Epigenetics and Diet in Pregnancy

  • Marian C. Aldhous
  • Kahyee Hor
  • Rebecca M. ReynoldsEmail author
Part of the Nutrition and Health book series (NH)


A good diet during pregnancy is essential for the well-being of the mother and the development of a healthy baby. There is evidence that long-term problems for the baby may arise when the mother’s nourishment is less than ideal. Epigenetic processes are proposed as a key mechanism by which maternal nutrition influences offspring’s life-long health. In this chapter, we consider the evidence supporting this hypothesis. We review the literature describing the effects of extreme under-nutrition in pregnancy on the offspring, through studies of the long-term effects of unexpected famine. We consider the effects of over-nutrition in pregnancy, addressing the long-term outcomes of maternal obesity and diabetes during pregnancy on the offspring. We describe the evidence for the involvement of epigenetic mechanisms, particularly DNA methylation, as mediators of these effects. Finally, we suggest that paternal nutrition may also affect offspring outcomes through epigenetic changes in sperm and that these may affect the health of subsequent generations through the paternal lineage.


Pregnancy Epigenetics Diet Famine Obesity Diabetes 



The authors wish to acknowledge the contributions of University of Edinburgh Biomedical Sciences Honours Students: Robyn Beaty, Lisa Hilferty, Claire Lynch, Lauren Murphy, Verna Palomurto, and Felicity Robinson. These students made a website: “The Vicious Cycle of Obesity: Do Epigenetics Play A Role?” over 8 weeks as part of their Reproductive Systems course of the following undergraduate students at the University of Edinburgh, supervised by Dr. Marian Aldhous. Some of the information contained therein was used in this manuscript.


  1. 1.
    Barker DJP. The origins of the developmental origins theory. J Intern Med. 2007;261:412–7.CrossRefGoogle Scholar
  2. 2.
    Wankhade UD, Thakali KM, Shankar K. Persistent influence of maternal obesity on offspring health: mechanisms from animal models and clinical studies. Mol Cell Endocrinol. 2016;435:7–19.CrossRefGoogle Scholar
  3. 3.
    Catalano PM. Obesity, insulin resistance, and pregnancy outcome. Reproduction. 2010;140:365–71.CrossRefGoogle Scholar
  4. 4.
    Girsen AI, Mayo JA, Carmichael SL, Phibbs CS, Shachar BZ, Stevenson DK, et al. Women’s prepregnancy underweight as a risk factor for preterm birth: a retrospective study. BJOG. 2016;123(12):2001–7.CrossRefGoogle Scholar
  5. 5.
    Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Hum Reprod. 2004;19:1644–6.CrossRefGoogle Scholar
  6. 6.
    Han Z, Mulla S, Beyene J, Liao G, McDonald SD, Group KS. Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and meta-analyses. Int J Epidemiol. 2011;40:65–101.CrossRefGoogle Scholar
  7. 7.
    Cressman AM, Piquette-Miller M. Epigenetics: a new link toward understanding human disease and drug response. Clin Pharmacol Ther. 2012;92:669–73.CrossRefGoogle Scholar
  8. 8.
    Bergman Y, Cedar H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol. 2013;20:274–81.CrossRefGoogle Scholar
  9. 9.
    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604–9.CrossRefGoogle Scholar
  10. 10.
    Busche S, Shao X, Caron M, Kwan T, Allum F, Cheung WA, et al. Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation. Genome Biol. 2015;16:290.CrossRefGoogle Scholar
  11. 11.
    Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, et al. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A. 2012;109:10522–7.CrossRefGoogle Scholar
  12. 12.
    Relton CL, Groom A, St. Pourcain B, Sayers AE, Swan DC, Embleton ND, et al. DNA methylation patterns in cord blood DNA and body size in childhood. PLoS One. 2012;7:e31821.CrossRefGoogle Scholar
  13. 13.
    Horsthemke B. In brief: genomic imprinting and imprinting diseases. J Pathol. 2014;232:485–7.CrossRefGoogle Scholar
  14. 14.
    Fowden AL, Coan PM, Angiolini E, Burton GJ, Constancia M. Imprinted genes and the epigenetic regulation of placental phenotype. Prog Biophys Mol Biol. 2011;106:281–8.CrossRefGoogle Scholar
  15. 15.
    Monk D. Genomic imprinting in the human placenta. Am J Obstet Gynecol. 2015;213(4 suppl):S152–S62.CrossRefGoogle Scholar
  16. 16.
