The Journal of Pediatrics
Volume 132, Issue 5 , Pages 768-776 , May 1998

Role of the prenatal environment in the development of obesity

Presented in part at a workshop entitled “Prevention and Treatment of Childhood Obesity: Research Directions,” sponsored by the National Institutes of Health, the National Task Force on Prevention and Treatment of Obesity, and the International Life Sciences Institute, Bethesda, Md., Sept. 11, 1995.

Received 11 January 1996 ,Revised 4 June 1997 ,Accepted 6 June 1997.

References 

  1. Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL. Overweight prevalence and trends for children and adolescents: National Health and Nu trition Examination Surveys, 1963 to 1991. Arch Pediatr Adolesc Med. 1995;149:1085–1091
  2. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among U.S. adults: National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994;272:205–211
  3. Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med. 1993;119:655–660
  4. Technology Assessment Conference Panel NIH. Methods for voluntary weight loss and control. Ann Intern Med. 1993;119:764–770
  5. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr. 1994;59:955–959
  6. Kraemer HC, Berkowitz RI, Hammer LD. Methodological difficulties in studies of obesity. I. Measurement issues. Ann Behav Med. 1990;12:112–118
  7. Robinson TN. Defining obesity in children and adolescents: clinical approaches. Crit Rev Food Sci Nutri. 1993;33:313–320
  8. Ragland DR. Dichotomizing continuous outcome variables: dependence of the magnitude of association and statistical power on the cutpoint. Epidemiology. 1992;3:434–440
  9. Charney E, Goodman H, McBride M, Lyon B, Pratt R. Childhood antecedents of adult obesity: do chubby infants become obese adults?. N Engl J Med. 1976;295:6–9
  10. Braddon FEM, Rodgers B, Wadsworth MEJ, Davies JMC. Onset of obesity in a 36-year birth cohort study. BMJ. 1986;293:299–303
  11. Miller FJW, Billewicz W, Thomson AM. Growth from birth to adult life of 442 Newcastle Upon Tyne children. Br J Prev Soc Med. 1972;26:224–230
  12. Fall CH, Osmond C, Barker DJ, Clark PM, Hales CN, Stirling Y, et al.  Fetal and infant growth and cardiovascular risk factors in women. BMJ. 1995;310:428–432
  13. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia. 1994;37:624–631
  14. Allison DB, Paultre F, Heymsfield SB, Pi-Sunyer FX. Is the intra-uterine period really a critical period for the development of adiposity?. Int J Obes Relat Metab Disord. 1995;19:397–402
  15. Curhan GC, Chertow GM, Willett WC, Spiegelman D, Colditz GA, Manson JE, et al.  Birth weight and adult hypertension and obesity in women. Circulation. 1996;94:1310–1315
  16. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in U.S. men. Circulation. 1996;94:3246–3250
  17. Seidman DS, Laor A, Gale R, Stevenson DK. Excessive intrauterine growth and being overweight at 17 years of age. [abstract] Pediatr Res. 1995;37(4, pt.2):115A
  18. Gross T, Sokol RJ, King KC. Obesity in pregnancy: risks and outcome. Obstet Gynecol. 1980;56:446–450
  19. Edwards LE, Dickes WF, Alton IR, Hakanson EY. Pregnancy in the massively obese: course, outcome, and obesity prognosis of the infant. Am J Obstet Gynecol. 1978;131:479–483
  20. Whitelaw AGL. Influence of maternal obesity on subcutaneous fat in the newborn. BMJ. 1976;24:985–986
  21. Udall JN, Harrison GG, Vaucher Y, Walson PD, Morrow G. Interaction of maternal and neonatal obesity. Pediatrics. 1978;62:17–21
  22. Harrison GG, Udall JN, Morrow G. Maternal obesity, weight gain in pregnancy, and infant birth weight. Am J Obstet Gynecol. 1980;136:411–412
