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The Rowett Research Institute,3 Bucksburn, Aberdeen, AB21 9SB United Kingdom
Perinatal Research Center,4 University of Colorado Health Sciences Center, Aurora, Colorado 80010
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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adolescent pregnancy, conceptus, developmental biology, fetal growth, implantation, nutrition, placenta, placental growth, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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Adolescent mothers have a particularly high risk of delivering premature and low birth weight babies [6, 7]. Although the rates of adolescent pregnancy are currently declining, the United States still has the highest rate of adolescent pregnancy in the developed world, while the rate in the United Kingdom is the highest in Western Europe (48.7 and 30.2 births per 1000 women aged < 19 yr, respectively, [8]). The risk of adverse pregnancy outcome in the adolescent has been attributed to poor socioeconomic status, gynecological immaturity, or the growth and nutritional status of the mother [9]. Gynecological immaturity undoubtedly predisposes adolescent girls to poor pregnancy outcome in that the rates of spontaneous miscarriage and of very preterm birth (<32 wk) are highest in girls aged 13–15 yr [10, 11]. However, maternal growth and nutritional status during pregnancy also appear to play a potentially modifiable role. 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 United States) has shown, using a sensitive knee-height measuring device, that almost 50% of adolescents (mean age at delivery: 16.5 yr) continue to grow while pregnant [12, 13]. This growth is associated with larger pregnancy weight gains, increased fat stores, and greater postpartum weight retention than nongrowing adolescents and mature women. Paradoxically, in spite of changes typically associated with increased fetal size, the offspring are smaller in growing versus nongrowing adolescents. This significant reduction in fetal growth rate is attributed to a competition for nutrients between the maternal body and her gravid uterus. It was against this clinical background that the overnourished adolescent model was initially developed.
Adolescent Sheep Model
The experimental model uses a single sire and embryo transfer techniques to establish singleton pregnancies on Day 4 of an induced estrous cycle in pubertal adolescent sheep [14]. This removes the potentially confounding influence of partial embryo loss and maximizes the homogeneity of the resulting fetuses. Immediately after embryo transfer, recipient dams are offered a high or moderate quantity of a complete diet (10.5 MJ metabolizable energy and 140 g crude protein per kg dry matter) to promote rapid or low maternal growth, respectively. Thus, maternal live weight gain during the first two thirds of gestation ranges from 200 to 350 g/day in high-intake compared with 50– 85 g/day in moderate-intake groups. The moderate-intake group is in fact a control group in that this level of dietary intake results in optimum placental and fetal growth in the genotype studied. Throughout the final third of gestation, the feed intake of the moderate-intake group is adjusted weekly to maintain maternal adiposity and to meet the increasing nutrient demands of the pregnant uterus. This approach allows effects to be attributed specifically to maternal nutrition rather than genetic polymorphisms.
Key Features and Similarities to Human Adolescent Pregnancy Outcome
The adolescent sheep model has proved highly robust. Table 1 summarizes pregnancy outcome data obtained after spontaneous delivery at term following the application of the high and moderate nutritional treatments throughout gestation in nine individual studies. These studies were all initiated during the midbreeding season using the same recipient genotype. Within studies, the adolescents were of equivalent age, live weight, and body condition score (adiposity) at the time of embryo transfer. Care was also taken to randomize for recipient dam ovulation rate and the maternity of the embryo. Overnourishing adolescent dams to promote rapid maternal growth results in a major restriction in placental growth and leads to a highly significant decrease in lamb birth weight relative to slow-growing adolescents (P < 0.001; Table 1). Within each of the individual studies, the degree of prenatal growth restriction observed in the rapidly growing adolescents is variable. A term fetus is considered to be markedly growth restricted if its mass is less than or equal to the mean of the control group minus two times the standard deviation of that group [15]. Thus, for this data set, 51 of 97 high-intake and 1 of 85 moderate-intake adolescents produced fetuses classified as growth restricted at birth (IUGR, birth weight < 3514 g). Categorizing the data in this way reveals that, in the growth-restricted group, both average placental mass and fetal weight are reduced by 48% relative to the moderate-intake control group (257 ± 9 and 2692 ± 69 g versus 493 ± 12 and 5140 ± 87 g, respectively, P < 0.001; Fig. 1). In the non-growth-restricted group, placental mass (376 ± 12.1 g) is reduced by 23% relative to the control group and is associated with a 10.5% reduction in birth weight (4513 ± 100 g). This results in a significant increase in the fetal:placental mass ratio in the non-growth-restricted group and reflects the functional reserve capacity of the ovine placenta. In spite of this, the mean placental and fetal weights for the high-intake group classified as non-growth-restricted were still significantly lower (P < 0.001) than those of the moderate-intake control group.
