Obesity: A Transgenerational Problem Linked to Nutrition during Pregnancy

Abstract

The increased obstetric risks of maternal obesity have been well described. These include increased risks of gestational diabetes mellitus, preeclampsia, stillbirth, and cesarean delivery. The fetal/neonatal consequences of prenatal maternal obesity have received less attention. In addition to an increased risk of stillbirth, the fetal/neonatal consequences include increased adiposity and a metabolic status that increases the lifetime risk of obesity and diabetes. This review focuses on the clinical obstetric consequences of maternal obesity and highlights recent mechanistic insights on fetal programming as well as evidence suggesting that prenatal care provides a unique opportunity to ameliorate these risks and decrease the cycle of childhood obesity.

Keywords

obesity - pregnancy - high fat diet - placenta - programming

• References

• 1 Kopelman PG. Obesity as a medical problem. Nature 2000; 404 (6778) 635-643
• 2 Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA 1999; 282 (16) 1523-1529
• 3 Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB. Annual deaths attributable to obesity in the United States. JAMA 1999; 282 (16) 1530-1538
• 4 Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children and adolescents, 2007–2008. JAMA 2010; 303 (3) 242-249
• 5 Caprio S. Relationship between abdominal visceral fat and metabolic risk factors in obese adolescents. Am J Hum Biol 1999; 11 (2) 259-266
• 6 Dietz WH, Bellizzi MC. Introduction: the use of body mass index to assess obesity in children. Am J Clin Nutr 1999; 70 (1) 123S-125S
• 7 Janssen I, Katzmarzyk PT, Srinivasan SR , et al. Combined influence of body mass index and waist circumference on coronary artery disease risk factors among children and adolescents. Pediatrics 2005; 115 (6) 1623-1630
• 8 Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 2005; 115 (3) e290-e296
• 9 Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008; 359 (1) 61-73
• 10 Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; 1 (8489) 1077-1081
• 11 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35 (7) 595-601
• 12 Barker DJ, Osmond C, Forsén TJ, Kajantie E, Eriksson JG. Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005; 353 (17) 1802-1809
• 13 Oken E, Gillman MW. Fetal origins of obesity. Obes Res 2003; 11 (4) 496-506
• 14 Perlow JH, Morgan MA, Montgomery D, Towers CV, Porto M. Perinatal outcome in pregnancy complicated by massive obesity. Am J Obstet Gynecol 1992; 167 (4 Pt 1) 958-962
• 15 Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol 2004; 191 (3) 964-968
• 16 Kim SY, Dietz PM, England L, Morrow B, Callaghan WM. Trends in pre-pregnancy obesity in nine states, 1993–2003. Obesity (Silver Spring) 2007; 15 (4) 986-993
• 17 Nohr EA, Vaeth M, Bech BH, Henriksen TB, Cnattingius S, Olsen J. Maternal obesity and neonatal mortality according to subtypes of preterm birth. Obstet Gynecol 2007; 110 (5) 1083-1090
• 18 Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol 2003; 189 (6) 1698-1704
• 19 Cnattingius S, Bergström R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998; 338 (3) 147-152
• 20 Kristensen J, Vestergaard M, Wisborg K, Kesmodel U, Secher NJ. Pre-pregnancy weight and the risk of stillbirth and neonatal death. BJOG 2005; 112 (4) 403-408
• 21 Nohr EA, Bech BH, Davies MJ, Frydenberg M, Henriksen TB, Olsen J. Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet Gynecol 2005; 106 (2) 250-259
• 22 Sullivan EL, Grove KL. Metabolic imprinting in obesity. Forum Nutr 2010; 63: 186-194
• 23 Strauss RS, Dietz WH. Effects of intrauterine growth retardation in premature infants on early childhood growth. J Pediatr 1997; 130 (1) 95-102
• 24 Ozanne SE, Hales CN. The long-term consequences of intra-uterine protein malnutrition for glucose metabolism. Proc Nutr Soc 1999; 58 (3) 615-619
• 25 Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Bleker OP. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 2000; 72 (5) 1101-1106
• 26 Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP. Obesity at the age of 50.  y in men and women exposed to famine prenatally. Am J Clin Nutr 1999; 70 (5) 811-816
• 27 Ravelli AC, van der Meulen JH, Michels RP , et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998; 351 (9097) 173-177
• 28 Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976; 295 (7) 349-353
