Nutritional Modulation of Adolescent Pregnancy Outcome – A Review

Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20 doi:10.1016/j.placenta.2005.12.002

Nutritional Modulation of Adolescent Pregnancy Outcome – A Review J. M. Wallacea,*, J. S. Luthera,b, J. S. Milnea, R. P. Aitkena, D. A. Redmerb, L. P. Reynoldsb and W. W. Hay Jrc a Development, Growth and Function Division, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, UK; b North Dakota State University, Fargo, ND 58105, USA; c Perinatal Research Center, University of Colorado Health Sciences Center, Aurora, CO 80045, USA Paper accepted 6 December 2005

The risks of miscarriage, prematurity and low birth weight are particularly acute in adolescent girls who are still growing at the time of conception. The role of maternal nutrition in mediating pregnancy outcome in this vulnerable group has been examined in sheep models. When singleton bearing adolescent dams are overnourished to promote rapid maternal growth throughout pregnancy, growth of both the placenta and fetus is impaired, and birth occurs prematurely relative to control adolescents of equivalent age. Studies at mid-gestation, prior to alterations in placental mass, suggest that reduced proliferation of the fetal trophectoderm, impaired angiogenesis, and attenuated uteroplacental blood flows are early defects in placental development. By late pregnancy, relative placental mass is reduced by 45% but uteroplacental metabolism and placental glucose transfer capacity remain normal when expressed on a placental weight specific basis. The asymmetrically growth-restricted fetuses are hypoxic, hypoglycemic and have reduced insulin and IGF-1 concentrations. Absolute umbilical nutrient uptakes are attenuated but fetal utilisation of glucose, oxygen and amino acids remains normal on a fetal weight basis. This suggests altered sensitivities to metabolic signals and may have implications for subsequent metabolic health. At the other end of the nutritional spectrum, many girls who become pregnant have inadequate or marginal nutritional status during pregnancy. This situation is replicated in a second model whereby dams are prevented from growing during pregnancy by relatively underfeeding. Limiting maternal intake in this way gradually depletes maternal body reserves leading to a lower transplacental glucose gradient and a modest slowing of fetal growth in late pregnancy. These changes appear to be independent of alterations in placental growth per se. Thus, while the underlying mechanisms differ, maternal intake at both ends of the nutritional spectrum is a powerful determinant of fetal growth in pregnant adolescents. Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20 Crown Copyright Ó 2005 Published by IFPA and Elsevier Ltd. Keywords: Adolescent pregnancy; Nutrition; Placental growth; Fetal growth

INTRODUCTION Each year, 15 million adolescents aged less than 19 years give birth, accounting for up to one-fifth of all births worldwide [1]. Although in some industrialised nations the incidence of pregnancy in adolescent girls appears to be slowly declining, the USA still has the highest rate of adolescent pregnancy in the developed world, while the rate in the UK is the highest in Western Europe (43.0 and 30.2 births per 1000 women aged !19 years, respectively [2]). In both cases, this corresponds to one in every 10 babies being born to an adolescent mother. This continues to be a major cause for concern as these pregnancies are associated with a variety of negative outcomes for both mother and child. The most serious and immediate of these include an increased risk of premature delivery, low birth * Corresponding author. Tel.: C44 1224 716665. E-mail address: [email protected] (J.M. Wallace). 0143e4004/$esee front matter

weight, neonatal and infant mortality and maternal death [3,4]. In the longer term, the offspring of adolescent mothers are variously reported as having poorer cognitive development, lower educational attainment, more frequent criminal activity, and a higher risk of abuse, neglect and behavioural problems during childhood [5]. Clearly a biologicalesocial interaction can be assumed and the increased risk of adverse pregnancy outcome in this vulnerable section of society has variously been attributed to poor socio-economic status, gynaecological immaturity and the growth and nutritional status of the mother [6]. SOCIAL DEPRIVATION In the UK, poverty is certainly a significant risk factor for becoming pregnant during adolescence since rates are up to six times higher in socially deprived areas [7]. Indeed, many of the antecedents of adolescent pregnancy are strongly linked to Crown Copyright Ó 2005 Published by IFPA and Elsevier Ltd.

