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Fetal growth factors and fetal nutrition
Seminars in Fetal & Neonatal Medicine 18 (2013) 118e123
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Fetal growth factors and fetal nutrition F.H. Bloomfield a, b, c, Ana-Mishel Spiroski a, b, J.E. Harding a, * a
Liggins Institute, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Gravida: National Centre for Growth and Development, University of Auckland, Auckland, New Zealand c Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand b
s u m m a r y Keywords: Diabetes Growth factors Insulin Pregnancy Prenatal nutrition Obesity
Optimal fetal growth is important for a healthy pregnancy outcome and also for lifelong health. Fetal growth is largely regulated by fetal nutrition, and mediated via the maternal and fetal glucose/insulin/ insulin-like growth factor axes. Fetal nutrition may reflect maternal nutrition, but abnormalities of placental function can also affect fetal growth, as the placenta plays a key intermediary role in nutritional signalling between mother and fetus. Fetal nutrition also impacts on the development of key fetal endocrine systems such as the glucoseeinsulin and insulin-like growth factor axes. This is likely to contribute to the link between both fetal growth restriction and fetal overgrowth, and increased risks of obesity and impaired glucose tolerance in later life. This review focuses on the associations between maternal and fetal nutrition, fetal growth and later disease risk, with particular emphasis on the role of insulin-like growth factors and the importance of the periconceptional period. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Maternal nutrition from before pregnancy through to delivery can affect fetal growth and size at birth. Maternal underweight, poor gestational weight gain and exposure to famine in mid or late gestation all decrease birthweight and are associated with increased risk for low birthweight (LBW) and small-forgestational-age (SGA) babies.1e3 Maternal obesity and excessive gestational weight gain are associated with increased birthweight and increased risk for large-for-gestational-age babies.4,5 However, the magnitude of effect, particularly of severe maternal undernutrition as experienced in the Dutch Famine, is relatively small (a decrease in birthweight of w200 g with official daily rations of 400e800 calories)3 reflecting the ability of the placenta and fetus to maintain nutrient supply and survival of the conceptus. Perhaps more surprising is the even smaller positive effect of a balanced protein-energy supplementation of undernourished women from mid-pregnancy on birthweight, reported in a meta-analysis to be only 73 g [95% confidence interval (CI): 30e117 g].6 This relatively small effect likely reflects both the fact that maternal nutrition does not equal fetal nutrition, because there are many other factors that can affect fetal nutritional supply,7 and also that placental size and efficiency themselves may be determined in part by factors, including maternal nutrition, that operate very early in, or
* Corresponding author. Tel.: þ64 9 3737599. E-mail address: [email protected] (J.E. Harding). 1744-165X/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.siny.2013.03.003
even before, pregnancy.8 Thus, nutrition of the developing conceptus should be thought of in two distinct phases: histiotrophic nutrition, prior to the establishment of placental blood flow in the latter half of the first trimester, and haemotrophic nutrition via the placenta.7 2. Role of the placenta in fetal nutrition During histiotrophic nutrition, the embryo receives nutrition directly from the surrounding milieu, for example, secretions from the uterine glands.9 Studies in rodents indicate that the embryo responds to maternal nutritional status in these very early stages of pregnancy, for example by altering allocation of embryonic cells to the inner cell mass and trophectoderm lineages and by altering cell proliferation rates.10 Reduced trophectoderm cell numbers, which may impact on later placental size and function, are also associated with fetal adaptations later in gestation, such as increased nutrient uptake by the visceral yolk sac endoderm, which preserve fetal growth but which are associated with postnatal overweight and increased blood pressure.11 In-vitro fertilization techniques and cloning both also have been associated with altered placental size, mostly overgrowth, with consequent fetal overgrowth.12,13 In bovine pregnancies generated by nuclear transfer, placental overgrowth is associated with increased expression of IGF binding proteins (IGFBP)-2 and -3 in placental tissue and with increased IGF-1 concentrations in fetal plasma and in allantoic fluid.14 Human epidemiological studies also suggest that placental size and morphometry may reflect maternal
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nutrient resource at the time of conception and may be related to lifelong risk of disease.15 Thus, the prevailing nutrient status in the very early stages of pregnancy can influence later placental development and hence fetal growth. During pregnancy, as conceptus size and nutrient requirements increase, placental transfer capacity must also increase.16 This is achieved through a variety of mechanisms, including increasing placental surface area for nutrient transfer, thinning of the trophoblast barrier, an increase in fetal capillary surface area, increases in placental nutrient transporter abundance and modulation of placental blood flow.17,18 A key example is the regulation of placental transfer capacity for glucose, the major substrate for fetal oxidative metabolism.19 Glucose is transported across the placenta by facilitated diffusion down a concentration gradient. The development of a degree of maternal insulin resistance during midelate pregnancy aids fetal glucose supply by increasing the magnitude of the gradient. In addition, data from in-vitro studies on human placentae suggest that there is a redistribution of the expression of insulin receptors throughout gestation, with increased expression on fetal surfaces in late gestation.20 The maternaleplacentalefetal IGF axis also plays a key role in fetal nutrient supply and in fetal growth. Maternal and fetal circulating IGF-1 and IGFBP concentrations are regulated by nutrition21,22 and are associated with fetal growth.23,24 The IGFs and their binding proteins have the potential to be involved in many aspects of placental development and function (reviewed by Forbes and Westwood23 and Sferruzzi-Perri et al.24) and are expressed in the placenta from early in gestation.25 In-vitro studies suggest that IGF-1 and IGF-2 stimulate both system A amino acid uptake and glucose uptake in cultured trophoblasts from first trimester and term placentae regulated in part by the nonphosphorylated form of IGFBP-1.26e28 These in-vitro studies are supported by experiments in healthy guinea-pigs, in which maternal IGF-1 infusion in mid-pregnancy increased placental transport via the system A transporter (slc38a2) in both mid and late pregnancy,29,30 and by studies in growth-restricted ovine fetuses, in which intra-amniotic IGF-1 treatment in late pregnancy increased fetal growth and placental mRNA expression of the system A (slc38a4) and L (slc7a8) amino acid transporters.31 Further, in-vivo studies in sheep show that maternal and fetal circulating IGF-1 concentrations interact to regulate partitioning of substrates between the fetus and placenta, with maternal IGF-1 stimulating placental glucose and amino acid uptake, whereas fetal IGF-1 stimulates fetal glucose and amino acid uptake from the placenta and inhibits fetal protein oxidation.32,33 These interactions provide a mechanism by which fetal growth is regulated according to substrate supply. The paternal IGF axis also influences placental function and fetal growth, particularly the imprinted igf2 and the igf2-H19 gene locus.34 Single nucleotide polymorphisms (SNPs) of the paternally transmitted igf2 gene in humans are associated with increased maternal glucose in response to a glucose tolerance test in midgestation and with increased placental IGF-2 protein content at birth, whereas maternally transmitted SNPs of igf2 are not.35 Although these data suggest a role of paternally inherited igf2 in both placentation and fetal nutrient availability, there was no association with birthweight, perhaps because the effect on maternal glucose concentrations was small. The potential importance of IGF-2 in placental development and function is clearly demonstrated by the phenotype in mice lacking the placental-specific transcript of the igf2 gene (P0). In these mice, placental growth is reduced, there is reduced diffusional exchange surface area and increased barrier thickness,36 resulting in decreased passive permeability for nutrients.37 However, initially