• 29 Silverman BL, Landsberg L, Metzger BE. Fetal hyperinsulinism in offspring of diabetic mothers. Association with the subsequent development of childhood obesity. Ann N Y Acad Sci 1993; 699: 36-45
• 30 Plagemann A, Harder T, Kohlhoff R, Rohde W, Dörner G. Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord 1997; 21 (6) 451-456
• 31 Garcia Carrapato MR. The offspring of gestational diabetes. J Perinat Med 2003; 31 (1) 5-11
• 32 Wilkin TJ, Metcalf BS, Murphy MJ, Kirkby J, Jeffery AN, Voss LD. The relative contributions of birth weight, weight change, and current weight to insulin resistance in contemporary 5-year-olds: the EarlyBird Study. Diabetes 2002; 51 (12) 3468-3472
• 33 Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121 (6) 2111-2117
• 34 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444 (7121) 860-867
• 35 Ramsay JE, Ferrell WR, Crawford L, Wallace AM, Greer IA, Sattar N. Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab 2002; 87 (9) 4231-4237
• 36 Xu H, Barnes GT, Yang Q , et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112 (12) 1821-1830
• 37 Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab 2007; 92 (3) 969-975
• 38 Madan JC, Davis JM, Craig WY , et al. Maternal obesity and markers of inflammation in pregnancy. Cytokine 2009; 47 (1) 61-64
• 39 Okereke NC, Huston-Presley L, Amini SB, Kalhan S, Catalano PM. Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance. Am J Physiol Endocrinol Metab 2004; 287 (3) E472-E479
• 40 Blackburn P, Després JP, Lamarche B , et al. Postprandial variations of plasma inflammatory markers in abdominally obese men. Obesity (Silver Spring) 2006; 14 (10) 1747-1754
• 41 Alipour A, Elte JW, van Zaanen HC, Rietveld AP, Cabezas MC. Postprandial inflammation and endothelial dysfunction. Biochem Soc Trans 2007; 35 (Pt 3) 466-469
• 42 Donath MY, Böni-Schnetzler M, Ellingsgaard H, Halban PA, Ehses JA. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol Metab 2010; 21 (5) 261-267
• 43 Ehses JA, Böni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem Soc Trans 2008; 36 (Pt 3) 340-342
• 44 Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integr Comp Physiol 2010; 299 (3) R711-R722
• 45 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259 (5091) 87-91
• 46 Straczkowski M, Dzienis-Straczkowska S, Stêpieñ A, Kowalska I, Szelachowska M, Kinalska I. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab 2002; 87 (10) 4602-4606
• 47 Chen YD, Golay A, Swislocki AL, Reaven GM. Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1987; 64 (1) 17-21
• 48 Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 2001; 276 (20) 16683-16689
• 49 Nguyen MT, Favelyukis S, Nguyen AK , et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 2007; 282 (48) 35279-35292
• 50 Laine PS, Schwartz EA, Wang Y , et al. Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. Biochem Biophys Res Commun 2007; 358 (1) 150-155
• 51 Hong EG, Ko HJ, Cho YR , et al. Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 2009; 58 (11) 2525-2535
• 52 Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 1996; 97 (4) 1111-1116
• 53 Ehrenberg HM, Huston-Presley L, Catalano PM. The influence of obesity and gestational diabetes mellitus on accretion and the distribution of adipose tissue in pregnancy. Am J Obstet Gynecol 2003; 189 (4) 944-948
• 54 Butte NF, Ellis KJ, Wong WW, Hopkinson JM, Smith EO. Composition of gestational weight gain impacts maternal fat retention and infant birth weight. Am J Obstet Gynecol 2003; 189 (5) 1423-1432
• 55 Pou KM, Massaro JM, Hoffmann U , et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 2007; 116 (11) 1234-1241
• 56 Williams IL, Wheatcroft SB, Shah AM, Kearney MT. Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes Relat Metab Disord 2002; 26 (6) 754-764
• 57 Silver AE, Beske SD, Christou DD , et al. Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress. Circulation 2007; 115 (5) 627-637
• 58 Roberts DJ, Post MD. The placenta in pre-eclampsia and intrauterine growth restriction. J Clin Pathol 2008; 61 (12) 1254-1260
• 59 Salafia CM, Vogel CA, Bantham KF, Vintzileos AM, Pezzullo J, Silberman L. Preterm delivery: correlations of fetal growth and placental pathology. Am J Perinatol 1992; 9 (3) 190-193
• 60 Kidron D, Bernheim J, Aviram R. Placental findings contributing to fetal death, a study of 120 stillbirths between 23 and 40 weeks gestation. Placenta 2009; 30 (8) 700-704