    Lim AL, Ng S, Leow SCP, Choo R, Ito M, Chan YH, et al. Epigenetic state and expression of imprinted genes in umbilical cord correlates with growth parameters in human pregnancy. J Med Genet. 2012;49:689–97.CrossRefGoogle Scholar
  17. 17.
    Shea TB, Rogers E. Lifetime requirement of the methionine cycle for neuronal development and maintenance. Curr Opin Psychiatry. 2014;27:138–42.CrossRefGoogle Scholar
  18. 18.
    Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5:3481–95.CrossRefGoogle Scholar
  19. 19.
    Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002;132(8 suppl):2333S–5S.CrossRefGoogle Scholar
  20. 20.
    The Nutrition Source, Harvard School of Public Health. Three of the B vitamins: folate, vitamin B6, and vitamin B12. 2016. Available at
  21. 21.
    Fraser RB, Fisk NM. Periconceptional folic acid and food fortification in the prevention of neural tube defects. In: Scientific Impact Paper No. 4. London: Royal College of Obstetricians and Gynaecologists; 2003. Available at Scholar
  22. 22.
    National Collaborating Centre for Women’s and Children’s Health (UK). Antenatal care: routine care for the healthy pregnant woman. London: RCOG Press; 2008.Google Scholar
  23. 23.
    Abramsky L, Botting B, Chapple J, Stone D. Has advice on periconceptional folate supplementation reduced neural-tube defects? Lancet. 1999;354:998–9.CrossRefGoogle Scholar
  24. 24.
    Breimer LH, Nilsson TK. Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation? Scand J Clin Lab Invest. 2012;72:185–91.CrossRefGoogle Scholar
  25. 25.
    Steegers-Theunissen RPM, Twigt J, Pestinger V, Sinclair KD. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Reprod Update. 2013;19:640–55.CrossRefGoogle Scholar
  26. 26.
    Brown AS, Susser ES. Prenatal nutritional deficiency and risk of adult schizophrenia. Schizophr Bull. 2008;34:1054–63.CrossRefGoogle Scholar
  27. 27.
    Muskiet FAJ, Kemperman RFJ. Folate and long-chain polyunsaturated fatty acids in psychiatric disease. J Nutr Biochem. 2006;17:717–27.CrossRefGoogle Scholar
  28. 28.
    Dolinoy DC. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev. 2008;66(suppl 1):S7–S11.CrossRefGoogle Scholar
  29. 29.
    Blewitt ME, Vickaryous NK, Paldi A, Koseki H, Whitelaw E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2006;2:e49.CrossRefGoogle Scholar
  30. 30.
    Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007;104:13056–61.CrossRefGoogle Scholar
  31. 31.
    Kaminen-Ahola N, Ahola A, Maga M, Mallitt K-A, Fahey P, Cox TC, et al. Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet. 2010;6:e1000811.CrossRefGoogle Scholar
  32. 32.
    Gupta KK, Gupta VK, Shirasaka T. An update on fetal alcohol syndrome—pathogenesis, risks, and treatment. Alcohol Clin Exp Res. 2016;40:1594–602.CrossRefGoogle Scholar
  33. 33.
    Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am J Hum Genet. 2016;98:680–96.CrossRefGoogle Scholar
  34. 34.
    Hoyo C, Murtha AP, Schildkraut JM, Jirtle R, Demark-Wahnefried W, Forman MR, et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics. 2011;6:928–36.CrossRefGoogle Scholar
  35. 35.
    Azzi S, Sas TCJ, Koudou Y, Le Bouc Y, Souberbielle J-C, Dargent-Molina P, et al. Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort. Epigenetics. 2014;9:338–45.CrossRefGoogle Scholar
  36. 36.
    McCullough LE, Miller EE, Mendez MA, Murtha AP, Murphy SK, Hoyo C. Maternal B vitamins: effects on offspring weight and DNA methylation at genomically imprinted domains. Clin Epigenetics. 2016;8:8.CrossRefGoogle Scholar
  37. 37.
    Joubert BR, den Dekker HT, Felix JF, Bohlin J, Ligthart S, Beckett E, et al. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat Commun. 2016;7:10577.CrossRefGoogle Scholar
  38. 38.
    Lumey LH, Stein AD, Kahn HS, van der Pal-de Bruin KM, Blauw GJ, Zybert PA, et al. Cohort profile: the Dutch hunger winter families study. Int J Epidemiol. 2007;36:1196–204.CrossRefGoogle Scholar
  39. 39.
    Stein AD, Zybert PA, van de Bor M, Lumey LH. Intrauterine famine exposure and body proportions at birth: the Dutch hunger winter. Int J Epidemiol. 2004;33:831–6.CrossRefGoogle Scholar
  40. 40.
    Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med. 1976;295:349–53.CrossRefGoogle Scholar
  41. 41.
    de Rooij SR, Painter RC, Phillips DI, Osmond C, Michels RP, Godsland IF, et al. Impaired insulin secretion after prenatal exposure to the Dutch famine. Diabetes Care. 2006;29:1897–901.CrossRefGoogle Scholar
  42. 42.
    Roseboom TJ, de Rooij SR, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006;82:485–91.CrossRefGoogle Scholar
  43. 43.
    Lumey LH, Stein AD, Kahn HS, Romijn JA. Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch hunger winter families study. Am J Clin Nutr. 2009;89:1737–43.CrossRefGoogle Scholar
  44. 44.
    Scholte RS, van den Berg GJ, Lindeboom M. Long-run effects of gestation during the Dutch hunger winter famine on labor market and hospitalization outcomes. J Health Econ. 2015;39:17–30.CrossRefGoogle Scholar
  45. 45.
    Franzek EJ, Sprangers N, Janssens ACJW, Van Duijn CM, Van De Wetering BJM. Prenatal exposure to the 1944-45 Dutch ‘hunger winter’ and addiction later in life. Addiction. 2008;103:433–8.CrossRefGoogle Scholar
  46. 46.
    Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. 2008;105:17046–9.CrossRefGoogle Scholar
  47. 47.
    Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.CrossRefGoogle Scholar
  48. 48.
    Tobi EW, Slieker RC, Stein AD, Suchiman HED, Slagboom PE, van Zwet EW, et al. Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. Int J Epidemiol. 2015;44:1211–23.CrossRefGoogle Scholar
  49. 49.
    World Health Organization. Obesity and overweight (fact sheet). 2016. Available at Scholar
  50. 50.
    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2014;384(9945):766–81.CrossRefGoogle Scholar
  51. 51.
    Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol. 2004;103:219–24.CrossRefGoogle Scholar
  52. 52.
    Guelinckx I, Devlieger R, Beckers K, Vansant G. Maternal obesity: pregnancy complications, gestational weight gain and nutrition. Obes Rev. 2008;9:140–50.CrossRefGoogle Scholar
  53. 53.
    Reynolds RM, Allan KM, Raja EA, Bhattacharya S, McNeill G, Hannaford PC, et al. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1,323,275 person years. BMJ. 2013;347:f4539. Scholar
  54. 54.
    Lee KK, Raja EA, Lee AJ, Bhattacharya S, Bhattacharya S, Norman JE, et al. Maternal obesity during pregnancy associates with premature mortality and major cardiovascular events in later life. Hypertension. 2015;66:938–44.CrossRefGoogle Scholar
  55. 55.
    Sullivan EL, Nousen EK, Chamlou KA. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav. 2014;123:236–42.CrossRefGoogle Scholar
  56. 56.
    Patel SP, Rodriguez A, Little MP, Elliott P, Pekkanen J, Hartikainen AL, et al. Associations between pre-pregnancy obesity and asthma symptoms in adolescents. J Epidemiol Community Health. 2012;66:809–14.CrossRefGoogle Scholar
  57. 57.
    Godfrey KM, Reynolds RM, Prescott SL, Nyirenda M, Jaddoe VWV, Eriksson JG, et al. Influence of maternal obesity on the long-term health of offspring. Lancet Diabetes Endocrinol. 2017;5(1):53–64.CrossRefGoogle Scholar
  58. 58.
    Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes. 2011;60:1528–34.CrossRefGoogle Scholar
  59. 59.
    Bouchard L, Thibault S, Guay SP, Santure M, Monpetit A, St Pierre J, et al. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care. 2010;33:2436–41.CrossRefGoogle Scholar
  60. 60.
    Allard C, Desgagné V, Patenaude J, Lacroix M, Guillemette L, Battista MC, et al. Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns. Epigenetics. 2015;10:342–51.CrossRefGoogle Scholar
  61. 61.
    Bouchard L, Hivert MF, Guay SP, St Pierre J, Perron P, Brisson D. Placental adiponectin gene DNA methylation levels are associated with mothers’ blood glucose concentration. Diabetes. 2012;61:1272–80.CrossRefGoogle Scholar
  62. 62.
    Houde A-A, Guay SP, Desgagne V, Hivert MF, Baillargeon J-P, St Pierre J, et al. Adaptations of placental and cord blood ABCA1 DNA methylation profile to maternal metabolic status. Epigenetics. 2013;8:1289–302.CrossRefGoogle Scholar
  63. 63.
