Developmental Origins of Disease: Emerging Prenatal Risk Factors and Future Disease Risk
- 10 Downloads
Purpose of Review
Many of the diseases and dysfunctions described in the paradigm of the developmental origins of health and disease have been studied in relation to prenatal nutrition or environmental toxicant exposures. Here, we selectively review the current research on four exposures—two nutritional and two environmental—that have recently emerged as prenatal risk factors for long-term health outcomes.
Recent studies have provided strong evidence that prenatal exposure to (1) excessive intake of sugar-sweetened beverages, (2) unhealthy dietary patterns, (3) perfluoroalkyl substances, and (4) fine particulate matter may increase risk of adverse health outcomes, such as obesity, cardiometabolic dysfunction, and allergy/asthma.
Emerging prenatal nutritional factors and environmental toxicants influence offspring long-term health. More work is needed to identify the role of paternal exposures and maternal exposures during the preconception period and to further elucidate causality through intervention studies. The ubiquity of these emerging nutritional and environmental exposures makes this area of inquiry of considerable public health importance.
KeywordsSugar-sweetened beverages Dietary patterns Perfluoroalkyl substances Fine particulate matter pollution Prenatal risk factors Developmental origins of disease
Izzuddin M Aris is supported by the National University of Singapore Overseas Postdoctoral Fellowship (NUS OPF/2017). Abby Fleisch is supported by the National Institutes of Health (K23 ES024803). Emily Oken is supported by the National Institutes of Health (UG3OD023286, P30 DK092924, R01AI102960, R01 HD034568).
Compliance with Ethical Standards
Conflict of Interest
Izzuddin M Aris and Abby F. Fleisch declare no conflicts of interest; Emily Oken reports grants from US National Institutes of Health, during the conduct of the study.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 6.Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res. 2004;56(3):311–7. https://doi.org/10.1203/01.PDR.0000135998.08025.FB.CrossRefPubMedGoogle Scholar
- 16.Zheng J, Feng Q, Zhang Q, Wang T, Xiao X. Early life fructose exposure and its implications for long-term cardiometabolic health in offspring. Nutrients. 2016;8(11).Google Scholar
- 19.•• Gillman MW, Rifas-Shiman SL, Fernandez-Barres S, Kleinman K, Taveras EM, Oken E. Beverage intake during pregnancy and childhood adiposity. Pediatrics 2017;140(2).(pii):peds.2017–0031. doi: https://doi.org/10.1542/peds.2017-0031. The most recent study from a US pre-birth cohort linking prenatal intake of sugar-sweetened beverages with increased child adiposity. Findings suggested that the associations were due primarily to maternal, not child, sugar-sweetened beverage intake and to sugary soda rather than fruit drinks or juice.
- 20.Jen V, Erler NS, Tielemans MJ, Braun KV, Jaddoe VW, Franco OH, et al. Mothers’ intake of sugar-containing beverages during pregnancy and body composition of their children during childhood: the generation R study. Am J Clin Nutr. 2017;105(4):834–41. https://doi.org/10.3945/ajcn.116.147934.CrossRefPubMedGoogle Scholar
- 21.Perng W, Gillman MW, Mantzoros CS, Oken E. A prospective study of maternal prenatal weight and offspring cardiometabolic health in midchildhood. Ann Epidemiol 2014;24(11):793–800.e1. doi: https://doi.org/10.1016/j.annepidem.2014.08.002.
- 22.•• Azad MB, Sharma AK, de Souza RJ, Dolinsky VW, Becker AB, Mandhane PJ, et al. Association between artificially sweetened beverage consumption during pregnancy and infant body mass index. JAMA Pediatr. 2016;170(7):662–70. https://doi.org/10.1001/jamapediatrics.2016.0301. This paper describes the first human evidence that prenatal consumption of artificial sweeteners during pregnancy may influence infant body mass index and risk of overweight.
- 23.Zhu Y, Olsen SF, Mendola P, Halldorsson TI, Rawal S, Hinkle SN, et al. Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. Int J Epidemiol. 2017;46(5):1499–508.Google Scholar
- 24.Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514(7521):181–6. https://doi.org/10.1038/nature13793.
