Epigenetic Consequences of Low Birth-Weight and Preterm Birth in Adult Twins

  • Qihua Tan
Reference work entry


Adverse birth outcomes including low birth-weight and preterm birth are associated with long-term morbidity and health consequences at adult ages. Molecular mechanisms including epigenetic modification may have been involved in the adaptation to the stressful condition in peridelivery period which could be detrimental to health later in life. Current epigenetic studies using genome-wide DNA methylation profiling have discovered molecular evidence confirming that, as important early life events, both low birth-weight and premature birth can result in long-lasting epigenetic consequences that impact health at adult ages. Results from our epigenome-wide association studies indicate that the two moderately correlated traits of adverse pregnancy outcome could be linked to increased susceptibility to different health problems with low birth-weight more relevant to metabolic disorders, while preterm birth mainly liked to neurodevelopmental disorders. High-resolution epigenetic profiling on multiple regulatory mechanisms should provide more novel molecular markers for intervention and prevention of potential health risks in adults of low birth-weight and premature birth.


Epigenetics Environment Health Birth-weight Preterm birth DNA methylation Twins Epigenome-wide association Early life events Adults 

List of Abbreviations


Preterm birth


Monozygotic twins


Epigenome-wide association study


False discovery rate


Differentially methylated region


Family-wise error rate


Genomic Regions Enrichment of Annotations Tool



This work was supported by the DFF Research Project One from the Danish Council for Independent Research, Medical Sciences (DFF-FSS), project number: DFF – 6110-00114.