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socio-economic status and include early sexual activity, poor knowledge of reproductive health, low educational expectations and attainment, age of partner, parental illiteracy, sexual or domestic abuse, substance abuse, disrupted or nonexistent family structure, family history of early childbearing (mother and siblings) and ethnicity [4,5,7]. While there is some evidence that targeted prenatal care programmes can partially ameliorate the rate of preterm births in adolescents [8], the effects on the incidence of low birth weight are equivocal [8,9] suggesting that other biological factors predominate. GYNAECOLOGICAL IMMATURITY There is compelling evidence that gynaecological immaturity predisposes adolescent girls to poor pregnancy outcome. Within the adolescent population per se, the rates of spontaneous miscarriage and very preterm birth (!32 weeks) are highest in girls aged 13e15 years [10,11]. Moreover, when only term births between 39 and 41 weeks of gestation are analysed, very young mothers (12e16 years) have lighter (P ! 0.001) and smaller infants than both older adolescents (17e19 years) and adult women (20e29 years, [12]). Very young mothers also have a higher risk of delivering a growthrestricted infant weighing less than 2500 g (11.3% and 8.9% in adolescents aged !15 years and 19 years, respectively, [2]). Pregnancy related complications are the major cause of death in the female adolescent population [13,14] with adolescent mothers being twice as likely to die during pregnancy compared with mature women. In very young girls the risk of maternal mortality is fourfold higher than in the women aged 20e24 years [15] and is partially attributed to obstetrical complications arising from incomplete growth of the mother. GROWTH AND NUTRITIONAL STATUS There is evidence that both the growth and nutritional status of the mother may play an important and potentially modifiable role in adolescent pregnancy outcome. Many adolescent girls retain the potential to grow while pregnant and data from the Camden Study in New Jersey (one of the poorest cities in the USA) have shown using a knee height measuring device that almost 50% of adolescents (mean age at delivery: 16.5 years) continue to grow while pregnant [16,17]. This growth is associated with larger pregnancy weight gains, increased fat deposition and greater post-partum weight retention than for non-growing adolescents and mature women. Counter-intuitively, birth weight is significantly reduced in the growing adolescents and is attributed to a competition for nutrients between the maternal body and her gravid uterus. Sub-optimal dietary intakes are commonplace in sections of the general adolescent population and many adolescent girls may be at risk of becoming pregnant with inadequate nutrient stores [18]. Irrespective of maternal age, both low maternal weight and low weight gain during the first trimester (proxy measures of poor nutritional status) have recently been associated with reduced placental growth and

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fetal size [19]. Within adolescents, the youngest mothers with the smaller babies are themselves smaller and lighter than their older and more biologically mature counterparts although relative weight gain is highest in the youngest age group [12]. Thus, the relationship between nutritional status and pregnancy outcome is complex when pregnancy coincides with the continued or incomplete growth of the mother. It is against this background that we have developed highly controlled ovine models to specifically examine the role of maternal nutrition in mediating pregnancy outcome in the growing adolescent. Relative to the human, the pregnant sheep offers distinct advantages over other animal models; these include the ability to study singleton pregnancies, comparable birth weight, similar organogenesis for all major organ systems and equivalent rates of fetal protein accretion relative to maternal weight. Furthermore, sheep have a relatively long gestation length and when required the mother and fetus can be catheterised to measure fetal endocrine status, nutrient uptakes and metabolism. ADOLESCENT SHEEP MODELS The basic experimental model involves using a single sire and embryo transfer techniques to establish singleton pregnancies at day 4 of an induced oestrous cycle in pubertal adolescent ewes of equivalent age, live weight, and adiposity score (Figure 1). Care is also taken to randomise for recipient dam ovulation rate and the maternity of the embryo [20]. This approach controls for many of the peri-conceptual factors known to influence feto-placental growth and maximises the genetic homogeneity of the resulting fetuses. Nutritional treatments commence immediately after embryo transfer and predominately involve offering different levels of the same complete diet (supplying 10.2 MJ metabolizable energy and 140 g crude protein per kg dry matter). Two contrasting nutritional perturbations have been developed (Figure 1). The first, and to date most intensively studied model, involves overnourishing the adolescent dam to promote rapid maternal growth (ad libitum intakes equivalent to approximately twice maintenance energy requirements). In contrast, in the second model adolescent dams are prevented from growing during pregnancy by relatively undernourishing (approximately 0.70! maintenance). The control group for both models involves offering a moderate quantity of the diet calculated to maintain normal maternal adiposity throughout gestation and hence meet the estimated metabolizable energy requirements for optimum conceptus growth and pregnancy outcome in this genotype. In practice this means step wise increasing maternal intake in control dams during the final third of gestation. PREGNANCY OUTCOME IN RAPIDLY GROWING ADOLESCENTS Overnourishing adolescent sheep to promote rapid maternal growth results in major placental and fetal growth restriction as assessed during late gestation [21,22] and following spontaneous

