PEDIATRICS Vol. 122 No. 6 December 2008, pp. 1229-1234 (doi:10.1542/peds.2008-0158)
ARTICLE |
Glucose Intolerance and Cardiometabolic Risk in Children Exposed to Maternal Gestational Diabetes Mellitus in Utero
a Departments of Obstetrics and Gynaecology
b Medicine and Therapeutics
c Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong Special Administrative Region
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. The goal was to examine the carbohydrate tolerance and cardiometabolic risk among children exposed to maternal gestational diabetes mellitus in utero.
METHODS. In this study, 164 Chinese children whose mothers had participated in a previous study on the screening and diagnosis of gestational diabetes mellitus (63 had gestational diabetes mellitus and 101 had normal glucose tolerance during the index pregnancies) underwent follow-up evaluations at a median age of 8 years (range: 7–10 years). Children's weight, height, hip and waist circumferences, and blood pressure were measured, and weight-adjusted oral glucose tolerance tests were performed.
RESULTS. Six children (3.7%) demonstrated impaired glucose regulation or diabetes mellitus at the follow-up evaluation. Children exposed to maternal gestational diabetes mellitus had significantly higher systolic (94 ± 1.2 vs 88 ± 0.9 mmHg) and diastolic (62 ± 0.8 vs 57 ± 0.6 mmHg) blood pressure values and lower high-density lipoprotein cholesterol (1.58 ± 0.04 vs 1.71 ± 0.03 mmol/L) levels, after adjustment for age and gender. A high (
90th percentile) umbilical cord insulin level at birth was associated with abnormal glucose tolerance in the offspring.
CONCLUSIONS. Maternal gestational diabetes mellitus increases the offspring's cardiometabolic risk, and in utero hyperinsulinemia is an independent predictor of abnormal glucose tolerance in childhood.
Key Words: gestational diabetes • children • blood pressure • cholesterol
Abbreviations: DM—diabetes mellitus • BP—blood pressure • OGTT—oral glucose tolerance test • NGT—normal glucose tolerance • PG—plasma glucose • GDM—gestational diabetes mellitus • IGR—impaired glucose regulation • AGT—abnormal glucose tolerance • HDL-C—high-density lipoprotein cholesterol • IGT—impaired glucose tolerance
Data indicate a rapid increase in the incidence of type 2 diabetes mellitus (DM) among children and adolescents worldwide.1,2 Among Japanese children, a 30-fold increase in the incidence of type 2 DM was observed over 2 decades, and type 2 DM is now 7 times more common than type 1 DM.3 Currently, type 2 DM represents up to 45% of all new cases of childhood DM in the United States.4 Childhood metabolic syndrome is also much more common than previously reported; its prevalence is highest in obese children, ranging between 40% and 50%, depending on the severity of obesity.5–8 Although obesity is an important factor in insulin resistance and type 2 DM, the prevalence of metabolic syndrome in childhood and adolescence will continue to increase as the rate of obesity increases.9–12
Barker and co-workers13–15 suggested that in utero programming during fetal growth restriction increases the risks of insulin resistance, type 2 DM, hypertension, and heart disease in adulthood. There are also studies that suggested that maternal gestational diabetes (GD) increases the DM susceptibility of the offspring, although the studies were limited by their retrospective study design and the absence of a control group for comparison.16–20 In the offspring of mothers with GD, the risk of metabolic syndrome in large-for-gestational age infants was found to be increased threefold at the age of 7 and fourfold at the age of 9, compared with children who were of appropriate size for gestational age at birth.21 The study also observed that obesity at 11 years of age was a strong predictor of insulin resistance.21
Although intrauterine exposure to hyperglycemia resulting from maternal DM is a known risk factor for type 2 DM developing in the offspring, its effect on childhood cardiometabolic risk factors, namely, obesity, lipid profile, insulin resistance, and blood pressure (BP), has not been studied systematically, especially in Chinese populations. In this prospective study, we recalled women recruited previously for a study on GD, to study their offspring's cardiometabolic status at a median age of 8 years.22
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
Subjects were children from a cohort of 1032 women who were recruited consecutively between 1992 and 1994 at the Prince of Wales Hospital for a study to define optimal screening and diagnostic criteria for GD in Chinese populations.23 The Prince of Wales Hospital is a tertiary referral teaching unit, and it performed 8000 deliveries per year at that time.
