Competition for Nutrients in Pregnant Adolescents: Consequences for Maternal, Conceptus and Offspring Endocrine Systems

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Journal of J M Wallace Adolescent pregnancy 242:1 T1–T19 Endocrinology THEMATIC REVIEW Competition for nutrients in pregnant adolescents: consequences for maternal, conceptus and offspring endocrine systems

Jacqueline M Wallace

Rowett Institute, University of Aberdeen, Aberdeen, UK

Correspondence should be addressed to J M Wallace: [email protected]

This paper is part of a thematic section on 30 Years of the Developmental Endocrinology of Health and Disease. The guest editors for this section were Sean Limesand, Kent Thornburg and Jane Harding.

Abstract

The competition for nutrients that arises when pregnancy coincides with continuing or Key Words incomplete growth in young adolescent girls increases the risk of preterm delivery and ff fetus low birthweight with negative after-effects for mother and child extending beyond the ff nutrition perinatal period. Sheep paradigms involving nutritional management of weight and ff placenta adiposity in young, biologically immature adolescents have allowed the consequences ff pregnancy of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented, and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood, whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young Journal of Endocrinology adolescents before and during pregnancy, and their offspring thereafter. (2019) 242, T1–T19

Introduction

Adolescent fertility rate as measured by births per present day (https://data.worldbank.org/indicator/sp.ado. 1000 females aged 15–19 years has steadily declined tfrt). Nevertheless, pregnancy during adolescence still in virtually all countries across the globe from 1960 to accounts for an estimated 11% of all births worldwide

-18-0670 Journal of J M Wallace Adolescent pregnancy 242:1 T2 Endocrinology with more than 95% of these occurring in developing Although the peak in growth velocity characteristic of countries (https://www.who.int/en/news-room/fact- adolescence is reached before menarche, girls continue sheets/detail/adolescent-pregnancy). The antecedents of to grow thereafter and on average gain a further 7 cm early childbearing are diverse and in the developed world in height before linear growth ceases (Roche & Davila include social disadvantage, low educational attainment, 1972). In the US-based Camden Adolescent Pregnancy dysfunctional family structures, ethnicity and an and Nutrition Project, approximately 50% of young intergenerational history of early childbirth, as well as a adolescents (≤16 years) continued to grow as indicated propensity for risky, aggressive and delinquent behaviours by increases in knee height over a 6-month period from (Meade et al. 2008, Gaudie et al. 2010). In contrast, in mid-pregnancy to 4–6 weeks post-partum. This drive to developing countries, early marriage and childbearing are maternal tissue growth as reflected by higher gestational often the cultural norm particularly in communities where weight gains, increased fat stores and greater post-partum access to education for girls is limited and the supporting weight retention was associated with a three-fold higher health infrastructure is weak (Das et al. 2017). Irrespective risk of small-for-gestational-age birth and lower average of geographical location there is commonality in the birthweights than in both non-growing adolescents of hazards associated with early childbearing, and systematic equivalent age and mature women (Scholl et al. 1994, reviews, multi-country surveys and population-based 1997). A similar alteration in nutritional priorities leading studies consistently report a higher risk of premature to smaller babies has been observed in young (<15 years) delivery, low birthweight and neonatal morbidity and ‘still-growing’ Peruvian girls: in this instance adolescent mortality in adolescent pregnancies (Salihu et al. 2006, growth was defined as continuing or complete based Gibbs et al. 2012, Malabarey et al. 2012, Kozuki et al. 2013, on their height at delivery relative to parental height Ganchimeg et al. 2014, De Azevedo et al. 2015). Relative (Frisancho et al. 1985). When pregnant adolescents are to adult women, pregnancy at any age during adolescence undernourished, it is likely that both mother and fetus is associated with a greater possibility of experiencing are compromised and in partial support there is evidence anaemia, eclampsia, puerperal endometritis and systemic from rural Bangladesh that pregnant adolescents (average infections, while heightened risk of preterm delivery, low age 16.3 years) cease linear growth and deplete their birthweight and neonatal mortality is most pronounced in fat stores compared with non-pregnant adolescents of very young girls (≤15 years of age and/or within 2 years of equivalent gynaecological age (Rah et al. 2008). Perinatal first menses) who are biologically immature (Ganchimeg outcomes were not reported, but the effects on maternal et al. 2014, Weng et al. 2014, Torvie et al. 2015, Neal et al. growth were most pronounced in the girls who became 2018). A short cervix, small uterine volume and immature pregnant at an earlier age. In contrast, in a UK-based study pelvis leading to cephalopelvic disproportion are more involving older adolescents (average age 17.8 years), common in younger mothers and may predispose them continuing maternal growth measured as a change in to early delivery and complications such as obstetric knee height of >2 mm between 13- and 29-weeks gestation fistula and other maternal near-miss events (Moerman did not limit fetal growth relative to non-growing 1982, Stevens-Simon et al. 2000, Gadelha Da Costa et al. adolescents but in this instance both macronutrient and 2004, Tebeu et al. 2012, Ganchimeg et al. 2014, Oliveira micronutrients intakes generally exceeded recommended et al. 2014). Maternal mortality is thankfully rare, but levels (Jones et al. 2010). Together these studies suggest in low resource settings the adjusted risk of mortality is that the competition for nutrients that arises between four times higher for very young mothers than for both the maternal body and gravid uterus when pregnancy older adolescents and adult women (Conde-Agudelo et al. coincides with adolescence is specific to very young girls 2005). and is likely to be moderated by maternal nutritional status and dietary intake.

