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The Feto-placental Dialogue and Diabesity
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Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e9
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The Feto-placental Dialogue and Diabesity Q5 Q1
Gernot Desoye a, *, Mireille van Poppel b a
Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
b
Keywords: glucose insulin hypothalamus fetal/neonatal fat first trimester of pregnancy lifestyle interventions
Recent studies have established that the neonate born to a pregnancy with maternal diabetes or obesity (‘diabesity’) is characterized by increased fat accumulation. The neonatal fat is the result of triglyceride synthesis and deposition stimulated by elevated fetal insulin levels combined with insulin's mitogenic activity directly stimulating the growth of the white adipocytes. Fetal insulin levels are determined by fetal glucose and some amino acids such as arginine. Although the placenta plays a key role in providing maternally derived nutrients to the growing fetus, there is currently no evidence that it actively contributes to an excessive maternal-to-fetal glucose flux at the end of gestation. Early in gestation, the maternal environment in diabesity, and in particular the glucoseeinsulin axis, can modify placental growth and development, which may contribute to an enhanced glucose flux to the fetus already early in pregnancy. This may have long-lasting effects on the fetal pancreas and accelerate beta-cell maturation. The association of fetal and neonatal insulin levels and the proportion of body fat with obesity later in the offspring's life calls for interventions during pregnancy to prevent or reduce fetal hyperinsulinaemia. Dietary and/or physical activity interventions initiated before or in early pregnancy would likely be most effective. Results from the very few studies with fetal insulin as the outcome are inconsistent. However, there is a major lack of randomized intervention trials on this topic. © 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Medical University of Graz, Department of Obstetrics and Gynaecology, Auenbruggerplatz 14, 8036 Graz, Austria. Tel.: þ43 316 385 84605. E-mail address: [email protected] (G. Desoye).
http://dx.doi.org/10.1016/j.bpobgyn.2014.05.012 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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The rapid increase in the prevalence of diabesity, that is, obesity, type 2 diabetes and associated complications, is a major problem for global health worldwide. The developmental origins of health and adult disease (DOHaD) concept puts pregnancy and its influences on the mother and the developing fetus in the focus of the transgenerational transmission of diabesity risk. Thus, the maternaleplacentalefetal interaction has received increasing research interest. The placenta is interposed between the maternal and fetal blood stream and thus constitutes the physical link between the two generations. The maternal environment associated with diabetes (type 1, type 2 and gestational) mellitus and/or obesity has an influence on placental development, structure and function, which has been summarized in several articles [1e14]. These placental alterations may be protective or adaptive responses to the maternal environment, with the ultimate purpose of allowing the fetus to grow and develop in a stable environment. Alternatively, these changes might be mechanistically linked to the fetal phenotype associated with maternal diabesity. It is not the purpose of this review to summarize once again placental changes associated with diabesity. Rather, we will focus on one particular concept, with the focus on the maternal and fetal glucose/insulin axis and its effects on the placenta and the fetus. This concept may explain the fetal phenotype and some aspects of intrauterine programming of childhood obesity in the wake of maternal diabesity. We further intend to discuss options to prevent this from happening. The fetal phenotype in diabesity Much work has been published demonstrating the increased incidence of ‘macrosomia’ and largefor-gestational age neonates, that is, >90th birth-weight centile, born to diabesity pregnancies. This research focus is largely based on the obstetric complications associated with a macrosomic neonate such as an increased rate of caesarean sections, shoulder dystocia and others. However, there is a growing body of evidence showing that the neonate of a diabetic mother, even when born in the appropriate-for-gestational age range (between the 5th or 10th and 90th birth-weight centile), has a phenotype different from those born to normal pregnancies. The major difference and thus the major effect of maternal diabesity on the neonate is on body composition: These neonates are born with a higher proportion of body fat independent of their birth weight or birth-weight category [15e18], whereas the fat-free mass appears unaltered (Fig. 1). Interestingly, gestational diabetes and maternal obesity are independent risk factors for neonatal percentage body fat and contribute additively [19]. The higher neonatal body fat is of key importance because the number of adipocytes for a human being seems to be determined very early in the life cycle if not already in utero [20]. The trajectory of
Fig. 1. Proportion (%) of body fat in neonates born to pregnancies with normal glucose tolerance of the mother (NGT) and mothers with gestational diabetes mellitus (GDM). GDM neonates have more body fat not only when born large-for-gestational age (LGA) but also with appropriate-for-gestational age birth weight (AGA). No data are available for small-for-gestational age (SGA) neonates in GDM pregnancies (left panel). Neonates from lean (BMI < 25) mothers have a lower percentage body fat than their counterparts born to overweight (BMI 25) mothers (right panel). Data taken from Refs. [15,18].
Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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adipocyte number cannot be changed not even when weight, that is, fat, is lost. Thus, once the growing fetus has developed more adipocytes in the wake of the diabesity environment, the neonate may be strongly predisposed to remain on this trajectory and have more adipocytes also in childhood. This is indeed the case as shown by the association of neonatal body fat with that in childhood at the age of 9 years, whereas total body weight is not associated [21]. The excessive accretion of body fat even in neonates with appropriate-for-gestational-age birth weight constitutes a major problem from the public health perspective. These neonates represent by far the majority of all neonates born to diabesity pregnancies. They are inconspicuous and yet are at a risk of childhood obesity. Therefore, measures meant to prevent the childhood obesity risk should perhaps include all neonates of diabetic mothers, regardless of birth weight. The role of the placenta in determining the fetal phenotype in diabesity More than 50 years ago, Jorgen Pedersen explained fetal overgrowth in diabetic pregnancies by his hyperglycaemiaehyperinsulinaemia concept: Maternal hyperglycaemia as in diabetes leads to fetal hyperglycaemia, which stimulates the fetal pancreas to produce and secrete more insulin ultimately resulting in fetal hyperinsulinaemia. This concept has been expanded later to include amino acids and fatty acids (fuel-mediated teratogenesis concept) [22]. In essence, fetal insulin is the man driver for the fetal phenotype, because of its dual activities as a mitogen to stimulate the growth of white adipocytes and as an anabolic hormone to drive triglyceride formation and deposition in fetal white adipocytes. Until now, the concepts have not been refuted and are still the key to our understanding of fetal development in a situation of maternal hyperglycaemia as is associated with diabesity. Although amino acids, and in particular arginine, can serve as insulin secretagogues [23] and may contribute to fetal hyperinsulinaemia in diabesity, glucose is the most important stimulator of insulin secretion. Thus, this has sparked research interest trying to understand the regulation of maternal-tofetal glucose transport across the placenta. Despite a number of molecular changes in the placenta at the level of glucose transporters and glucose metabolism, the total glucose flux across the placenta is unaltered in placentas from gestational diabetic pregnancies [24e26]. Thus, at least at the end of gestation, maternal-to-fetal glucose flux is mostly dictated by the maternal-to-fetal concentration gradient of glucose, perhaps with some contribution of utero-placental and feto-placental blood flow [27]. This has important implications for the clinical care of the obese or diabetic woman: Adequate glycaemic control of the mother after diagnosis of gestational diabetes mellitus (GDM) may not be sufficient to prevent excess fetal fat accretion once the fetal pancreas has already been overstimulated by maternal hyperglycaemia prior to gestational diabetes diagnosis. The level of fetal hyperinsulinaemia has to be taken into account in the clinical decisions of how to manage diabetes in the pregnant women. Directly measuring amniotic fluid insulin levels has been advocated [28], but not been accepted because of the invasive nature of amniocentesis. Elevated levels of fetal insulin will have multiple consequences. It can stimulate (1) placental growth and also growth of the fetal heart, at least in non-human primates [29,30], (2) glycogen deposition in the placental endothelium (Desoye, Hiden unpublished) and (3) aerobic fetal metabolism. The latter will raise the demand for oxygen in the fetus. At the same time, in diabetic pregnancies, maternal haemoglobin is glycosylated to a greater extent and, thus, has a lower oxygen transport capacity. Along with potentially reduced utero-placental blood flow in maternal diabetes mellitus, this may result in an imbalance between oxygen supply and demand with a net oxygen deficit. This stimulates fetal erythropoietin synthesis and erythropoiesis [31,32]. In synergy with increased oxygen transport capacity within the fetal circulation, the placental vascular network is expanded and the capillary surface enlarged [3,33]. Fetal insulin contributes to placental angiogenesis through multiple cellular mechanisms [10,34e37]. One further consequence of fetal hyperinsulinaemia is not only the stimulation of triglyceride synthesis and fat deposition but also aerobic metabolism and stimulation of glucose uptake into fetal tissues. This insulin-induced shift of circulating glucose into tissue will remove glucose from the circulation and thus transiently steepen the concentration gradient between the maternal and fetal circulations, thus increasing the glucose flux until steady-state concentrations have been reached again. Thus, fetal insulin will siphon maternal glucose and direct it to the fetus. The term ‘glucose steal Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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phenomenon’ was coined for this effect, which was shown in rat [38] and sheep [39,40] and indirectly demonstrated also in humans. [41] The important consequence for clinical care of the diabetic mother is that late in gestation normalization of maternal glucose levels may not be enough to prevent fat accretion (or ‘macrosomia’), because the fetus is also involved in determining transplacental glucose flux. This will always be the case when the fetal pancreas is already altered by hyperplasia earlier in pregnancy [42,43] and fetal hyperinsulinaemia has become manifest. This raises the question about the onset of fetal hyperplasia and, thus, hyperinsulinaemia. Insulin depots in the human fetal pancreas were demonstrated as early as at week 8 or 9 of gestation [44e46]; insulin is secreted into the fetal circulation as early as at 11 weeks of gestation [47] and can be measured in the fetal amniotic fluid at week 14 of gestation [48]. Importantly, amniotic fluid insulin in this early period was associated with the risk of birth weight >90th centile. Thus, early fetal hyperinsulinaemia as a result of maternal and fetal hyperglycaemia can have consequences for further fetal development. The importance of the glucoseeinsulin axis in the first trimester is also highlighted by the correlation of maternal fasting glucose levels at weeks 9e10 of gestation with the risk of fetal macrosomia [49]. The maternal glucoseeinsulin axis in the first trimester of pregnancy and its effect on the placenta There is a growing body of evidence that the placenta early in gestation may influence fetal growth and development with manifestations at the end of pregnancy. The placental volume at week 14 of gestation and the rate of placental growth between weeks 14 and 17 of gestation were associated directly with fetal anthropometric parameters such as abdominal circumference [50]. In another study, the placental volume at 19 weeks was associated with neonatal fat mass both absolute and relative to birth weight [51]. Despite the importance of knowing the regulatory factors for placental growth early in gestation, surprisingly little is known about this, if anything. It is also unclear what the effect of pre-gestational diabetes on the early placenta is. There are conflicting reports on the degree of placental vascularization, that is, more or less, as compared to non-diabetic pregnancies [52,53]. There is indirect evidence to suggest a delayed placental development in pre-gestational, that is, type I, diabetes: In these pregnancies, fetal growth is delayed [54]. Although placental volume measurements at this early stage in type I diabetic pregnancies are pending, the lower levels of circulating human placental lactogen (hPL) and pregnancy-associated plasma protein-A (PAPP-A) [55], which are both produced in the placental trophoblast, suggest also a reduced trophoblast, that is, placental, growth. In vitro evidence demonstrates an interaction of hyperglycaemia and higher/lower levels of oxygen levels resulting in a slower trophoblast growth [56]. Maternal insulin may also have an independent effect on early placental development. It upregulates matrix metalloproteinase 14, one key enzyme, which is involved in growth regulation, invasion, inflammation and also in angiogenesis. The placental levels of this enzyme correlate with the daily insulin dose given to type 1 diabetes mellitus (T1DM) women in the first trimester [37,58]. Thus, the combined effects of hyperglycaemia and compensatory hyperinsulinaemia may alter the dynamics of placental growth already in the first trimester and have a long-lasting influence on fetal growth and development including body composition. The mothereplacentaefetus dialogue in diabesity Based on the above, we propose the following model linking first-trimester events to the childhood diabesity risk (Fig. 2). Although maternal diabetes and/or obesity per se independently and additively increase the risk of overproportional neonatal fat accumulation [19], changes of the maternal glucose/insulin axis are a continuum and show a more or less linear association between maternal glucose, fetal growth and neonatal body composition [49,58]. Thus, small changes in maternal glucose homeostasis can also gear fetal metabolism towards more fat accretion already at levels below those Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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Fig. 2. The mothereplacentaefetus dialogue. The scheme links early maternal metabolism to neonatal adiposity and obesity risk in later life. For details, see text above.