• 61 Amir H, Weintraub A, Aricha-Tamir B, Apel-Sarid L, Holcberg G, Sheiner E. A piece in the puzzle of intrauterine fetal death: pathological findings in placentas from term and preterm intrauterine fetal death pregnancies. J Matern Fetal Neonatal Med 2009; 22 (9) 759-764
• 62 Khan IY, Taylor PD, Dekou V , et al. Gender-linked hypertension in offspring of lard-fed pregnant rats. Hypertension 2003; 41 (1) 168-175
• 63 Khan IY, Dekou V, Douglas G , et al. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol 2005; 288 (1) R127-R133
• 64 Caluwaerts S, Lambin S, van Bree R, Peeters H, Vergote I, Verhaeghe J. Diet-induced obesity in gravid rats engenders early hyperadiposity in the offspring. Metabolism 2007; 56 (10) 1431-1438
• 65 Shankar K, Harrell A, Liu X, Gilchrist JM, Ronis MJ, Badger TM. Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol 2008; 294 (2) R528-R538
• 66 Howie GJ, Sloboda DM, Kamal T, Vickers MH. Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. J Physiol 2009; 587 (Pt 4) 905-915
• 67 Taylor PD, Khan IY, Lakasing L , et al. Uterine artery function in pregnant rats fed a diet supplemented with animal lard. Exp Physiol 2003; 88 (3) 389-398
• 68 Hartil K, Vuguin PM, Kruse M , et al. Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero. Pediatr Res 2009; 66 (4) 368-373
• 69 Samuelsson AM, Matthews PA, Argenton M , et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 2008; 51 (2) 383-392
• 70 Mark PJ, Sisala C, Connor K , et al. A maternal high-fat diet in rat pregnancy reduces growth of the fetus and placental junctional zone, but not placental labyrinth zone growth. J Dev Origins Health Dis 2011; 2 (1) 63-70
• 71 Carter AM. Animal models of human placentation—a review. Placenta 2007; 28 (Suppl A) S41-S47
• 72 Rossant J, Cross JC. Placental development: lessons from mouse mutants. Nat Rev Genet 2001; 2 (7) 538-548
• 73 Wallace JM, Milne JS, Matsuzaki M, Aitken RP. Serial measurement of uterine blood flow from mid to late gestation in growth restricted pregnancies induced by overnourishing adolescent sheep dams. Placenta 2008; 29 (8) 718-724
• 74 Wallace JM, Bourke DA, Aitken RP, Leitch N, Hay Jr WW. Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep. Am J Physiol Regul Integr Comp Physiol 2002; 282 (4) R1027-R1036
• 75 Redmer DA, Luther JS, Milne JS , et al. Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation. Reproduction 2009; 137 (4) 749-757
• 76 Reynolds LP, Borowicz PP, Vonnahme KA , et al. Animal models of placental angiogenesis. Placenta 2005; 26 (10) 689-708
• 77 Challier JC, Basu S, Bintein T , et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 2008; 29 (3) 274-281
• 78 Roberts VH, Smith J, McLea SA, Heizer AB, Richardson JL, Myatt L. Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta 2009; 30 (2) 169-175
• 79 Jones HN, Jansson T, Powell TL. IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2. Am J Physiol Cell Physiol 2009; 297 (5) C1228-C1235
• 80 Thongsong B, Subramanian RK, Ganapathy V, Prasad PD. Inhibition of amino acid transport system a by interleukin-1beta in trophoblasts. J Soc Gynecol Investig 2005; 12 (7) 495-503
• 81 Jones HN, Woollett LA, Barbour N, Prasad PD, Powell TL, Jansson T. High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J 2009; 23 (1) 271-278
• 82 McCurdy CE, Bishop JM, Williams SM , et al. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest 2009; 119 (2) 323-335
• 83 Frias AE, Morgan TK, Evans AE , et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology 2011; 152 (6) 2456-2464
• 84 Grant WF, Gillingham MB, Batra AK , et al. Maternal high fat diet is associated with decreased plasma n-3 fatty acids and fetal hepatic apoptosis in nonhuman primates. PLoS ONE 2011; 6 (2) e17261
• 85 Grayson BE, Levasseur PR, Williams SM, Smith MS, Marks DL, Grove KL. Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. Endocrinology 2010; 151 (4) 1622-1632
• 86 Sullivan EL, Grayson B, Takahashi D , et al. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring. J Neurosci 2010; 30 (10) 3826-3830
• 87 Ismail-Beigi F, Catalano PM, Hanson RW. Metabolic programming: fetal origins of obesity and metabolic syndrome in the adult. Am J Physiol Endocrinol Metab 2006; 291 (3) E439-E440
• 88 Igosheva N, Abramov AY, Poston L , et al. Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS ONE 2010; 5 (4) e10074
• 89 Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 2010; 467 (7318) 963-966