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Ovine Adolescent Paradigms Superovulated Donor Ewe Intrauterine Insemination (single sire) Multiple Embryos Recovered Synchronous transfer of a single embryo

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Figure 1. Ovine adolescent paradigms in relation to maternal live weight changes and fat deposition throughout gestation. Singleton bearing adolescent dams were offered a high (C), moderate-control (B) or low (:) dietary intake throughout pregnancy.

delivery at term [20,23]. At both time-points, placental mass and fetal weight are highly correlated within both rapidly growing and control groups. Recent analyses of multiple and identical studies using this paradigm indicate that an average of 52% of rapidly growing dams produce fetuses categorised as markedly growth restricted at term [23]. For these pregnancies both average placental mass and fetal weight are reduced by 48% relative to the control group. In contrast in the remaining pregnancies the relative reduction in placental and fetal weights are 23% and 10.5%, respectively. While the latter pregnancies clearly represent a much less perturbed cohort, both placental and fetal weights remain significantly (P ! 0.001) lower than in the control group. This alteration in nutrient partitioning appears to be unique to the young adolescent in that it does not occur in overnourished primiparous adult sheep studied under identical experimental conditions [24]. Overnourishing young pregnant adolescent sheep is also associated with an increased incidence of non-infectious

spontaneous abortion or stillbirth in late gestation. Low or absent secretion of pregnancy-specific protein B by the binucleate cells of the placenta implies that this is preceded by severe placental insufficiency during mid-gestation [25]. This feature of the model appears to be particularly acute when very young adolescent animals are used. This indicates an interaction between overnutrition and gynaecological age and mirrors the higher rates of spontaneous miscarriages reported in extremely young human adolescents [10]. Growth restriction in the rapidly growing sheep dams is also characterised by a consistent and significant reduction in mean gestation length of approximately 3 days, with viable lambs being born as early as day 135 of gestation (mean gestation length Z 145.2 G 0.25 days in 85 control ewes [20,23]). In general, within the overnourished group, gestation length is shortest in the most severely growth-restricted fetuses (141.2 G 0.44 compared with 142.7 G 0.30 days in the less perturbed cohort, P ! 0.01, n Z 51 and 46 pregnancies per

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category, respectively). This is also reflected in the positive correlation between gestation length and birth weight when the overnourished group is considered as a whole (r Z 0.335, n Z 97, P ! 0.001). The mechanisms underlying premature parturition in these rapidly growing adolescents have not been examined in detail but may be initiated by the previously documented nutritionally induced alterations in placental hormone secretion (primarily progesterone [25,26]). Additionally, in the most severely perturbed pregnancies, placental insufficiency resulting in fetal hypoxia and hypoglycemia (detailed below) may accelerate the maturation of the fetal hypothalamicepituitary-adrenal axis which is central to the initiation of parturition [27]. While the higher relative weight of the adrenal gland in growth-restricted fetuses autopsied at day 130 of gestation supports the latter concept, fetal cortisol concentrations do not appear to be perturbed [23,28]. Rapid maternal growth is also associated with a major reduction in the initial yield, nutrient composition and IgG content of colostrum accumulated prenatally (reviewed in Ref. [29]). Within the overnourished group, colostrum yield was lowest in the most severely growth-restricted pregnancies (148 G 13.3 compared with 235 G 17.3 ml in the less perturbed cohort, P ! 0.001, n Z 51 and 46 pregnancies per category, respectively). Relative to the control groups this represents a decrease in yield of 68% and 49%, respectively. These low colostrum yields immediately after parturition are closely associated with both the reduction in placental mass and attenuated lactogenic hormone secretion during the second half of gestation (growth hormone, progesterone, placental lactogen [29,30]). Failure to ingest sufficient quantities of quality colostrum in the early neonatal period makes low birth weight lambs vulnerable to hypothermia and infection. Indeed, at the outset of this project few of the most premature and growthrestricted individuals survived [20]. However, with meticulous neonatal care procedures the majority of these fragile neonates are now expected to survive to adulthood. PLACENTAL DEVELOPMENT AND UTEROPLACENTAL BLOOD FLOWS In the rapidly growing adolescent sheep, restricted placental development is clearly the primary limitation to fetal growth.

