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Maternal folate status and obesity/insulin resistance in the offspring: a systematic review

International Journal of Obesity volume 40, pages 1–9 (2016)Cite this article

Subjects

Abstract

OBJECTIVE:

Prenatal folic acid supplementation or maternal folate sufficiency may protect the offspring from obesity and insulin resistance. This study aims to summarize the findings of association between prenatal folic acid supplementation/maternal folate sufficiency and obesity/insulin resistance in the offspring.

METHODS:

Twelve databases were searched for both published and unpublished work of prenatal folic acid supplementation/maternal folate status up to 1 July 2014. Experimental and observational studies on animals and human beings were included based on the eligibility criteria. There were no limits to the time period and language of publication. The study quality was assessed with a 10-Point Scale for Scientific Methodology.

RESULTS:

The search identified 2548 records. Nine animal studies and five human studies satisfied search criteria were included. Five of these nine animal studies showed a protective effect of folic acid. Of the five human studies, one showed a protective effect of folic acid, two showed a harmful effect and two showed uncertain results.

CONCLUSIONS:

Data from both animal studies and human studies are inconsistent. Future researches with sophisticated designs are needed to demonstrate the potential protective effect of maternal folate on obesity/insulin resistance in the offspring in animal models and human pregnancies.

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References

  1. International Diabetes Federation. 2013. IDF Diabetes Atlas, 6th edn. Available at: http://www.idf.org/diabetesatlas.

  2. Shea J, Diamandis EP, Sharma AM, Despres JP, Ezzat S, Greenway F . The obesity epidemic. Clin Chem 2012; 58: 968–973.

    Article  Google Scholar 

  3. Khandelwal S, Reddy KS . Eliciting a policy response for the rising epidemic of overweight-obesity in India. Obes Rev 2013; 14: 114–125.

    Article  Google Scholar 

  4. Chen S, Binns CW, Maycock B, Zhao Y, Liu Y . Chinese mothers’ perceptions of their child’s weight and obesity status. Asia Pac J Clin Nutr 2014; 23: 452–458.

    PubMed  Google Scholar 

  5. Ogden CL, Carroll MD, Kit BK, Flegal KM . Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. JAMA 2012; 307: 483–490.

    Article  Google Scholar 

  6. National Center for Health Statistics Health, United States, 2011: With Special Features on Socioeconomic Status and Health. US Department of Health and Human Services: : Hyattsville, 2012.

  7. 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: 766–781.

    Article  Google Scholar 

  8. Guo SS, Chumlea WC . Tracking of body mass index in children in relation to overweight in adulthood. Am J Clin Nutr 1999; 70: S145–S148.

    Article  Google Scholar 

  9. Freedman DS, Kettel L, Serdula MK, Dietz WH, Srinivasan SR, Berenson GS . The relation of childhood BMI to adult adiposity: the Bogalusa Heart Study. Pediatrics 2005; 115: 22–27.

    Article  Google Scholar 

  10. CDC National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. US Department of Health and Human Services: : Atlanta, 2011.

  11. Chiarelli F, Marcovecchio ML . Insulin resistance and obesity in childhood. Eur J Endocrinol 2008; 159: S67–S74.

    Article  CAS  Google Scholar 

  12. Freedman DS, Khan LK, Dietz WH, Srinivasan SA, Berenson GS . Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study. Pediatrics 2001; 108: 712–718.

    Article  CAS  Google Scholar 

  13. Freedman DS, Zuguo M, Srinivasan SR, Berenson GS, Dietz WH . Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J Pediatr 2007; 150: 12–17.

    Article  Google Scholar 

  14. Barker DJP, Osmond C, Winter PD, Margetts B, Simmonds SJ . Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 577–580.

    Article  CAS  Google Scholar 

  15. Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD . Birthweight, bodymass index in middle age, and incident coronary heart disease. Lancet 1996; 348: 1478–1480.

    Article  CAS  Google Scholar 

  16. Leon DA . Fetal growth and adult disease. Eur J Clin Nutr 1998; 52: S78–S82.

    Google Scholar 

  17. Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds SJ . Early growth and death from cardiovascular disease in women. BMJ 1993; 307: 1519–1524.

    Article  CAS  Google Scholar 

  18. Ross MG, Desai M . Developmental programming of offspring obesity, adipogenesis and appetite. Clin Obstet Gynecol 2013; 56: 529–536.

    Article  Google Scholar 

  19. Entringer S, Buss C, Swanson JM, Cooper DM, Wing DA, Waffarn F et al. Fetal programming of body composition, obesity and metabolic function: the role of intrauterine stress and stress biology. J Nutr Metab 2012; 2012: 632548.