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In this paradigm, rapid maternal growth is also associated with higher spontaneous abortion rates and, for those ewes delivering live young, with a consistent and significant reduction in gestation length [16]. The precise endocrine changes underlying premature parturition in the overnourished adolescent sheep have not been examined in detail but may be initiated by the previously documented nutritionally induced alterations in placental hormone secretion (primarily progesterone [17, 18]). Alternatively, limitations in placental nutrient transfer resulting in fetal hypoxia and hypoglycemia during late gestation (detailed below) may accelerate the maturation of the fetal hypothalamic-pituitary-adrenal axis, which is central to the initiation of parturition [19]. In support of this concept, the relative weight of the fetal adrenal gland is higher (P < 0.01) in growth-restricted compared with normal-weight fetuses from the high- and moderate-intake groups, respectively, when autopsied at 
Day 130 of gestation (0.167 ± 0.009 versus 0.130 ± 0.01 g/kg fetus, respectively; n = 27 per group; unpublished data).
Overfeeding to promote rapid maternal growth is also associated with a marked decrease in the initial yield, nutrient composition, and IgG content of colostrum accumulated prenatally [reviewed in 16]. Comparable data for human adolescents at parturition is unavailable, but girls who choose to breast feed have significantly less breast milk volume than mature breastfeeding mothers [20].
Thus, the rapidly growing adolescent sheep paradigm replicates the key features of human adolescent pregnancy, namely, an increased risk of abortion, preterm delivery, and low birth weight [6, 10, 11]. As the adolescent dams used in these studies are of equivalent age, weight, and adiposity at the time of embryo transfer, these results strongly support the concept that postconception nutritional status is a major determinant of pregnancy outcome in the young adolescent. Indeed, it appears that, in both humans and sheep, the hierarchy of nutrient partitioning in young growing females is altered to promote the growth of the maternal tissues at the expense of the nutrient requirements of the gravid uterus and mammary gland. This paradoxical 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 [21].
It is axiomatic that the placenta is a major player in the partitioning process in the young growing adolescent, but to date, there is only one published human study that reports placental data. This study involved nonsmoking primiparous adolescents living in Peru who were classified as still growing or having completed their growth, depending on their height relative to that of their parents [22]. 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 suggest that this is due to impaired placental blood flow and nutrient uptake in the immature growing adolescent, but to date, these parameters have not been measured in adolescent cohorts.
Diet Composition
The balance between energy and protein may be an important factor influencing the extent to which placental and fetal growth is perturbed in adolescents. However, studies assessing nutritional status in human adolescents are poorly controlled and the delivery of low birth weight babies has been associated with both the consumption of high sugar diets [23] and with protein supplementation during late gestation [24]. Similar controversy exists in clinical studies involving older women. Historically, protein deficiency was implicated in depressed fetal growth and impaired infant development (reviewed in [25]). However, both high protein supplements in low-income women and high protein intakes in women consuming a self-selected diet (n = 2341 pregnancies) are associated with a modest but significant decrease in birth weight [25]. Unfortunately, none of these studies reported placental data. In contrast, a much smaller trial involving 500 women has suggested that high carbohydrate intakes in early pregnancy suppress placental growth, especially if combined with low dairy protein intake in late pregnancy [26]. To date, the adolescent sheep paradigm has largely involved feeding two levels of the same complete diet throughout pregnancy. Thus, the overnourished animals who are fed ad libitum receive a diet high in both energy and protein. To determine whether high protein intakes are the cause of adverse pregnancy outcome in rapidly growing adolescents, two isocaloric diets fed ad libitum and containing 12% versus 17% crude protein have been compared and contrasted with pregnancy outcome in our moderate-intake (14% crude protein) control group (unpublished data). Weekly dry matter intakes in the ad libitum-fed ewes (high intake) were equivalent in the 12% and 17% crude protein groups and significantly higher (P < 0.001) than in the moderate-intake group (Fig. 2). Circulating maternal urea concentrations confirmed that the diets had produced the predicted differential in protein status (nitrogen balance). Both high-intake groups demonstrated a significant reduction in gestation length, placental weight, lamb birth weight, and colostrum yield relative to the moderate-intake control group (Table 2). In addition, gestation length was shorter (P < 0.05) in the ad libitum-fed groups receiving the diet containing 17% compared with 12% protein. However, neither placental mass, lamb birth weight, or colostrum yield were significantly different between the two ad libitum-fed groups, implying that it is high energy intakes that are the primary cause of adverse pregnancy outcome in rapidly growing adolescent sheep.