- 26.•• Wright LS, Rifas-Shiman SL, Oken E, Litonjua AA, Gold DR. Prenatal and early life fructose, fructose-containing beverages, and midchildhood asthma. Ann Am Thorac Soc. 2018;15(2):217–24. https://doi.org/10.1513/AnnalsATS.201707-530OC. The most recent study conducted in a US pre-birth cohort that details the relationship between higher prenatal sugar-sweetened beverage intake and risk of asthma during mid-childhood. The observed associations were independent of child adiposity. CrossRefPubMedGoogle Scholar
- 27.Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, et al. Metabolic syndrome is associated with increased oxo-nitrative stress and asthma-like changes in lungs. PLoS One. 2015;10(6):e0129850. https://doi.org/10.1371/journal.pone. eCollection 2015.
- 28.Perng W, Oken E. Chapter 15—programming long-term health: maternal and fetal nutrition and diet needs A2 - Saavedra, Jose M. In: Dattilo AM, editor. Early nutrition and long-term health. Woodhead Publishing; 2017. p. 375–411.Google Scholar
- 30.Brantsaeter AL, Olafsdottir AS, Forsum E, Olsen SF, Thorsdottir I. Does milk and dairy consumption during pregnancy influence fetal growth and infant birthweight? A systematic literature review. Food Nutr Res. 2012;56(pii):–20050. https://doi.org/10.3402/fnr.v56i0.
- 34.•• Chia AR, Tint MT, Han CY, Chen LW, Colega M, Aris IM, et al. Adherence to a healthy eating index for pregnant women is associated with lower neonatal adiposity in a multiethnic Asian cohort: the Growing Up in Singapore Towards healthy Outcomes (GUSTO) Study. Am J Clin Nutr. 2018;107(1):71–9. https://doi.org/10.1093/ajcn/nqx003. A recent paper that observed significant associations between higher maternal diet quality lower neonatal adiposity. One of the few studies in the world to detail this relationship in a multi-ethnic Asian birth cohort. CrossRefPubMedGoogle Scholar
- 35.Dhana K, Zong G, Yuan C, Schernhammer E, Zhang C, Wang X, et al. Lifestyle of women before pregnancy and the risk of offspring obesity during childhood through early adulthood. Int J Obes. 2018;3(10):018–0052.Google Scholar
- 36.• Chen LW, Aris IM, Bernard JY, Tint MT, Chia A, Colega M, et al. Associations of maternal dietary patterns during pregnancy with offspring adiposity from birth until 54 months of age. Nutrients. 2016;9(1) Another paper from a multi-ethnic Asian birth cohort that describes the associations of a “healthy dietary pattern” with lower offspring adiposity. These associations were observed only at ages 18 months and older, until 54 months of age. Google Scholar
- 37.Martin CL, Siega-Riz AM, Sotres-Alvarez D, Robinson WR, Daniels JL, Perrin EM, et al. Maternal dietary patterns during pregnancy are associated with child growth in the first 3 years of life. J Nutr. 2016;146(11):2281–8. https://doi.org/10.3945/jn.116.234336.
- 38.van den Broek M, Leermakers ET, Jaddoe VW, Steegers EA, Rivadeneira F, Raat H, et al. Maternal dietary patterns during pregnancy and body composition of the child at age 6 y: the generation R study. Am J Clin Nutr. 2015;102(4):873–80. https://doi.org/10.3945/ajcn.114.102905.CrossRefPubMedGoogle Scholar
- 39.Leermakers ETM, Tielemans MJ, van den Broek M, Jaddoe VWV, Franco OH, Kiefte-de Jong JC. Maternal dietary patterns during pregnancy and offspring cardiometabolic health at age 6 years: the generation R study. Clin Nutr. 2017;36(2):477–84. https://doi.org/10.1016/j.clnu.2015.12.017.CrossRefPubMedGoogle Scholar
- 42.Fernandez-Barres S, Romaguera D, Valvi D, Martinez D, Vioque J, Navarrete-Munoz EM, et al. Mediterranean dietary pattern in pregnant women and offspring risk of overweight and abdominal obesity in early childhood: the INMA birth cohort study. Pediatr Obes. 2016;11(6):491–9. https://doi.org/10.1111/ijpo.12092.CrossRefPubMedGoogle Scholar
- 43.•• Chatzi L, Rifas-Shiman SL, Georgiou V, Joung KE, Koinaki S, Chalkiadaki G, et al. Adherence to the Mediterranean diet during pregnancy and offspring adiposity and cardiometabolic traits in childhood. Pediatr Obes. 2017;12(Suppl 1):47–56. https://doi.org/10.1111/ijpo.12191. This study pooled data from two longitudinal birth cohorts in the USA and Greece to illustrate that greater adherence to Mediterranean diet during pregnancy protected against excess offspring cardiometabolic risk.