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fetal growth is maintained secondary to upregulation of placental glucose and amino acid transporters38 with growth restriction becoming apparent only in late gestation. Intriguingly, placental amino acid transporters remain upregulated and this adaptation is only abolished if fetal igf2 is removed in addition to the placental transcript. Thus, it appears the placenta can respond to fetal nutrient demand signals through regulation of its nutrient transporters and that this regulation may occur, at least in part, through actions of the insulin-like growth factors and their binding proteins. 3. Maternal nutrition and fetal growth 3.1. Effects of maternal nutrient restriction in early pregnancy on fetal growth and development There is increasing evidence that maternal nutritional status preconception and in early pregnancy, when nutrient requirements of the developing embryo are tiny, is signalled to the fetus and can influence both fetal growth and organ development throughout pregnancy. For example, a systematic review of 20 studies including 171,806 women found that maternal underweight was associated with a relative risk for low birthweight of 1.58 (95% CI: 1.37e1.82).2 In a prospective study in women of childbearing age, active dieting or a poor nutritional intake preconception was associated with decreased shunting of fetal blood through the ductus venosus, resulting in increased flow to the liver.39 This, in turn, was associated with greater offspring adiposity at birth and 4 years of age.40 However, it is important to note that the effects of nutritional status in early pregnancy on long-term metabolic risk may be independent of altered size at birth. Follow-up of offspring of women exposed to the Dutch Famine at the end of World War II found increased risks of heart disease, hyperlipidaemia and obesity in those conceived during the famine and impaired glucose tolerance in those exposed to famine in utero in late gestation, while only the latter group showed reduction in birthweight.3 There has been a recent explosion of interest in the potential role of epigenetics as a mediator of the long-term effects of an adverse intrauterine environment. Offspring from the Dutch Famine studied in the seventh decade of life showed increased methylation in seven loci, including igf2 and inisigf (a fusion transcript between the insulin promoter and the igf2 gene that arises from igf2/H19 locus in early development), in those exposed to famine preconception, whereas exposure in late gestation was associated with increased methylation in only one locus (gnasas).41,42 Epigenetic differences in metastable epialleles also have been reported in 7-year-old offspring of women in the Gambia who conceived during the rainy season (a season of famine) compared with the harvest season.43 Interestingly, a study of epigenetic modifications in the igf2/H19 locus in babies born small-forgestational-age did not find methylation differences,44 indicating once again that fetal developmental adaptations in response to maternal nutrition are not causally related to altered fetal growth. Further, the relationship between maternal nutritional status and the metabolic regulation of the offspring may extend beyond the next generation.45,46 4. Fetal nutrition, fetal growth factors and fetal growth Many fetal hormones are regulated by nutrition7 and this includes the IGFs and their binding proteins and insulin. Whereas insulin is a passive regulator of fetal growth, dependent upon substrate supply,47 the nutritional regulation of IGFs and their
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binding proteins is thought to be important for the regulation of fetal growth. IGF-2 is most important in embryonic and early fetal growth48 and IGF-1 is thought to be the principal endocrine regulator of late gestation fetal growth.49 Studies in sheep have demonstrated that fetal plasma IGF-1 concentrations are regulated by fetal glucose and insulin concentrations21 and studies in rats have reported that maternal undernutrition increases fetal plasma concentrations of IGFBP-1 and -2, thereby restricting IGF-1 bioavailability.50 IGF-1 supplementation of ovine fetuses through a variety of routes has been shown to result in both growth of specific organs in normally grown fetuses (intravenous treatment with supraphysiological does of IGF-1)51 and increased growth trajectory in growth-restricted fetuses.31,52 In humans, cord plasma IGF-1 and IGFBP-3 concentrations are significantly decreased in growth-restricted infants53 and are related to postnatal growth patterns.54 Thus, the fetal somatotrophic axis responds to maternal and fetal nutritional signals to play a key role in fetal growth. 4.1. Fetal nutritient restriction and development of the glucoseinsulin axis Experimental studies also have demonstrated that maternal nutritional status before and in early pregnancy influences not only fetal growth trajectory but also development of the fetal glucosee insulin axis and, in turn, postnatal glucose tolerance and insulin sensitivity. In sheep, moderate maternal nutrient restriction from two months prior to mating and continuing only one month into a five-month pregnancy (with ad-libitum intake thereafter) decreased fetal growth trajectory in late gestation.55 Size at birth was not greatly altered, but there was perturbation of the normal postnatal relationships between factors normally regulating neonatal growth.56 Of note, fetuses of periconceptionally undernourished ewes demonstrated altered regulation of insulin secretion in response to stimulation consistent with accelerated maturation of the fetal glucoseeinsulin axis.57 However, after birth offspring showed a progressive decline in glucose tolerance with age.58 Numerous other paradigms of fetal nutrient restriction secondary to placental insufficiency also have been reported to result in altered development of the fetal glucoseeinsulin axis (reviewed by Green et al.59). For example, placental insufficiency secondary to maternal hyperthermia in sheep results in impaired fetal b-cell mass and insulin secretion in late gestation.60,61 These changes were associated with increased insulin sensitivity,62 also reported in rats born growth-restricted following maternal uterine artery and vein ligation,63 perhaps as an adaptive mechanism to maintain tissue substrate supply. These findings are mirrored by observations that severely growth-restricted human infants have reduced b-cell fraction and smaller islets64 and deficits in b-cell function persisting for 48 h after birth.65 SGA babies also have a degree of hepatic resistance to insulin shortly after birth, with loss of the relationship between hepatic glucose production rate and plasma insulin concentrations.66 However, these deficits may be masked by increased peripheral insulin sensitivity.65 These adaptations in the fetus can be seen as mechanisms to promote fetal survival in the face of an impaired nutrient supply. They promote peripheral glucose utilisation, essential for brain and heart, and reduce the demand for amino acids for growth, thereby maintaining energy supply at the expense of growth. These tissuespecific adaptations in insulin sensitivity may, however, then have postnatal consequences once the restricted nutritional environment is no longer present.67 Indeed, a longitudinal study of 55 babies with a birthweight below the 5th percentile reported that, despite increased insulin