defined as diabetes. Any elevation in maternal glucose and/or insulin early in gestation modifies placental growth and development. These alterations in the placenta may or may not (unclear yet) imply a change in transplacental glucose transfer, which along with a higher glucose concentration gradient will increase glucose flux to the fetus. At what period in gestation this happens will depend on the maternal glucose/insulin axis. Continuous glucose flux across the placenta will lead to stimulation of beta-cell growth and insulin secretion. Fetal insulin promotes glucose uptake into peripheral tissues and steepens the maternal-to-fetal glucose concentration gradient with ensuing glucose flux to the fetus, which also becomes dependent on fetal insulin levels. Fetal insulin also increases the number of adipocytes and triglyceride deposition in them. Importantly, insulin is able to malprogram the neuroendocrine systems regulating body weight, food intake and metabolism, at least in the rat [59]. This increases the risk of becoming obese and of developing diabetes throughout life, also because of the ß-cell hyperplasia developed in utero which may lead to their earlier exhaustion. This concept thus links early maternal derangements of the glucose/insulin axis with events in the fetus later in gestation or even postnatally. The placenta directly affects fetal development early in pregnancy by responding to the maternal environment. At later stages in pregnancy, it will primarily respond to fetal signals and adapt its structure, for example, by hypervascularization, and likely also its function to fetal needs. Thus, maternal influences diminish from early to late gestation whereas the fetus gradually takes over control. Insulin plays a central role. The shift in insulin receptors from the trophoblast, that is, the surface facing the maternal circulation to the endothelial cells interacting or sensing circulating fetal insulin, provides the molecular basis for the topological change of insulin regulation [36,37,60,61]. On purpose, this concept is reductionistic in its design. By putting the glucose/insulin axis in its focus, it can explain some of the factors that have been shown to be associated with neonatal birth weight or adiposity and obesity risk in later life. For example, high triglyceride levels in the first trimester are just a manifestation of insulin resistance, and high neonatal leptin levels are the consequence of adiposity and thus correlate with cord blood insulin [62]. Most importantly, fetal insulin levels already at around weeks 32e34 of gestation, measured in the amniotic fluid, are associated with the risk of impaired glucose tolerance at age 10e16 years [63] and childhood obesity (age 5e15 years: Ref. [64]; age 6 years: Ref. [65]) further demonstrating the relevance of fetal insulin and the need to prevent high levels of fetal insulin. The concept described above can only explain one of the principal mechanisms associated with the risk of obesity-associated chronic diseases later in life, which is based on fetal overnutrition (‘fuel-mediated in utero hypothesis’). However, offspring born with a low birth weight also have an increased later risk of non-communicable diseases. For these associations, other concepts are in place such as fetal undernutrition and postnatal overnutrition (‘mismatch hypothesis’) and the postnatal overnutrition (‘accelerated postnatal growth hypothesis’) [66]. Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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How to prevent the fetal changes in maternal diabesity Given the central role of fetal/neonatal hyperglycaemia and hyperinsulinaemia in determining neonatal adiposity and thus the diabesity risk later in life, the question remains of how this can be avoided or prevented. As maternal obesity and/or diabetes in early pregnancy have been described here as driving factors for fetal hyperglycaemia and hyperinsulinaemia, the most logical answer for how to avoid or prevent this would be to reduce maternal obesity and prevent diabetes before or in early pregnancy. Although this solution seems straightforward, actually achieving it is not. First of all, women need to be targeted before or in very early pregnancy. However, this is before they have initiated contact with health-care providers because of their pregnancy. Identifying and targeting women who want to become pregnant or who just conceived is very difficult in general. That is why most interventions aimed at reducing weight and weight gain in pregnancy, or aimed at the prevention of GDM, were initiated in the second or third trimester of pregnancy. Lifestyle interventions initiated before pregnancy were mostly aimed at specific groups that are in contact with health-care providers, for instance, because of polycystic ovary syndrome (PCOS) or with other fertility problems. Second, although the solution of reducing weight and improving diet and physical activity levels sounds easy, in practice adopting a healthier lifestyle is challenging for many women. Although pregnancy provides a limited and specific time frame, with the health of the baby as an extra motivation to adopt a healthy lifestyle, pregnancy complaints can be important (additional) barriers for women to change their lifestyle behaviour. From studies with interventions initiated before pregnancy (e.g., the Radiel study [67] or LIFESTYLE study [68]), no data are available on percentage body fat or fetal insulin levels at present. Hopefully, these data will become available in the coming years. A review, including meta-analyses of lifestyle interventions in pregnancy, reported that dietary interventions were effective in reducing weight gain in pregnancy, more than a mixed approach or physical activity interventions [69]. Based on four studies, in this same review, it was concluded that dietary interventions also reduced neonatal fat mass, but not other types of interventions. The effects on neonatal percentage body fat were not reported, nor was cord blood insulin taken into account in this review, very likely because very few studies included measured these outcomes. The results of the very few intervention studies that measured cord blood insulin are not very promising. In a large dietary intervention study, women in the intervention group were advised to maintain a low glycaemic diet at on average 15 weeks of pregnancy [70]. This intervention was compared with usual care, and although women in the intervention group gained less weight, no effects were found on maternal glucose, insulin sensitivity or on cord blood insulin [71]. In a small intervention study, a diet enriched with docosahexaenoic acid (DHA, an omega-3 fatty acid) initiated in the second half of pregnancy led to lower cord blood insulin levels [72]. Landon et al. found a reduction of the risk of elevated (>95th percentile) C-peptide levels in the neonates of mothers in a dietary intervention group compared to a usual care group, although the difference was not statistically significant [73]. They did not report differences in the mean levels of Cpeptide between the groups. Hopkins et al. conducted a physical activity intervention trial, in which they managed to achieve higher levels of moderate to vigorous physical activity