Maternal–fetal competition for nutrients Consequences for mother and child beyond Greater prevalence of adverse perinatal outcomes in the perinatal period very young adolescent mothers may additionally reflect that a significant proportion are either still growing or The negative impact of adolescent pregnancy for mother have the potential to grow at the time of conception and infant extends beyond the perinatal period. For setting up a maternal–fetal competition for nutrients. adolescent mothers themselves longer-term health

Journal of J M Wallace Adolescent pregnancy 242:1 T3 Endocrinology outcomes include poorer mental health scores and a two- child feeding practice, educational attainment, but fold higher rate of suicide (Webb et al. 2011, Aitken et al. residual confounding is likely to be an issue as it is unlikely 2016), more premature deaths due to cervical and lung that all the socioeconomic, environmental and biological/ cancer (Otterblad-Olausson et al. 2004, Webb et al. 2011) genetic influences that impact a young mother and her and a three-fold higher risk of diabetes-related mortality offspring from the peri-conception period forwards are (Vandenheede et al. 2012). A young age at first birth is also sufficiently well documented. Animal models are of value associated with a higher prevalence of hypertension and in that specific known confounders can be controlled or osteoporosis in postmenopausal women (Cho et al. 2012, removed, allowing researchers to better study the exposure Park et al. 2016), and with poor physical performance of interest. This was the rationale behind the development and greater risk scores for cardiovascular disease in later of a sheep paradigm to explore the competition for life (Pirkle et al. 2014, Rosendaal et al. 2017). In contrast, nutrients when pregnancy coincides with continuing or women with an early first birth have a reduced risk of incomplete growth of the young adolescent mother. breast cancer, and the earlier the pregnancy, the lower the risk (Kelsey & Berstein 1996). While some of these relationships likely reflect the complex psychosocial needs Adolescent sheep paradigms: approach and life choices of women who experience early childbirth, others could have a physiological basis originating close to Sheep producers generally avoid breeding young females the initial pregnancy. For example, women who give birth during adolescence because relative to adults, they have during adolescence in the developed world are prone to an inferior reproductive performance characterised by a greater weight retention and adiposity than adolescents variable onset of puberty and short first breeding season, who did not experience pregnancy and older pregnant low ovulation rate, failure to be mated, fertilisation failure women, and this may influence their metabolic health in and high embryo loss (Beck et al. 1996, Kenyon et al. 2014, later life (Gunderson et al. 2009, Thame et al. 2010). Edwards et al. 2016). The approach developed at the Rowett For the offspring of adolescent mothers, Demographic Institute bypasses many of these issues by using assisted Health Surveys reveal evidence of low height or stunting conception procedures to synchronise breeding and in infancy in 9 of 18 developing countries studied (Africa, establish singleton pregnancies in peripubertal adolescent Asia, Latin America and so on; Yu et al. 2016) and similarly ewes of equivalent age (~7.5 months), and standardised pooled data from five birth cohorts (Brazil, Guatemala, live-weight and adiposity at conception. Adult ewes of India, The Philippines and South Africa, n ~ 13,000; Fall known reproductive history act as embryo donors, thus et al. 2015) reveal a 46% higher risk of stunting at 2 years avoiding the inherently low viability of embryos arising of age and a greater likelihood of offspring failing to from adolescents themselves (Quirke & Hanrahan 1977, complete their secondary education. The latter study also McMillan & McDonald 1985, Morton 2008). Donor ewes found a relationship between young maternal age and in optimal body condition for breeding are superovulated elevated offspring fasting glucose concentrations in early using exogenous hormones, and semen from a single sire adulthood (n ~ 10,000) independent of any difference is deposited directly into the uterus to ensure fertilisation. in body composition or blood pressure. In high-income Within each study high-quality embryos harvested from countries, an association between young maternal age any given embryo donor are then distributed evenly across (particularly ≤15 years) and greater developmental the adolescent recipient study groups: this approach issues in offspring aged 5 as assessed by school teachers minimises the impact of the main peri-conceptual factors has been reported (n = 99,950; Falster et al. 2018) and in known to influence feto-placental growth and maximises a smaller study (n = 2643), offspring born to adolescent the genetic homogeneity of the resulting fetuses (Wallace mothers had a lower IQ score and a higher risk of low et al. 1996). IQ at 21 years of age (Khatun et al. 2017). Furthermore, Nutritional treatments normally begin immediately a nationwide evaluation in Denmark (n = 1,793,681) has after embryo transfer and involve presenting the young linked early childbearing (12–19 years) with a greater risk still-growing adolescent recipient with different quantities of criminality, substance abuse and attempted suicide in of a nutritionally complete diet to manipulate gestational offspring aged between 15 and 40 years (Mok et al. 2017). weight gain and thus her growth and body composition. Depending on the context, each of the aforementioned In the overnourished adolescent model, this involves offering studies adjusts the data to some degree for potential a high dietary intake throughout gestation (ad libitum confounders, for example, maternal smoking, intake, ~2× maintenance requirements) to promote rapid

Table 1 Key characteristics of adolescent pregnancy and offspring outcomes in the overnourished and undernourished models expressed relative to optimally nourished (maintenance-fed) controls.

Overnourished model Undernourished model Maternal dietary intake High, 2× maintenance Low, 0.7× maintenance Maternal growth Rapid Prevented Maternal body composition Progressive fat deposition Progressive fat depletion Maternal metabolic hormones High insulin, IGF1 and leptin Low insulin, IGF1 and leptin

High T3, T4 and prolactin Normal cortisol Low GH, normal cortisol Maternal nutrients High glucose and urea Low glucose, urea and individual Low NEFA amino acids High NEFA Placental growth Impaired, ~40% smaller at term Normal

Placental hormones Low placental lactogen, P4 and E2 High P4 and E2 Uterine blood flow Reduced by 40% at 0.6 gestation Mildly attenuated, 0.6–0.9 gestation Fetal growth Impaired, ~30% smaller at term Impaired, ~10% smaller at term Fetal body composition Marked brain sparing and increased relative adiposity Reduced adiposity, preserved skeletal growth Fetal hormones and nutrients Low insulin, IGF1 and glucose Low insulin and glucose, normal IGF1 Incidence of marked FGR* (%) 45 14 Gestation length ~5 days shorter Normal Colostrum yield Inadequate in >50% of mothers Inadequate in <15% of mothers Neonatal morbidity and mortality Increased but largely preventable Normal Offspring growth Rapid compensatory growth but reduced adult size Normal Offspring metabolism Persistent glucose intolerance Normal Offspring body composition Persistently low bone mineral density Normal Higher adiposity in adult life

*Categorised as marked FGR if birthweight is more than two standard deviations below the mean sex-specific birthweight of fetuses in the optimally nourished control group.