sensitivity at birth, insulin resistance had developed by 3 years of age and was correlated with degree of ‘catch-up’, or accelerated postnatal, growth.68 The relationship between insulin sensitivity and accelerated postnatal growth was already present at 1 year of age in another cohort of 85 SGA babies.69 Similar findings were reported for IGF-1 concentrations, which were decreased at birth in SGA infants but increased at 3 years, indicative of relative IGF-1 resistance, and correlated with degree of accelerated postnatal growth between birth and 3 years.70 4.2. Fetal nutrition and growth in twin pregnancies Twins, as a population, can be thought of as being relatively growth-restricted71 with studies in sheep suggesting that a decreased growth trajectory likely is set in early pregnancy.72 Twins within a pair are often discordant for growth. The more growthrestricted twin has been reported to have lower cord plasma concentrations of insulin and IGF-1 and higher concentrations of IGFBP-1 than the appropriately grown twin, with IGFBP-1 concentrations inversely associated with plasma concentrations of insulin and amino acids.73 In sheep, twin fetal size is less than that of singletons by two-thirds of gestation and daily fetal growth rate is less.74 As with maternal undernutrition, altered fetal growth in twin sheep is associated with evidence of accelerated maturation of the pancreas.74 Twin fetal sheep also have been reported to be more insulin sensitive than their singleton counterparts.75 Postnatally, glucose tolerance in twin lambs is related to birthweight, with the more growth-restricted lamb of a pair displaying increased glucose tolerance,76 consistent with the greater insulin sensitivity in growth-restricted children described above. However, by early adulthood twin sheep have similar glucose tolerance to singletons.77,78 Consistent with these findings, recent human twin studies have found that in their seventh decade twins are more insulin resistant, have greater abdominal obesity and a greater incidence of type 2 diabetes than singletons.79 Insulin sensitivity and abdominal fat mass both have been reported to be inversely related to birthweight differences within twin pairs, with a one standard deviation increase in birthweight associated with a 16% decrease in insulin sensitivity in elderly twins80 and with a 3.2 volume/% decrease in intra-abdominal fat mass in young twins.81 Thus, twin conception, a naturally occurring phenomenon, is associated with altered fetal growth and endocrine development with consequences for life-long metabolic health. This has implications not only for the epidemic of twins that has accompanied assisted reproductive techniques82,83 but potentially also, as the origins of these effects appears to be in early pregnancy, for our understanding of the fundamental mechanisms that underlie these observations. 5. Fetal nutritional abundance Maternal obesity and impaired glucose tolerance are increasing problems in current obstetric practice, and are associated with altered fetal growth and long-term health of the offspring.84 Increased maternal glycaemia may be present with maternal obesity,85 gestational diabetes86 or insulin-dependent diabetes,87 and results in an increased glucose supply to the fetus, associated with the delivery of an LGA infant.88 Both maternal and gestational diabetes are associated with accelerated early fetal growth rate,89,90 fetal hyperinsulinaemia, increased cord plasma IGF-1 and IGF-2 concentrations91 correlating with larger size at birth92 and increased adiposity at term.89,93 Studies of women with a mutation or polymorphism in the glucokinase gene have demonstrated elegantly the role of
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maternal glycaemia in fetal growth. Women with a mutation in the glucokinase gene have elevated basal circulating glucose concentrations. Offspring of these women are more likely to be macrosomic and babies most at risk are those who have not themselves inherited the mutation (and who, therefore, do not have a problem with glucose sensing).94 Even a common polymorphism of the b-cell specific promoter of the glucokinase gene in the mother, which is associated with only a 0.06 mmol/l increase in fasting plasma glucose concentration, is associated with a small but statistically significant (64 g) increase in birthweight.95 Fetuses developing in an environment of impaired maternal glucose tolerance are themselves at increased risk of impaired glucose tolerance and type 2 diabetes in later life, and this risk is greater than that expected by genetic factors alone.96 It appears that this is due to reduced b-cell function, as non-diabetic offspring of mothers with type 2 diabetes have decreased insulin secretion compared with non-diabetic offspring of fathers with type 2 diabetes, despite similar degrees of insulin sensitivity.97,98 Experimental studies in rats also have found that maternal hyperglycaemia leads to increased fetal growth, together with increased placental transporter activity for amino acids (systems A and L) and glucose (GLUTs 1 and 3).99 In adulthood, offspring of rat dams made mildly hyperglycaemic in the last third of pregnancy exhibited impaired insulin secretion100 and offspring of rats with gestational diabetes developed diabetes associated with decreased b-cell mass by 6 months of age.101 In the diabetic mothers of these rats, b-cell mass was also decreased, associated with epigenetic silencing of the key b-cell transcription factor Pdx1.102 Whether this epigenetic regulation was transmitted to the offspring, resulting in their decreased bcell mass and diabetes, is not yet known. Similarly, fetal sheep exposed to chronic hyperglycaemia with superimposed pulses mimicking postprandial surges in blood glucose concentrations also had impaired insulin secretion and decreased insulin content in the pancreas.103 These data demonstrate that exposure of the developing fetus to an abundant substrate supply in the form of glucose e the major metabolic substrate for the mammalian fetus e results in increased fetal growth, altered fetal pancreatic development, and consequent decreased b-cell mass, impaired insulin secretion and an increased risk of diabetes in later life. 6. Conclusion The fetal nutritional environment regulates circulating concentrations of the key fetal growth factors and, therefore, fetal growth. Decreased e and increased e fetal nutrient supply may reflect a poor or excessive maternal nutritional state but may also reflect alterations in placental function. The fetal nutritional environment also is associated with development and regulation of key fetal endocrine systems, most notably the pancreas and the glucoseeinsulin axis, that may have consequences for b-cell mass, pancreatic function and, therefore, glucose tolerance, throughout life. In multiple pregnancies, alterations in fetal growth and endocrine development appear to have origins in early pregnancy, before competition for nutrient supply is likely to be an issue. This suggests that more subtle nutritional or hormonal signals between the developing embryo and the mother must also influence fetal growth and development of the glucoseeinsulin axis, consistent with the effects of an altered maternal nutritional plane before or only in very early pregnancy. Understanding these signals may lead to better insights into interventions in early pregnancy that may optimise fetal growth and development and, therefore, postnatal health.