In the original study, all mothers who had no previous history of DM underwent a 75-g oral glucose tolerance test (OGTT) administered between 24 and 28 weeks of gestation. Of those 1032 mothers, 942 had complete data collection during their index pregnancy and were eligible for the present study. On the basis of their 75-g OGTT results, the mothers were classified into normal glucose tolerance (NGT) (ie, fasting plasma glucose [PG] level of <7.0 mmol/L and 2-hour PG level of <7.8 mmol/L; n = 808), gestational impaired glucose tolerance (IGT) (ie, fasting PG level of <7.0 mmol/L and 2-hour PG level of 7.8–11.1 mmol/L; n = 127), and GDM (ie, fasting PG level of 7.0 mmol/L and/or 2-hour PG level of 11.1 mmol/L; n = 7) groups according to the 1999 World Health Organization criteria, with the GD group including both gestational IGT and GDM.24 C-peptide and insulin levels were measured in umbilical cord blood collected at the time of delivery.
All 134 mother-child pairs from the mothers with GD and 268 pairs from the mothers with NGT, matched with respect to maternal age, were invited for a follow-up study in 2002.25 Maternal metabolic status at the time of follow-up evaluation was reported earlier.25
Children whose mothers consented to the study underwent an OGTT (at a glucose load of 1.75 g/kg body weight) after an overnight fast of 8 hours. Venous blood samples were obtained for PG and insulin assays, before (0 minute) and 15, 30, 60, and 120 minutes after the glucose load. Body weight, height, and hip and waist circumferences were measured with the children in light clothing. BP was measured in each child's nondominant arm by using a Dinamap PRO-100 device (Critikon, Milwaukee, WI) with pediatric cuffs of appropriate size that covered at least two thirds of the arm circumference. Measurements were performed thrice, at 1-minute intervals, after 5 minutes of rest. The mean BP reading was used for analysis.
The latest American Diabetes Association diagnostic criteria were used to define glycemic status, that is, DM was defined as a fasting PG level of 7.0 mmol/L or a 2-hour PG level of 11.1 mmol/L; IGT was defined as a fasting PG level of <7.0 mmol/L and a 2-hour PG level of 7.8 and <11.1 mmol/L; and impaired fasting PG level was defined as a fasting PG level of 5.6 mmol/L and <7.0 mmol/L.26 Impaired fasting PG level and IGT were classified as impaired glucose regulation (IGR), according to World Health Organization 1999 recommendations.24 Abnormal glucose tolerance (AGT) was defined as IGR (impaired fasting PG level and/or IGT) and/or DM. Plasma triglyceride and high-density lipoprotein cholesterol (HDL-C) levels were measured with enzymatic methods with a DP Modular Analytics system (Roche Diagnostics, Indianapolis, IN), whereas PG levels were measured with the hexokinase method.
Insulin sensitivity was calculated by using the homeostasis model assessment insulin resistance index and the Matsuda insulin sensitivity index, with the formula 10000/
(fasting PG level x fasting plasma insulin level) x (mean PG level x mean insulin level), whereas the pancreatic β-cell capacity was determined as the area under the plasma insulin level-time curve from 0 minutes to 120 minutes divided by the area under the PG level-time curve from 0 minutes to 120 minutes in the OGTT.27,28 The study was approved by the Chinese University of Hong Kong Clinical Research Ethics Committee. Written informed consent was obtained from all participants.
Statistical Analyses
All data are expressed as median and range, mean ± SEM, or proportion. Between-group differences were compared by using Student's t tests, 
2 tests, or Fisher's exact tests as appropriate. Multivariate logistic regression analysis was used to obtain adjusted odds ratios with 95% confidence intervals, with forced entry of high umbilical cord insulin level, GD status during the index pregnancy, macrosomia at birth, childhood obesity (waist circumference of 85th percentile), and mother's current glycemic status as independent variables. A stepwise algorithm (P = .10 for entry and P = .05 for removal) was used to select other variables. Model fit was assessed by using the Hosmer-Lemeshow goodness-of-fit test. A P value of <.05 for 2-tailed statistical tests was used to indicate significance. Statistical analysis was performed by using SPSS 13.0 (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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As we reported previously, the response rate for women selected from the original cohort was 50%, but maternal characteristics such as maternal age, BMI, parity, and rate of family history of DM were not significantly different between the responders and nonresponders.25 A total of 164 children (101 mothers with NGT and 63 mothers with GD, of whom 7 were treated with diet during the index pregnancy, according to our previous treatment criteria) completed both the physical examination and the biochemical blood testing. There were no differences in clinical parameters during the index pregnancy between the mothers with NGT and the mothers with GD except for the fasting and 2-hour PG levels. A larger proportion of infants of mothers with GD were delivered through cesarean section (33.3% vs 9.9%; P < .001) (Table 1). Children of mothers with GD were slightly younger than those of mothers with NGT at the follow-up evaluation (7.7 vs 8.4 years; P < .001).