among the women in the intervention group. However, they did not find effects on maternal glucose or insulin sensitivity. Although the birth weight of the neonates of exercising women was lower, cord blood insulin levels were not different between the intervention and control group, nor was percentage body fat 17 days after birth [74]. Although some longitudinal or cross-sectional observational studies are available on the relationship between maternal lifestyle and cord blood insulin, controlling for all relevant confounders is impossible when the exact underlying mechanisms are unclear. Therefore, information from randomized controlled studies is preferred. Because of randomization, all known and unknown confounders should be equal in the different intervention arms. For this reason, only those studies have been described here. However, it is clear that, at this moment, there is an enormous lack of randomized controlled studies, with dietary and/or physical activity interventions initiated before or in very early pregnancy, which not only were effective in improving maternal lifestyle or weight gain but also measured fetal or neonatal insulin and neonatal body composition. Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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Summary For >50 years, evidence has accumulated that fetal insulin is a main driver for fetal fat accumulation. Both fetal insulin in the third trimester of pregnancy and the proportion of neonatal fat are associated with the degree of obesity and insulin resistance in childhood and adolescence. Therefore, events in utero and in early childhood may have a long-lasting effect on offspring health. Insulin seems to play a central role because of its manifold effects, which also include programming of the fetal and neonatal hypothalamus. Thus, attempts to prevent childhood obesity and associated metabolic diseases should begin before or early in pregnancy and use fetal/neonatal insulin as a main outcome measure. However, at the moment, there is a lack of studies investigating the effects of (lifestyle) interventions on this outcome. Results from the very few studies available are inconsistent.
Practice points Excessive fat is characteristic for neonates born to diabetic or overweight/obese pregnant mothers independent of birth weight. Excessive fat accumulation in the neonate can also occur despite excellent glycaemic control after GDM diagnosis, because of the fetal glucose steal phenomenon. First-trimester fasting glucose levels are important determinants of neonatal fat deposition. Neonatal insulin levels reflect the quality of glycaemic control during pregnancy Lifestyle interventions, especially dietary interventions, are effective in reducing gestational weight gain.
Research agenda To demonstrate the effect of first-trimester maternal glucose levels on neonatal body composition, that is, percentage body fat. To demonstrate the association of fetal (amniotic fluid) insulin early in gestation with neonatal body composition, that is, percentage body fat. How does the maternal intrauterine environment in diabesity modify placental growth and development early in gestation? Are there distinct sites in the fetus/neonate that preferentially store excess body fat? To demonstrate in randomized controlled trials that lifestyle interventions before and in early pregnancy can reduce fetal hyperinsulinaemia and percentage body fat.
Conflict of interest The authors have no conflict of interest to disclose. Uncited reference Q4
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[41] Weiss PA, Scholz HS, Haas J, et al. Effect of fetal hyperinsulinism on oral glucose tolerance test results in patients with gestational diabetes mellitus. Am J Obstet Gynecol 2001;184(3):470e5. [42] Van Assche FA. Symmetric and asymmetric fetal macrosomia in relation to long-term consequences. Am J Obstet Gynecol 1997;177(6):1563e4. [43] Van Assche FA, Holemans K, Aerts L. Long-term consequences for offspring of diabetes during pregnancy. Br Med Bull 2001;60:173e82. [44] Polak M, Bouchareb-Banaei L, Scharfmann R, et al. Early pattern of differentiation in the human pancreas. Diabetes 2000; 49(2):225e32. [45] In 't Veld PA, Zhang F, Madsen OD, et al. Islet amyloid polypeptide immunoreactivity in the human fetal pancreas. Diabetologia 1992;35(3):272e6. [46] Adesanya T, Grillo I, Shima K. Insulin content and enzyme histochemistry of the human foetal pancreatic islet. J Endocrinol 1966;36(2):151e8. [47] Adam PA, Teramo K, Raiha N, et al. Human fetal insulin metabolism early in gestation. Response to acute elevation of the fetal glucose concentration and placental transfer of human insulin-I-131. Diabetes 1969;18(6):409e16. [48] Tisi DK, Burns DH, Luskey GW, et al. Fetal exposure to altered amniotic fluid glucose, insulin, and insulin-like growth factor-binding protein 1 occurs before screening for gestational diabetes mellitus. Diabetes Care 2011;34(1):139e44. [49] Riskin-Mashiah S, Younes G, Damti A, et al. First-trimester fasting hyperglycemia and adverse pregnancy outcomes. Diabetes Care 2009;32(9):1639e43. [50] Thame M, Osmond C, Bennett F, et al. Fetal growth is directly related to maternal anthropometry and placental volume. Eur J Clin Nutr 2004;58(6):894e900. [51] Holroyd CR, Harvey NC, Crozier SR, et al. Placental size at 19 weeks predicts offspring bone mass at birth: findings from the Southampton Women's Survey. Placenta 2012;33(8):623e9. [52] Gonzalez Gonzalez NL, Gonzalez Davila E, Castro A, et al. Effect of pregestational diabetes mellitus on first trimester placental characteristics: three-dimensional placental volume and power Doppler indices. Placenta 2014;35(3):147e51. [53] Jones NW, Deshpande R, Mousa HA, et al. Fractional volume of placental vessels in women with diabetes using a novel stereological 3D power Doppler technique. Placenta 2013;34(11):1002e8. [54] Brown ZA, Mills JL, Metzger BE, et al. Early sonographic evaluation for fetal growth delay and congenital malformations in pregnancies complicated by insulin-requiring diabetes. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care 1992;15(5):613e9. [55] Pedersen JF, Sorensen S, Molsted-Pedersen L. Serum levels of human placental lactogen, pregnancy-associated plasma protein A and endometrial secretory protein PP14 in first trimester of diabetic pregnancy. Acta Obstet Gynecol Scand 1998; 77(2):155e8. [56] Frohlich JD, Huppertz B, Abuja PM, et al. Oxygen modulates the response of first-trimester trophoblasts to hyperglycemia. Am J Pathol 2012;180(1):153e64. [57] Hiden U, Glitzner E, Ivanisevic M, et al. MT1-MMP expression in first-trimester placental tissue is upregulated in type 1 diabetes as a result of elevated insulin and tumor necrosis factor-alpha levels. Diabetes 2008;57(1):150e7. [58] HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358(19):1991e2002. [59] Plagemann A. Perinatal nutrition and hormone-dependent programming of food intake. Horm Res 2006;65(3):83e9. [60] Desoye G, Hartmann M, Blaschitz A, et al. Insulin receptors in syncytiotrophoblast and fetal endothelium of human placenta. Immunohistochemical evidence for developmental changes in distribution pattern. Histochemistry 1994;101(4):277e85. [61] Hiden U, Maier A, Bilban M, et al. Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy. Diabetologia 2006;49(1):123e31. [62] Wolf HJ, Ebenbichler CF, Huter O, et al. Fetal leptin and insulin levels only correlate in large-for-gestational age infants. Eur J Endocrinol 2000;142(6):623e9. [63] Silverman BL, Metzger BE, Cho NH, et al. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18(5):611e7. [64] Weiss PA, Scholz HS, Haas J, et al. Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care 2000;23(7):905e11. [65] Metzger BE, Silverman BL, Freinkel N, et al. Amniotic fluid insulin concentration as a predictor of obesity. Arch Dis Child 1990;65(10):1050e2. [66] Koletzko B, Symonds ME, Olsen SF. Early Nutrition Programming Project, Early Nutrition Academy. Programming research: where are we and where do we go from here? Am J Clin Nutr 2011;94(6):2036e43. € no € K, Stach-Lempinen B, Klemetti MM, et al. Prevention of gestational diabetes through lifestyle intervention: study [67] Ro design and methods of a Finnish randomized controlled multicenter trial (RADIEL). BMC Pregnancy Childbirth 2014;14:70. [68] Mutsaerts MA, Groen H, ter Bogt NC, et al. The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve reproductive outcome. A randomised controlled trial. BMC Womens Health 2010;10:22. ska E, Jolly K, et al. Interventions to reduce or prevent obesity in pregnant women: a systematic [69] Thangaratinam S, Rogozin review. Health Technology Assessment 2012;16:31. [70] Walsh JM, McGowan CA, Mahony R, et al. Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomised control trial. BMJ 2012;345:5605. 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The Feto-placental Dialogue and Diabesity Q5 Q1
Gernot Desoye a, *, Mireille van Poppel b a
Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
b
Keywords: glucose insulin hypothalamus fetal/neonatal fat first trimester of pregnancy lifestyle interventions
Recent studies have established that the neonate born to a pregnancy with maternal diabetes or obesity (‘diabesity’) is characterized by increased fat accumulation. The neonatal fat is the result of triglyceride synthesis and deposition stimulated by elevated fetal insulin levels combined with insulin's mitogenic activity directly stimulating the growth of the white adipocytes. Fetal insulin levels are determined by fetal glucose and some amino acids such as arginine. Although the placenta plays a key role in providing maternally derived nutrients to the growing fetus, there is currently no evidence that it actively contributes to an excessive maternal-to-fetal glucose flux at the end of gestation. Early in gestation, the maternal environment in diabesity, and in particular the glucoseeinsulin axis, can modify placental growth and development, which may contribute to an enhanced glucose flux to the fetus already early in pregnancy. This may have long-lasting effects on the fetal pancreas and accelerate beta-cell maturation. The association of fetal and neonatal insulin levels and the proportion of body fat with obesity later in the offspring's life calls for interventions during pregnancy to prevent or reduce fetal hyperinsulinaemia. Dietary and/or physical activity interventions initiated before or in early pregnancy would likely be most effective. Results from the very few studies with fetal insulin as the outcome are inconsistent. However, there is a major lack of randomized intervention trials on this topic. © 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Medical University of Graz, Department of Obstetrics and Gynaecology, Auenbruggerplatz 14, 8036 Graz, Austria. Tel.: þ43 316 385 84605. E-mail address: [email protected] (G. Desoye).
http://dx.doi.org/10.1016/j.bpobgyn.2014.05.012 1521-6934/© 2014 Elsevier Ltd. All rights reserved.
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The rapid increase in the prevalence of diabesity, that is, obesity, type 2 diabetes and associated complications, is a major problem for global health worldwide. The developmental origins of health and adult disease (DOHaD) concept puts pregnancy and its influences on the mother and the developing fetus in the focus of the transgenerational transmission of diabesity risk. Thus, the maternaleplacentalefetal interaction has received increasing research interest. The placenta is interposed between the maternal and fetal blood stream and thus constitutes the physical link between the two generations. The maternal environment associated with diabetes (type 1, type 2 and gestational) mellitus and/or obesity has an influence on placental development, structure and function, which has been summarized in several articles [1e14]. These placental alterations may be protective or adaptive responses to the maternal environment, with the ultimate purpose of allowing the fetus to grow and develop in a stable environment. Alternatively, these changes might be mechanistically linked to the fetal phenotype associated with maternal diabesity. It is not the purpose of this review to summarize once again placental changes associated with diabesity. Rather, we will focus on one particular concept, with the focus on the maternal and fetal glucose/insulin axis and its effects on the placenta and the fetus. This concept may explain the fetal phenotype and some aspects of intrauterine programming of childhood obesity in the wake of maternal diabesity. We further intend to discuss options to prevent this from happening. The fetal phenotype in diabesity Much work has been published demonstrating the increased incidence of ‘macrosomia’ and largefor-gestational age neonates, that is, >90th birth-weight centile, born to diabesity pregnancies. This research focus is largely based on the obstetric complications associated with a macrosomic neonate such as an increased rate of caesarean sections, shoulder dystocia and others. However, there is a growing body of evidence showing that the neonate of a diabetic mother, even when born in the appropriate-for-gestational age range (between the 5th or 10th and 90th birth-weight centile), has a phenotype different from those born to normal pregnancies. The major difference and thus the major effect of maternal diabesity on the neonate is on body composition: These neonates are born with a higher proportion of body fat independent of their birth weight or birth-weight category [15e18], whereas the fat-free mass appears unaltered (Fig. 1). Interestingly, gestational diabetes and maternal obesity are independent risk factors for neonatal percentage body fat and contribute additively [19]. The higher neonatal body fat is of key importance because the number of adipocytes for a human being seems to be determined very early in the life cycle if not already in utero [20]. The trajectory of
Fig. 1. Proportion (%) of body fat in neonates born to pregnancies with normal glucose tolerance of the mother (NGT) and mothers with gestational diabetes mellitus (GDM). GDM neonates have more body fat not only when born large-for-gestational age (LGA) but also with appropriate-for-gestational age birth weight (AGA). No data are available for small-for-gestational age (SGA) neonates in GDM pregnancies (left panel). Neonates from lean (BMI < 25) mothers have a lower percentage body fat than their counterparts born to overweight (BMI 25) mothers (right panel). Data taken from Refs. [15,18].
