Background To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring. Methods/Principal Findings We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations. Conclusions This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
References
[1]
Carstensen B, Kristensen JK, Ottosen P, Borch-Johnsen K (2008) The Danish National Diabetes Register: trends in incidence, prevalence and mortality. Diabetologia 51: 2187–2196.
[2]
Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053.
[3]
Hawdon JM (2011) Babies born after diabetes in pregnancy: what are the short- and long-term risks and how can we minimise them? Best Pract Res Clin Obstet Gynaecol 25: 91–104.
[4]
Schwartz R, Teramo KA (2000) Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol 24: 120–135.
[5]
Bunt JC, Tataranni PA, Salbe AD (2005) Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. J Clin Endocrinol Metab 90: 3225–3229.
[6]
Krishnaveni GV, Veena SR, Hill JC, Kehoe S, Karat SC, et al. (2010) Intrauterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care 33: 402–404.
[7]
Tam WH, Ma RC, Yang X, Li AM, Ko GT, et al. (2010) Glucose Intolerance and Cardiometabolic Risk in adolescent exposed to maternal Gestational Diabetes–a 15-year follow-up study. Diabetes Care.
[8]
Schwartz R (1990) Hyperinsulinemia and macrosomia. N Engl J Med 323: 340–342.
[9]
Mellemkjaer L, Olsen ML, Sorensen HT, Thulstrup AM, Olsen J, et al. (2003) Birth weight and risk of early-onset breast cancer (Denmark). Cancer Causes Control 14: 61–64.
[10]
Ross JA (2006) High birthweight and cancer: evidence and implications. Cancer Epidemiol Biomarkers Prev 15: 1–2.
[11]
Caughey RW, Michels KB (2009) Birth weight and childhood leukemia: a meta-analysis and review of the current evidence. Int J Cancer 124: 2658–2670.
[12]
Xue F, Michels KB (2007) Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. Lancet Oncol 8: 1088–1100.
[13]
Song Y, Niu T, Manson JE, Kwiatkowski DJ, Liu S (2004) Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies. Am J Hum Genet 74: 208–222.
[14]
Knudsen LB, Olsen J (1998) The Danish Medical Birth Registry. Dan Med Bull 45: 320–323.
[15]
Pedersen CB, Gotzsche H, Moller JO, Mortensen PB (2006) The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 53: 441–449.
[16]
Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH (1999) The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 46: 263–268.
[17]
Carstensen B, Kristensen JK, Marcussen MM, Borch-Johnsen K (2011) The National Diabetes Register. Scand J Public Health 39: 58–61.
[18]
Damm P, Molsted-Pedersen L (1989) Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women. Am J Obstet Gynecol 161: 1163–1167.
[19]
Aberg A, Westbom L, Kallen B (2001) Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev 61: 85–95.
[20]
Freinkel N (1980) Banting Lecture 1980. Of pregnancy and progeny. Diabetes 29: 1023–1035.
[21]
Pedersen J?rgen (1977) The Pregnant Diabetic and Her Newborn. Baltimore: The Williams & Wilkins Company. 195 p.
[22]
Reece EA, Homko CJ (2007) Prepregnancy care and the prevention of fetal malformations in the pregnancy complicated by diabetes. Clin Obstet Gynecol 50: 990–997.
[23]
Reece EA (2012) Diabetes-induced birth defects: what do we know? What can we do? Curr Diab Rep 12: 24–32.
[24]
Aberg A, Westbom L (2001) Association between maternal pre-existing or gestational diabetes and health problems in children. Acta Paediatr 90: 746–750.
[25]
Westbom L, Aberg A, Kallen B (2002) Childhood malignancy and maternal diabetes or other auto-immune disease during pregnancy. Br J Cancer 86: 1078–1080.
[26]
Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, et al. (2009) Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab 94: 2464–2470.
[27]
Moore TR (2010) Fetal exposure to gestational diabetes contributes to subsequent adult metabolic syndrome. Am J Obstet Gynecol 202: 643–649.
[28]
Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, et al. (2008) High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31: 340–346.
[29]
Wright CS, Rifas-Shiman SL, Rich-Edwards JW, Taveras EM, Gillman MW, et al (2009) Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure. Am J Hypertens 22: 215–220.
[30]
Chen YW, Chenier I, Tran S, Scotcher M, Chang SY, et al. (2010) Maternal diabetes programs hypertension and kidney injury in offspring. Pediatr Nephrol 25: 1319–1329.
[31]
Buchanan TA (2004) Intermediary Metabolism During Pregnancy: Implications for Diabetes Mellitus. In: Derek LeRoith, Jerrold M, Simeon ITaylor, editors. Diabetes Mellitus: A Fundamental and Clinical Text. pp. 1237–1250.
[32]
Simeoni U, Barker DJ (2009) Offspring of diabetic pregnancy: long-term outcomes. Semin Fetal Neonatal Med 14: 119–124.
[33]
Silverman BL, Rizzo TA, Cho NH, Metzger BE (1998) Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. Diabetes Care 21: Suppl 2B142–B149.
[34]
Glumer C, Jorgensen T, Borch-Johnsen K (2003) Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diabetes Care 26: 2335–2340.