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Practice points Maternal weight and body composition before conception are critical for fetal growth, pregnancy outcome and lifetime health of the offspring. Poor maternal nutrition increases adiposity and the risk of cardiovascular disease in the offspring. The effects of maternal nutrition on long-term metabolic health of the offspring may be independent of size at birth. The maternal-placental-fetal IGF axis is central in integrating nutrient supply and fetal growth. The reduced fetal growth of twins is established in very early gestation, and is associated with altered metabolic homeostasis in adulthood. Maternal obesity and impaired glucose tolerance result in impaired glucose tolerance in the offspring.
Research agenda Mechanisms by which nutrition before and around the time of conception influence fetal growth, gestation length and later health of offspring. Public health interventions to improve nutritional status in women of child-bearing age. Mechanisms by which paternal nutrition and IGF axis function influence fetal growth. Mechanisms operating in early pregnancy in twins that lead to reduced fetal growth. Evidence-based interventions during pregnancy in obese and glucose intolerant mothers to improve later health of their offspring.
Conflict of interest statement None declared. Funding sources This work was supported by the Health Research Council of New Zealand and Gravida: National Centre for Growth and Development. Acknowledgements Members of the LiFePATH Research Group of the Liggins Institute provided invaluable support for much of the research presented here. References 1. Chung JG, Taylor RS, Thompson JM, et al. Gestational weight gain and adverse pregnancy outcomes in a nulliparous cohort. Eur J Obstet Gynecol Reprod Biol 2013;167:149e53. 2. Han Z, Mulla S, Beyene J, Liao G, McDonald SD. Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and metaanalyses. Int J Epidemiol 2011;40:65e101. 3. Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 2005;20:345e52. 4. Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG 2006;113:1126e33. 5. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001;25:1175e82.
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Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I) and type 1 IGF receptor (IGF1r). Cell 1993;75:59e72. 50. Holt RI. Fetal programming of the growth hormoneeinsulin-like growth factor axis. Trends Endocrinol Metab 2002;13:392e7. 51. Lok F, Owens JA, Mundy L, Robinson JS, Owens PC. Insulin-like growth factor-I promotes growth selectively in fetal sheep in late gestation. Am J Physiol 1996;270:R1148e55. 52. Eremia SC, de Boo HA, Bloomfield FH, Oliver MH, Harding JE. Fetal and amniotic insulin-like growth factor-I supplements improve growth rate in intrauterine growth restriction fetal sheep. Endocrinology 2007;148:2963e72. 53. Verkauskiene R, Beltrand J, Claris O, et al. Impact of fetal growth restriction on body composition and hormonal status at birth in infants of small and appropriate weight for gestational age. Eur J Endocrinol 2007;157:605e12. 54. Orbak Z, Darcan S, Coker M, Goksen D. Maternal and fetal serum insulin-like growth factor-I (IGF-I) IGF binding protein-3 (IGFBP-3), leptin levels and early postnatal growth in infants born asymmetrically small for gestational age. J Pediatr Endocrinol Metab 2001;14:1119e27. 55. Oliver MH, Hawkins P, Harding JE. Periconceptional undernutrition alters growth trajectory, endocrine and metabolic responses to fasting in late gestation fetal sheep. Pediatr Res 2005;57:591e8. 56. Jaquiery AL, Oliver MH, Bloomfield FH, Harding JE. Periconceptional events perturb postnatal growth regulation in sheep. Pediatr Res 2011;70:261e6. 57. Oliver MH, Hawkins P, Breier BH, Van Zijl PL, Sargison SA, Harding JE. Maternal undernutrition during the periconceptual period increases plasma taurine levels and insulin response to glucose but not arginine in the late gestational fetal sheep. Endocrinology 2001;142:4576e9. 58. Todd SE, Oliver MH, Jaquiery AL, Bloomfield FH, Harding JE. Periconceptional undernutrition of ewes impairs glucose tolerance in their adult offspring. Pediatr Res 2009;65:409e13. 59. Green AS, Rozance PJ, Limesand SW. Consequences of a compromised intrauterine environment on islet function. J Endocrinol 2010;205:211e24. 60. Limesand SW, Jensen J, Hutton JC, Hay Jr WW. Diminished beta-cell replication contributes to reduced beta-cell mass in fetal sheep with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 2005;288:R1297e 305. 61. Limesand SW, Rozance PJ, Zerbe GO, Hutton JC, Hay Jr WW. Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology 2006;147:1488e97. 62. Limesand SW, Rozance PJ, Smith D, Hay Jr WW. Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction. Am J Physiol Endocrinol Metab 2007;293:E1716e25.
F.H. Bloomfield et al. / Seminars in Fetal & Neonatal Medicine 18 (2013) 118e123 63. Tran M, Gallo LA, Wadley GD, Jefferies AJ, Moritz KM, Wlodek ME. Effect of pregnancy for females born small on later life metabolic disease risk. PLoS One 2012;7:e45188. 64. Van Assche FA, De Prins F, Aerts L, Verjans M. The endocrine pancreas in small-for-dates infants. Br J Obstet Gynaecol 1977;84:751e3. 65. Bazaes RA, Salazar TE, Pittaluga E, et al. Glucose and lipid metabolism in small for gestational age infants at 48 hours of age. Pediatrics 2003;111:804e9. 66. Diderholm B, Ewald U, Ahlsson F, Gustafsson J. Energy substrate production in infants born small for gestational age. Acta Paediatr 2007;96:29e34. 67. Thorn SR, Rozance PJ, Brown LD, Hay Jr WW. The intrauterine growth restriction phenotype: fetal adaptations and potential implications for later life insulin resistance and diabetes. Semin Reprod Med 2011;29:225e36. 68. Mericq V, Ong KK, Bazaes R, et al. Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate-forgestational-age children. Diabetologia 2005;48:2609e14. 69. Soto N, Bazaes RA, Pena V, et al. Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab 2003;88:3645e50. 70. Iniguez G, Ong K, Bazaes R, et al. Longitudinal changes in insulin-like growth factor-I, insulin sensitivity, and secretion from birth to age three years in small-for-gestational-age children. J Clin Endocrinol Metab 2006;91:4645e9. 71. Muhlhausler BS, Hancock SN, Bloomfield FH, Harding R. Are twins growth restricted? Pediatr Res 2011;70:117e22. 72. Hancock SN, Oliver MH, McLean C, Jaquiery AL, Bloomfield FH. Size at birth and adult fat mass in twin sheep are determined in early gestation. J Physiol 2012;590(Pt 5):1273e85. 73. Bajoria R, Sooranna SR, Ward S, Hancock M. Placenta as a link between amino acids, insulineIGF axis, and low birth weight: evidence from twin studies. J Clin Endocrinol Metab 2002;87:308e15. 74. Rumball CW, Harding JE, Oliver MH, Bloomfield FH. Effects of twin pregnancy and periconceptional undernutrition on maternal metabolism, fetal growth and glucoseeinsulin axis function in ovine pregnancy. J Physiol 2008;586: 1399e411. 75. Green AS, Macko AR, Rozance PJ, et al. Characterization of glucoseeinsulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus. Am J Physiol Endocrinol Metab 2011;300:E817e23. 76. Clarke L, Firth K, Heasman L, et al. Influence of relative size at birth on growth and glucose homeostasis in twin lambs during juvenile life. Reprod Fertil Dev 2000;12:69e73. 77. Bloomfield FH, Oliver MH, Harding JE. Effects of twinning, birth size and postnatal growth on glucose tolerance and hypothalamo-pituitary-adrenal function in post-pubertal sheep. Am J Physiol Endocrinol Metab 2007;292: E231e7. 78. Gardner DS, Tingey K, Van Bon BW, et al. Programming of glucoseeinsulin metabolism in adult sheep after maternal undernutrition. Am J Physiol Regul Integr Comp Physiol 2005;289:R947e54. 79. Poulsen P, Grunnet LG, Pilgaard K, et al. Increased risk of type 2 diabetes in elderly twins. Diabetes 2009;58:1350e5. 80. Monrad RN, Grunnet LG, Rasmussen EL, Malis C, Vaag A, Poulsen P. Agedependent nongenetic influences of birth weight and adult body fat on insulin sensitivity in twins. J Clin Endocrinol Metab 2009;94:2394e9. 81. Pilgaard K, Hammershaimb Mosbech T, Grunnet L, et al. Differential nongenetic impact of birth weight versus third-trimester growth velocity on glucose metabolism and magnetic resonance imaging abdominal obesity in young healthy twins. J Clin Endocrinol Metab 2011;96:2835e43. 82. Chauhan SP, Scardo JA, Hayes E, Abuhamad AZ, Berghella V. Twins: prevalence, problems, and preterm births. Am J Obstet Gynecol 2010;203:305e15.
