Abstract
Purpose of Review
This review will focus on the long-term outcomes in offspring exposed to in utero hyperglycemia and gestational diabetes (GDM), including obesity, adiposity, glucose metabolism, hypertension, hyperlipidemia, nonalcoholic fatty liver disease, and puberty.
Recent Findings
There is evidence, mostly from observational studies, that offspring of GDM mothers have increased risk of obesity, increased adiposity, disorders of glucose metabolism (insulin resistance and type 2 diabetes), and hypertension. In contrast, evidence from the two intervention studies of treatment of mild GDM and childhood measures of BMI, adiposity, and glucose tolerance do not demonstrate that GDM treatment significantly reduces adverse childhood metabolic outcomes. Thus, more evidence is needed to understand the impact of maternal GDM on offspring’s adiposity, glucose metabolism, lipid metabolism, risk of fatty liver disease, and pubertal onset.
Summary
Offspring of GDM mothers may have increased risk for metabolic and cardiovascular complications. Targeting this group for intervention studies to prevent obesity and disorders of glucose metabolism is one potential strategy to prevent adverse metabolic health outcomes.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Nanditha A, Ma RC, Ramachandran A, Snehalatha C, Chan JC, Chia KS, et al. Diabetes in Asia and the Pacific: implications for the global epidemic. Diabetes Care. 2016;39(3):472–85.
Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991–2002.
Falavigna M, Schmidt MI, Trujillo J, Alves LF, Wendland ER, Torloni MR, et al. Effectiveness of gestational diabetes treatment: a systematic review with quality of evidence assessment. Diabetes Res Clin Pract. 2012;98(3):396–405.
•• Lowe WL Jr, Scholtens DM, Lowe LP, Kuang A, Nodzenski M, Talbot O, et al. Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity. Jama. 2018;320(10):1005–16. Findings in this study suggest that untreated, mild GDM is assoicated with increased adiposity in childhood.
Pettitt DJ, Knowler WC. Long-term effects of the intrauterine environment, birth weight, and breast-feeding in Pima Indians. Diabetes Care. 1998;21(Suppl 2):B138–41.
Schaefer-Graf UM, Buchanan TA, Xiang A, Songster G, Montoro M, Kjos SL. Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol. 2000;182(2):313–20.
Wendland EM, Torloni MR, Falavigna M, Trujillo J, Dode MA, Campos MA, et al. Gestational diabetes and pregnancy outcomes--a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) diagnostic criteria. BMC pregnancy and childbirth. 2012;12:23.
Dudley DJ. Diabetic-associated stillbirth: incidence, pathophysiology, and prevention. Obstet Gynecol Clin N Am. 2007;34(2):293–307 ix.
Salvesen DR, Brudenell JM, Snijders RJ, Ireland RM, Nicolaides KH. Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Am J Obstet Gynecol. 1993;168(1 Pt 1):88–94.
Metzger BE, Persson B, Lowe LP, Dyer AR, Cruickshank JK, Deerochanawong C, et al. Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia. Pediatrics. 2010;126(6):e1545–52.
Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477–86.
Moore TR. A comparison of amniotic fluid fetal pulmonary phospholipids in normal and diabetic pregnancy. Am J Obstet Gynecol. 2002;186(4):641–50.
Wexler DJ, Powe CE, Barbour LA, Buchanan T, Coustan DR, Corcoy R, et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop. Obstet Gynecol. 2018;132(2):496–505.
Silverman BL, Rizzo TA, Cho NH, Metzger BE. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care. 1998;(21 Suppl 2):B142–9.
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(1):76–80.
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):121–5.
Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49(12):2208–11.
Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families. Circulation. 2011;123(3):258–65.
Gillman MW, Oakey H, Baghurst PA, Volkmer RE, Robinson JS, Crowther CA. Effect of treatment of gestational diabetes mellitus on obesity in the next generation. Diabetes Care. 2010;33(5):964–8.
Landon MB, Mele L, Varner MW, Casey BM, Reddy UM, Wapner RJ, et al. The relationship of maternal glycemia to childhood obesity and metabolic dysfunction(double dagger). J Matern Fetal Neonatal Med. 2018:1–9.
Nehring I, Chmitorz A, Reulen H, von Kries R, Ensenauer R. Gestational diabetes predicts the risk of childhood overweight and abdominal circumference independent of maternal obesity. Diabet Med. 2013;30(12):1449–56.
Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ. Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30(9):2287–92.
Wang J, Wang L, Liu H, Zhang S, Leng J, Li W, et al. Maternal Gestational Diabetes and Different Indicators of Childhood Obesity - A Large Study. Endocr Connect. 2018.
Hockett CW, Harrall KK, Moore BF, Starling AP, Bellatorre A, Sauder KA, et al. Persistent effects of in utero overnutrition on offspring adiposity: the exploring perinatal outcomes among children (EPOCH) study. Diabetologia. 2019.
Vohr BR, McGarvey ST, Tucker R. Effects of maternal gestational diabetes on offspring adiposity at 4-7 years of age. Diabetes Care. 1999;22(8):1284–91.