    Article  Google Scholar 

  20. Wild SH, Byrne CD . Evidence for fetal programming of obesity with a focus on putative mechanisms. Nutr Res Rev 2004; 17: 153–162.

    Article  Google Scholar 

  21. Gluckman PD, Hanson MA, Cooper C, Thornburg KL . Effect of in utero and early-life conditions on adult health and disease. N Eng J Med 2008; 359: 61–73.

    Article  CAS  Google Scholar 

  22. Bird A . DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16: 6–21.

    Article  CAS  Google Scholar 

  23. Callinan PA, Feinberg AP . The emerging science of epigenomics. Hum Mol Genet 2006; 15: R95–101.

    Article  CAS  Google Scholar 

  24. Salbaum JM, Kappen C . Genetic and epigenomic footprints of folate. Prog Mol Biol Transl Sci 2012; 108: 129–158.

    Article  CAS  Google Scholar 

  25. Scholl TO, Hediger ML, Schall JI, Khoo CS, Fischer RL . Dietary and serum folate: their influence on the outcome of pregnancy. Am J Clin Nutr 1996; 63: 520–525.

    Article  CAS  Google Scholar 

  26. Relton CL, Pearce MS, Parker L . The influence of erythrocyte folate and serum vitamin B12 status on birthweight. Br J Nutr 2005; 93: 593–599.

    Article  CAS  Google Scholar 

  27. Sinclair KD, Allegeucci C, Singh R, Gardner DS, Sebastian S, Bispham J et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007; 104: 19351–19356.

    Article  CAS  Google Scholar 

  28. Sena E, van der Worp HB, Howells DW, Macleod M . How can we improve the ore-clinical development of drugs for stroke. Trends Neurosci 2007; 30: 433–439.

    Article  CAS  Google Scholar 

  29. Macleod MR, O'collins T, Howells DW, Donnan GA . Pooling of animal experimental data reveals influence of study-design and publication bias. Stroke 2004; 35: 1203–1208.

    Article  Google Scholar 

  30. Amarasingh S, Macleod MR, Whittle IR . What is the translational efficacy of chemotherapeutic drug research in neuro-oncology? A systematic review and meta-analysis of the efficacy of BCNU and CCNU in animal models of glioma. J Neurooncol 2009; 91: 117–125.

    Article  CAS  Google Scholar 

  31. Krauth D, Woodruff TJ, Bero L . Instruments for assessing risk of bias and other methodological criteria of published animal studies: a systematic review. Environ Health Perspect 2013; 121: 985–992.

    Article  Google Scholar 

  32. Hooijmans CR, Rovers MM, DeVries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW . SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 43.

    Article  Google Scholar 

  33. Cho CE, Sanchez-Hernandez D, Reza-Lopez SA, Huot PS, Kim YI, Anderson GH . High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 2013; 8: 710–719.

    Article  CAS  Google Scholar 

  34. Hoile SP, Lillycrop KA, Grenfell LR, Hanson MA, Burdge GC . Increasing the folic acid content of maternal or post-weaning diets induces differential changes in phosphoenolpyruvate carboxykinase mRNA expression and promoter methylation in rats. Br J Nutr 2012; 108: 852–827.

    Article  CAS  Google Scholar 

  35. Huang Y, He Y, Sun X, He Y, Li Y, Sun C . Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet. Int J Mol Sci 2014; 15: 6298–6313.

    Article  Google Scholar 

  36. Huot PS, Dodington DW, Mollard RC, Reza-López SA, Sánchez-Hernández D, Cho CE et al. High folic acid intake during pregnancy lowers body weight and reduces femoral area and strength in female rat offspring. J Osteoporos 2013; 2013: 154109.

    Article  Google Scholar 

  37. Kumar KA, Lalitha A, Pavithra D, Padmavathi IJ, Ganeshan M, Rao KR et al. Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. J Nutr Biochem 2013; 24: 25–31.

    Article  CAS  Google Scholar 

  38. Waterland RA, Jirtle RL . Transposable elements: target for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003; 23: 5293–5300.

    Article  CAS  Google Scholar 

  39. Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG . Maternal methyl supplements increase offspring DNA methylation at axin Fused. Genesis 2006; 44: 401–406.

    Article  CAS  Google Scholar 

  40. Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S . Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 2008; 32: 1373–1379.