Journal of J M Wallace Adolescent pregnancy 242:1 T5 Endocrinology

Figure 1 Placental weight (A), lamb birthweight (B), gestation length (C) and early pregnancy maternal weight gain (D) in adolescent sheep carrying a single male or female fetus and offered a control nutrient intake or overnourished (ON) throughout gestation. Overnourished pregnancies were categorised as fetal growth-restricted (FGR) if lamb birthweight was less than two standard deviations below the sex-specific birthweight of the optimally nourished control group, thus <4108 g for males and <3798 g for females. Numbers per group shown in (A) and summarised from eight studies (Wallace 2016). The significance of main effects is shown and there were no significant nutrition/growth category × sex interactions. Post hoc Tukey comparisons are shown and where letters differ,P < 0.01. are less perturbed (Fig. 1D). This competition for nutrients the supply of essential immunoglobulins and nutrients, between mother and fetus is independent of dietary making the lambs vulnerable to hypothermia and protein content (Wallace et al. 2006b) and exclusive to the infection (Wallace et al. 2006b). In the first study with young adolescent in that it does not occur in identically this model, neonatal mortality rate was 62% (Wallace treated primiparous adult ewes of the same genotype et al. 1996), but subsequently a pre-emptive neonatal care (Wallace et al. 2005a). protocol involving intensive monitoring, supplementary One of the most predictable features of pregnancy feeding and prophylactic antibiotic usage, irrespective of outcome in overnourished adolescents is a reduction size at birth, ensured that most lambs survived. in gestation length with viable lambs being born as early as day 135 (term = 145 days in controls). Within overnourished adolescents, gestation length is unrelated Pregnancy outcome in undernourished to maternal growth or weight gain at any stage of adolescent sheep pregnancy and the difference in gestation length for growth-restricted vs less perturbed fetuses of both sexes is Relative to the overnourished model, the perinatal outcomes less than 1 day (Fig. 1C). This implies that it is primarily associated with undernourishing pregnant adolescents high dietary intakes that underlie premature delivery are much less severe: placental size and gestation and a rapid labour relative to controls. Lambs tolerate length are comparable with the control group and no premature delivery badly irrespective of size, but it is fetal or neonatal deaths have been observed (Table 1). the smallest individuals that face the most significant Preventing maternal growth by holding body weight at challenges in the neonatal period. Colostrum yield at peri-conception levels progressively depletes maternal parturition reflects placental mass Wallace( et al. 1996, fat reserves and directly limits nutrient availability in the 2001) and is attenuated in overnourished dams (Wallace maternal and fetal circulations. This leads to a slowing of 2016). The lambs are generally vigorous at birth and fetal soft tissue growth and by late gestation, and following display normal teat seeking behaviour, but the mothering spontaneous delivery at term, the fetus is 10–17% smaller abilities of the adolescent dams are often poor, and the than controls (Luther et al. 2007a,b, Wallace et al. 2012). extremely low colostrum availability delays the formation Thus, while undernourishing adolescent mothers has a of an appropriate ewe–lamb bond and severely limits modest effect on fetal growth, it is the overnourished model

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-18-0670 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 11:49:06AM via free access Journal of J M Wallace Adolescent pregnancy 242:1 T6 Endocrinology which most closely mimics the human with respect to immediately after embryo transfer and accordingly the adverse perinatal outcomes. adolescent recipients were deliberately of equivalent Two other laboratories have tried to replicate the weight and adiposity level at conception. It is well effects of differentially feeding adolescent sheep, with established that pre-pregnancy underweight is associated variable success. Both groups have used natural mating with an increased risk of preterm delivery and low following a synchronised oestrus, but the timing and birthweight in adult women relative to those with extent of nutritional manipulation and thereby maternal normal BMI (Han et al. 2011). Similarly, although human growth rate differed. Swanson et al. (2008) report a adolescents enter pregnancy from a range of nutritional shorter gestation length and a small overall reduction in backgrounds, the majority in the developing world are birthweight (9%) when adolescents carrying singletons likely to be underweight with low nutrient reserves at or twins were overnourished beginning on day 50 of conception, and in very young girls, this may interact with gestation, whereas when rations were restricted, gestation their gestational growth status to influence pregnancy length was unperturbed and birthweight reduced by 13% outcome. This scenario has been modelled in two studies relative to controls. In contrast, Peel et al. (2012) exposed using different approaches: both involved selecting two singleton-bearing adolescents to ad libitum intakes groups of adolescent sheep of the same age but with a throughout pregnancy in two identical trials, and, in the marked difference in weight and adiposity prior to embryo trial where maternal weight and adiposity diverged earlier transfer. In the first study, adolescents were subsequently and to a greater extent, gestation length was reduced by overnourished, undernourished or fed a control intake 5 days independent of an effect on lamb birthweight. to drive maternal growth and gestational weight gain in Placental size was either unaffected (Swanson et al. 2008) contrasting directions as described earlier (Wallace et al. or not reported (Peel et al. 2012). It is accepted that the 2010), whereas in the second study the nutritional status of use of assisted conception procedures may influence how the embryo donor(s) was additionally manipulated (obese the early embryo responds to differences in maternal vs control); all these recipients were then overnourished nutritional status or diet in the Rowett model, but it is throughout gestation and a contemporaneous control important to emphasise that maternal nutrition is the group was included as a reference point for optimal fetal only variable that is manipulated with all other aspects growth (Wallace et al. 2017). Together the design of these controlled. Moreover, unlike human IVF/embryo transfer, studies uniquely allows segregation of pre-, peri and post- the animals used have no known reproductive defects conception nutritional exposures to evaluate their separate at baseline in that they respond appropriately to oestrus and/or interdependent influences. Donor ewe obesity did synchronisation and ovulation induction and conceive not influence conception rate or the feto-placental growth in high numbers following embryo transfer. Thus, it trajectory of high-quality embryos following transfer is the ability to achieve rapid maternal growth rates in into adolescent recipients, and irrespective of donor early pregnancy that is most likely the root cause of ewe nutrition and gestational intake, adolescents that placental growth restriction and the adverse perinatal were relatively light and thin at conception gave birth to events described. Uterine immaturity is proposed as a lambs that were smaller than those born to adolescents primary driver of the placental dysfunction underlying who were relatively heavy and fat at conception (555 g preeclampsia, fetal growth restriction and preterm lighter in study 1 and 665 g in study 2, P < 0.05). This delivery in young human adolescents (Brosens et al. 2017) reduction in birthweight was mirrored by corresponding and the suggestion that preconditioning of the immature reductions in placental size but was independent of uterus by exposure to regular ovulatory menstrual cycles gestation length. The differences in estimated body fat is required to prepare for appropriate trophoblast invasion at the point of embryo transfer were relatively small, has considerable merit bearing in mind that the studies but irrespective, the thin adolescent dams had high lipid reported here involve peripubertal animals. levels indicative of active catabolism, and low circulating nutrient and metabolic hormone concentrations which are likely to have directly impacted the early uterine Maternal weight and adiposity at conception environment contributing to compromised conceptus and pregnancy outcome development. Accordingly, the incidence of marked fetal growth restriction was two-fold higher in recipients that In the above-mentioned studies, the emphasis was to were thin vs fat at conception when all were subsequently manipulate gestational weight gain and growth status overnourished (Wallace et al. 2017). This clearly indicates