  23. Fisch RO, Bilek MK, Ulstrom R. Obesity and leanness at birth and their relationship to body habitus in later childhood. Pediatrics. 1975;56:521–528
  24. Simpson JW, Lawless RW, Mitchell AC. Responsibility of the obstetrician to the fetus. II. Influence of prepregnancy weight and pregnancy weight gain in birthweight. Am J Obstet Gynecol. 1975;45:481–487
  25. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull World Health Organ. 1987;65:663–737
  26. Eastman NJ, Jackson E. Weight relationships in pregnancy. I. The bearing of maternal weight gain and prepregnancy weight and birthweight in full term pregnancies. Obstet Gynecol Surv. 1968;23:1003–1025
  27. Niswander K, Jackson EC. Physical characteristics of the gravida and their association with birth weight and perinatal death. Am J Obstet Gynecol. 1974;119:306–313
  28. Subcommittee on Nutritional Status and Weight Gain During Pregnancy Subcommittee on Dietary Intake and Nutrient Supplements During Pregnancy, Committee on Nutritional Status During Pregnancy and Lactation, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences . Nutrition during pregnancy. Part I: Weight gain. Part II: Nutrient supplements. Washington (DC): National Academy Press; 1990;
  29. Abrams BF, Laros RK. Prepregnancy weight, weight gain, and birth weight. Am J Obstet Gynecol. 1986;154:503–509
  30. Abrams B, Parker JD. Maternal weight gain in women with good pregnancy outcome. Obstet Gynecol. 1990;76:1–7
  31. Rush D, Davis H, Susser M. Antece dents of low birthweight in Harlem, New York City. Int J Epidemiol. 1972;1:375–387
  32. Seidman DS, Laor A, Shemer J, Gale R, Stevenson DK. Excessive maternal weight gain during pregnancy and being overweight at 17 years of age. [abstract] Pediatr Res. 1996;39:112A
  33. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med. 1976;295:349–353
  34. Lumey LH, Stam GA, Ravelli GP, Stein ZA. Birth weight, birth cohort, and adult weight among women born during the Dutch Famine of 1944–1945. [abstract] Am J Epidemiol. 1992;136:951–952
  35. Susser M. Maternal weight gain, infant birthweight, and diet: causal sequences. Am J Clin Nutr. 1991;53:1384–1396
  36. Stein Z, Susser M, Saenger G, Marolla F. Famine and human development: the Dutch Hunger Winter of 1944–1945. New York: Oxford University Press; 1975;
  37. Fiorotto ML, Davis TA, Schoknecht P, Mersmann HJ, Pond WG. Both maternal over- and undernutrition during gestation increase the adiposity of young adult progeny in rats. Obes Res. 1995;3:131–141
  38. Jones AAP, Friedman MI. Obesity and adipocyte abnormalities in offspring of rats undernourished during pregnancy. Science. 1982;215:1518–1519
  39. Jones AP, Simson EL, Friedman MI. Gestational undernutrition and the development of obesity in rats. J Nutr. 1984;114:1484–1492
  40. Jones AP, Assimon SA, Friedman MI. The effect of diet on food intake and adiposity in rats made obese by gestational undernutrition. Physiol Behav. 1986;37:381–386
  41. Pond WG, Mersmann HJ, Yen JT. Severe feed restriction of pregnant swine and rats: effects on postweaning growth and body composition of progeny. J Nutr. 1985;115:179–189
  42. Enns MP, Wilson MW, Grinker JA, Faust IM. Prenatal food restriction and subsequent weight gain in male rats. Science. 1983;219:1093–1094
  43. Barker DJ. The intrauterine origins of cardiovascular disease. Acta Paediatr. 1993;82(Suppl 391):93–99
  44. Goldberg GR, Prentice AM. Maternal and fetal determinants of adult diseases. Nutr Rev. 1994;52:191–200
  45. Reaven GM. Role of insulin resistance in human disease. [Banting Lecture 1988] Diabetes. 1988;37:1595–1607
  46. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, et al.  Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991;303:1019–1022