At day 81 of gestation, co-incident with the predicted apex in placental growth [31], the placentae of rapidly growing dams exhibit less proliferative activity in the fetal trophectoderm, increased protein level of bax (the pro-apoptosis gene product of the bcl-2 family) and reduced mRNA expression of several angiogenic growth factors/receptors including VEGF, Ang-1, Ang-2, eNOS and VEGFR-1 [32,33]. Furthermore, most of these parameters were negatively correlated with maternal live weight gain during the first half of gestation. These nutritionally-mediated changes in indices of proliferation, apoptosis and angiogenesis occur before differences in placental mass become apparent but clearly these placentae are already on a different haemodynamic and growth trajectory by mid-gestation. Indeed, we have recently demonstrated that uterine blood flow (measured using a Transonic flow probe) in the artery supplying the gravid uterine horn was reduced (P ! 0.001) in overnourished compared with control pregnancies, at wday 88 of gestation (Figure 2). Moreover, uterine flow at this early stage of gestation (day 88) was positively correlated (r Z 0.581, P ! 0.01) with fetal weight at term some 50 days later (JM Wallace, M Matsuzaki, JS Milne, RP Aitken, unpublished data). The mechanism whereby overnutrition influences the development and hence function of the adolescent placenta has not been elucidated. One possibility worthy of further examination is that nutritionally induced suppression of the major sex steroids in the overnourished dams may be influencing both uteroplacental angiogenesis and blood flow. Maternal progesterone concentrations are significantly attenuated throughout gestation in overnourished dams [25,26] and oestrogen concentrations are likely to be similarly affected. In addition, oestradiol upregulates expression of angiogenic factors in uterine endometrium [34], thus nutritional factors may affect steroid levels and hence influence angiogenic factor production. Irrespective of the specific mechanisms, by late gestation major reductions in absolute uterine (ÿ36%) and umbilical (ÿ37%) blood flows are evident. These reduced flows are in proportion to the observed reduction (ÿ45%) in total placentome mass in the rapidly growing compared with control pregnancies [22]. Alternatively, nutritionally-mediated alterations in the placental growth trajectory may reflect differences in circulating somatotrophic hormones. Insulin and insulin-like growth

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Figure 2. Uterine blood flow in the artery supplying the gravid uterine horn at wday 88 of gestation (a) and fetal weight at term, adjusted to day 145 of gestation (b), in singleton bearing adolescent sheep offered a control (n Z 9, ,) or high (n Z 10, -) dietary intake throughout pregnancy. Values are mean G sem. Unpublished results.

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IMPAIRED NUTRIENT SUPPLY AND FETAL DEVELOPMENT IN RAPIDLY GROWING ADOLESCENTS Statistically significant decreases in placental mass in rapidly growing adolescents do not become apparent until around day 100 of the 145-day pregnancy [20,38] and similarly the growth trajectory of the fetus is not perturbed until the final third of gestation. Figure 3 details the relationship between placental mass and fetal weight at day 130 of gestation. By late gestation, fetal weight is reduced by w30%, and while no major change in the allometric growth coefficients of the major organs per se has been detected, growth of the brain is somewhat preserved