Journal of J M Wallace Adolescent pregnancy 242:1 T7 Endocrinology that maternal nutritional status at the time of conception insulin post glucose challenge. The high circulating is an important consideration in predicting pregnancy glucose should in theory favour fetal growth but the outcome in still-growing adolescents, but comparison reduction in placental size in these animals is a major with the control groups in both studies unequivocally constraint to fetal nutrient supply (see the 'Placental demonstrates that it is the high nutritional intake to drive development' section below). Indeed, reduced placental continued maternal growth and adiposity after conception size and the attendant decrease in placental hormone which is most closely linked to the high incidence of fetal secretion may compromise several of the maternal growth restriction in young sheep (Wallace et al. 2010, adaptations that normally underlie successful pregnancy 2017). Similarly, a recent study in human adolescents and lactation (Napso et al. 2018), thereby contributing (n = 600) reported that gestational weight gains above the to the poor perinatal outcomes characteristic of these recommended levels for individual pre-pregnancy BMI rapidly growing adolescents. Notably, the overnourished categories were associated with an increased risk of low adolescent dams are characterised by attenuated placental birthweight (Sámano et al. 2018), but whether the girls lactogen (also known as chorionic somatomammotropin (mean age 16 years) were still growing was not assessed. hormone, CSH) – relative to controls, the detection of This increased risk of low birthweight is unique to the hormone in the maternal circulation is delayed, and adolescent pregnancies as gestational weight gain above concentrations are reduced throughout the second two- recommendations in adult women reduces the risk of SGA thirds of pregnancy (Lea et al. 2007). The generation of birth (Goldstein et al. 2017). CSH-deficient sheep pregnancies by lentiviral-mediated RNA interference in vivo has recently provided convincing evidence of a causative role for this hormone in conceptus growth. Major reductions in placental and fetal weights Consequences for maternal and placental were evident in late gestation corresponding to the endocrine systems decrease in CSH mRNA and protein (Baker et al. 2016), and an equivalent study terminated at day 50 revealed Overnourished model that the growth of the fetus was perturbed from early in The consequence of different dietary-intakes for maternal pregnancy, possibly due to deficits in the paracrine actions hormone and nutrient status in adolescent sheep has been of the hormone within the placenta (Jeckel et al. 2018). extensively described. Relative to controls and consistent In addition to low CSH concentrations, overnourished with the oversupply of nutrients, the overnourished dams are typified by low placental reproductive steroid dams have elevated peripheral insulin, insulin-like concentrations. This may reflect increased metabolic growth factor 1 (IGF1), urea and glucose concentrations (hepatic) clearance due to the high dietary intakes or from ~day 25 to 28 of gestation facilitating an early and reduced placental steroid capacity, and there is evidence sustained stimulus to maternal tissue growth at a time to support both scenarios (Lea et al. 2007, Redmer when the nutrient requirements of the fetus are negligible et al. 2012). Irrespective of the cause, progesterone and (Wallace et al. 1997b, 1999, 2010). Accordingly, maternal oestradiol-17β levels are reduced relative to controls early weight gains are rapid, and body weight-specific peri- in pregnancy and remain attenuated thereafter (Wallace renal fat depots and peripheral leptin concentrations are et al. 1997a, 2003b, 2008a). Together low concentrations enhanced by day 50 of gestation (Thomas et al. 2001, of these three lactogenic hormones, as well as reduced Redmer et al. 2009), with the proportion of fat in the growth hormone concentrations (Wallace et al. 1997b) maternal carcass per se increasing between mid and late are likely to underlie the impaired early lactation robustly gestation (Wallace et al. 2004a). In adult sheep, maternal observed in overnourished adolescents. Moreover, the insulin concentrations normally decline during the attenuated concentrations of reproductive steroids, and final third of gestation to promote increased fatty acid an early decline in progesterone particularly (Taylor 1987), mobilisation from adipose stores and to reduce glucose most likely triggers premature and rapid delivery in these utilisation by non-uterine tissues (McNeill et al. 1997). pregnancies, while the deficit in circulating oestradiol However, high insulin concentrations are maintained is likely to be the origin of the poor mothering abilities throughout in adolescent mothers, and metabolic (Dwyer 2014) regularly observed in the adolescent dams challenges at ~day 97 of gestation reveal enhanced insulin that give birth to the most growth-perturbed lambs. insensitivity, namely greater glucose area-under-the-curve In human pregnancies, failure of maternal plasma post insulin challenge, and higher glucose-stimulated volume expansion and altered iron homeostasis are