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Children of mothers with GD were found to have significantly higher systolic (94 ± 1.2 vs 88 ± 0.9 mmHg; P < .001) and diastolic (62 ± 0.8 vs 57 ± 0.6 mmHg; P < .001) BP values and lower HDL-C levels (1.58 ± 0.04 vs 1.71 ± 0.03 mmol/L; P = .019), compared with children of mothers with NGT, after adjustment for age and gender (Table 1). A total of 6 children had abnormal OGTT results (IGR for 5 children and DM for 1 child). There were no significant differences in AGT prevalence, insulin resistance, β-cell function, BMI, or waist circumference between the children of mothers with GD and mothers with NGT. Mothers with GD had significantly higher rates of IGR and DM at the follow-up evaluation.25
A high umbilical cord insulin level (90th percentile) was found to be an independent risk factor for AGT (odds ratio: 8.9; 95% confidence interval: 1.08–72.7), whereas macrosomia (birth weight of 4 kg), child's waist circumference of 85th percentile, maternal GD, and mother's current glycemic status were not shown to be risk factors (Table 2). Figure 1 shows the receiver operating characteristic curve for cord insulin level prediction of childhood AGT; the sensitivity and specificity were 80% and 83%, respectively, at the point of inflection, which represents a cutoff value for cord insulin levels of 92 pmol/L.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In this first prospective controlled study examining the effects of maternal GD on children's cardiometabolic risks in a Chinese population, maternal GD was associated with significantly increased BP and decreased HDL-C levels in the children at a median age of 8 years. This result is similar to the findings of Bunt et al,29 who showed higher systolic BP values and lower HDL-C levels for children born during a pregnancy with DM than for those born before the mothers developed DM. Recently, data from the Fels Longitudinal Study suggested a link between the child's BP as early as 5 years of age and the development of hypertension and metabolic syndrome in adulthood.30 This may indicate a link between maternal GD and long-term risk of hypertension and metabolic syndrome in adulthood. Although we did not show a higher prevalence of AGT among the offspring of mothers with GD, a high umbilical cord insulin level was found to be an independent predictor of childhood AGT. The rate of AGT in our cohort of children was similar to that reported for obese children from mainland China.31 A previous study of children of mothers with DM also showed rates of AGT similar to those for normal control subjects at <10 years age, but there was a 20% increase in the prevalence between 10 and 16 years of age.32
Excessive in utero insulin secretion was an independent predictor of both obesity and AGT in childhood and adolescence in previous studies.32–34 This might also explain why children born large for gestational age to mothers with GD are at risk of insulin resistance and metabolic syndrome in childhood.21 It implies that in utero hyperinsulinemia, which reflects prenatal glycemic control, has a long-term effect on the development of DM in the offspring. In our previous study of the mothers in this cohort, we reported that the umbilical cord insulin level was higher among the mothers with GD who had not received treatment.35 Although the International Diabetes Federation does not recommend a diagnostic category for metabolic syndrome in children <10 years of age, children with a waist circumference of 90th percentile are more likely to have multiple risk factors for cardiovascular disease and to be at risk of future metabolic syndrome.36 It has been recommended that childhood obesity between 6 and 10 years of age should receive attention and additional measurements should be made if there is a family history of metabolic syndrome.36,37 Abdominal obesity and hyperinsulinemia were the 2 characteristic features of metabolic syndrome in obese Japanese children, whereas waist circumference was found to be a predictor of insulin resistance syndrome in children and adolescents.38,39 Metabolic syndrome has been reported to occur in up to 18% of overweight and 38% of obese Chinese children.40 Therefore, it is important to identify children at risk of developing metabolic syndrome, to prevent them from experiencing progression to type 2 DM and cardiovascular disease in later life, given that the presence of maternal GD is a risk factor for childhood obesity and dysglycemia.41,42
In this follow-up study, we observed that a maternal history of GD increased certain cardiometabolic risk factors during childhood. This may have a role in the future risk of developing type 2 DM and metabolic syndrome. Additional study is required to investigate the longer-term risks in this cohort as the children enter adolescence. Children of mothers with GD may benefit from regular screening for metabolic derangement, as well as education on lifestyle modification.