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factor (IGF-1) concentrations are elevated from early in gestation in overnourished dams and provide a sustained anabolic stimulus to maternal tissue deposition [30]. The resulting progressive increase in adiposity (Figure 1) may compromise blood flow to the gravid uterus and hence compromise placental development. Maternal cardiac output during pregnancy normally increases by w70% in the sheep and results in a redistribution of the percentage of cardiac output going to the various organs, particularly the gravid uterus [35]. Clearly, both cardiac output and the partitioning of blood to the maternal versus gravid uterine tissues may be influenced by the increasing adiposity of the dams but this aspect has not yet been directly measured in the overnourished paradigm. In contrast to the high maternal insulin and IGF-1 levels, growth hormone (GH) concentrations are reduced in rapidly growing dams and positively associated with placental weight at term [30]. Furthermore, we have demonstrated that exogenous bovine GH (bGH) administration to overnourished dams throughout the period of placental proliferation (days 35e80) alters nutrient partitioning in favour of uteroplacental and fetal growth, as assessed at day 81 of gestation [36]. A recent study has determined whether these effects persist to term and investigated whether bGH influences fetal growth by increasing placental size per se or by altering maternal metabolism [37]. Exogenous GH was administered to overnourished high-intake dams between days 35 and 65 (early GH) or days 95 and 125 of gestation (late GH). Groups of high and moderate intake animals acted as contemporaneous controls and ewes were autopsied at day 130 of gestation. GH administration had a profound effect on maternal metabolism and significantly reduced various indices of maternal adiposity (% fat in maternal carcass, internal fat depots, plasma leptin concentrations), predominantly in the late GH group. In the latter group, the resulting increase in maternal glucose availability stimulated both fetal growth and fetal adiposity but was independent of the mass of the placenta. Thus, it appears that the still maturing somatotrophic axis of the rapidly growing adolescent dam is acutely sensitive to both nutrient intake and external hormone manipulation.

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Maternal Intake Figure 3. Relationship between total placentome mass and fetal weight (a) and fetal brain:liver weight ratio (b) at wday 130 of gestation in adolescent sheep offered a control (1! maintenance, n Z 34, B) or high (w2! maintenance, n Z 36, C) dietary intake throughout pregnancy. Data summarised from Refs. [21,22].

at the expense of the abdominal organs, resulting in a higher brain:liver weight ratio ([21,22]; Figure 3). In spite of the ready availability of nutrients in the maternal circulation (glucose, oxygen and amino acids [38e40]), the growthrestricted fetuses of overnourished dams are modestly but significantly hypoxic and hypoglycemic relative to the normally growing control fetuses. In addition, fetal insulin and IGF-1 concentrations are low while lactate levels are elevated [22,39] compared with control fetuses. This implies a defect in either uteroplacental nutrient uptake, metabolism, or transport of essential nutrients resulting in a reduction in umbilical nutrient supply. Despite this expectation, we have demonstrated that uteroplacental metabolism per unit placenta is normal in that uteroplacental glucose and oxygen consumption together with uteroplacental lactate production are decreased in proportion to the decrease in placental mass [22]. In addition, although absolute placental glucose transport capacity was reduced by w47% in the growth restricted versus the control pregnancies, there was no difference between groups when expressed on a placental weight basis [39]. Thus, it is the small size of the placenta per se rather than alterations in its metabolism or transport function which is the major limitation to fetal nutrient supply in the overnourished and rapidly growing adolescent sheep. Quantification of absolute umbilical nutrient uptakes of glucose, oxygen and amino acids reveals that they are significantly attenuated in the growth-restricted fetus. However, all umbilical nutrient uptakes are equivalent to the normally growing control fetuses when expressed on a fetal weight specific basis [39,40].

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PREGNANCY OUTCOME IN UNDERNOURISHED ADOLESCENTS

Although relatively normal fetal nutrient utilisation rates are preserved, fetal glucose and insulin concentrations remain significantly reduced (Figure 4) and fetal body growth slows. The adaptive mechanisms that allow a growth-restricted fetus to maintain normal fetal weight specific nutrient uptakes in a substrate deficient environment are currently being evaluated and may have implications for metabolic health beyond the fetal period. Placental data in relation to continued growth in the adolescent human are scarce. In a study of non-smoking Peruvian women, adolescents were classified as still growing or having completed their growth on the basis of their height relative to that of their parents [41]. This subjective assessment of growth status and path analysis examining the determinants of birth weight revealed that the contribution of placental weight to birth weight was less in girls who were still growing during pregnancy than in girls who had completed their growth. The authors attribute the reduction in birth weight in the putatively still growing adolescents to reductions in fetal nutrient uptake. To date, ethical constraints have limited the ability to measure essential fetal nutrient uptakes in relation to continued maternal growth in the human. However, measurement of umbilical artery waveforms by Doppler Ultrasound in the Camden Study has revealed that girls who continue to grow during pregnancy have a twofold higher risk of an elevated systolic/diastolic (S/D) ratio compared with nongrowing adolescents and adult women [17]. As high S/D ratios are indicative of placental vascular resistance and reduced blood flow [42], these data suggest that absolute umbilical nutrient uptakes may be impaired in growing adolescent humans, hence mirroring our sheep data.