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-18-0670 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 11:49:06AM via free access Journal of J M Wallace Adolescent pregnancy 242:1 T8 Endocrinology implicated in several adverse outcomes (Vricella 2017) hypothalamic–pituitary axis promoting prolactin and although a causative link has not been established, secretion, but intriguingly maternal cortisol low placental progesterone and oestradiol concentrations concentrations were either equivalent or reduced relative have been associated with the reduced maternal plasma to controls in all these animal models (Bell et al. 1989, volume expansion observed in normotensive women Wallace et al. 2000, 2005b, Fernandez-Twinn et al. 2003). with idiopathic fetal growth restriction (Salas et al. 1993, 2006). Similarly, deficits in these placental steroids may Undernourished model impact the renin–angiotensin–aldosterone system (Scaife & Mohaupt 2017) and hence salt and water retention in The maternal endocrine profiles and nutrient status of our animal model of fetal growth restriction. Although undernourished adolescent dams have been less rigorously this has not been directly examined, cross-sectional studied but relative to optimally fed controls are typified by studies reveal that rapid growth during the first half of lower peripheral insulin, IGF-1 and leptin concentrations pregnancy is linked to increased utilisation and hence and similar cortisol levels (Luther et al. 2007a, Wallace early depletion of maternal liver iron stores, and a failure et al. 2010). In contrast, decreased metabolic (hepatic) of normal blood volume expansion between mid and clearance rates in undernourished dams are thought late pregnancy (Luther et al. 2010). The accompanying to underlie the elevated concentrations of placental increase in haematocrit, haemoglobin and plasma protein reproductive steroids observed during the final third of concentrations is associated with an increase in blood pregnancy independent of any change in placental size viscosity by late gestation (Wallace et al. 2017), and this (Luther et al. 2007b). By late pregnancy maternal glucose, in turn may influence uteroplacental blood flow and fetal urea and specific amino-acid concentrations are reduced, nutrient supply. and greater NEFA concentrations reflect dwindling Plasma tri-iodothyronine and thyroxine internal adipose and carcass fat stores. Although maternal concentrations mirror maternal nutrient intake across liver iron stores are independent of dietary treatment, a a range of diet levels during pregnancy and around low haematocrit and haemoglobin is consistent with mild parturition (Lemley et al. 2014) but do not significantly anaemia by this stage and collectively low availability diverge in overnourished compared with control of nutrients in the maternal circulation is the principal adolescents until the final third of gestation (Wallace et al. cause of the modest reduction in fetal growth observed. 1997b). This suggests that these hormones are unlikely This is in stark contrast to overnourished pregnancies to play a causative role in placental growth restriction where regardless of an oversupply of nutrients in the although two independent human studies suggest that maternal circulation, fetal growth is directly constrained elevated maternal thyroid hormones negatively impact by impaired placental development and function. fetal growth (León et al. 2015) and associate with the risk of miscarriage and fetal distress (Yang et al. 2018). Higher plasma thyroid levels in overnourished dams may however Consequences for placental development and influence colostrum IgG supply to the newborn as others uteroplacental blood flows: have shown that supplementing a basal sheep diet with overnourished model excess iodine for 4 weeks prior to parturition reduces serum IgG concentration in the neonate (McGovern et al. The competition for nutrients in the overnourished and 2016). Maternal plasma prolactin similarly reflects dietary rapidly growing adolescent dams influences placental intake level (Lemley et al. 2014) predominately in the final development from early in gestation. At day 50, cellular third of pregnancy when circulating concentrations are proliferation rates within both placental compartments elevated in overnourished dams and negatively correlated are reduced (Rensick et al. 2008), and capillary vessel with fetal weight (Matsuzaki et al. 2006). The significance size within the fetal cotyledon is compromised (Redmer of high maternal prolactin concentrations, if any, is et al. 2009), while delayed and reduced appearance of unknown but aligns with similar observations in different placental lactogen and pregnancy-specific protein-B models of fetal growth restriction including hyperthermic concentrations in the maternal circulation suggests sheep (Bell et al. 1989, Regnault et al. 1999) and protein- impaired trophoblast cell migration (Wallace et al. restricted rats (Fernandez-Twinn et al. 2003). A degree 1997a, Lea et al. 2007). By mid-pregnancy, angiogenic of physiological stress is arguably common to these growth factor ligand and receptor mRNA expression, as models and could theoretically impinge on the well as markers of proliferation and apoptosis within

Journal of J M Wallace Adolescent pregnancy 242:1 T9 Endocrinology the placenta are perturbed (Lea et al. 2005, Redmer et al. approach to manipulating the placental growth trajectory 2005). These adaptations precede the change in placental of overnourished dams has involved supplementing mass which does not significantly diverge from controls maternal hormones. Progesterone supplementation of until 0.72 gestation (Wallace 2011), but nonetheless overnourished dams from day 5 to 55 of gestation restored they are commensurate with an altered developmental circulating hormone levels to control levels and increased and haemodynamic trajectory. Accordingly, uterine lamb birthweight by 30%, but this change was independent blood flow was attenuated by ~40%, and umbilical of a corresponding change in placental size at delivery, artery Doppler indices were greater in overnourished suggesting a direct effect of progesterone on the embryonic pregnancies at mid-gestation and predictive of reduced inner cell mass (Wallace et al. 2003b). Similarly, oestrogen fetal growth later in pregnancy (Wallace et al. 2008b, replacement from day 50 to day 90 of gestation failed Carr et al. 2012). The latter is in line with observations at to impact feto-placental growth or placental vascularity ~32 weeks gestation in growing vs non-growing human as assessed in late gestation (Yunusova et al. 2011). In adolescents (Scholl et al. 1997). By ~day 133 of the ovine contrast, when adolescent mothers received exogenous pregnancies, placental mass was ~45% lower than that growth hormone (GH) during the main placental growth in controls and proportionate reductions in uterine and phase (day 35–80), their accretion of adipose tissue was umbilical blood flows, uteroplacental glucose and oxygen reduced, and in GH-treated overnourished dams, this consumption and lactate production, as well as placental alteration in nutrient partitioning priorities favoured glucose transport, were observed (Wallace et al. 2002, uteroplacental and fetal growth at study end (day 81, 2003a). Wallace et al. 2004b). In a second study, GH treatment of overnourished dams targeted either the placental growth phase (day 35–65) or later in pregnancy when Potential for manipulating placental function placental growth is complete, and the nutrient demands in overnourished adolescents of the fetus are high (day 95–125). Both exposures had a profound influence on maternal metabolism resulting As restricted placental development is central to the in insulin resistance, reduced lipogenesis and three-times pathology of fetal growth restriction in this model, higher circulating glucose concentrations. However, in a few approaches have attempted to manipulate the this study, GH treatment during early pregnancy did not placental growth trajectory to enhance fetal growth. The have a sustained effect on placental or fetal size, whereas first of these simply involved switching dietary intakes treatment during late pregnancy increased fetal weight by during specific windows of gestation and showed that ~25% and had a large impact on fetal adiposity as measured normal placental development and fetal growth could be at day 130 of pregnancy, independent of placental size achieved by reducing maternal intakes from a high to a (Wallace et al. 2006a). On balance GH supplementation control level at day 50 of gestation, whereas an abrupt has dramatic effects on maternal endocrinology and increase in dietary intake at this stage reduced placental the partitioning of nutrients within the maternal body, and fetal growth to the same degree as in continuously but the effects on the fetus reflect an abnormally high overnourished dams (Wallace et al. 1999). However, fetal transplacental glucose supply rather than a modified growth could not be rescued by radically reducing dietary placental growth trajectory. Furthermore, while increased intake and switching the mothers from a highly anabolic fetal lipid deposition and the associated increase in hepatic to a catabolic state during the final third of pregnancy, glycogen stores could be an important energy source and despite changes in placental angiogenic growth factor protect the newborn from hypothermia in the neonatal and receptor gene expression consistent with blood period, it is likely to be maladaptive in the longer term. vessel re-modelling (Redmer et al. 2012). Together these More worryingly, a similar GH treatment regime in late studies highlight that the placenta is most sensitive to pregnancy in a different model of fetal growth restriction nutrition during its main proliferative growth phase. involving placental embolisation was associated with While fetal growth cannot be recovered once placental hydanencephalic brain lesions in three of five fetuses De( mass is reduced beyond its functional capacity, there is Boo et al. 2008). Recently an alternative approach directly evidence of differential placental vascular adaptations in targeting the uteroplacental circulation of compromised the late gestation placenta of continuously overnourished adolescent pregnancies has been evaluated. This was adolescent’s dependent on the degree of fetal growth based on the premise that local uterine artery adenovirus restriction observed (Carr et al. 2016a). The second (Ad.)-mediated overexpression of vascular endothelial