    Article  CAS  Google Scholar 

  41. Stewart CP, Christian P, Schulze KJ, LeClerq SC, West KP Jr, Khatry SK . Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal. J Nutr 2009; 139: 1575–1581.

    Article  CAS  Google Scholar 

  42. Stewart CP, Christian P, Schulze KJ, Arguello M, LeClerq SC, Khatry SK et al. Low maternal vitamin B12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. J Nutr 2011; 141: 1912–1917.

    Article  CAS  Google Scholar 

  43. Krishnaveni GV, Veena SR, Karat SC, Yajnik CS, Fall CH . Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia 2014; 57: 110–121.

    Article  CAS  Google Scholar 

  44. Lewis SJ, Leary S, Smith GD, Ness A . Body composition at age 9 years, maternal folate intake during pregnancy and methyltetrahydrofolate reductase (MTHFR) C677T genotype. Br J Nutr 2009; 102: 493–496.

    Article  CAS  Google Scholar 

  45. Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune maternal nutrition study. Diabetologia 2008; 51: 29–38.

    Article  CAS  Google Scholar 

  46. Charles D, Ness AR, Campbell D, Smith GD, Hall MH . Taking folate in pregnancy and risk of maternal breast cancer. BMJ 2004; 329: 1375–1376.

    Article  Google Scholar 

  47. Larsson SC, Giovannucci E, Wolk A . Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 2007; 99: 64–76.

    Article  CAS  Google Scholar 

  48. Oakley GP, Mandel JS . Folic acid fortification remains an urgent health priority. BMJ 2004; 329: 1376.

    Article  Google Scholar 

  49. Mahajan NN, Mahajan KN, Soni RN, Gaikwad NL . Justifying the ‘Folate trap’ in folic acid fortification programs. J Perinat Med 2007; 35: 241–242.

    PubMed  Google Scholar 

  50. Binia A, Contreras AV, Canizales-Quinteros S, Alonzo VA, Tejero ME, Silva-Zolezzi I . Geographical and ethnic distribution of single nucleotide polymorphisms within genes of the folate/homocysteine pathway metabolism. Genes Nutr 2014; 9: 421.

    Article  Google Scholar 

  51. Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 2007; 50: 63–67.

    Article  CAS  Google Scholar 

  52. Yajnik CS, Janipalli CS, Bhaskar S, Kulkarni SR, Freathy RM, Prakash S et al. FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians. Diabetologia 2009; 52: 247–252.

    Article  CAS  Google Scholar 

  53. Bird JK, Ronnenberg AG, Choi SW, Du F, Mason JB, Liu Z . Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations. J Nutr 2015; 145: 79–86.

    Article  CAS  Google Scholar 

  54. Said HM, Mee L, Sekar VT, Ashokkumar B, Pandol SJ . Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption. Am J Physiol Gastrointest Liver Physiol 2010; 298: G985–G993.

    Article  CAS  Google Scholar 

  55. Tinker SC, Hamner HC, Berry RJ, Bailey LB, Pfeiffer CM . Does obesity modify the association of supplemental folic acid with folate status among nonpregnant women of childbearing age in the United States? Birth Defects Res A Clin Mol Teratol 2012; 94: 749–755.

    Article  CAS  Google Scholar 

  56. Keating E, Gonçalves P, Campos I, Costa F, Martel F . Folic acid uptake by the human syncytiotrophoblast: interference by pharmacotherapy, drugs of abuse and pathological conditions. Reprod Toxicol 2009; 28: 511–520.

    Article  CAS  Google Scholar 

  57. Sen S, Iyer C, Meydani SN . Obesity during pregnancy alters maternal oxidant balance and micronutrient status. J Perinatol 2014; 34: 105–111.

    Article  CAS  Google Scholar 

  58. Yaremco E, Inglis A, Innis SM, Hippman C, Carrion P, Lamers Y et al. Red blood cell folate levels in pregnant women with a history of mood disorders: a case series. Birth Defects Res A Clin Mol Teratol 2013; 97: 416–420.

    Article  CAS  Google Scholar 

  59. Fenech M . Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity, 2012. Mutat Res 2012; 733: 21–33.

    Article  CAS  Google Scholar 

  60. Duthie SJ, Hawdon A . DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 1998; 12: 1491–1497.

    Article  CAS  Google Scholar 

  61. Steegers-Theunissen RP, Smith SC, Steeger EA, Guilbert LJ, Baker PN . Folate affects apoptosis in human trophoblastic cells. BJOG 2000; 107: 1513–1515.

    Article  CAS  Google Scholar 

  62. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999; 341: 1485–1490.