  47. Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health. 1992;46:184–186
  48. Fee BA, Weil WB. Body composition of infants of diabetic mothers by direct analysis. Ann N Y Acad Sci. 1963;110:869–897
  49. Naeye RL. Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics. 1965;35:980–988
  50. Osler M. Body water of newborn infants of diabetic mothers. Acta Endocrinol. 1960;34:261–276
  51. Osler M. Body fat of newborn infants of diabetic mothers. Acta Endocrinol. 1960;34:277–286
  52. Krew MA, Kehl RJ, Thomas A, Catalano PM. Relation of amniotic fluid C-peptide levels to neonatal body composition. Am J Obstet Gynecol. 1994;84:96–100
  53. Sacks DA. Fetal macrosomia and gestational diabetes: what's the problem?. Obstet Gynecol. 1993;81:775–781
  54. White P, Koshy P, Duckers J. The management of pregnancy complicating diabetes and of children of diabetic mothers. Med Clin North Am. 1953;37:1481–1496
  55. Hagbard L, Olow I, Reinand T. A follow-up study of 514 children of diabetic mothers. Acta Paediatr. 1959;48:184–197
  56. Breidahl HD. The growth and development of children born to mothers with diabetes. Med J Aust. 1966;1:268–270
  57. Farquhar JW. Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Child. 1969;44:36–47
  58. Cummins M, Norrish M. Follow-up of diabetic mothers. Arch Dis Child. 1980;55:259–264
  59. Seidman DS, Laor A, Stevenson DK, Sivan E, Gale R, Shemer J. Macrosomia does not predict overweight in late adolescence in infants of diabetic mothers. Acta Obstet Gynecol Scand. 1998;77:58–62
  60. Vohr BR, Lipsitt LP, Oh W. Somatic growth of children of diabetic mothers with reference to birth size. J Pediatr. 1980;97:196–199
  61. Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC. Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med. 1983;308:242–245
  62. Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, et al.  Long-term prospective evaluation of offspring of diabetic mothers. Diabetes. 1991;40(Suppl 2):121–125
  63. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care. 1995;18:611–617
  64. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics. 1998;101:e5
  65. Schaubert DR, Mayer DA, Shireley LA. Pregnancies complicated by diabetes—North Dakota, 1980–1992. MMWR Mortal Morbid Wkly Rep. 1994;43:837–839
  66. Peterson CM, Jovanovic-Peterson L, Mills JL, Conley MR, Knopp RH, Reed GF, et al.  The Diabetes in Early Pregnancy Study: changes in cholesterol, tri glycerides, body weight, and blood pressure. Am J Obstet Gynecol. 1992;166:513–518
  67. Knopp RH, Magee MS, Walden CE, Bonet B, Benedetti TJ. Prediction of infant birth weight by GDM screening tests: importance of plasma triglyceride. Diabetes Care. 1992;15:1605–1613
  68. Knopp RH, Van Allen MI, McNeely M, Walden CE, Plovie B, Shiota K, et al.  Effect of insulin-dependent diabetes on plasma lipoproteins in diabetic pregnancy. J Reprod Med. 1993;38:703–710
  69. Hollingsworth DR, Grundy SM. Pregnancy-associated hypertriglyceridemia in normal and diabetic women: differences in insulin-dependent, non-insulin-dependent, and gestational diabetes. Diabetes. 1982;31:1092–1097
  70. Metzger BE, Silverman BL, Freinkel N, Dooley SL, Ogata ES, Green OC. Amniotic fluid insulin concentration as a predictor of obesity. Arch Dis Child. 1990;65:1050–1052
  71. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett PH, Knowler WC. Congenital susceptibility to NIDDM: role of intrauterine environment. Diabetes. 1988;37:622–628
  72. Aerts L, van Assche FA. Endocrine pancreas in the offspring of rats with experimentally induced diabetes. J Endocrinol. 1981;88:81–88