- 44.Sedaghat F, Naja F, Darand M, Beyzai B, Rashidkhani B. Adherence to a Mediterranean dietary pattern and overweight and obesity among female adolescents in Iran. Int J Adolesc Med Health. 2017;23(10):2016–0160.Google Scholar
- 45.• Sen S, Rifas-Shiman SL, Shivappa N, Wirth MD, Hebert JR, Gold DR, et al. Dietary inflammatory potential during pregnancy is associated with lower fetal growth and breastfeeding failure: results from Project Viva. J Nutr. 2016;146(4):728–36. https://doi.org/10.3945/jn.115.225581. Most recent study from a US pre-birth cohort that describes associations of a pro-inflammatory diet during pregnancy with impaired fetal growth. CrossRefPubMedPubMedCentralGoogle Scholar
- 46.• Sen S, Rifas-Shiman SL, Shivappa N, Wirth MD, Hebert JR, Gold DR, et al. Associations of prenatal and early life dietary inflammatory potential with childhood adiposity and cardiometabolic risk in Project Viva. Pediatr Obes. 2017;10(10):12221. Most recent study from a US pre-birth cohort that describes associations of a pro-inflammatory diet during pregnancy may promote development of adiposity in the offspring. Google Scholar
- 50.Olsen GW, Burris JM, Ehresman DJ, Froehlich JW, Seacat AM, Butenhoff JL, et al. Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect. 2007;115(9):1298–305.Google Scholar
- 55.Taxvig C, Dreisig K, Boberg J, Nellemann C, Schelde AB, Pedersen D, et al. Differential effects of environmental chemicals and food contaminants on adipogenesis, biomarker release and PPARgamma activation. Mol Cell Endocrinol. 2012;361(1–2):106–15. https://doi.org/10.1016/j.mce.2012.03.021.
- 56.Hines EP, White SS, Stanko JP, Gibbs-Flournoy EA, Lau C, Fenton SE. Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: low doses induce elevated serum leptin and insulin, and overweight in mid-life. Mol Cell Endocrinol. 2009;304(1–2):97–105. https://doi.org/10.1016/j.mce.2009.02.021.CrossRefPubMedGoogle Scholar
- 57.•• Braun JM, Chen A, Romano ME, Calafat AM, Webster GM, Yolton K, et al. Prenatal perfluoroalkyl substance exposure and child adiposity at 8 years of age: the HOME study. Obesity (Silver Spring). 2016;24(1):231–7. https://doi.org/10.1002/oby.21258. One of the more recent studies in humans that have detailed associations between exposure to higher prenatal PFAS and greater adiposity in mid-childhood.
- 58.Hoyer BB, Ramlau-Hansen CH, Vrijheid M, Valvi D, Pedersen HS, Zviezdai V, et al. Anthropometry in 5- to 9-year-old Greenlandic and Ukrainian children in relation to prenatal exposure to perfluorinated alkyl substances. Environ Health Perspect. 2015;123(8):841–6. https://doi.org/10.1289/ehp.1408881.PubMedPubMedCentralGoogle Scholar
- 59.Mora AM, Fleisch AF, Rifas-Shiman SL, Woo Baidal JA, Pardo L, Webster TF, et al. Early life exposure to per- and polyfluoroalkyl substances and mid-childhood lipid and alanine aminotransferase levels. Environ Int. 2018;111:1–13. https://doi.org/10.1016/j.envint.2017.11.008.CrossRefPubMedGoogle Scholar
- 60.Lauritzen HB, Larose TL, Oien T, Sandanger TM, Odland JO, van de Bor M, et al. Prenatal exposure to persistent organic pollutants and child overweight/obesity at 5-year follow-up: a prospective cohort study. Environ Health. 2018;17(1):9. https://doi.org/10.1186/s12940-017-0338-x.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.•• Fleisch AF, Rifas-Shiman SL, Mora AM, Calafat AM, Ye X, Luttmann-Gibson H, et al. Early-life exposure to perfluoroalkyl substances and childhood metabolic function. Environ Health Perspect. 2017;125(3):481–7. https://doi.org/10.1289/EHP303. A recent study form a US pre-birth cohort that showed prenatal PFAS plasma concentrations were not associated with markers of cardiometabolic risk (leptin, adiponectin, and insulin resistance) in children.
- 62.•• Mora AM, Oken E, Rifas-Shiman SL, Webster TF, Gillman MW, Calafat AM, et al. Prenatal exposure to perfluoroalkyl substances and adiposity in early and mid-childhood. Environ Health Perspect. 2017;125(3):467–73. https://doi.org/10.1289/EHP246. In this recent study, although prenatal PFAS exposure was associated with small increases in adiposity measurements in mid-childhood, the confidence intervals were wide and crossed the null.