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ACKNOWLEDGMENTS |
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We thank all of the mothers and children for participating in this study, and we thank our research nurses, Delanda Wong, Yee-Mui Lee, and Cherry Chiu, for their dedication and professionalism in conducting this survey.
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FOOTNOTES |
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Accepted Mar 12, 2008.
Address correspondence to Wing Hung Tam, MBChB, Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, First Floor, E Block, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR. E-mail: tamwh{at}cuhk.edu.hk
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Both maternal diabetes mellitus and gestational diabetes increase the offspring's type 2 diabetes mellitus susceptibility. The risk of metabolic syndrome is increased for children born to mothers with gestational diabetes or born large for gestational age.
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| What This Study Adds Children exposed to maternal gestational diabetes had increased blood pressure and decreased HDL-C levels at a median age of 8 years. In utero hyperinsulinemia was found to be associated with carbohydrate intolerance in childhood.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Aanstoot H-J, Anderson BJ, Daneman D, et al. Diabetes in children: epidemiology. Pediatr Diabetes. 2007;8 (suppl 8):10 –18[CrossRef]
2. Kaufman FR. Type 2 diabetes in children and youth. Endocrinol Metab Clin North Am. 2005;34 (3):659 –676[CrossRef][Web of Science][Medline]
3. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth.
Diabetes Care. 1999;22
(2):345
–354
4. Silverstein JH, Rosenbloom AL. Type 2 diabetes in children. Curr Diab Rep. 2001;1 (1):19 –27[Medline]
5. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents.
N Engl J Med. 2004;350
(23):2362
–2374
6. Csábi G, Török K, Jeges S, Molnár D. Presence of metabolic cardiovascular syndrome in obese children. Eur J Pediatr. 2000;159 (1–2):91 –94[CrossRef][Web of Science][Medline]
7. Cruz ML, Weigensberg MJ, Huang TT, Ball G, Shaibi GQ, Goran MI. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity.
J Clin Endocrinol Metab. 2004;89
(1):108
–113
8. Eisenmann JC. Secular trends in variables associated with the metabolic syndrome of North American children and adolescents: a review and synthesis. Am J Hum Biol. 2003;15 (6):786 –794[CrossRef][Web of Science][Medline]
9. Caprio S, Bronson M, Sherwin RS, Rife F, Tamborlane WV. Co-existence of severe insulin resistance and hyperinsulinaemia in pre-adolescent obese children. Diabetologia. 1996;39 (12):1489 –1497[CrossRef][Web of Science][Medline]
10. Caprio S, Tamborlane WV. Metabolic impact of obesity in childhood. Endocrinol Metab Clin North Am. 1999;28 (4):731 –747[CrossRef][Web of Science][Medline]
11. Caprio S. Insulin resistance in childhood obesity. J Pediatr Endocrinol Metab. 2002;15 (suppl 1):487 –492[Web of Science][Medline]
12. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the Third National Health and Nutrition Examination Survey, 1988–1994.