Conflict of Interest

No conflict of interest declared


  1. Adkins RM, Somes G, Morrison JC, Hill JB, Watson EM, Magann EF, Krushkal J (2010) Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes. Pediatr Res 68:429–434PubMedPubMedCentralGoogle Scholar
  2. Barker DJ (2007) The origins of the developmental origins theory. J Intern Med 261:412–417CrossRefGoogle Scholar
  3. Bol V, Desjardins F, Reusens B, Balligand JL, Remacle C (2010) Does early mismatched nutrition predispose to hypertension and atherosclerosis, in male mice? PLoS One 5(9):e12656Google Scholar
  4. Bouwland-Both MI, van Mil NH, Stolk L, Eilers PH, Verbiest MM, Heijmans BT, Tiemeier H, Hofman A, Steegers EA, Jaddoe VW, Steegers-Theunissen RP (2013) DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study. PLoS One 8(12):e81731CrossRefGoogle Scholar
  5. Bustamante M, Danileviciute A, Espinosa A, Gonzalez JR, Subirana I, Cordier S, Chevrier C, Chatzi L, Grazuleviciene R, Sunyer J, Ibarluzea J, Ballester F, Villanueva CM, Nieuwenhuijsen M, Estivill X, Kogevinas M (2012) Influence of fetal glutathione S-transferase copy number variants on adverse reproductive outcomes. BJOG 119:1141–1146CrossRefGoogle Scholar
  6. Carless MA (2015) Determination of DNA methylation levels using Illumina HumanMethylation450 BeadChips. In: Chellappan SP (ed) Chromatin protocols, methods in molecular biology, vol 1288. © Springer Science+Business Media, New York, pp 143–192. Scholar
  7. Chen M, Baumbach J, Vandin F, Röttger R, Barbosa E, Dong M, Frost M, Christiansen L, Tan Q (2016) Differentially methylated genomic regions in birth-weight discordant twin pairs. Ann Hum Genet 80(2):81–87CrossRefGoogle Scholar
  8. Cruickshank MN, Oshlack A, Theda C, Davis PG, Martino D, Sheehan P, Dai Y, Saffery R, Doyle LW, Craig JM (2013) Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy. Genome Med 5:96CrossRefGoogle Scholar
  9. Frost M, Petersen I, Brixen K, Beck-Nielsen H, Holst JJ, Christiansen L, Højlund K, Christensen K (2012) Adult glucose metabolism in extremely birthweight-discordant monozygotic twins. Diabetologia 55:3204–3212CrossRefGoogle Scholar
  10. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS (2009) Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 5:401–408CrossRefGoogle Scholar
  11. Goldenberg RL, Culhane JF, Iams JD, Romero R (2008) Epidemiology and causes of preterm birth. Lancet 371(9606):75–84CrossRefGoogle Scholar
  12. Hales CN, Barker DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20CrossRefGoogle Scholar
  13. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, ... Lumey LH (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049Google Scholar
  14. Heijmans BT, Tobi EW, Lumey LH, Slagboom PE (2009) The epigenome: archive of the prenatal environment. Epigenetics 4(8):526–531CrossRefGoogle Scholar
  15. Iliadou A, Cnattingius S, Lichtenstein P (2004) Low birthweight and type 2 diabetes: a study on 11 162 Swedish twins. Int J Epidemiol 33:948–953CrossRefGoogle Scholar
  16. Jaffe AE, Murakami P, Lee H, Leek JT, Fallin MD, Feinberg AP, Irizarry RA (2012) Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. Int J Epidemiol 41:200–209CrossRefGoogle Scholar
  17. Koutsaki M, Sifakis S, Zaravinos A, Koutroulakis D, Koukoura O, Spandidos DA (2011) Decreased placental expression of hPGH, IGF-I and IGFBP-1 in pregnancies complicated by fetal growth restriction. Growth Horm IGF Res 21:31–36CrossRefGoogle Scholar
  18. Langley SC, Jackson AA (1994) Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci (Lond) 86:217–222CrossRefGoogle Scholar
  19. Liu Y, Tang YB, Chen J, Huang ZX (2014) Meta-analysis of GSTT1 null genotype and preterm delivery risk. Int J Clin Exp Med 7:1537–1541PubMedPubMedCentralGoogle Scholar
  20. Luu TM, Katz SL, Leeson P, Thébaud B, Nuyt AM (2016) Preterm birth: risk factor for early-onset chronic diseases. CMAJ 188:736–746CrossRefGoogle Scholar
  21. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28:495–501CrossRefGoogle Scholar
  22. McMinn J, Wei M, Schupf N, Cusmai J, Johnson EB, Smith AC, Weksberg R, ... Tycko B (2006) Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 27:540–549Google Scholar
  23. Nukui T, Day RD, Sims CS, Ness RB, Romkes M (2004) Maternal/newborn GSTT1 null genotype contributes to risk of preterm, low birthweight infants. Pharmacogenetics 14:569–576CrossRefGoogle Scholar
  24. Ong K, Kratzsch J, Kiess W, Costello M, Scott C, Dunger D (2000) Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGFbinding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC study team. Avon longitudinal study of pregnancy and childhood. J Clin Endocrinol Metab 85:426–4269Google Scholar
  25. Parveen F, Faridi RM, Das V, Tripathi G, Agrawal S (2010) Genetic association of phase I and phase II detoxification genes with recurrent miscarriages among North Indian women. Mol Hum Reprod 16:207–214CrossRefGoogle Scholar
  26. Perera F, Herbstman J (2011) Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol 31:363–373CrossRefGoogle Scholar
