime). Plasma leptin concentrations were higher (control, n = 5; well-fed, n = 7; F = 5.09, P < 0.05), however, in the well-fed ewes than in the control ewes between 121 and 141 days gestation (Fig. 1B).
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Fetal Arterial Blood Gas Status and Plasma Glucose and Insulin Concentrations
There was no difference in fetal arterial PO2 (control, 22.8 ± 0.6 mm Hg; well-fed, 21.8 ± 0.4 mm Hg), PCO2 (control, 49.9 ± 0.7 mm Hg; well-fed, 51.0 ± 0.9 mm Hg), or pH (control, 7.39 ± 0.002; well-fed, 7.39 ± 0.005) between the well-fed and control groups throughout late gestation. Fetal plasma glucose concentrations were higher (F = 5.76, P < 0.04) in the fetuses of well-fed ewes compared with those of controls between 115 and 141 days gestation (Fig. 2A). Fetal plasma insulin concentrations were not significantly different between the control and well-fed groups during late gestation (control, 7.9 ± 1.1 µU/ml, n = 5; well-fed, 9.8 ± 1.4 µU/ml, n = 8).
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Fetal Fat Mass and Leptin Concentrations
There was no difference between the control and well-fed groups in the proportions of fetal unilocular or multilocular cells in either perirenal fat (unilocular: control, 40.3% ± 6.1%; well-fed, 44.6% ± 2.9%; multilocular: control, 57.9% ± 3.8%; well-fed, 52.4% ± 2.8%) or interscapular fat (unilocular: control, 46.3% ± 9.2%; well-fed, 54.3% ± 3.1%; multilocular: control, 50.0% ± 9.3%; well-fed, 38.6% ± 2.7%). Increasing maternal nutrient intake did not alter the total or relative mass of perirenal and interscapular fat or the mass of unilocular or multilocular fat present within these depots (Table 1). Similarly, there was no effect of either increased maternal nutrient intake or gestational age on the fetal plasma concentrations of leptin (Fig. 2B). There was, however, a significant positive correlation between plasma leptin concentration and the relative mass of fat in each fetus: plasma leptin = 1.07 (relative fat mass) - 0.69 (R = 0.65, P < 0.05, n = 11). There was also a positive correlation between plasma leptin concentration and the relative mass of unilocular fat, but not multilocular fat, in each fetus: plasma leptin = 1.51 (relative mass of unilocular fat) + 1.70 (R = 0.76, P < 0.01, n = 11) (Fig. 3). In contrast, there was no relationship between fetal plasma insulin concentrations and either the relative mass of fat or the relative mass of unilocular fat in each fetus. There was no difference in plasma leptin concentrations between male and female fetuses across late gestation (male, 4.8 ± 0.4 ng/ml; female, 5.2 ± 0.6 ng/ml) or at 139 days gestation (male, 5.3 ± 0.7 ng/ml; female, 4.5 ± 1.2 ng/ml).
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Placental and Fetal Growth
The mean weights of each of the type A, B, and C placentomes were greater (control, n = 6; well-fed, n = 8; F = 5.90, P < 0.05) in the well-fed ewes than in the control group (Table 2). The mean weight of type D placentomes was not different (P = 0.09) between the control and well-fed groups (Table 2). There was no difference in placentome number or the proportion of each placentome type between the well-fed and control groups. There was no effect of increased maternal nutrient intake on fetal or organ weights or fetal crown-rump length (Table 3). Fetal body weight was, however, positively correlated with mean fetal plasma insulin concentrations between 131 and 139 days gestation when the data from both groups were combined: fetal weight = 0.19 (plasma insulin) + 2.91 (R = 0.69, P < 0.02, n = 12) (Fig. 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, the increase in maternal nutrient intake during late pregnancy resulted in an increase in maternal plasma glucose and leptin concentrations. Thomas and colleagues [22] recently reported that when the dietary intake of adolescent pregnant ewes was increased from a moderate to a high plane at Day 50 of pregnancy, maternal plasma leptin concentrations increased within 48 h and that 50–90 days after the change in diet, circulating leptin concentrations in the ewe were correlated with indices of maternal body composition. These findings indicate that circulating leptin concentrations in both the pregnant and nonpregnant [2, 3] sheep are dependent on both body fat content and current nutritional intake.
Wallace and colleagues [23, 24] reported that overfeeding of the adolescent pregnant ewe promotes maternal growth at the expense of placental and fetal development. In this model, there was a negative correlation between maternal plasma leptin concentrations and placental and fetal size [22]. This finding is in contrast to that in the present study of well-fed mature ewes in which an increase in maternal leptin concentrations was not associated with a decrease in either placental or fetal weight. If maternal leptin plays a role in placental or fetal adaptations to an increase in maternal nutrition, then this role must be secondary to other maternal hormonal and metabolic responses in the adolescent and mature ewe.
In the pregnant ewe, the number of placentomes is generally considered to be constant from around 30 days of gestation, whereas placental growth increases to reach a maximum at 75–90 days gestation [25]. Previous studies have established that there is a decrease in placentome weight from around 110–120 days gestation in pregnant sheep fed maintenance diets [26]. In the present study, the mean weights of the type A, B, and C placentomes were consistently increased by around 1–3 g in the well-fed group, which suggests that an increase in maternal nutrient supply may reverse this normal gestational decline in placentome weight. The impact of the increase in maternal nutrition appeared relatively constant across all placentome types, although the change in the mean weight of the small number of type D placentomes present in each of the treatment groups failed to reach significance. Although there was no significant increase in fetal body weight in the well-fed group, there was a trend toward a decrease in the fetal:placental weight ratio in the well-fed ewes. This finding suggests that there was a preferential uptake of the increased substrate supply by placental rather than fetal tissues during the period of overnutrition.