- 63.Manzano-Salgado CB, Casas M, Lopez-Espinosa MJ, Ballester F, Iniguez C, Martinez D, et al. Prenatal exposure to perfluoroalkyl substances and cardiometabolic risk in children from the Spanish INMA birth cohort study. Environ Health Perspect. 2017;125(9):097018. https://doi.org/10.1289/EHP1330. CrossRefPubMedPubMedCentralGoogle Scholar
- 66.Okada E, Sasaki S, Kashino I, Matsuura H, Miyashita C, Kobayashi S, et al. Prenatal exposure to perfluoroalkyl acids and allergic diseases in early childhood. Environ Int. 2014;65:127–34. https://doi.org/10.1016/j.envint.2014.01.007.
- 67.Impinen A, Nygaard UC, Lodrup Carlsen KC, Mowinckel P, Carlsen KH, Haug LS, et al. Prenatal exposure to perfluoralkyl substances (PFASs) associated with respiratory tract infections but not allergy- and asthma-related health outcomes in childhood. Environ Res. 2018;160:518–23. https://doi.org/10.1016/j.envres.2017.10.012.CrossRefPubMedGoogle Scholar
- 68.Timmermann CA, Budtz-Jorgensen E, Jensen TK, Osuna CE, Petersen MS, Steuerwald U, et al. Association between perfluoroalkyl substance exposure and asthma and allergic disease in children as modified by MMR vaccination. J Immunotoxicol. 2017;14(1):39–49. https://doi.org/10.1080/1547691X.2016.254306.CrossRefPubMedGoogle Scholar
- 69.Kannan S, Misra DP, Dvonch JT, Krishnakumar A. Exposures to airborne particulate matter and adverse perinatal outcomes: a biologically plausible mechanistic framework for exploring potential effect modification by nutrition. Environ Health Perspect. 2006;114(11):1636–42.PubMedPubMedCentralGoogle Scholar
- 70.Xu X, Yavar Z, Verdin M, Ying Z, Mihai G, Kampfrath T, et al. Effect of early particulate air pollution exposure on obesity in mice: role of p47phox. Arterioscler Thromb Vasc Biol. 2010;30(12):2518–27. https://doi.org/10.1161/ATVBAHA.110.215350.
- 72.•• Fleisch AF, Rifas-Shiman SL, Koutrakis P, Schwartz JD, Kloog I, Melly S, et al. Prenatal exposure to traffic pollution: associations with reduced fetal growth and rapid infant weight gain. Epidemiology. 2015;26(1):43–50. https://doi.org/10.1097/EDE.0000000000000203. One of the few studies that have shown associations between increased prenatal exposure to traffic-related pollution and rapid weight gain in infancy.
- 73.•• Schembari A, de Hoogh K, Pedersen M, Dadvand P, Martinez D, Hoek G, et al. Ambient air pollution and newborn size and adiposity at birth: differences by maternal ethnicity (the born in Bradford study cohort). Environ Health Perspect. 2015;123(11):1208–15. One of the few recent studies that have described associations of fine particulate matter exposure during pregnancy with newborn size and adiposity. Google Scholar
- 74.• Lavigne E, Ashley-Martin J, Dodds L, Arbuckle TE, Hystad P, Johnson M, et al. Air pollution exposure during pregnancy and fetal markers of metabolic function: the MIREC study. Am J Epidemiol. 2016;183(9):842–51. https://doi.org/10.1093/aje/kwv256. One of the few epidemiological studies that have assessed the association between prenatal exposure to air pollution and indicators of fetal metabolic function, in a relative large cohort ( n = 1,257).
- 76.Chiu YH, Hsu HH, Wilson A, Coull BA, Pendo MP, Baccarelli A, et al. Prenatal particulate air pollution exposure and body composition in urban preschool children: examining sensitive windows and sex-specific associations. Environ Res. 2017;158:798–805. https://doi.org/10.1016/j.envres.2017.07.026.CrossRefPubMedGoogle Scholar
- 77.Mao G, Nachman RM, Sun Q, Zhang X, Koehler K, Chen Z, et al. Individual and joint effects of early-life ambient exposure and maternal prepregnancy obesity on childhood overweight or obesity. Environ Health Perspect. 2017;125(6):067005. https://doi.org/10.1289/EHP261.