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-18-0670 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 11:49:06AM via free access Journal of J M Wallace Adolescent pregnancy 242:1 T10 Endocrinology growth factor (VEGF) in overnourished dams would pituitary, thyroid, adrenal glands, gonads and pancreas) increase uterine blood flow as demonstrated in normally were predicted by the weight of the fetus (P = 0.001 or developing adult pregnancies (Mehta et al. 2011). In less), rather than the dam’s nutritional treatment. The two separate studies Ad.VEGF administration in mid- allometric plots of the fetal brain compared with the liver, pregnancy (day 89) increased fetal growth velocity as and the lungs compared with the kidneys, are illustrated measured by ultrasound 3 and 4 weeks after injection. At and serve to emphasise the extent of brain sparing in 0.9 gestation, there were fewer markedly growth-restricted fetuses of overnourished dams (Fig. 2A and B). The latter fetuses (Carr et al. 2014) and at term average birthweight fetuses were further categorised as markedly growth was increased by 20% (Carr et al. 2016b). Importantly, restricted when their bodyweight was more than two there were no adverse responses to the gene therapy and standard deviations below the mean sex-specific weight of lambs continued to thrive and exhibit appropriate growth fetuses in the control group. This approach revealed that, and body composition for their size in the early postnatal in addition to the brain, the relative pituitary, kidney and period. adrenal gland weights were higher in growth-restricted compared with non-perturbed and control groups (Fig. 2C, D, E and F). Consequences for placental development and Ovine paradigms permit access to the placental and uteroplacental blood flows: fetal circulations to examine fetal endocrine and nutrient undernourished model status, nutrient uptakes and fetal metabolism. Accordingly, by late gestation and relative to normally growing controls, Final placental size is unperturbed in undernourished the growth-restricted fetuses of overnourished dams are adolescents, but the relatively low nutrient availability hypoglycaemic, mildly hypoxic, have low insulin and in these mothers does significantly impact on vascular IGF-1 concentrations and high lactate levels. Absolute development within the placenta. Thus, a 20% reduction umbilical (fetal) uptakes of glucose, oxygen and amino in capillary area density within the maternal caruncle acids are reduced but are normal when expressed on a fetal was observed at both mid and late gestation (Luther et al. weight-specific basis (Wallace et al. 2002, 2003b). Similarly, 2007b), and closely mirrored an average reduction in when the fetal sensitivity to insulin and glucose was uterine blood flow of 22% measured between these two examined during fetal hyperinsulinaemic–euglycaemic stages using perivascular flow probes Wallace( 2016). These and hyperglycaemic–euinsulinaemic clamps, normal haemodynamic differences between undernourished body weight-specific responses to short-term experimental and control groups are likely to contribute to low fetal increases in insulin and/or glucose were observed nutrient supply, but the increasingly hypoglycaemic (Wallace et al. 2007). These maintained mechanisms of conditions in undernourished dams are still considered insulin action and glucose uptake/utilisation capacity the major limitation to fetal growth in these pregnancies. allow the fetus to protect essential metabolic functions In support, the reduction in capillary area density while growth velocity slows. Surprisingly, these growth- persisted when underfed mothers were switched to control restricted fetuses have a comparatively fat phenotype intakes between mid and late gestation, but despite this prenatally in that bodyweight-specific perirenal fat mass fetal weight was partially restored in direct response to and carcass fat content are modestly increased compared re-alimentation by study end (Luther et al. 2007b). to controls by late gestation (Matsuzaki et al. 2006), and plasma cholesterol and LDL concentrations are higher at birth (Wallace et al. 2012). Greater adiposity in these Consequences for fetal and offspring otherwise growth-restricted fetuses may be caused by endocrine systems: overnourished model exposure to higher maternal and thus fetal glucose early in gestation in overnourished dams (Redmer et al. 2009) Serial ultrasonography of multiple indices of prenatal size influencing adipocyte development before placental size reveals reduced growth velocity from around day 100 of and hence fetal glucose supply is impaired. Definitive gestation forwards in fetuses of overnourished dams (Carr causation in the overnourished model is lacking, but in the et al. 2012). Regression analysis using natural logarithms undernourished model, key genes involved in adipocyte of data obtained from fetuses necropsied at day 130 of proliferation and function are expressed in fetal perirenal gestation demonstrates that individual organ weights, fat tissue at mid-gestation when they are downregulated including those of the main endocrine organs (namely, by maternal undernutrition and the associated low