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83. Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005;11:575e93. 84. O’Reilly JR, Reynolds RM. The risk of maternal obesity to the long-term health of the offspring. Clin Endocrinol (Oxf) 2013;78:9e16. 85. Harmon KA, Gerard L, Jensen DR, et al. Continuous glucose profiles in obese and normal-weight pregnant women on a controlled diet. Diabetes Care 2011;34:2198e204. 86. Higgins M, Auliffe FM, Soubt M, Dunning BE, Foley JE. A review of maternal and fetal growth factors in diabetic pregnancy. Curr Diabetes Rev 2010;6: 116e25. 87. Persson M, Pasupathy D, Hanson U, Norman M. Birth size distribution in 3,705 infants born to mothers with type 1 diabetes. Diabetes Care 2011;34:1145e9. 88. Middleton P, Crowther CA, Simmonds L. Different intensities of glycaemic control for pregnant women with pre-existing diabetes. Cochrane Database Syst Rev 2012;(8):CD008540. http://dx.doi.org/10.1002/14651858.CD00 8540.pub3. 89. Nobile de Santis MS, Taricco E, Radaelli T, et al. Growth of fetal lean mass and fetal fat mass in gestational diabetes. Ultrasound Obstet Gynecol 2010;36:328e37. 90. Keller J, Metzger BE, Dooley S, Tamura R, Sabbagha R, Freinkel N. Infants of diabetic mothers with accelerated fetal growth by ultrasonography: are they all alike? Am J Obstet Gynecol 1990;163:893e7. 91. Yan-Jun L, Tsushima T, Minei S, et al. Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBP-1, -2 and -3) in diabetic pregnancy: relationship to macrosomia. Endocr J 1996;43:221e31. 92. Lindsay RS, Westgate JA, Beattie J, et al. Inverse changes in fetal insulin-like growth factor (IGF)-1 and IGF binding protein-1 in association with higher birth weight in maternal diabetes. Clin Endocrinol 2007;66:322e8. 93. Westgate JA, Lindsay RS, Beattie J, et al. Hyperinsulinemia in cord blood in mothers with type 2 diabetes and gestational diabetes mellitus in New Zealand. Diabetes Care 2006;29:1345e50. 94. Spyer G, Hattersley AT, Sykes JE, Sturley RH, MacLeod KM. Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am J Obstet Gynecol 2001;185:240e1. 95. Weedon MN, Frayling TM, Shields B, et al. Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene. Diabetes 2005;54:576e81. 96. Sobngwi E, Boudou P, Mauvais-Jarvis F, et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 2003;361(9372):1861e5. 97. Gautier JF, Wilson C, Weyer C, et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001;50: 1828e33. 98. Singh R, Pearson E, Avery PJ, et al. Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes. Diabetologia 2006;49:1876e80. 99. Ericsson A, Säljö K, Sjöstrand E, et al. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol 2007;581(Pt 3):1323e32. 100. Bihoreau MT, Ktorza A, Kinebanyan MF, Picon L. Impaired glucose homeostasis in adult rats from hyperglycemic mothers. Diabetes 1986;35:979e84. 101. Boloker J, Gertz SJ, Simmons RA. Gestational diabetes leads to the development of diabetes in adulthood in the rat. Diabetes 2002;51:1499e506. 102. Park JH, Stoffers DA, Nicholls RD, Simmons RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008;118:2316e24. 103. Green AS, Chen X, Macko AR, et al. Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets. J Endocrinol 2012;212:327e42.