- 78.Lee A, Leon Hsu HH, Mathilda Chiu YH, Bose S, Rosa MJ, Kloog I, et al. Prenatal fine particulate exposure and early childhood asthma: effect of maternal stress and fetal sex. J Allergy Clin Immunol. 2017;8(17):31273–3.Google Scholar
- 79.Rosa MJ, Just AC, Kloog I, Pantic I, Schnaas L, Lee A, et al. Prenatal particulate matter exposure and wheeze in Mexican children: effect modification by prenatal psychosocial stress. Ann Allergy Asthma Immunol. 2017;119(3):232–7.e1. https://doi.org/10.1016/j.anai.2017.06.016.CrossRefPubMedGoogle Scholar
- 80.Pennington AF, Strickland MJ, Klein M, Zhai X, Bates JT, Drews-Botsch C, et al. Exposure to mobile source air pollution in early-life and childhood asthma incidence: the Kaiser air pollution and pediatric asthma study. Epidemiology. 2018;29(1):22–30. https://doi.org/10.1097/EDE.0000000000000754.
- 83.•• Leung YK, Govindarajah V, Cheong A, Veevers J, Song D, Gear R, et al. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk. Endocr Relat Cancer. 2017;24(7):365–78. https://doi.org/10.1530/ERC-17-0006. An animal study that describes the concurrent effects of exposure to a high-fat diet and bisphenol A during pregnancy with incidence in mammary tumor formation, alterations in mammary gland development, and gene expression. This study illustrates the potential synergistic effects of exposure to nutritional imbalances and environmental chemicals.
- 84.•• Schaider LA, Balan SA, Blum A, Andrews DQ, Strynar MJ, Dickinson ME, Lunderberg DM, Lang JR, Peaslee GF Fluorinated compounds in US fast food packaging. Environ Sci Technol Lett 2017;4(3):105–11. A recent study that details the prevalence of fluorinated chemicals in fast food packaging and demonstrates their potentially significant contribution to dietary PFAS exposure and environmental contamination during production and disposal. Google Scholar
- 89.Hatch EE, Wesselink AK, Hahn KA, Michiel JJ, Mikkelsen EM, Sorensen HT, et al. Intake of sugar-sweetened beverages and fecundability in a North American Preconception Cohort. Epidemiology. 2018;29(3):369–78. https://doi.org/10.1097/EDE.0000000000000812.
- 90.• Zhang C, Sundaram R, Maisog J, Calafat AM, Barr DB, Buck Louis GM. A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes. Fertil Steril. 2015;103(1):184–9. https://doi.org/10.1016/j.fertnstert.2014.10.001. One of the few studies that have examined exposure to perfluoroalkyl substances during preconception and its associated risks with gestational diabetes during pregnancy, which is suggestive of a possible environmental etiology for gestational diabetes. CrossRefPubMedGoogle Scholar
- 91.Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics. 2015;7:120. https://doi.org/10.1186/s13148-015-0155-4. eCollection 2015.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.•• Schagdarsurengin U, Steger K. Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health. Nat Rev Urol. 2016;13(10):584–95. https://doi.org/10.1038/nrurol.2016.157. An important review that summarizes various studies in animal models and human epidemiological data describing the transgenerational effect of the paternally contributed sperm epigenome on long-term health outcomes of the offspring. CrossRefPubMedGoogle Scholar
- 93.Harris MH, Rifas-Shiman SL, Calafat AM, Ye X, Mora AM, Webster TF, et al. Predictors of per- and polyfluoroalkyl substance (PFAS) plasma concentrations in 6–10 year old American children. Environ Sci Technol. 2017;51(9):5193–204. https://doi.org/10.1021/acs.est.6b05811.
- 96.Abdel Rahman A, Jomaa L, Kahale LA, Adair P, Pine C. Effectiveness of behavioral interventions to reduce the intake of sugar-sweetened beverages in children and adolescents: a systematic review and meta-analysis. Nutr Rev. 2018;76(2):88–107. https://doi.org/10.1093/nutrit/nux061.CrossRefPubMedGoogle Scholar
- 99.Allen RW, Barn PK, Lanphear BP. Randomized controlled trials in environmental health research: unethical or underutilized? PLoS Med. 2015;12(1):e1001775. https://doi.org/10.1371/journal.pmed. eCollection 2015 Jan.
- 100.•• Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, Prentice AM, Stephenson J, et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet. 2018;16(18):30312-X. The most recent review from Lancet describing the evidence for the effects of preconception health on the growth, development, and long-term health of the offspring. This paper also discusses potential strategies for preconception interventions that are scalable, which could have positive effects on a range of health outcomes. Google Scholar