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adipocyte number cannot be changed not even when weight, that is, fat, is lost. Thus, once the growing fetus has developed more adipocytes in the wake of the diabesity environment, the neonate may be strongly predisposed to remain on this trajectory and have more adipocytes also in childhood. This is indeed the case as shown by the association of neonatal body fat with that in childhood at the age of 9 years, whereas total body weight is not associated [21]. The excessive accretion of body fat even in neonates with appropriate-for-gestational-age birth weight constitutes a major problem from the public health perspective. These neonates represent by far the majority of all neonates born to diabesity pregnancies. They are inconspicuous and yet are at a risk of childhood obesity. Therefore, measures meant to prevent the childhood obesity risk should perhaps include all neonates of diabetic mothers, regardless of birth weight. The role of the placenta in determining the fetal phenotype in diabesity More than 50 years ago, Jorgen Pedersen explained fetal overgrowth in diabetic pregnancies by his hyperglycaemiaehyperinsulinaemia concept: Maternal hyperglycaemia as in diabetes leads to fetal hyperglycaemia, which stimulates the fetal pancreas to produce and secrete more insulin ultimately resulting in fetal hyperinsulinaemia. This concept has been expanded later to include amino acids and fatty acids (fuel-mediated teratogenesis concept) [22]. In essence, fetal insulin is the man driver for the fetal phenotype, because of its dual activities as a mitogen to stimulate the growth of white adipocytes and as an anabolic hormone to drive triglyceride formation and deposition in fetal white adipocytes. Until now, the concepts have not been refuted and are still the key to our understanding of fetal development in a situation of maternal hyperglycaemia as is associated with diabesity. Although amino acids, and in particular arginine, can serve as insulin secretagogues [23] and may contribute to fetal hyperinsulinaemia in diabesity, glucose is the most important stimulator of insulin secretion. Thus, this has sparked research interest trying to understand the regulation of maternal-tofetal glucose transport across the placenta. Despite a number of molecular changes in the placenta at the level of glucose transporters and glucose metabolism, the total glucose flux across the placenta is unaltered in placentas from gestational diabetic pregnancies [24e26]. Thus, at least at the end of gestation, maternal-to-fetal glucose flux is mostly dictated by the maternal-to-fetal concentration gradient of glucose, perhaps with some contribution of utero-placental and feto-placental blood flow [27]. This has important implications for the clinical care of the obese or diabetic woman: Adequate glycaemic control of the mother after diagnosis of gestational diabetes mellitus (GDM) may not be sufficient to prevent excess fetal fat accretion once the fetal pancreas has already been overstimulated by maternal hyperglycaemia prior to gestational diabetes diagnosis. The level of fetal hyperinsulinaemia has to be taken into account in the clinical decisions of how to manage diabetes in the pregnant women. Directly measuring amniotic fluid insulin levels has been advocated [28], but not been accepted because of the invasive nature of amniocentesis. Elevated levels of fetal insulin will have multiple consequences. It can stimulate (1) placental growth and also growth of the fetal heart, at least in non-human primates [29,30], (2) glycogen deposition in the placental endothelium (Desoye, Hiden unpublished) and (3) aerobic fetal metabolism. The latter will raise the demand for oxygen in the fetus. At the same time, in diabetic pregnancies, maternal haemoglobin is glycosylated to a greater extent and, thus, has a lower oxygen transport capacity. Along with potentially reduced utero-placental blood flow in maternal diabetes mellitus, this may result in an imbalance between oxygen supply and demand with a net oxygen deficit. This stimulates fetal erythropoietin synthesis and erythropoiesis [31,32]. In synergy with increased oxygen transport capacity within the fetal circulation, the placental vascular network is expanded and the capillary surface enlarged [3,33]. Fetal insulin contributes to placental angiogenesis through multiple cellular mechanisms [10,34e37]. One further consequence of fetal hyperinsulinaemia is not only the stimulation of triglyceride synthesis and fat deposition but also aerobic metabolism and stimulation of glucose uptake into fetal tissues. This insulin-induced shift of circulating glucose into tissue will remove glucose from the circulation and thus transiently steepen the concentration gradient between the maternal and fetal circulations, thus increasing the glucose flux until steady-state concentrations have been reached again. Thus, fetal insulin will siphon maternal glucose and direct it to the fetus. The term ‘glucose steal Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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phenomenon’ was coined for this effect, which was shown in rat [38] and sheep [39,40] and indirectly demonstrated also in humans. [41] The important consequence for clinical care of the diabetic mother is that late in gestation normalization of maternal glucose levels may not be enough to prevent fat accretion (or ‘macrosomia’), because the fetus is also involved in determining transplacental glucose flux. This will always be the case when the fetal pancreas is already altered by hyperplasia earlier in pregnancy [42,43] and fetal hyperinsulinaemia has become manifest. This raises the question about the onset of fetal hyperplasia and, thus, hyperinsulinaemia. Insulin depots in the human fetal pancreas were demonstrated as early as at week 8 or 9 of gestation [44e46]; insulin is secreted into the fetal circulation as early as at 11 weeks of gestation [47] and can be measured in the fetal amniotic fluid at week 14 of gestation [48]. Importantly, amniotic fluid insulin in this early period was associated with the risk of birth weight >90th centile. Thus, early fetal hyperinsulinaemia as a result of maternal and fetal hyperglycaemia can have consequences for further fetal development. The importance of the glucoseeinsulin axis in the first trimester is also highlighted by the correlation of maternal fasting glucose levels at weeks 9e10 of gestation with the risk of fetal macrosomia [49]. The maternal glucoseeinsulin axis in the first trimester of pregnancy and its effect on the placenta There is a growing body of evidence that the placenta early in gestation may influence fetal growth and development with manifestations at the end of pregnancy. The placental volume at week 14 of gestation and the rate of placental growth between weeks 14 and 17 of gestation were