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Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Fetal growth factors and fetal nutrition F.H. Bloomfield a, b, c, Ana-Mishel Spiroski a, b, J.E. Harding a, * a
Liggins Institute, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Gravida: National Centre for Growth and Development, University of Auckland, Auckland, New Zealand c Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand b
s u m m a r y Keywords: Diabetes Growth factors Insulin Pregnancy Prenatal nutrition Obesity
Optimal fetal growth is important for a healthy pregnancy outcome and also for lifelong health. Fetal growth is largely regulated by fetal nutrition, and mediated via the maternal and fetal glucose/insulin/ insulin-like growth factor axes. Fetal nutrition may reflect maternal nutrition, but abnormalities of placental function can also affect fetal growth, as the placenta plays a key intermediary role in nutritional signalling between mother and fetus. Fetal nutrition also impacts on the development of key fetal endocrine systems such as the glucoseeinsulin and insulin-like growth factor axes. This is likely to contribute to the link between both fetal growth restriction and fetal overgrowth, and increased risks of obesity and impaired glucose tolerance in later life. This review focuses on the associations between maternal and fetal nutrition, fetal growth and later disease risk, with particular emphasis on the role of insulin-like growth factors and the importance of the periconceptional period. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Maternal nutrition from before pregnancy through to delivery can affect fetal growth and size at birth. Maternal underweight, poor gestational weight gain and exposure to famine in mid or late gestation all decrease birthweight and are associated with increased risk for low birthweight (LBW) and small-forgestational-age (SGA) babies.1e3 Maternal obesity and excessive gestational weight gain are associated with increased birthweight and increased risk for large-for-gestational-age babies.4,5 However, the magnitude of effect, particularly of severe maternal undernutrition as experienced in the Dutch Famine, is relatively small (a decrease in birthweight of w200 g with official daily rations of 400e800 calories)3 reflecting the ability of the placenta and fetus to maintain nutrient supply and survival of the conceptus. Perhaps more surprising is the even smaller positive effect of a balanced protein-energy supplementation of undernourished women from mid-pregnancy on birthweight, reported in a meta-analysis to be only 73 g [95% confidence interval (CI): 30e117 g].6 This relatively small effect likely reflects both the fact that maternal nutrition does not equal fetal nutrition, because there are many other factors that can affect fetal nutritional supply,7 and also that placental size and efficiency themselves may be determined in part by factors, including maternal nutrition, that operate very early in, or
* Corresponding author. Tel.: þ64 9 3737599. E-mail address: [email protected] (J.E. Harding). 1744-165X/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.siny.2013.03.003
even before, pregnancy.8 Thus, nutrition of the developing conceptus should be thought of in two distinct phases: histiotrophic nutrition, prior to the establishment of placental blood flow in the latter half of the first trimester, and haemotrophic nutrition via the placenta.7 2. Role of the placenta in fetal nutrition During histiotrophic nutrition, the embryo receives nutrition directly from the surrounding milieu, for example, secretions from the uterine glands.9 Studies in rodents indicate that the embryo responds to maternal nutritional status in these very early stages of pregnancy, for example by altering allocation of embryonic cells to the inner cell mass and trophectoderm lineages and by altering cell proliferation rates.10 Reduced trophectoderm cell numbers, which may impact on later placental size and function, are also associated with fetal adaptations later in gestation, such as increased nutrient uptake by the visceral yolk sac endoderm, which preserve fetal growth but which are associated with postnatal overweight and increased blood pressure.11 In-vitro fertilization techniques and cloning both also have been associated with altered placental size, mostly overgrowth, with consequent fetal overgrowth.12,13 In bovine pregnancies generated by nuclear transfer, placental overgrowth is associated with increased expression of IGF binding proteins (IGFBP)-2 and -3 in placental tissue and with increased IGF-1 concentrations in fetal plasma and in allantoic fluid.14 Human epidemiological studies also suggest that placental size and morphometry may reflect maternal
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nutrient resource at the time of conception and may be related to lifelong risk of disease.15 Thus, the prevailing nutrient status in the very early stages of pregnancy can influence later placental development and hence fetal growth. During pregnancy, as conceptus size and nutrient requirements increase, placental transfer capacity must also increase.16 This is achieved through a variety of mechanisms, including increasing placental surface area for nutrient transfer, thinning of the trophoblast barrier, an increase in fetal capillary surface area, increases in placental nutrient transporter abundance and modulation of placental blood flow.17,18 A key example is the regulation of placental transfer capacity for glucose, the major substrate for fetal oxidative metabolism.19 Glucose is transported across the placenta by facilitated diffusion down a concentration gradient. The development of a degree of maternal insulin resistance during midelate pregnancy aids fetal glucose supply by increasing the magnitude of the gradient. In addition, data from in-vitro studies on human placentae suggest that there is a redistribution of the expression of insulin receptors throughout gestation, with increased expression on fetal surfaces in late gestation.20 The maternaleplacentalefetal IGF axis also plays a key role in fetal nutrient supply and in fetal growth. Maternal and fetal circulating IGF-1 and IGFBP concentrations are regulated by nutrition21,22 and are associated with fetal growth.23,24 The IGFs and their binding proteins have the potential to be involved in many aspects of placental development and function (reviewed by Forbes and Westwood23 and Sferruzzi-Perri et al.24) and are expressed in the placenta from early in gestation.25 In-vitro studies suggest that IGF-1 and IGF-2 stimulate both system A amino acid uptake and glucose uptake in cultured trophoblasts from first trimester and term placentae regulated in part by the nonphosphorylated form of IGFBP-1.26e28 These in-vitro studies are supported by experiments in healthy guinea-pigs, in which maternal IGF-1 infusion in mid-pregnancy increased placental transport via the system A transporter (slc38a2) in both mid and late pregnancy,29,30 and by studies in growth-restricted ovine fetuses, in which intra-amniotic IGF-1 treatment in late pregnancy increased fetal growth and placental mRNA expression of the system A (slc38a4) and L (slc7a8) amino acid transporters.31 Further, in-vivo studies in sheep show that maternal and fetal circulating IGF-1 concentrations interact to regulate partitioning of substrates between the fetus and placenta, with maternal IGF-1 stimulating placental glucose and amino acid uptake, whereas fetal IGF-1 stimulates fetal glucose and amino acid uptake from the placenta and inhibits fetal protein oxidation.32,33 These interactions provide a mechanism by which fetal growth is regulated according to substrate supply. The paternal IGF axis also influences placental function and fetal growth, particularly the imprinted igf2 and the igf2-H19 gene locus.34 Single nucleotide polymorphisms (SNPs) of the paternally transmitted igf2 gene in humans are associated with increased maternal glucose in response to a glucose tolerance test in midgestation and with increased placental IGF-2 protein content at birth, whereas maternally transmitted SNPs of igf2 are not.35 Although these data suggest a role of paternally inherited igf2 in both placentation and fetal nutrient availability, there was no association with birthweight, perhaps because the effect on maternal glucose concentrations was small. The potential importance of IGF-2 in placental development and function is clearly demonstrated by the phenotype in mice lacking the placental-specific transcript of the igf2 gene (P0). In these mice, placental growth is reduced, there is reduced diffusional exchange surface area and increased barrier thickness,36 resulting in decreased passive permeability for nutrients.37 However, initially