Arch Pediatr Adolesc Med. 2003;157
(8):821
–827
13. Barker DJ, Barker DJP. The origins of the developmental origins theory. J Intern Med. 2007;261 (5):412 –417[CrossRef][Medline]
14. Barker DJ, Barker DJP. The developmental origins of insulin resistance. Horm Res. 2005;64 (suppl 3):2 –7[CrossRef][Web of Science][Medline]
15. Barker DJ, Bagby SP, Hanson MA, Barker DJP, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006;2 (12):700 –707[CrossRef][Web of Science][Medline]
16. Dörner G, Plagemann A, Reinagel H. Familial diabetes aggregation in type I diabetics: gestational diabetes an apparent risk factor for increased diabetes susceptibility in the offspring. Exp Clin Endocrinol. 1987;89 (1):84 –90[Web of Science][Medline]
17. Harder T, Plagemann A. A role for gestational diabetes in the excess maternal transmission of type 2 diabetes? Diabetes Care. 2000;23 (3):431 –432[CrossRef][Web of Science][Medline]
18. Persson B, Gentz J, Moller E. Follow-up of children of insulin dependent (type I) and gestational diabetic mothers: growth pattern, glucose tolerance, insulin response, and HLA types. Acta Paediatr Scand. 1984;73 (6):778 –784[Web of Science][Medline]
19. Van Assche FA, Aerts L, Holemans K. The effects of maternal diabetes on the offspring. Baillieres Clin Obstet Gynaecol. 1991;5 (2):485 –492[CrossRef][Web of Science][Medline]
20. Plagemann A, Harder T, Kohlhoff R, Rohde W, Dörner G. Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia. 1997;40 (9):1094 –1100[CrossRef][Web of Science][Medline]
21. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115 (3). Available at: www.pediatrics.org/cgi/content/full/115/3/e290
22. Fung H, Wong S, Rogers M. The influence of glucose tolerance tests on subsequent carbohydrate metabolism in pregnancy. Acta Obstet Gynecol Scand. 1996;75 (4):347 –351[CrossRef][Web of Science][Medline]
23. Tam WH, Rogers MS, Yip SK, Lau TK, Leung TY. Which screening test is the best for gestational impaired glucose tolerance and gestational diabetes mellitus? Diabetes Care. 2000;23 (9):1432[Web of Science][Medline]
24. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation, Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, Switzerland: World Health Organization; 1999
25. Tam WH, Yang XL, Chan JC, et al. Progression to impaired glucose regulation, diabetes and metabolic syndrome in Chinese women with a past history of gestational diabetes. Diabetes Metab Res Rev. 2007;23 (6):485 –489[CrossRef][Web of Science][Medline]
26. American Diabetes Association. Diagnosis and classification of diabetes mellitus.
Diabetes Care. 2006;29
(suppl 1):S43
–S48
27. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.
Diabetes Care. 1999;22
(9):1462
–1470
28. Stumvoll M, Mitrakou A, Pimenta W, et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care. 2000;23 (3):295 –301[Abstract]
29. Bunt JC, Tataranni PA, Salbe AD. Intrauterine exposure to diabetes is a determinant of hemoglobin A1c and systolic blood pressure in Pima Indian children.
J Clin Endocrinol Metab. 2005;90
(6):3225
–3229
30. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life.
Pediatrics. 2007;119
(2):237
–246
31. Fu JF, Liang L, Zou CC, et al. Prevalence of the metabolic syndrome in Zhejiang Chinese obese children and adolescents and the effect of metformin combined with lifestyle intervention. Int J Obes (Lond). 2007;31 (1):15 –22[CrossRef][Medline]
32. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers: relationship to fetal hyperinsulinism. Diabetes Care. 1995;18 (5):611 –617[Abstract]
33. 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 –B149[Web of Science][Medline]
34. Metzger BE, Silverman BL, Freinkel N, Dooley SL, Ogata ES, Green OC. Amniotic fluid insulin concentration as a predictor of obesity.
Arch Dis Child. 1990;65
(10 spec no):1050
–1052
35. Roach VJ, Fung H, Cockram CS, Lau TK, Rogers MS. Evaluation of glucose intolerance in pregnancy using biochemical markers of fetal hyperinsulinemia. Gynecol Obstet Invest. 1998;45 (3):174 –176[CrossRef][Web of Science][Medline]
36. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet. 2007;369 (9579):2059 –2061[CrossRef][Web of Science][Medline]
37. Zimmet P, Alberti KGMM, Kaufman F, et al. The metabolic syndrome in children and adolescents: an IDF consensus report. Pediatr Diabetes. 2007;8 (5):299 –306[CrossRef][Web of Science][Medline]
38. Yoshinaga M, Tanaka S, Shimago A, et al. Metabolic syndrome in overweight and obese Japanese children. Obes Res. 2005;13 (7):1135 –1140[CrossRef][Web of Science][Medline]
39. Hirschler V, Aranda C, Calcagno Mde L, Maccalini G, Jadzinsky M. Can waist circumference identify children with the metabolic syndrome?
Arch Pediatr Adolesc Med. 2005;159
(8):740
–744
40. Li YP, Yang XG, Zhai FY, et al. Disease risks of childhood obesity in China. Biomed Environ Sci. 2005;18 (6):401 –410[Web of Science][Medline]
41. Petitt DJ, Bennett PH, Knowler WC, Baird HR, Aleck KA. Gestational diabetes mellitus and impaired glucose tolerance during pregnancy: long-term effects on obesity and glucose tolerance in the offspring. Diabetes. 1985;34 (suppl 2):119 –122
42. 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[Abstract]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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