    Xie X, Gao H, Zeng W, Chen S, Feng L, Deng D, et al. Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level. Clin Sci. 2015;129:385–94.CrossRefGoogle Scholar
  64. 64.
    Guénard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, Vohl M-C. Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proc Natl Acad Sci U S A. 2013;110:11439–44.CrossRefGoogle Scholar
  65. 65.
    Guénard F, Tchernof A, Deshaies Y, Cianflone K, Kral JG, Marceau P, et al. Methylation and expression of immune and inflammatory genes in the offspring of bariatric bypass surgery patients. J Obes. 2013;2013:492170.CrossRefGoogle Scholar
  66. 66.
    West NA, Kechris K, Dabelea D. Exposure to maternal diabetes in utero and DNA methylation patterns in the offspring. Immunometabolism. 2013;1:1–9.CrossRefGoogle Scholar
  67. 67.
    Ruchat S-M, Houde A-A, Voisin G, St Pierre J, Perron P, Baillargeon J-P, et al. Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases. Epigenetics. 2013;8:935–43.CrossRefGoogle Scholar
  68. 68.
    del Rosario MC, Ossowski V, Knowler WC, Bogardus C, Baier LJ, Hanson RL. Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism. 2014;63:654–60.CrossRefGoogle Scholar
  69. 69.
    Finer S, Mathews C, Lowe R, Smart M, Hillman S, Foo L, et al. Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring. Hum Mol Genet. 2015;24:3021–9.CrossRefGoogle Scholar
  70. 70.
    El Hajj N, Pliushch G, Schneider E, Dittrich M, Müller T, Korenkov M, et al. Metabolic programming of MEST DNA methylation by intrauterine exposure to gesatational diabetes mellitus. Diabetes. 2013;62:1320–8.CrossRefGoogle Scholar
  71. 71.
    Chen D, Zhang A, Fang M, Fang R, Ge J, Jiang Y, et al. Increased methylation at differentially methylated region of GNAS in infants born to gestational diabetes. BMC Med Genet. 2014;15:108.CrossRefGoogle Scholar
  72. 72.
    Hoyo C, Fortner K, Murtha AP, Schildkraut JM, Soubry A, Demark-Wahnefried W, et al. Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight. Cancer Causes Control. 2012;23:635–45.CrossRefGoogle Scholar
  73. 73.
    Perkins E, Murphy SK, Murtha AP, Schildkraut JM, Jirtle RL, Demark-Wahnefried W, et al. Insulin-like growth factor 2/H19 methylation at birth and risk of overweight and obesity in children. J Pediatr. 2012;161:31–9.CrossRefGoogle Scholar
  74. 74.
    Skinner MK. Metabolic disorders: fathers’ nutritional legacy. Nature. 2010;467:922–3.CrossRefGoogle Scholar
  75. 75.
    Soubry A, Schildkraut JM, Murtha A, Wang F, Huang Z, Bernal A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a newborn epigenetics study (NEST) cohort. BMC Med. 2013;11:29.CrossRefGoogle Scholar
  76. 76.
    Soubry A, Murphy SK, Wang F, Huang Z, Vidal AC, Fuemmeler BF, et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes. 2015;39:650–7.CrossRefGoogle Scholar
  77. 77.
    Soubry A, Guo L, Huang Z, Hoyo C, Romanus S, Price T, et al. Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenetics. 2016;8:51.CrossRefGoogle Scholar
  78. 78.
    Painter RC, Osmond C, Gluckman P, Hanson M, Phillips DI, Roseboom TJ. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG. 2008;115:1243–9.CrossRefGoogle Scholar
  79. 79.
    Bygren LO. Intergenerational health responses to adverse and enriched environments. Annu Rev Public Health. 2013;34:49–60.CrossRefGoogle Scholar
  80. 80.
    Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet. 2002;10:682–8.CrossRefGoogle Scholar
  81. 81.
    Kaati G, Bygren LO, Pembrey M, Sjöström M. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet. 2007;15:784–90.CrossRefGoogle Scholar
  82. 82.
    Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet. 2006;14:159–66.CrossRefGoogle Scholar
  83. 83.
    NHS UK. Healthy start. 2016. Available at Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Marian C. Aldhous
    • 1
  • Kahyee Hor
    • 2
  • Rebecca M. Reynolds
    • 1
    • 3
    Email author
  1. 1.Tommy’s Centre for Maternal and Fetal Health, MRC Centre for Reproductive HealthQueens’s Medical Research Institute, University of EdinburghEdinburghUK
  2. 2.Centre for Cardiovascular ScienceQueen’s Medical Research Institute, University of EdinburghEdinburghUK
  3. 3.Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of EdinburghEdinburghUK

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