Adolescent girls who have not achieved their predicted adult height at the time of conception and hence still have the potential to grow while pregnant may be particularly vulnerable to poor pregnancy outcome if dietary intakes are inadequate during gestation [43]. We have recently begun to model part of this problem by relatively undernourishing adolescent sheep throughout pregnancy. This is achieved by maintaining maternal body weight at the levels determined at conception (i.e. not allowing any gain in maternal body weight per se) and results in a gradual depletion of maternal nutrient reserves (primarily fat) throughout pregnancy (Figure 1). In a preliminary study, pregnancies were terminated at either day 90 or 130 of gestation. At day 90, mean fetal weight was equivalent in the underfed and control groups, but by day 130 fetal weight was modestly but significantly reduced (ÿ17%, P ! 0.01) in the underfed dams [44]. In contrast to the overnourished paradigm described previously, this alteration in the fetal growth trajectory was completely independent of changes in placental mass or cellular proliferation. At necropsy the transplacental glucose gradient was reduced and fetal glucose and insulin concentrations suppressed implying that the slowing of fetal growth observed in the underfed dams was largely due to reduced nutrient availability in the maternal circulation [45]. Support for this concept comes from the observation that when underfed dams were offered a dietary level equivalent to the control group from days 90 to 130 of gestation, fetal weight was intermediate between the control (ÿ9%) and underfed (C8%) group values. Clearly, we require

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Figure 4. Fetal weight specific utilisation of glucose (a) and oxygen (b) and spontaneous fetal arterial plasma glucose (c) and insulin (d) concentrations at wday 130 of gestation in normally growing (B) and growth-restricted (C) fetuses gestated by adolescent sheep offered a control (B) or high (C) dietary intake throughout pregnancy (n Z 5 per group). Values are mean G sem. Unpublished data.

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to study instrumented pregnancies to examine the specifics of fetal nutrient uptakes and utilisation in late pregnancy in this undernourished model and facilitate comparison with the data from the overnourished model as described above. We have recently established that in marked contrast to the overnourished paradigm, fetal growth restriction in undernourished adolescent sheep is not associated with spontaneous miscarriage or premature delivery (JM Wallace, JS Luther, JS Milne and RP Aitken, unpublished data). In addition, preliminary evidence suggests that the growth-restricted fetuses from the two nutritional models have a different phenotype. Relative (i.e. fetal weight specific) perirenal fat mass and carcass fat content are higher in growth-restricted fetuses from rapidly growing dams compared with controls and indicate a ‘fat’ phenotype [46]. In contrast, in the more modestly growth-restricted fetuses from the underfed adolescents, relative perirenal fat mass was reduced while relative carcass ash content (an index of bone mass) was increased suggesting that skeletal growth was largely preserved while

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lipid stores were depleted [45]. We are currently investigating whether these differences in body composition have any implications beyond the fetal period. In conclusion, these nutritional paradigms demonstrate that when gynaecological age, maternal weight and adiposity at conception are controlled, dietary intake at both ends of the nutritional spectrum is a powerful determinant of fetal growth in young adolescents. The competition for nutrients and the pivotal role of the placenta in mediating fetal growth restriction in the rapidly growing but not the undernourished animals indicates that formulating appropriate dietary advice for young adolescent girls is important and likely to be complex. Further animal studies are required to examine the role of maternal nutrient reserves at conception and the possible interaction with subsequent dietary intake. Biomarkers of growth and nutritional status at the time of conception and the use of ultrasound to diagnose early deficiencies in uteroplacental growth or umbilical blood flow may prove beneficial in human adolescents.

ACKNOWLEDGEMENTS Financial support from the Scottish Executive Environment and Rural Affairs Department (JMW, JSM, RPA, JSL) and National Institutes of Health ((HL64141 e DAR, LPR), (HD45784 e LPR, DAR, JMW), (HD20764, DK52138 e WWH)) is gratefully acknowledged.

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