Zhao P, Liu E, Qiao Y, Katzmarzyk PT, Chaput JP, Fogelholm M, et al. Maternal gestational diabetes and childhood obesity at age 9-11: results of a multinational study. Diabetologia. 2016;59(11):2339–48.
Kearney M, Perron J, Marc I, Weisnagel SJ, Tchernof A, Robitaille J. Association of prenatal exposure to gestational diabetes with offspring body composition and regional body fat distribution. Clin Obes. 2018;8(2):81–7.
Crume TL, Ogden L, West NA, Vehik KS, Scherzinger A, Daniels S, et al. Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the exploring perinatal outcomes among children (EPOCH) study. Diabetologia. 2011;54(1):87–92.
Wright CS, Rifas-Shiman SL, Rich-Edwards JW, Taveras EM, Gillman MW, Oken E. Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure. Am J Hypertens. 2009;22(2):215–20.
Gingras V, Rifas-Shiman SL, Derks IPM, Aris IM, Oken E, Hivert MF. Associations of gestational glucose tolerance with offspring body composition and estimated insulin resistance in early adolescence. Diabetes Care. 2018;41(12):e164–e6.
Freedman DS, Mei Z, 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(1):12–7.e2.
Tam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In utero exposure to maternal hyperglycemia increases childhood Cardiometabolic risk in offspring. Diabetes Care. 2017;40(5):679–86.
Lowe WL Jr, Scholtens DM, Kuang A, Linder B, Lawrence JM, Lebenthal Y, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care. 2019;42(3):372–80.
• Scholtens DM, Kuang A, Lowe LP, Hamilton J, Lawrence JM, Lebenthal Y, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal Glycemia and childhood glucose metabolism. Diabetes Care. 2019;42(3):381–92. Findings from this study suggest that hyperglycemia in utero is associated with increased childhood glucose and insulin resistance.
Landon MB, Rice MM, Varner MW, Casey BM, Reddy UM, Wapner RJ, et al. Mild gestational diabetes mellitus and long-term child health. Diabetes Care. 2015;38(3):445–52.
Kawasaki M, Arata N, Miyazaki C, Mori R, Kikuchi T, Ogawa Y, et al. Obesity and abnormal glucose tolerance in offspring of diabetic mothers: a systematic review and meta-analysis. PLoS One. 2018;13(1):e0190676.
Holder T, Giannini C, Santoro N, Pierpont B, Shaw M, Duran E, et al. A low disposition index in adolescent offspring of mothers with gestational diabetes: a risk marker for the development of impaired glucose tolerance in youth. Diabetologia. 2014;57(11):2413–20.
Dabelea D, Mayer-Davis EJ, Lamichhane AP, D'Agostino RB Jr, Liese AD, Vehik KS, et al. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH case-control study. Diabetes Care. 2008;31(7):1422–6.
Blotsky AL, Rahme E, Dahhou M, Nakhla M, Dasgupta K. Gestational diabetes associated with incident diabetes in childhood and youth: a retrospective cohort study. CMAJ. 2019;191(15):E410–e7.
Tam WH, Ma RC, Yang X, Li AM, Ko GT, Kong AP, et al. Glucose intolerance and cardiometabolic risk in adolescents exposed to maternal gestational diabetes: a 15-year follow-up study. Diabetes Care. 2010;33(6):1382–4.
Hao G, Wang X, Treiber FA, Harshfield G, Kapuku G, Su S. Blood Pressure Trajectories From Childhood to Young Adulthood Associated With Cardiovascular Risk: Results From the 23-Year Longitudinal Georgia Stress and Heart Study. Hypertension. 2017;69(3):435–42.
Theodore RF, Broadbent J, Nagin D, Ambler A, Hogan S, Ramrakha S, et al. Childhood to Early-Midlife Systolic Blood Pressure Trajectories: Early-Life Predictors, Effect Modifiers, and Adult Cardiovascular Outcomes. Hypertension. 2015;66(6):1108–15.
Urbina EM, Khoury PR, McCoy C, Daniels SR, Kimball TR, Dolan LM. Cardiac and vascular consequences of pre-hypertension in youth. J Clin Hypertens. 2011;13(5):332–42.
National Clinical Guideline C. National Institute for Health and Clinical Excellence: Guidance. Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34. London: Royal College of Physicians (UK). National Clinical Guideline Centre.; 2011.
Amri K, Freund N, Vilar J, Merlet-Benichou C, Lelievre-Pegorier M. Adverse effects of hyperglycemia on kidney development in rats: in vivo and in vitro studies. Diabetes. 1999;48(11):2240–5.
Ritz E, Amann K, Koleganova N, Benz K. Prenatal programming-effects on blood pressure and renal function. Nat Rev Nephrol. 2011;7(3):137–44.
Wichi RB, Souza SB, Casarini DE, Morris M, Barreto-Chaves ML, Irigoyen MC. Increased blood pressure in the offspring of diabetic mothers. Am J Phys Regul Integr Comp Phys. 2005;288(5):R1129–33.