  73. Pettitt DJ, Knowler WC, Bennett PH, Aleck KA, Baird HR. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care. 1987;10:76–80
  74. Pedersen J. Hyperglycemia-hyperinsu linism theory and birth weight. In: 2nd ed.  Pedersen J editors. The pregnant diabetic and her newborn: problems and management. Baltimore: Williams &Wilkins; 1977;p. 211–220
  75. Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol. 1954;16:330–342
  76. Hellerstrom C, Swenne I. Functional maturation and proliferation of fetal pancreatic β-cells. Diabetes. 1991;40(Suppl 2):89–93
  77. Reiher H, Fuhrmann K, Noack S, Woltanski KP, Jutzi E, Dorsche HH, et al.  Age-dependent insulin secretion of the endocrine pancreas in vitro from fetuses of diabetic and nondiabetic patients. Diabetes Care. 1983;6:446–451
  78. Milner RD, Ashworth MA, Barson AJ. Insulin release from human fetal pancreas in response to glucose, leucine and arginine. J Endocrinol. 1972;52:497–505
  79. Persson B, Pschera H, Lunell NO, Barley J, Gumaa KA. Amino acid concentrations in maternal plasma and amniotic fluid in relation to fetal insulin secretion during the last trimester of pregnancy in gestational and type I diabetic women and women with small-for-gestational-age infants. Am J Perinatol. 1986;3:98–103
  80. Metzger BE, Phelps RL, Freinkel N, Navickas IA. Effects of gestational diabetes on diurnal profiles of plasma glucose, lipids, and individual amino acids. Diabetes Care. 1980;3:402–409
  81. Sosenko IR, Kitzmiller JL, Loo SW, Blix P, Rubenstein AH, Gabbay KH. The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N Engl J Med. 1979;301:859–862
  82. Ogata ES, Freinkel N, Metzger BE, Phelps RL, Depp R, Boehm JJ, et al.  Perinatal islet function in gestational diabetes: assessment by cord plasma C-peptide and amniotic fluid insulin. Diabetes Care. 1980;3:425–429
  83. Metzger BE. Biphasic effects of maternal metabolism onfetal growth: quintessential expression of fuel-mediated teratogenesis. Diabetes. 1991;40(Suppl 2):99–105
  84. Lin CC, River P, Moawad AH, Lowensohn RI, Blix PM, Abraham M, et al.  Prenatal assessment of fetal outcome by amniotic fluid C-peptide levels in pregnant diabetic women. Am J Obstet Gynecol. 1981;141:671–676
  85. Whitelaw A. Subcutaneous fat in newborn infants of diabetic mothers: an indication of quality of diabetic control. Lancet. 1977;1:15–18
  86. Enzi G, Inelmen EM, Caretta F, Villani F, Zanardo V, DeBiasi F. Development of adipose tissue in newborns of gestational-diabetic and insulin-dependent diabetic mothers. Diabetes. 1980;29:100–104
  87. Ginsberg-Fellner F. Growth of adipose tissue in infants, children and adolescents: variations in growth disorders. Int J Obes Relat Metab Disord. 1981;5:605–611
  88. Bjorntorp P, Enzi G, Karlsson K, Krotkiewski M, Sjostrom L, Smith U. The effect of maternal diabetes on adipose tissue cellularity in man and rat. Diabetologia. 1974;10:205–209
  89. Freinkel N, Metzger BE. Pregnancy as a tissue culture experience: the critical implications of maternal metabolism for fetal development. In: Pregnancy metabolism, diabetes and the fetus. Amsterdam: Excerpta Medica; 1979;p. 3–28 (CIBA Found Symposium No. 63)
  90. Freinkel N. Of pregnancy and progeny. [Banting Lecture 1980.] Diabetes. 1980;29:1023–1035
  91. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, et al.  Acute and chronic effect of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes. 1996;45:699–701
  92. Pettitt DJ. The long-range impact of diabetes during pregnancy: the Pima Indian experience. IDF Bulletin. 1986;31:70–71
  93. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993;36:62–67
  94. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrify phenotype hypothesis. Diabetologia. 1992;35:595–601