    Article  CAS  Google Scholar 

  63. Czeizel AE, Dudás I . Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–1835.

    Article  CAS  Google Scholar 

  64. MRC. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991; 338: 131–137.

    Article  Google Scholar 

  65. Botto LD, Khoury MJ, Mulinare J, Erickson JD . Periconceptional multivitamin use and the occurrence of conotruncal heart defects: results from a population-based, case-control study. Pediatrics 1996; 98: 911–917.

    CAS  PubMed  Google Scholar 

  66. Czeizel AE . Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996; 62: 179–183.

    Article  CAS  Google Scholar 

  67. Shaw GM, O'Malley CD, Wasserman CR, Tolarova MM, Lammer EJ . Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 1995; 59: 536–545.

    Article  CAS  Google Scholar 

  68. Czeizel AE . Folic acid and prevention of birth defects. JAMA 1996; 275: 1635–1636.

    Article  CAS  Google Scholar 

  69. Shaw GM, Lammer EJ, Wasserman CR, O’Malley CD, Tolarova MM . Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995; 346: 393–396.

    Article  CAS  Google Scholar 

  70. Werler MM, Hayes C, Louik C, Shapiro S, Mitchell AA . Multivitamin supplementation and risk of birth defects. Am J Epidemiol 1999; 150: 675–682.

    Article  CAS  Google Scholar 

  71. Li DK, Daling JR, Mueller BA, Hickok DE, Fantel AG, Weiss NS . Periconceptional multivitamin use in relation to the risk of congenital urinary tract anomalies. Epidemiology 1995; 6: 212–218.

    Article  CAS  Google Scholar 

  72. Fraser JL, Watt HJ . Megaloblastic anemia in pregnancy and the puerperium. Am J Obstet Gynecol 1964; 89: 532–534.

    Article  CAS  Google Scholar 

  73. Hibbard BM, Hibbard ED, Jeffcoate TN . Folic acid and reproduction. Acta Obstet Gynecol Scand 1965; 44: 375–400.

    Article  CAS  Google Scholar 

  74. Faron G, Drouin R, Pedneault L, Poulin LD, Laframboise R, Garrido-Russo M et al. Recurrent cleft lip and palate in siblings of a patient with malabsorption syndrome, probably caused by hypovitaminosis a associated with folic acid and vitamin B(2) deficiencies. Teratology 2001; 63: 161–163.

    Article  CAS  Google Scholar 

  75. Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 2013; 155: 81–93.

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the support and encourage of Dr Jacquetta Trasler from McGill University, and helpful discussions with Alain Mayhew and Marc Avey from the Ottawa Hospital Research Institute. This study was supported, in part, by grants from Canadian Institutes for Health Research (CIHR; grant # MOP 86562 & grant # MOP 115183). Dr Wen is a recipient of Mid-Career Investigator of CIHR Institute for Gender & Health and Ontario Women’s Health Council. Dr Walker is Tier I Clinical Research Chair in perinatal health of the University of Ottawa. Dr Retnakaran holds an Ontario Ministry of Research and Innovation Early Researcher Award.

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Author notes

  1. R-h Xie and Y-j Liu: These authors contributed and credited to the study equally.

Authors and Affiliations

  1. Dean’s office, School of Nursing, Hunan University of Medicine, Huaihua, China

    R-h Xie

  2. McLaughlin Center for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada,

    R-h Xie

  3. Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China

    Y-j Liu

  4. Department of Obstetrics and Gynecology, Central South University, Changsha, China

    Y-j Liu & S W Wen

  5. Department of Obstetrics and Gynecology, OMNI Research Group, University of Ottawa, Ottawa, Ontario, Canada,

    Y-j Liu, M C Walker & S W Wen

  6. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,

    Y-j Liu, M C Walker & S W Wen

  7. Division of Endocrinology, Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada,

    R Retnakaran

  8. Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada,

    A J MacFarlane

  9. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada,

    J Hamilton

  10. Department of Obstetrics and Gynecology, Queen’s University, Kingston, Ontario, Canada,

    G Smith

  11. Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada,

    M C Walker & S W Wen

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  1. R-h Xie
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  8. S W Wen
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Correspondence to S W Wen.

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Xie, Rh., Liu, Yj., Retnakaran, R. et al. Maternal folate status and obesity/insulin resistance in the offspring: a systematic review. Int J Obes 40, 1–9 (2016). https://doi.org/10.1038/ijo.2015.189

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  • DOI: https://doi.org/10.1038/ijo.2015.189

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