Journal of J M Wallace Adolescent pregnancy 242:1 T11 Endocrinology

Figure 2 Allometric plots of brain, liver (A), kidneys and lungs (B) of fetuses from adolescent dams offered a control nutrient intake (blue symbols) or overnourished (red symbols) and killed at day 130 of gestation. Bodyweight-specific weight of fetal brain (C), pituitary (D), kidneys (E) and adrenals (F) in relation to maternal nutrition and growth status. Overnourished (ON) pregnancies were categorised as FGR if fetal weight was less than two standard deviations below the sex-specific weight of the optimally nourished control group, thus <3755 g for males and <3638 g for females. Numbers per group shown in (C) and summarised from four studies (Wallace et al. 2006a, Yunusova et al. 2011, Carr et al. 2014 and J M Wallace, unpublished observations). For (C, D, E and F), post hoc Tukey comparisons are shown and where letters differ,P < 0.01. glucose supply leading to reduced fetal adiposity by late the life-course (11, 41, 64 and 107 weeks). The small fat gestation (Wallace et al. 2015). Glucose is the main fetal phenotype observed in growth-restricted fetuses in late fuel and it is notable also that anorexigenic neuropeptide gestation was also apparent in both sexes at weaning expression in the fetal hypothalamus is sensitive to fetal but not at the adolescent or early adult stages when lean hyperglycaemia at mid-gestation with effects persisting tissue growth was the dominant nutrient partitioning throughout fetal life (Adam et al. 2008, 2011). Once priority. The metabolic phenotype of these lambs has released from the nutritional constraint imposed by the also been serially documented: during the suckling period in utero environment, growth-restricted lambs born to and into adolescent life, fasting insulin concentrations overnourished adolescents display rapid fractional growth and insulin secretion after glucose challenge are greater rates relative to their size at birth. Growth is particularly in growth-restricted offspring, in line with their higher rapid during the suckling period and the extent of growth fractional growth rates and increased body fat percentage compensation at the point of weaning (11 weeks of age) at weaning. This enhanced insulin sensitivity does not depends on the degree of prenatal growth impairment. persist but the prenatally growth-restricted offspring Thus, when average birthweight is reduced by a modest of overnourished dams are consistently characterised 22% relative to controls, complete catch-up in terms of across studies by higher fasting glucose concentrations weight is observed by weaning (Wallace et al. 2010, 2012), and/or greater glucose area-under-the-curve after glucose but when birthweight is ~40% lower, the lambs remain challenge, indicative of glucose intolerance (Wallace lighter at weaning and continue to have modestly reduced et al. 2012, 2014a, 2018). During the suckling period in weight and stature at study end in mid-adulthood despite offspring of overnourished dams, relatively higher fasting being fed to appetite (109 weeks, Wallace et al. 2018). In glucose concentrations in prenatally growth-restricted the latter study, serial dual-energy X-ray absorptiometry vs non-perturbed lambs reflect an inverse relationship (DEXA) revealed that prenatally growth-restricted lambs between birthweight and hepatic mRNA expression had lower bone mineral density than controls throughout and activity of a key gluconeogenic enzyme, glucose

6-phosphatase (Fig. 3). In the life-course study, altered glucose metabolism was evident at all ages, and by the time mature body size had been reached in mid-adulthood, the animals had experienced a prolonged period of glucose intolerance and the associated alteration in tissue glucose uptake, and hence, an obese phenotype was once again evident, particularly in females that reach peak bone mass and adult size before their male counterparts (Wallace et al. 2018). Further there is evidence that the metabolic forerunner of this adverse phenotype, namely glucose intolerance at ~12 months of age, can be ameliorated by restricting nutrient intake between adolescent and young adult life – an effect specific to females (Wallace et al. 2012). Thus, when considering any potential target of developmental programming, it is important to differentiate between the sexes when possible. For example, differences in adipose tissue development are evident in fetal life with normally growing females having a greater carcass fat percentage at mid-pregnancy, and a higher bodyweight-specific perirenal fat mass and leptin gene expression in late pregnancy than males (Fig. 4). This early dissimilarity in adiposity is likely to reflect differences in sex steroid status and is maintained postnatally: independent of birthweight at 11 weeks of age, females are characterised by greater visceral fat mass, leptin gene expression, adipocyte size and carcass fat, while males exhibit faster growth rates in line with reduced hepatic IGF-1 DNA methylation, higher IGF-1 mRNA expression and greater plasma IGF-1 concentrations (Wallace et al. 2014a,b, Carr et al. 2015). The early divergence in growth and body composition is also reflected in the brain centres involved in energy balance with females having higher hypothalamic expression of anorexigenic genes and lower expression of orexigenic genes than males (Adam et al. 2013). Furthermore, serial DEXA measurements suggest that sex differences in adiposity (females > males) and bone mineral density (males > females) are life-long (Wallace et al. 2018). Theoretically, altered hypothalamic–pituitary– adrenal (HPA) axis function may underlie and contribute to the adverse metabolic phenotype of growth-restricted offspring. The greater bodyweight-specific adrenal gland Figure 3 mass (Fig. 2F) and premature activation of the fetal HPA Mean fasting glucose concentrations at 7 weeks of age in male and axis leading to early delivery (Fig. 1C) in the most severely female offspring of overnourished dams in relation to prenatal growth growth-restricted pregnancies are arguably commensurate category (A). Pregnancies were categorised as FGR or non-FGR based on a two times standard deviation cut-off below the mean birthweight of with enhanced in-utero stress, although no evidence of normally-grown controls from earlier studies. Relationship between altered cortisol concentrations in mother or fetus was birthweight and relative hepatic glucose-6-phosphatase gene expression found, albeit measured at a single timepoint in late (B) and between birthweight and hepatic glucose-6-phosphatase enzyme activity in the same animals at 11 weeks of age. Glucose data from gestation (Wallace et al. 2000). Similarly, when stress tests Wallace et al. (2014a), other data from JM Wallace, JS Milne, RP Aitken, involving corticotropin-releasing hormone plus arginine unpublished observations.

Journal of J M Wallace Adolescent pregnancy 242:1 T13 Endocrinology

Figure 4 Carcass fat percentage at day 80 of gestation (A), relative perirenal fat mass (B) and relative leptin gene expression (C) at day 90 and 130 of gestation in normally growing male and female fetuses from optimally nourished control adolescents. Inset in (C) is haematoxylin and eosin-stained sections of perirenal fat from a representative male and female fetus showing differences in unilocular cell size (JM Wallace, JS Milne, RP Aitken, unpublished observations). Hepatic IGF-1 DNA methylation percentage in male and female offspring of overnourished dams (D) and the relationship between relative hepatic IGF-1 mRNA gene expression and plasma IGF-1 concentrations in the same animals at 11 weeks of age (E). Data from Carr et al. (2015). vasopressin challenge were performed in growth-restricted programmed alterations in the development and function vs normally grown females at three ages up to 24 months of the HPA axis are unlikely to be central to the phenotype (40% birthweight differential) or in growth-restricted of the prenatally growth-restricted offspring described or normal offspring of both sexes at 6 months of age earlier. (20% birthweight differential), baseline and stimulated In contrast, there is robust evidence that the adrenocorticotrophin and cortisol concentrations were developing reproductive axis is impacted by maternal independent of maternal nutrition and birthweight nutrition, particularly in female fetuses. The resting category (Wallace et al. 2011). On this basis, nutritionally reserve of primordial follicles that determines lifetime