Pinter E, Haigh J, Nagy A, Madri JA. Hyperglycemia-induced vasculopathy in the murine conceptus is mediated via reductions of VEGF-A expression and VEGF receptor activation. Am J Pathol. 2001;158(4):1199–206.
Bunt JC, Tataranni PA, Salbe AD. Intrauterine exposure to diabetes is a determinant of hemoglobin a(1)c and systolic blood pressure in pima Indian children. J Clin Endocrinol Metab. 2005;90(6):3225–9.
Tam WH, Ma RC, Yang X, Ko GT, Tong PC, Cockram CS, et al. Glucose intolerance and cardiometabolic risk in children exposed to maternal gestational diabetes mellitus in utero. Pediatrics. 2008;122(6):1229–34.
Beyerlein A, Nehring I, Rosario AS, von Kries R. Gestational diabetes and cardiovascular risk factors in the offspring: results from a cross-sectional study. Diabet Med. 2012;29(3):378–84.
Aceti A, Santhakumaran S, Logan KM, Philipps LH, Prior E, Gale C, et al. The diabetic pregnancy and offspring blood pressure in childhood: a systematic review and meta-analysis. Diabetologia. 2012;55(11):3114–27.
•• Miranda JO, Cerqueira RJ, Barros H, Areias JC. Maternal Diabetes Mellitus as a Risk Factor for High Blood Pressure in Late Childhood. Hypertens. 2019;73(1):e1–7. Finding of this study suggest that maternal diabetes is associated with higher blood pressure in childhood.
Blondeau B, Joly B, Perret C, Prince S, Bruneval P, Lelievre-Pegorier M, et al. Exposure in utero to maternal diabetes leads to glucose intolerance and high blood pressure with no major effects on lipid metabolism. Diabetes Metab. 2011;37(3):245–51.
Song Y, Li J, Zhao Y, Zhang Q, Liu Z, Li J, et al. Severe maternal hyperglycemia exacerbates the development of insulin resistance and fatty liver in the offspring on high fat diet. Exp Diabetes Res. 2012;2012:254976.
Pereira TJ, Fonseca MA, Campbell KE, Moyce BL, Cole LK, Hatch GM, et al. Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome. J Physiol. 2015;593(14):3181–97.
Brumbaugh DE, Tearse P, Cree-Green M, Fenton LZ, Brown M, Scherzinger A, et al. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J Pediatr. 2013;162(5):930–6.e1.
Bellatorre A, Scherzinger A, Stamm E, Martinez M, Ringham B, Dabelea D. Fetal Overnutrition and Adolescent Hepatic Fat Fraction: the Exploring Perinatal Outcomes in Children Study. J Pediatr. 2018;192:165–70.e1.
Davis JN, Gunderson EP, Gyllenhammer LE, Goran MI. Impact of gestational diabetes mellitus on pubertal changes in adiposity and metabolic profiles in Latino offspring. J Pediatr. 2013;162(4):741–5.
Grunnet LG, Hansen S, Hjort L, Madsen CM, Kampmann FB, Thuesen ACB, et al. Adiposity, Dysmetabolic traits, and earlier onset of female puberty in adolescent offspring of women with gestational diabetes mellitus: a clinical study within the Danish National Birth Cohort. Diabetes Care. 2017;40(12):1746–55.
Lauridsen LLB, Arendt LH, Ernst A, Brix N, Parner ET, Olsen J, et al. Maternal diabetes mellitus and timing of pubertal development in daughters and sons: a nationwide cohort study. Fertil Steril. 2018;110(1):35–44.
Aksglaede L, Juul A, Olsen LW, Sorensen TI. Age at puberty and the emerging obesity epidemic. PLoS One. 2009;4(12):e8450.
Crocker MK, Stern EA, Sedaka NM, Shomaker LB, Brady SM, Ali AH, et al. Sexual dimorphisms in the associations of BMI and body fat with indices of pubertal development in girls and boys. J Clin Endocrinol Metab. 2014;99(8):E1519–29.
Kampmann FB, Thuesen ACB, Hjort L, Olsen SF, Pires SM, Tetens I, et al. Exposure to gestational diabetes is a stronger predictor of Dysmetabolic traits in children than size at birth. J Clin Endocrinol Metab. 2019;104(5):1766–76.
Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456.
Ijas H, Vaarasmaki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months. BJOG. 2015;122(7):994–1000.
Tertti K, Eskola E, Ronnemaa T, Haataja L. Neurodevelopment of two-year-old children exposed to metformin and insulin in gestational diabetes mellitus. J Dev Behav Pediatr. 2015;36(9):752–7.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Monica E. Bianco and Jami Josefson declare that they have no conflict of interest.
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.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Diabetes and Pregnancy
Rights and permissions
About this article
Cite this article
Bianco, M.E., Josefson, J.L. Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr Diab Rep 19, 143 (2019). https://doi.org/10.1007/s11892-019-1267-6
Published:
DOI: https://doi.org/10.1007/s11892-019-1267-6