Increasing maternal feed intake in late pregnancy resulted in an 20% increase in fetal glucose concentrations in the absence of any change in fetal plasma leptin concentrations. Furthermore, there was no relation between either fetal glucose or fetal insulin concentrations and circulating leptin concentrations in the normally fed and well-fed ewes during late gestation. A major finding of the present study is that although fetal leptin was less sensitive than glucose to a moderate increase in maternal nutrient intake, there was a significant correlation between fetal leptin concentrations and fetal adiposity in this cohort of pregnant ewes. These results support the conclusion that circulating leptin concentration may be a signal of fat mass in fetal life, as it is in the neonate [8] and adult [27].
In contrast to human neonates, in which umbilical cord blood leptin concentrations are higher in females than in males [28, 29], we did not identified any sex-based differences in plasma leptin concentrations in fetal sheep in ewes fed either at or above maintenance energy requirements. This species difference may be related in part to the higher proportion of body fat in the human than in the sheep fetus in late gestation [16].
Fetal plasma leptin concentrations were correlated most strongly with the relative mass of unilocular adipose tissue, suggesting that unilocular adipocytes may be the principal source of leptin in the fetal circulation in sheep. In adults, unilocular adipocytes are white adipose cells and are the major sites of lipid storage and of leptin synthesis [12]. Ultrastructural studies have demonstrated, however, that both unilocular and multilocular cells within fetal adipose tissue contain an abundance of mitochondria, a characteristic feature of thermogenic or brown adipose tissue [13]. In fetal life, the unilocular adipocyte may be a transitional cell type that has both the lipid storage and thermogenic characteristics of white and brown adipocytes, respectively. Although leptin mRNA is expressed in fetal sheep adipose tissue [30], it is not clear to what extent leptin is expressed in either unilocular or multilocular adipocytes. Further work is required to determine the relative roles of these adipose cell subtypes within fetal adipose tissue.
Although placental leptin production contributes to fetal plasma leptin concentrations in humans and rodents [31, 32], leptin is expressed at low levels in the sheep placenta [22]. Thus, fetal plasma concentrations of leptin probably are derived predominantly, if not exclusively, from fetal tissues.
The significant relationship between fetal fat stores and leptin concentrations in the fetal circulation indicates that leptin may act as a signal of fetal adiposity. In the adult, leptin acts centrally via receptors within the hypothalamus and caudal brain stem to induce satiety and increase energy expenditure to counteract increases in energy intake [1, 33, 34], thereby acting as a potent adipostat. The leptin receptor is expressed in the fetal hypothalamus [35], and leptin may therefore play a role in the central regulation of fetal energy balance. Because fetal nutrients are supplied by transplacental transfer from the maternal circulation [36], the predominant actions of leptin on fetal energy balance are presumably mediated via an increase in endogenous energy expenditure. Uncoupling proteins (UCPs), which mediate increases in endogenous energy expenditure in the adult [37] and neonatal [38] lamb, are expressed in the perirenal adipose tissue of the fetal sheep in late gestation [39]. UCP abundance is higher in perirenal fat in fetuses of ewes fed above maintenance requirements in late pregnancy, but fetal leptin concentrations were not measured in this study [40].
Although fetal plasma glucose concentrations were increased in well-fed ewes throughout late pregnancy, there was no corresponding increase in fetal fat mass at 139–141 days gestation. This finding is in contrast with the increased adiposity reported at term in the fetal sheep made chronically hyperglycemic by intrafetal glucose infusion in late gestation [41]. The accumulation of adipose tissue in the hyperglycemic fetus has been attributed to the lipogenic actions of insulin [42]. In the present study, however, fetal insulin concentrations were positively correlated with fetal weight but there was no relationship between fetal insulin concentrations and relative fat mass. This finding suggests that in the well-nourished growing fetus any increase in fetal nutrient supply is directed proportionally to nonadipose and adipose tissues. A disproportionate increase in fetal adiposity may occur if there is a substantial increase in fetal nutrient supply above that generated by a moderate increase in maternal nutrient intake. Alternatively, an increase in fetal lipogenesis may be dependent on an alteration in the relative abundance of circulating substrates, such as glucose, and mediators of substrate uptake, such as insulin. In humans, maternal diabetes mellitus, gestational diabetes, or even mildly impaired glucose tolerance during pregnancy are all risk factors for fetal macrosomia and an increase in fetal adiposity [10, 43]. In one long-term study of infants of diabetic mothers, 50% of newborn infants had weights that placed them above the 90th percentile for gestational age, and by 8 yr of age, half of the group whose mothers were diabetic in pregnancy had weights that placed them above the 90th percentile [11]. Further work is needed to identify those periods in intrauterine life when an increase in nutrient supply initiates changes in the development of the adipocyte and leptin signaling systems that underlie the association between altered fetal nutrient supply and postnatal obesity.
A moderate increment in maternal nutrient intake above maintenance requirements increases maternal leptin concentrations and mean placentome weight. Although there was no concomitant increase in fetal fat mass or in fetal plasma leptin concentrations, there was a significant relation between the relative mass of the unilocular component of perirenal and interscapular fat and circulating leptin concentrations in both control and well-fed ewes. Thus, fetal leptin may play a role as a signal of unilocular fat mass in the fetus when ewes are fed at or above maintenance energy requirements during late pregnancy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by the National Health and Medical Research Council. 
2 Correspondence. FAX: 61 8 8 303 3356; caroline.mcmillen{at}adelaide.edu.au
Accepted: February 27, 2002.
Received: December 5, 2001.
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