associated directly with fetal anthropometric parameters such as abdominal circumference [50]. In another study, the placental volume at 19 weeks was associated with neonatal fat mass both absolute and relative to birth weight [51]. Despite the importance of knowing the regulatory factors for placental growth early in gestation, surprisingly little is known about this, if anything. It is also unclear what the effect of pre-gestational diabetes on the early placenta is. There are conflicting reports on the degree of placental vascularization, that is, more or less, as compared to non-diabetic pregnancies [52,53]. There is indirect evidence to suggest a delayed placental development in pre-gestational, that is, type I, diabetes: In these pregnancies, fetal growth is delayed [54]. Although placental volume measurements at this early stage in type I diabetic pregnancies are pending, the lower levels of circulating human placental lactogen (hPL) and pregnancy-associated plasma protein-A (PAPP-A) [55], which are both produced in the placental trophoblast, suggest also a reduced trophoblast, that is, placental, growth. In vitro evidence demonstrates an interaction of hyperglycaemia and higher/lower levels of oxygen levels resulting in a slower trophoblast growth [56]. Maternal insulin may also have an independent effect on early placental development. It upregulates matrix metalloproteinase 14, one key enzyme, which is involved in growth regulation, invasion, inflammation and also in angiogenesis. The placental levels of this enzyme correlate with the daily insulin dose given to type 1 diabetes mellitus (T1DM) women in the first trimester [37,58]. Thus, the combined effects of hyperglycaemia and compensatory hyperinsulinaemia may alter the dynamics of placental growth already in the first trimester and have a long-lasting influence on fetal growth and development including body composition. The mothereplacentaefetus dialogue in diabesity Based on the above, we propose the following model linking first-trimester events to the childhood diabesity risk (Fig. 2). Although maternal diabetes and/or obesity per se independently and additively increase the risk of overproportional neonatal fat accumulation [19], changes of the maternal glucose/insulin axis are a continuum and show a more or less linear association between maternal glucose, fetal growth and neonatal body composition [49,58]. Thus, small changes in maternal glucose homeostasis can also gear fetal metabolism towards more fat accretion already at levels below those Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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Fig. 2. The mothereplacentaefetus dialogue. The scheme links early maternal metabolism to neonatal adiposity and obesity risk in later life. For details, see text above.
defined as diabetes. Any elevation in maternal glucose and/or insulin early in gestation modifies placental growth and development. These alterations in the placenta may or may not (unclear yet) imply a change in transplacental glucose transfer, which along with a higher glucose concentration gradient will increase glucose flux to the fetus. At what period in gestation this happens will depend on the maternal glucose/insulin axis. Continuous glucose flux across the placenta will lead to stimulation of beta-cell growth and insulin secretion. Fetal insulin promotes glucose uptake into peripheral tissues and steepens the maternal-to-fetal glucose concentration gradient with ensuing glucose flux to the fetus, which also becomes dependent on fetal insulin levels. Fetal insulin also increases the number of adipocytes and triglyceride deposition in them. Importantly, insulin is able to malprogram the neuroendocrine systems regulating body weight, food intake and metabolism, at least in the rat [59]. This increases the risk of becoming obese and of developing diabetes throughout life, also because of the ß-cell hyperplasia developed in utero which may lead to their earlier exhaustion. This concept thus links early maternal derangements of the glucose/insulin axis with events in the fetus later in gestation or even postnatally. The placenta directly affects fetal development early in pregnancy by responding to the maternal environment. At later stages in pregnancy, it will primarily respond to fetal signals and adapt its structure, for example, by hypervascularization, and likely also its function to fetal needs. Thus, maternal influences diminish from early to late gestation whereas the fetus gradually takes over control. Insulin plays a central role. The shift in insulin receptors from the trophoblast, that is, the surface facing the maternal circulation to the endothelial cells interacting or sensing circulating fetal insulin, provides the molecular basis for the topological change of insulin regulation [36,37,60,61]. On purpose, this concept is reductionistic in its design. By putting the glucose/insulin axis in its focus, it can explain some of the factors that have been shown to be associated with neonatal birth weight or adiposity and obesity risk in later life. For example, high triglyceride levels in the first trimester are just a manifestation of insulin resistance, and high neonatal leptin levels are the consequence of adiposity and thus correlate with cord blood insulin [62]. Most importantly, fetal insulin levels already at around weeks 32e34 of gestation, measured in the amniotic fluid, are associated with the risk of impaired glucose tolerance at age 10e16 years [63] and childhood obesity (age 5e15 years: Ref. [64]; age 6 years: Ref. [65]) further demonstrating the relevance of fetal insulin and the need to prevent high levels of fetal insulin. The concept described above can only explain one of the principal mechanisms associated with the risk of obesity-associated chronic diseases later in life, which is based on fetal overnutrition (‘fuel-mediated in utero hypothesis’). However, offspring born with a low birth weight also have an increased later risk of non-communicable diseases. For these associations, other concepts are in place such as fetal undernutrition and postnatal overnutrition (‘mismatch hypothesis’) and the postnatal overnutrition (‘accelerated postnatal growth hypothesis’) [66]. Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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How to prevent the fetal changes in maternal diabesity Given the central role of fetal/neonatal hyperglycaemia and hyperinsulinaemia in determining neonatal adiposity and thus the diabesity risk later in life, the question remains of how this can be avoided or prevented. As maternal obesity and/or diabetes in early pregnancy have been described here as driving factors for fetal hyperglycaemia and hyperinsulinaemia, the most logical answer for how to avoid or prevent this would be to reduce maternal obesity and prevent diabetes before or in early pregnancy. Although this solution seems straightforward, actually achieving it is not. First of all, women need to be targeted before or in very early pregnancy. However, this is before they have initiated contact with health-care providers because of their pregnancy. Identifying and targeting women who want to become pregnant or who just conceived is very difficult in general. That is why most interventions aimed at reducing weight and weight gain in pregnancy, or aimed at the prevention of GDM, were initiated in the second or third trimester of pregnancy. Lifestyle interventions initiated before pregnancy were mostly aimed at specific groups that are in contact with health-care providers, for instance, because of polycystic ovary syndrome (PCOS) or with other fertility problems. Second, although the solution of reducing weight and improving diet and physical activity levels sounds easy, in practice adopting a healthier lifestyle is challenging for many women. Although pregnancy provides a limited and specific time frame, with the health of the baby as an extra motivation to adopt a healthy lifestyle, pregnancy complaints can be important (additional) barriers for women to change their lifestyle behaviour. From studies with interventions initiated before pregnancy (e.g., the Radiel study [67] or LIFESTYLE study [68]), no data are available on percentage body fat or fetal insulin levels at present. Hopefully, these data will become available in the coming years. A review, including meta-analyses of lifestyle interventions in pregnancy, reported that dietary interventions were effective in reducing weight gain in pregnancy, more than a mixed approach or physical activity interventions [69]. Based on four studies, in this same review, it was concluded that dietary interventions also reduced neonatal fat mass, but not other types of interventions. The effects on neonatal percentage body fat were not reported, nor was cord blood insulin taken into account in this review, very likely because very few studies included measured these outcomes. The results of the very few intervention studies that measured cord blood insulin are not very promising. In a large dietary intervention study, women in the intervention group were advised to maintain a low glycaemic diet at on average 15 weeks of pregnancy [70]. This intervention was compared with usual care, and although women in the intervention group gained less weight, no effects were found on maternal glucose, insulin sensitivity or on cord blood insulin [71]. In a small intervention study, a diet enriched with docosahexaenoic acid (DHA, an omega-3 fatty acid) initiated in the second half of pregnancy led to lower cord blood insulin levels [72]. Landon et al. found a reduction of the risk of elevated (>95th percentile) C-peptide levels in the neonates of mothers in a dietary intervention group compared to a usual care group, although the difference was not statistically significant [73]. They did not report differences in the mean levels of Cpeptide between the groups. Hopkins et al. conducted a physical activity intervention trial, in which they managed to achieve higher levels of moderate to vigorous physical activity among the women in the intervention group. However, they did not find effects on maternal glucose or insulin sensitivity. Although the birth weight of the neonates of exercising women was lower, cord blood insulin levels were not different between the intervention and control group, nor was percentage body fat 17 days after birth [74]. Although some longitudinal or cross-sectional observational studies are available on the relationship between maternal lifestyle and cord blood insulin, controlling for all relevant confounders is impossible when the exact underlying mechanisms are unclear. Therefore, information from randomized controlled studies is preferred. Because of randomization, all known and unknown confounders should be equal in the different intervention arms. For this reason, only those studies have been described here. However, it is clear that, at this moment, there is an enormous lack of randomized controlled studies, with dietary and/or physical activity interventions initiated before or in very early pregnancy, which not only were effective in improving maternal lifestyle or weight gain but also measured fetal or neonatal insulin and neonatal body composition. Please cite this article in press as: Desoye G, van Poppel M, The Feto-placental Dialogue and Diabesity, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.05.012
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Summary For >50 years, evidence has accumulated that fetal insulin is a main driver for fetal fat accumulation. Both fetal insulin in the third trimester of pregnancy and the proportion of neonatal fat are associated with the degree of obesity and insulin resistance in childhood and adolescence. Therefore, events in utero and in early childhood may have a long-lasting effect on offspring health. Insulin seems to play a central role because of its manifold effects, which also include programming of the fetal and neonatal hypothalamus. Thus, attempts to prevent childhood obesity and associated metabolic diseases should begin before or early in pregnancy and use fetal/neonatal insulin as a main outcome measure. However, at the moment, there is a lack of studies investigating the effects of (lifestyle) interventions on this outcome. Results from the very few studies available are inconsistent.
Practice points Excessive fat is characteristic for neonates born to diabetic or overweight/obese pregnant mothers independent of birth weight. Excessive fat accumulation in the neonate can also occur despite excellent glycaemic control after GDM diagnosis, because of the fetal glucose steal phenomenon. First-trimester fasting glucose levels are important determinants of neonatal fat deposition. Neonatal insulin levels reflect the quality of glycaemic control during pregnancy Lifestyle interventions, especially dietary interventions, are effective in reducing gestational weight gain.
Research agenda To demonstrate the effect of first-trimester maternal glucose levels on neonatal body composition, that is, percentage body fat. To demonstrate the association of fetal (amniotic fluid) insulin early in gestation with neonatal body composition, that is, percentage body fat. How does the maternal intrauterine environment in diabesity modify placental growth and development early in gestation? Are there distinct sites in the fetus/neonate that preferentially store excess body fat? To demonstrate in randomized controlled trials that lifestyle interventions before and in early pregnancy can reduce fetal hyperinsulinaemia and percentage body fat.
Conflict of interest The authors have no conflict of interest to disclose. Uncited reference Q4
[57].. References
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