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fetal growth is maintained secondary to upregulation of placental glucose and amino acid transporters38 with growth restriction becoming apparent only in late gestation. Intriguingly, placental amino acid transporters remain upregulated and this adaptation is only abolished if fetal igf2 is removed in addition to the placental transcript. Thus, it appears the placenta can respond to fetal nutrient demand signals through regulation of its nutrient transporters and that this regulation may occur, at least in part, through actions of the insulin-like growth factors and their binding proteins. 3. Maternal nutrition and fetal growth 3.1. Effects of maternal nutrient restriction in early pregnancy on fetal growth and development There is increasing evidence that maternal nutritional status preconception and in early pregnancy, when nutrient requirements of the developing embryo are tiny, is signalled to the fetus and can influence both fetal growth and organ development throughout pregnancy. For example, a systematic review of 20 studies including 171,806 women found that maternal underweight was associated with a relative risk for low birthweight of 1.58 (95% CI: 1.37e1.82).2 In a prospective study in women of childbearing age, active dieting or a poor nutritional intake preconception was associated with decreased shunting of fetal blood through the ductus venosus, resulting in increased flow to the liver.39 This, in turn, was associated with greater offspring adiposity at birth and 4 years of age.40 However, it is important to note that the effects of nutritional status in early pregnancy on long-term metabolic risk may be independent of altered size at birth. Follow-up of offspring of women exposed to the Dutch Famine at the end of World War II found increased risks of heart disease, hyperlipidaemia and obesity in those conceived during the famine and impaired glucose tolerance in those exposed to famine in utero in late gestation, while only the latter group showed reduction in birthweight.3 There has been a recent explosion of interest in the potential role of epigenetics as a mediator of the long-term effects of an adverse intrauterine environment. Offspring from the Dutch Famine studied in the seventh decade of life showed increased methylation in seven loci, including igf2 and inisigf (a fusion transcript between the insulin promoter and the igf2 gene that arises from igf2/H19 locus in early development), in those exposed to famine preconception, whereas exposure in late gestation was associated with increased methylation in only one locus (gnasas).41,42 Epigenetic differences in metastable epialleles also have been reported in 7-year-old offspring of women in the Gambia who conceived during the rainy season (a season of famine) compared with the harvest season.43 Interestingly, a study of epigenetic modifications in the igf2/H19 locus in babies born small-forgestational-age did not find methylation differences,44 indicating once again that fetal developmental adaptations in response to maternal nutrition are not causally related to altered fetal growth. Further, the relationship between maternal nutritional status and the metabolic regulation of the offspring may extend beyond the next generation.45,46 4. Fetal nutrition, fetal growth factors and fetal growth Many fetal hormones are regulated by nutrition7 and this includes the IGFs and their binding proteins and insulin. Whereas insulin is a passive regulator of fetal growth, dependent upon substrate supply,47 the nutritional regulation of IGFs and their
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binding proteins is thought to be important for the regulation of fetal growth. IGF-2 is most important in embryonic and early fetal growth48 and IGF-1 is thought to be the principal endocrine regulator of late gestation fetal growth.49 Studies in sheep have demonstrated that fetal plasma IGF-1 concentrations are regulated by fetal glucose and insulin concentrations21 and studies in rats have reported that maternal undernutrition increases fetal plasma concentrations of IGFBP-1 and -2, thereby restricting IGF-1 bioavailability.50 IGF-1 supplementation of ovine fetuses through a variety of routes has been shown to result in both growth of specific organs in normally grown fetuses (intravenous treatment with supraphysiological does of IGF-1)51 and increased growth trajectory in growth-restricted fetuses.31,52 In humans, cord plasma IGF-1 and IGFBP-3 concentrations are significantly decreased in growth-restricted infants53 and are related to postnatal growth patterns.54 Thus, the fetal somatotrophic axis responds to maternal and fetal nutritional signals to play a key role in fetal growth. 4.1. Fetal nutritient restriction and development of the glucoseinsulin axis Experimental studies also have demonstrated that maternal nutritional status before and in early pregnancy influences not only fetal growth trajectory but also development of the fetal glucosee insulin axis and, in turn, postnatal glucose tolerance and insulin sensitivity. In sheep, moderate maternal nutrient restriction from two months prior to mating and continuing only one month into a five-month pregnancy (with ad-libitum intake thereafter) decreased fetal growth trajectory in late gestation.55 Size at birth was not greatly altered, but there was perturbation of the normal postnatal relationships between factors normally regulating neonatal growth.56 Of note, fetuses of periconceptionally undernourished ewes demonstrated altered regulation of insulin secretion in response to stimulation consistent with accelerated maturation of the fetal glucoseeinsulin axis.57 However, after birth offspring showed a progressive decline in glucose tolerance with age.58 Numerous other paradigms of fetal nutrient restriction secondary to placental insufficiency also have been reported to result in altered development of the fetal glucoseeinsulin axis (reviewed by Green et al.59). For example, placental insufficiency secondary to maternal hyperthermia in sheep results in impaired fetal b-cell mass and insulin secretion in late gestation.60,61 These changes were associated with increased insulin sensitivity,62 also reported in rats born growth-restricted following maternal uterine artery and vein ligation,63 perhaps as an adaptive mechanism to maintain tissue substrate supply. These findings are mirrored by observations that severely growth-restricted human infants have reduced b-cell fraction and smaller islets64 and deficits in b-cell function persisting for 48 h after birth.65 SGA babies also have a degree of hepatic resistance to insulin shortly after birth, with loss of the relationship between hepatic glucose production rate and plasma insulin concentrations.66 However, these deficits may be masked by increased peripheral insulin sensitivity.65 These adaptations in the fetus can be seen as mechanisms to promote fetal survival in the face of an impaired nutrient supply. They promote peripheral glucose utilisation, essential for brain and heart, and reduce the demand for amino acids for growth, thereby maintaining energy supply at the expense of growth. These tissuespecific adaptations in insulin sensitivity may, however, then have postnatal consequences once the restricted nutritional environment is no longer present.67 Indeed, a longitudinal study of 55 babies with a birthweight below the 5th percentile reported that, despite increased insulin