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Endocrine Regulators of Nutrient Partitioning: The Maternal Somatotrophic Axis
The partitioning of glucose, oxygen, and amino acids between the dam and her gravid uterus may be orchestrated by a number of endocrine hormones of maternal, placental, and fetal origin (reviewed in [27, 28]). The circulating concentrations of many of these maternal and placental hormones have been extensively documented throughout pregnancy in the adolescent paradigm and may operate by influencing maternal or placental metabolism, placental growth, uteroplacental blood flows, and nutrient transport functions (reviewed in [14, 29, 30]). The maternal somatotrophic axis may play a major role in coordinating nutrient use in the pregnant adolescent. In the overnourished adolescent dams, maternal insulin and insulin-like growth factor (IGF-I) concentrations are elevated from early in gestation and it is probable that these hormones provide a sustained anabolic stimulus to maternal tissue deposition. The nutritionally induced changes in maternal body composition are highlighted in Figure 3. The overnourished dams become increasingly obese as pregnancy progresses and, by late gestation, this typically represents 16% more fat per kilogram maternal carcass and 66% more perirenal fat per kilogram maternal body compared with the moderate-intake dams. The elevated maternal leptin concentrations detected in the overnourished dams from the end of the first third of pregnancy are thought to reflect this increasing adiposity/ lipogenesis [31].
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In contrast, growth hormone (GH) pulse frequency and mean concentrations during mid and late gestation are lower in overnourished compared with moderate-intake dams and positively associated with placental weight at term [18]. Similarly, human IUGR is associated with lower than normal concentrations of GH in the maternal circulation and reduced placental mRNA expression in the term placenta [32, 33]. Studies investigating the impact of maternal GH treatment on placental and fetal growth in normal adult sheep pregnancies are equivocal. Treatment of pregnant ewes with recombinant growth hormone for 14 days from Day 70 to Day 83 or Day 98 to Day 111 of gestation did not influence placental size, but the later period of treatment was associated with increased fetal weight as determined at Day 112 of gestation [34]. In contrast, treatment between Days 97 and 124 of pregnancy did not influence fetal weight at Day 125 or at term [35]. As growth of the placenta per se limits fetal growth in the overnourished adolescent, we have recently investigated whether treatment of high- versus moderate-intake dams with recombinant bovine growth hormone (bGH) during the period of rapid placental proliferation alters nutrient partitioning between the maternal, placental, and fetal tissues [36]. Maternal growth hormone treatment from Day 35 to Day 80 of gestation significantly decreased fat synthesis and increased protein deposition in both overnourished and moderate-intake adolescent dams as assessed at autopsy on Day 81. In the overnourished but not the moderate-intake dams, this alteration in maternal metabolism was also associated with a significant increase in uteroplacental mass, higher fetal liver and kidney weights, and elevated fetal insulin, glucose, and lactate concentrations. It is well established that GH inhibits tissue responsiveness to insulin, resulting in decreased lipogenesis and increased availability of glucose in the maternal circulation [37]. Indeed, maternal glucose concentrations were twofold higher in response to bGH in overnourished compared with moderate-intake dams and resulted in a corresponding increase in the transplacental glucose gradient. Thus, in the growing pregnant adolescents treated with bGH, the glucose destined for lipid synthesis was redirected to favor uteroplacental and fetal growth.
Exogenous GH treatment may also influence the growth of the uteroplacenta directly or indirectly via the IGF system. Placental growth hormone has been detected in the ovine placentome between Days 30 and 75 of pregnancy, while GH receptor mRNA is expressed in the endometrium and placentome throughout pregnancy [38]. Furthermore, the components of the IGF system have been localized in the ovine uteroplacenta, where they express spatial and temporal patterns of expression [39], some of which are sensitive to maternal nutrition [40]. In spite of these observations, studies in our laboratory using real-time reverse transcription-polymerase chain reaction (RT-PCR) and a selection of ovine-specific probes have failed to detect significant GH or GH receptor mRNA expression in placentomes collected at Days 50, 81, or 130 of gestation (unpublished data).