  95. Weinkove C, Weinkove EA, Pimstone BL. Insulin release and pancreatic islet volume in malnourished rats. [abstract] South Afr Med J. 1974;48:1888
  96. Snoeck A, Remacle C, Reusens B, Hoet JJ. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate. 1990;57:107–118
  97. Szabo AJ, Szabo O. Placental free-fatty-acid transfer and fetal adipose-tissue development: an explanation of fetal adiposity in infants of diabetic mothers. Lancet. 1974;2:498–499
  98. Szabo AJ, Oppermann W, Hanover B, Gugliucci C, Szabo O. Fetal adipose tissue development: relationship to maternal free fatty acid levels. In:  Camerini-Davalos RA,  Cole HS editor. Early diabetes in early life. New York: Academia Press; 1975;p. 167–176
  99. Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R. Relation of glucose tolerance to complications ofpregnancy in nondiabetic women. N Engl J Med. 1986;315:989–992
  100. Knopp RH, Bergelin RO, Wahl PW, Walden CE, Chapman M, Irvin S. Population-based lipoprotein lipid reference values for pregnant women compared to nonpregnant women classified by sex hormone usage. Am J Obstet Gynecol. 1982;143:626–637
  101. Knopp R, Magee S, Bonet B, Gomez-Coronado D. Lipid metabolism in pregnancy. In:  Cowet RM editors. Principles of perinatal and neonatal metabolism. New York: Springer Verlag; 1991;p. 169–191
  102. Coustan DR. Diagnosis of gestational diabetes: what are our objectives?. Diabetes. 1991;40(Suppl 2):14–17
  103. Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H, et al.  Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate. 1986;50:297–317
  104. Bonet B, Brunzell JD, Gown AM, Knopp RH. Metabolism of very-low-density lipoprotein triglyceride by human placental cells: the role of lipoprotein lipase. Metabolism. 1992;41:596–603
  105. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell. 1994;79:1147–1156
  106. Roche AF. The adipocyte-number hypothesis. Child Dev. 1981;52:31–43
  107. Kliegman R, Gross T, Morton S, Dunnington R. Intrauterine growth and postnatal fasting metabolism in infants of obese mothers. J Pediatr. 1984;104:601–607
  108. Knopp RH, Bergelin RO, Wahl PW, Walden CE. Relationships of infant birth size to maternal lipoproteins, apoproteins, fuels, hormones, clinical chemistries, and body weight at 36 weeks' gestation. Diabetes. 1985;34(Suppl 2):71–77
  109. Enzi G, Inelmen EM, Caretta F, Rubaltelli F, Grella P, Baritussio A. Adipose tissue development "in utero": relationships between some nutritional and hormonal factors and body fat mass enlargement in newborns. Diabetologia. 1980;18:135–140
  110. Widdowson EM. Undernutrition and retarded growth before and after birth. Nutr Metab. 1977;21:76–87
  111. Weigle DS. Human obesity: exploding the myths. West J Med. 1990;153:421–428
  112. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al.  Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271

☆ From the Department of Pediatrics, Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, and the Department of Pediatrics, New England Medical Center, Boston, Massachusetts.

☆☆ Supported in part by the Generalist Physician Faculty Scholars Award from the Robert Wood Johnson Foundation, Princeton, N.J. (Dr. Whitaker), and by grants DK/HD 50537 and P30-DK46200 from the National Institutes of Health (Dr. Dietz).

★ Reprint requests: Robert C. Whitaker, MD, MPH, Children's Hospital Medical Center, Division of General and Community Pediatrics, CH-1S, 3333 Burnet Avenue, Cincinnati, OH 45229-3039.

★★ 9/19/83970

PII: S0022-3476(98)70302-6

The Journal of Pediatrics
Volume 132, Issue 5 , Pages 768-776 , May 1998

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