sensitivity at birth, insulin resistance had developed by 3 years of age and was correlated with degree of ‘catch-up’, or accelerated postnatal, growth.68 The relationship between insulin sensitivity and accelerated postnatal growth was already present at 1 year of age in another cohort of 85 SGA babies.69 Similar findings were reported for IGF-1 concentrations, which were decreased at birth in SGA infants but increased at 3 years, indicative of relative IGF-1 resistance, and correlated with degree of accelerated postnatal growth between birth and 3 years.70 4.2. Fetal nutrition and growth in twin pregnancies Twins, as a population, can be thought of as being relatively growth-restricted71 with studies in sheep suggesting that a decreased growth trajectory likely is set in early pregnancy.72 Twins within a pair are often discordant for growth. The more growthrestricted twin has been reported to have lower cord plasma concentrations of insulin and IGF-1 and higher concentrations of IGFBP-1 than the appropriately grown twin, with IGFBP-1 concentrations inversely associated with plasma concentrations of insulin and amino acids.73 In sheep, twin fetal size is less than that of singletons by two-thirds of gestation and daily fetal growth rate is less.74 As with maternal undernutrition, altered fetal growth in twin sheep is associated with evidence of accelerated maturation of the pancreas.74 Twin fetal sheep also have been reported to be more insulin sensitive than their singleton counterparts.75 Postnatally, glucose tolerance in twin lambs is related to birthweight, with the more growth-restricted lamb of a pair displaying increased glucose tolerance,76 consistent with the greater insulin sensitivity in growth-restricted children described above. However, by early adulthood twin sheep have similar glucose tolerance to singletons.77,78 Consistent with these findings, recent human twin studies have found that in their seventh decade twins are more insulin resistant, have greater abdominal obesity and a greater incidence of type 2 diabetes than singletons.79 Insulin sensitivity and abdominal fat mass both have been reported to be inversely related to birthweight differences within twin pairs, with a one standard deviation increase in birthweight associated with a 16% decrease in insulin sensitivity in elderly twins80 and with a 3.2 volume/% decrease in intra-abdominal fat mass in young twins.81 Thus, twin conception, a naturally occurring phenomenon, is associated with altered fetal growth and endocrine development with consequences for life-long metabolic health. This has implications not only for the epidemic of twins that has accompanied assisted reproductive techniques82,83 but potentially also, as the origins of these effects appears to be in early pregnancy, for our understanding of the fundamental mechanisms that underlie these observations. 5. Fetal nutritional abundance Maternal obesity and impaired glucose tolerance are increasing problems in current obstetric practice, and are associated with altered fetal growth and long-term health of the offspring.84 Increased maternal glycaemia may be present with maternal obesity,85 gestational diabetes86 or insulin-dependent diabetes,87 and results in an increased glucose supply to the fetus, associated with the delivery of an LGA infant.88 Both maternal and gestational diabetes are associated with accelerated early fetal growth rate,89,90 fetal hyperinsulinaemia, increased cord plasma IGF-1 and IGF-2 concentrations91 correlating with larger size at birth92 and increased adiposity at term.89,93 Studies of women with a mutation or polymorphism in the glucokinase gene have demonstrated elegantly the role of
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maternal glycaemia in fetal growth. Women with a mutation in the glucokinase gene have elevated basal circulating glucose concentrations. Offspring of these women are more likely to be macrosomic and babies most at risk are those who have not themselves inherited the mutation (and who, therefore, do not have a problem with glucose sensing).94 Even a common polymorphism of the b-cell specific promoter of the glucokinase gene in the mother, which is associated with only a 0.06 mmol/l increase in fasting plasma glucose concentration, is associated with a small but statistically significant (64 g) increase in birthweight.95 Fetuses developing in an environment of impaired maternal glucose tolerance are themselves at increased risk of impaired glucose tolerance and type 2 diabetes in later life, and this risk is greater than that expected by genetic factors alone.96 It appears that this is due to reduced b-cell function, as non-diabetic offspring of mothers with type 2 diabetes have decreased insulin secretion compared with non-diabetic offspring of fathers with type 2 diabetes, despite similar degrees of insulin sensitivity.97,98 Experimental studies in rats also have found that maternal hyperglycaemia leads to increased fetal growth, together with increased placental transporter activity for amino acids (systems A and L) and glucose (GLUTs 1 and 3).99 In adulthood, offspring of rat dams made mildly hyperglycaemic in the last third of pregnancy exhibited impaired insulin secretion100 and offspring of rats with gestational diabetes developed diabetes associated with decreased b-cell mass by 6 months of age.101 In the diabetic mothers of these rats, b-cell mass was also decreased, associated with epigenetic silencing of the key b-cell transcription factor Pdx1.102 Whether this epigenetic regulation was transmitted to the offspring, resulting in their decreased bcell mass and diabetes, is not yet known. Similarly, fetal sheep exposed to chronic hyperglycaemia with superimposed pulses mimicking postprandial surges in blood glucose concentrations also had impaired insulin secretion and decreased insulin content in the pancreas.103 These data demonstrate that exposure of the developing fetus to an abundant substrate supply in the form of glucose e the major metabolic substrate for the mammalian fetus e results in increased fetal growth, altered fetal pancreatic development, and consequent decreased b-cell mass, impaired insulin secretion and an increased risk of diabetes in later life. 6. Conclusion The fetal nutritional environment regulates circulating concentrations of the key fetal growth factors and, therefore, fetal growth. Decreased e and increased e fetal nutrient supply may reflect a poor or excessive maternal nutritional state but may also reflect alterations in placental function. The fetal nutritional environment also is associated with development and regulation of key fetal endocrine systems, most notably the pancreas and the glucoseeinsulin axis, that may have consequences for b-cell mass, pancreatic function and, therefore, glucose tolerance, throughout life. In multiple pregnancies, alterations in fetal growth and endocrine development appear to have origins in early pregnancy, before competition for nutrient supply is likely to be an issue. This suggests that more subtle nutritional or hormonal signals between the developing embryo and the mother must also influence fetal growth and development of the glucoseeinsulin axis, consistent with the effects of an altered maternal nutritional plane before or only in very early pregnancy. Understanding these signals may lead to better insights into interventions in early pregnancy that may optimise fetal growth and development and, therefore, postnatal health.
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Practice points Maternal weight and body composition before conception are critical for fetal growth, pregnancy outcome and lifetime health of the offspring. Poor maternal nutrition increases adiposity and the risk of cardiovascular disease in the offspring. The effects of maternal nutrition on long-term metabolic health of the offspring may be independent of size at birth. The maternal-placental-fetal IGF axis is central in integrating nutrient supply and fetal growth. The reduced fetal growth of twins is established in very early gestation, and is associated with altered metabolic homeostasis in adulthood. Maternal obesity and impaired glucose tolerance result in impaired glucose tolerance in the offspring.
Research agenda Mechanisms by which nutrition before and around the time of conception influence fetal growth, gestation length and later health of offspring. Public health interventions to improve nutritional status in women of child-bearing age. Mechanisms by which paternal nutrition and IGF axis function influence fetal growth. Mechanisms operating in early pregnancy in twins that lead to reduced fetal growth. Evidence-based interventions during pregnancy in obese and glucose intolerant mothers to improve later health of their offspring.
Conflict of interest statement None declared. Funding sources This work was supported by the Health Research Council of New Zealand and Gravida: National Centre for Growth and Development. Acknowledgements Members of the LiFePATH Research Group of the Liggins Institute provided invaluable support for much of the research presented here. References 1. Chung JG, Taylor RS, Thompson JM, et al. Gestational weight gain and adverse pregnancy outcomes in a nulliparous cohort. Eur J Obstet Gynecol Reprod Biol 2013;167:149e53. 2. Han Z, Mulla S, Beyene J, Liao G, McDonald SD. Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and metaanalyses. Int J Epidemiol 2011;40:65e101. 3. Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 2005;20:345e52. 4. Catalano PM, Ehrenberg HM. The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG 2006;113:1126e33. 5. Sebire NJ, Jolly M, Harris JP, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001;25:1175e82.
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