https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-18-0670 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 11:49:06AM via free access Journal of J M Wallace Adolescent pregnancy 242:1 T14 Endocrinology supply of potentially fertilisable eggs is established gestation necropsy are consistent with hypoglycaemia, before birth (McNatty et al. 1995). Accordingly, in the there is only a tendency towards lower peripheral insulin adolescent paradigm, large reductions in primordial concentrations, and IGF-1 levels are not perturbed (Luther follicle number (up to 80% less) were measured at both et al. 2007a). Liver glycogen stores are depleted, and body mid and late gestation in fetuses from overnourished composition analysis indicates a thin phenotype with dams and reflected the attenuated placental weight, and reduced adiposity but preserved skeletal growth (Luther hence, fetal nutrient supply, measured at both stages (Da et al. 2007a, Wallace et al. 2015). Unlike the overnourished Silva et al. 2002, 2003). Pituitary gonadotrophin mRNA model, the fetal phenotype with respect to glycaemia, was unaffected at mid-pregnancy but by late gestation, bodyweight and carcass fat percentage can be partially LHβ mRNA was higher in the most growth-restricted rescued by switching undernourished dams to a control fetuses. This indicates reduced oestrogen feedback from intake between mid and late pregnancy. The impact of the placenta and/or fetal ovary directly regulating fetal this switch is also seen within the fetal hypothalamus pituitary function, or alternatively a temporal delay in in that the increased expression of three orexigenic the maturation of the pituitary gland. Irrespective, these neuropeptides in response to nutrient deficit can largely be prenatally growth-restricted females reach puberty at an normalised after improving nutrition (Adam et al. 2015). equivalent weight and age as normally grown controls, and After delivery, there was no evidence of compensatory the normality and duration of ovarian cyclicity during the growth in the offspring of continuously undernourished first breeding season is also similar (Da Silva et al. 2001). dams and likewise at 6 months of age glucose metabolism Nevertheless, the severely diminished ovarian reserve is and adrenal responses to stress tests in both sexes were likely to impact ovulation rate and hence fertility as the equivalent to the same sex control groups (Wallace et al. animal ages. Although males continuously produce new 2010, 2011, 2012). spermatozoa after puberty, the number of Sertoli cells, the primary determinant of sperm production and testes size in adulthood are determined by proliferation during the Conclusion fetal, neonatal and peripubertal periods (Sharpe et al. 2003). Nonetheless, the number of Sertoli cells, seminiferous These ovine paradigms unequivocally demonstrate that cords and pituitary gonadotroph mRNA expression was the maternal–fetal competition for nutrients that arises not impacted by maternal nutrition when assessed at mid- during pregnancy in young adolescents is sensitive to gestation in our model (Da Silva et al. 2003). However, in maternal nutrition. While nutrient reserves at conception contrast to females, male lambs with a 47% suppression in play a role, it is the dietary manipulation of maternal birthweight had slower absolute growth rates, delayed age growth and body composition thereafter which has the at puberty, attenuated testosterone concentrations and a most negative influence on pregnancy outcome: rapid smaller testicular volume per unit live-weight between 28 maternal growth constrains placental development and 35 weeks of age (Da Silva et al. 2001). As Sertoli cells and function and is more detrimental than preventing set the upper limit for sperm production and continue maternal growth. Maternal and placental endocrine to proliferate until puberty, it is likely that impaired fetal systems and associated nutrient partitioning priorities are growth velocity and a delay in reaching an appropriate differentially altered in both paradigms with downstream pubertal weight will impact initial sperm quality and consequences for fetal nutrient supply, organ system quantity, but this has not been expressly tested. development, body composition and metabolism, some of which are life-long. From a public health perspective, strategies to prevent pregnancy occurring during Consequences for fetal and offspring adolescence should remain the priority, but in cultures endocrine systems: undernourished model where early marriage soon after menarche is the norm, girls with a low BMI should be counselled to gain weight and The phenotype of fetuses and offspring from achieve a normal BMI before conception. Subsequently undernourished adolescent dams has been less dietary intakes should be sufficient to maintain maternal intensively studied. Relative to controls, the modestly nutrient reserves throughout pregnancy and thereby meet growth-restricted fetuses of undernourished dams do fetal fuel requirements in the final trimester: documenting exhibit relative brain sparing but all other organ weights changes in skinfold thickness as well as measuring weight are unperturbed, and while plasma glucose levels at late gain may be a simple and effective approach and requires

Journal of J M Wallace Adolescent pregnancy 242:1 T15 Endocrinology evaluation. Where pregnancies are unplanned and Bell AW, McBride BW, Slepetis R, Early RJ & Currie WB 1989 Chronic heat food readily available, biologically immature mothers stress and prenatal development in sheep: 1. Conceptus growth and maternal plasma hormones and metabolites. Journal of Animal Science should be made aware of the potential consequences of 67 3289–3299. (https://doi.org/10.2527/jas1989.67123289x) excessive gestational weight gain with respect to placental Brosens I, Muter J, Gargett CE, Puttemans P, Benagiano G & Brosens JJ development, and additional early monitoring of placental 2017 The impact of uterine immaturity on obstetrical syndromes during adolescence. American Journal of Obstetrics and Gynecology 217 size and uteroplacental blood flows may help identify 546–555. (https://doi.org/10.1016/j.ajog.2017.05.059) those at risk of perinatal complications. For the offspring Carr DJ, Aitken RP, Milne JS, David AL & Wallace JM 2012 Fetoplacental of young adolescent mothers, individuals with the lowest biometry and umbilical artery Doppler velocimetry in the overnourished adolescent model of fetal growth restriction. American birthweight are likely to be vulnerable to impaired fertility Journal of Obstetrics and Gynecology 207 141.e6–141.e15. (https://doi. and adverse metabolic health and should be cognisant of org/10.1016/j.ajog.2012.05.008) this when making their own life choices. Carr DJ, Wallace JM, Aitken RP, Milne JS, Mehta V, Martin JF, Zachary IC, Peebles DM & David AL 2014 Uteroplacental adenovirus VEGF gene therapy increases fetal growth velocity in growth-restricted sheep pregnancies. Human Gene Therapy 25 375–384. 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Received in final form 2 January 2019 Accepted 7 January 2019 Accepted Preprint published online 7 January 2019