Placental Development and Uteroplacental Blood Flows
The size and nutrient transfer capacity of the placenta play a central role in determining the prenatal growth trajectory of the fetus and hence directly influences its birth weight and postnatal viability (reviewed in [29, 41–43]). In the sheep, as in most other mammals, the major phase of placental growth occurs during the first half of pregnancy, while the fetus accumulates almost 80% of its eventual mass during the final third of gestation. Absolute placental and fetal nutrient requirements are at a maximum in late pregnancy; thus, it is not surprising that positive correlations between placental and fetal weights become progressively stronger as birth approaches [43]. Blood flow to the utero-placenta increases threefold between midgestation and term [44] to keep pace with fetal growth. During the final third of pregnancy, both uterine and umbilical blood flows are well established as critical regulators of nutrient partitioning between the maternal, placental, and fetal compartments [45, 46]. Clinically, increased vascular resistance and reduced uterine blood flow are used as predictors of high risk pregnancies and are associated with intrauterine growth restriction [47, 48]. Similarly, in our growth-restricted adolescent sheep pregnancies, we have shown that absolute uterine and umbilical blood flows are attenuated in late pregnancy (Day 130; [49]). These reductions in uterine and umbilical flow of 36% and 37%, respectively, were positively correlated (P < 0.001) with placentome mass and fetal weight. It is axiomatic that the factors that influence placental vascular development and angiogenesis during the first half of pregnancy set the trajectory for these later hemodynamic changes and hence have a major impact on the rate of transplacental nutrient exchange and fetal growth [50]. A complex range of angiogenic growth factors are emerging as putative regulators of the vascularization process, and these include the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiopoietin (ANG) protein families and their receptors [51]. The sheep placenta produces these angiogenic factors throughout gestation and tissue- and cell-specific patterns of expression have been documented in normal pregnancies [51] and in those where placental insufficiency and fetal growth restriction have been induced by maternal hyperthermia [52]. Using our paradigm, the impact of maternal nutritional status and the associated endocrine perturbations on the placental expression of a range of angiogenic factors is being examined using quantitative real-time PCR. In a preliminary study of placental tissue collected at midgestation (Day 81), expression of VEGF (P < 0.01), ANG1 (P < 0.002), ANG2 (P < 0.05), endothelial nitric oxide synthase (eNOS, P < 0.05), and hypoxia-inducible factor (HIF1a, P < 0.01) was reduced in high- versus moderate-intake dams [53]. Similarly, the expression of VEGFR-1(flt), VEGFR-2 (KDR), Tie-2 (angiopoietin receptor), and soluble guanylate cyclase (NO receptor) tended to be less in the high-intake group, reaching statistical significance for VEGFR-1 only (P < 0.01). The midgestation placentae of overnourished dams also exhibited significantly less proliferation in the fetal trophectoderm compared with the moderate-intake group [54]. These changes in proliferation and angiogenic factor gene expression occur before differences in placental mass are apparent, but they clearly impact on the subsequent growth and vascularity of the placenta.
Inappropriate Nutrient Supply and the Consequences for the Fetus
By late pregnancy (Day 130), placentome mass in the rapidly growing overnourished dams is reduced by 45% relative to control dams and is associated with a 30% reduction in fetal weight. While no major change in the allometric growth coefficients of the major fetal organs have been detected [55], there is evidence of brain sparing in that the brain to liver weight ratio is significantly higher in the growth-restricted (IUGR) compared with the normally growing (control) fetuses [49]. Intriguing, relative fetal perirenal fat mass is higher (P < 0.01) in IUGR compared with control fetuses (4.88 ± 0.28 versus 3.86 ± 0.17 g/kg fetus, respectively, n = 27 per group; unpublished data). Similarly, there is a trend (P < 0.06) for an increase in fetal carcass fat content (34.4 ± 1.41 versus 30.6 ± 1.24 g/kg, n = 14 and 13 for IUGR and control fetuses, respectively; unpublished data). These data may underline our failure to detect differences in absolute plasma leptin concentrations at birth in IUGR (birth weight 3134 ± 101 g, n = 19) and control (birth weight 5428 ± 162 g, n = 23) lambs (0.32 ± 0.05 versus 0.33 ±0.03 ng leptin/ml; unpublished data). While the mechanistic basis of these observations have yet to be determined, it is possible that the increase in relative adiposity in growth-restricted fetuses is due to higher fetal glucose availability earlier in gestation, prior to placental limitation of fetal glucose supply. Maternal glucose concentrations are elevated throughout gestation in overnourished dams [18, 56], and in a cohort of fetuses autopsied at Day 77 of gestation, glucose concentrations were also higher (0.89 ± 0.12 versus 0.42 ± 0.04 mmol/L in fetuses from overnourished compared with moderate-intake groups, respectively, n = 8 per group, P < 005; unpublished data). These elevated glucose concentrations may drive an increased preadipocyte pool in early pregnancy and thus increased potential for fat accumulation later in prenatal development. Furthermore, this increase in relative adiposity may have implications for the programming of postnatal body composition and disease susceptibility. Indeed, an increase in central adiposity has been reported in low birth weight human infants and may provide a link between prenatal growth restriction and the development of adult-onset obesity and metabolic disease [57].