  27. Petersen I, Nielsen MM, Beck-Nielsen H, Christensen K (2011) No evidence of a higher 10 year period prevalence of diabetes among 77,885 twins compared with 215,264 singletons from the Danish birth cohorts 1910–1989. Diabetologia 54:2016–2024CrossRefGoogle Scholar
  28. Qi Q, Menzaghi C, Smith S, Liang L, De Rekeneire N, Garcia ME, Lohman KK, Miljkovic I, Strotmeyer ES, Cummings SR, Kanaya AM, Tylavsky FA, Satterfield S, Ding J, Rimm EB (2012) Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels. Hum Mol Genet 21(21):4774–4780Google Scholar
  29. Sheikh IA, Ahmad E, Jamal MS, Rehan M, Assidi M, Tayubi IA, AlBasri SF, Bajouh OS, Turki RF, Abuzenadah AM, Damanhouri GA, Beg MA, Al-Qahtani M (2016) Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genomics 17(Suppl 9):759CrossRefGoogle Scholar
  30. Slieker RC, Roost MS, van Iperen L, Suchiman HE, Tobi EW, Carlotti F, de Koning EJ, Slagboom PE, Heijmans BT, Chuva de Sousa Lopes SM (2015) DNA methylation landscapes of human fetal development. PLoS Genet 11(10):e1005583CrossRefGoogle Scholar
  31. Souren NY, Lutsik P, Gasparoni G, Tierling S, Gries J, Riemenschneider M, Fryns JP, Derom C (2013) Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles. Genome Biol 14(5):R44Google Scholar
  32. Straughen JK, Sipahi L, Uddin M, Misra DP, Misra VK (2015) Racial differences in IGF1 methylation and birth weight. Clin Epigenetics 7:47CrossRefGoogle Scholar
  33. Suter M, Abramovici A, Aagaard-Tillery K (2010) Genetic and epigenetic influences associated with intrauterine growth restriction due to in utero tobacco exposure. Pediatr Endocrinol Rev 8:94–102PubMedPubMedCentralGoogle Scholar
  34. Tan H, Wen SW, Fung Kee Fung K, Walker M, Demissie K (2005) The distribution of intra-twin birth weight discordance and its association with total twin birth weight, gestational age, and neonatal mortality. Eur J Obstet Gynecol Reprod Biol 121:27–33CrossRefGoogle Scholar
  35. Tan Q, Ohm Kyvik K, Kruse TA, Christensen K (2010) Dissecting complex phenotypes using the genomics of twins. Funct Integr Genomics 10(3):321–327CrossRefGoogle Scholar
  36. Tan Q, Christiansen L, Thomassen M, Kruse TA, Christensen K (2013) Twins for epigenetic studies of human aging and development. Ageing Res Rev 12:182–187CrossRefGoogle Scholar
  37. Tan Q, Frost M, Heijmans BT, von Bornemann Hjelmborg J, Tobi EW, Christensen K, Christiansen L (2014) Epigenetic signature of birth weight discordance in adult twins. BMC Genomics 15:1062CrossRefGoogle Scholar
  38. Tan Q, Christiansen L, von Bornemann Hjelmborg J, Christensen K (2015) Twin methodology in epigenetic studies. J Exp Biol 218(Pt 1):134–139CrossRefGoogle Scholar
  39. Tielsch JM (2015) Global incidence of preterm birth. Nestle Nutr Inst Workshop Ser 81:9–15PubMedGoogle Scholar
  40. Tobi EW, Heijmans BT, Kremer D, Putter H, Delemarre-van de Waal HA, Finken MJ, Wit JM, Slagboom PE (2011) DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age. Epigenetics 6(2):171–176CrossRefGoogle Scholar
  41. Tobi EW, Slagboom PE, van Dongen J, Kremer D, Stein AD, Putter H, Heijmans BT, Lumey LH (2012) Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLoS One 7(5):e37933CrossRefGoogle Scholar
  42. Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, Slieker RC, Stok AP, Thijssen PE, Müller F, van Zwet EW, Bock C, Meissner A, Lumey LH, Eline Slagboom P, Heijmans BT (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 5:5592CrossRefGoogle Scholar
  43. Tobi EW, Slieker RC, Stein AD, Suchiman HE, Slagboom PE, van Zwet EW, Heijmans BT, Lumey LH (2015) Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. Int J Epidemiol 44(4):1211–1223CrossRefGoogle Scholar
  44. Tsai PC, Dongen JV, Tan Q, Willemsen G, Christiansen L, Boomsma DI, Spector TD, Valdes AM, Bell JT (2015) DNA methylation changes in the IGF1R gene in birthweight discordant adult monozygotic twins. Twin Res Hum Genet 18:635–646CrossRefGoogle Scholar
  45. Vaiserman AM (2015) Epigenetic programming by early-life stress: evidence from human populations. Dev Dyn 244:254–265CrossRefGoogle Scholar
  46. Ventura-Junca R, Herrera LM (2012) Epigenetic alterations related to early-life stressful events. Acta Neuropsychiatr 24:255–265CrossRefGoogle Scholar
  47. Wannamethee SG, Lawlor DA, Whincup PH, Walker M, Ebrahim S, Davey-Smith G (2004) Birthweight of offspring and paternal insulin resistance and paternal diabetes in late adulthood: cross sectional survey. Diabetologia 47:12–18CrossRefGoogle Scholar
  48. Zheng X, Feingold E, Ryckman KK, Shaffer JR, Boyd HA, Feenstra B, Melbye M, Marazita ML, Murray JC, Cuenco KT (2013) Association of maternal CNVs in GSTT1/GSTT2 with smoking, preterm delivery, and low birth weight. Front Genet 4:196CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Epidemiology and Biostatistics, Department of Public Health, Unit of Human Genetics, Department of Clinical Research, Faculty of Health SciencesUniversity of Southern DenmarkOdenseDenmark

Personalised recommendations