The ability to instrument the adolescent dam and her fetus allows us to study fetal endocrine and nutrient status, nutrient uptakes, and utilization in some detail. In spite of the ready availability of nutrients in the maternal circulation [56], the growth-restricted fetuses in the overnourished dams are relatively hypoxic and hypoglycemic during late gestation [49, 55]. Moreover, fetal insulin and IGF-I concentrations are lower, while lactate and urea concentrations are elevated. This implies a defect in uteroplacental uptake, metabolism, or transport of essential nutrients resulting in a reduction in umbilical nutrient supply and hence a slowing of fetal growth during the final third of gestation. We have examined spontaneous fetal and uteroplacental nutrient uptakes in these growth-restricted pregnancies. Major reductions in absolute uterine and umbilical blood flows lead to attenuated absolute umbilical (fetal) uptakes of glucose, oxygen, and 12 of the 17 amino acids measured ([49, 58, 59]; Fig. 4). However, all fetal nutrient uptakes are normal when expressed on a weight-specific basis. Furthermore, we found no evidence that uteroplacental metabolism per unit placenta was altered at the expense of the fetus in that uteroplacental glucose and oxygen consumptions and uteroplacental lactate production were attenuated in proportion to the observed decrease in placental mass [49]. Glucose clamp procedures have been used to assess placental glucose transport over a range of maternal-fetal glucose concentration gradients to determine whether reduced placental glucose capacity is responsible for the observed fetal hypoglycemia and growth restriction. Linear regression analysis of umbilical glucose uptake at three steady-state uterine-umbilical arterial transplacental plasma glucose concentration gradients revealed that absolute placental glucose transport capacity in the growth-restricted pregnancies was approximately half of that measured in the moderate-intake control group [58]. However, the difference in placental mass at autopsy between these groups was 46% and, when umbilical uptake was expressed per kilogram placenta, weight-specific placental transport capacity was shown to be similar in both groups. Glucose transport across the uteroplacenta is mediated by the steady-state expression and activity of saturable membrane-localized glucose transporters (GLUT-1 and GLUT-3) on both the maternal-facing microvillus and fetal-facing basal trophoblast [60]. We have recently quantified the expression of both transporters in whole placentomes at Days 81 and 133 of gestation (Fig. 5). As originally reported by others [60], we have confirmed that mRNA levels of these transporters increase several fold from midgestation to term, commensurate with the fivefold increase in placental glucose transport capacity measured in vivo over this period [61]. However, consistent with our own observation that placental weight-specific glucose transport in late gestation is normal, placental GLUT-1 and GLUT-3 mRNA expression was independent of maternal growth and nutritional status ([36] and unpublished data). Thus, it is inadequate growth and vascularization of the placenta rather than alterations in its nutrient metabolism or transfer capacity that is the major limitation to fetal growth in the rapidly growing adolescent. To date, uteroplacental blood flows and nutrient fluxes have not been reported for human adolescent pregnancies, but the available data suggest that our paradigm mirrors many of the key features of human intrauterine growth restriction per se (Table 3). Thus, in addition to a marked reduction in placental mass, IUGR in third-trimester human pregnancies is characterized by impaired umbilical blood flows and nutrient uptakes resulting in fetal hypoxia, hypoglycemia, and asymmetric organ growth [62–64].
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Jacqueline Wallace, The Rowett Research Institute, Greenburn Drive, Bucksburn, Aberdeen, AB21 9SB United Kingdom. FAX: 44 1224 716622; Jacqueline.Wallace{at}rri.sari.ac.uk
Received: 19 April 2004.
First decision: 11 May 2004.
Accepted: 8 June 2004.
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TOPABSTRACTINTRODUCTIONREFERENCES |
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