Download PDF
Am J Perinatol 2016; 33(13): 1273-1281
DOI: 10.1055/s-0036-1586509
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Sex-Specific Associations of Maternal Gestational Glycemia with Hormones in Umbilical Cord Blood at Delivery

Emily Oken
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
2   Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
,
Emma Morton-Eggleston
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
,
Sheryl L. Rifas-Shiman
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
,
Karen M. Switkowski
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
,
Marie-France Hivert
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
3   Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
,
Abby F. Fleisch
4   Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts
,
Christos Mantzoros
5   Department of Medicine, Beth Israel Deaconess Hospital, Boston, Massachusetts
,
Matthew W. Gillman
1   Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts
2   Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

26 February 2016

12 June 2016

Publication Date:
04 August 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Background Few studies have examined sex-specific associations of maternal gestational glycemia with cord blood hormones, which might predict later health.

Methods In 976 women without pre-existing diabetes in the Project Viva cohort, we used linear regression to examine associations of maternal gestational glycemia with cord hormone concentrations, adjusted for maternal characteristics and stratified by infant sex.

Results A total of 6.1% of women had gestational diabetes mellitus (GDM), 8.8% isolated hyperglycemia, 3.2% gestational impaired glucose tolerance, and 81.9% were normoglycemic. In boys, compared with infants of normoglycemic mothers, infants of GDM mothers had higher cord levels of IGF-2 (β 35.55 ng/mL; 95% CI: 2.60, 68.50), IGFBP-3 (111.2 ng/mL; 5.53, 216.8), insulin (4.66 uU/mL; 2.38, 6.95), C-peptide (0.46 ng/mL; 0.25, 0.67), and leptin (3.51 ng/mL; 1.37, 5.64), but lower IGF-1 (−6.71 ng/mL; −12.7, − 0.76, adjusted for IGFBP-3). In girls, GDM offspring had higher cord blood levels of IGF-1 adjusted for IGFBP-3 (12.45 ng/mL; 4.85, 20.04). Boys, but not girls, of mothers with abnormal glucose tolerance but not GDM also had higher levels of some hormones.

Conclusion GDM was associated with growth factors and adipokines in cord blood from boys, but only IGF-1 in girls. These findings suggest sex differences in responses to fetal overnutrition.

Keywords

gestational diabetes mellitus - pregnancy - umbilical cord blood - hormones - insulin-like growth factor (IGF) - leptin - C-peptide

Note

These results were presented in part at the 2015 Diabetes in Pregnancy Study Group of North America (DPSG-NA) meeting.


 

  • References

  • 1 Pedersen J. Diabetes mellitus and pregnancy: present status of the hyperglycaemia—hyperinsulinism theory and the weight of the newborn baby. Postgrad Med J 1971; ;(Suppl): 66-67
    PubMedGoogle Scholar
  • 2 Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?. Am J Obstet Gynecol 2011; 204 (6) 479-487
    CrossrefPubMedGoogle Scholar
  • 3 Catalano PM, Thomas A, Huston-Presley L, Amini SB. Increased fetal adiposity: a very sensitive marker of abnormal in utero development. Am J Obstet Gynecol 2003; 189 (6) 1698-1704
    CrossrefPubMedGoogle Scholar
  • 4 Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre-eclampsia. Clin Endocrinol (Oxf) 2012; 76 (1) 2-11
    CrossrefPubMedGoogle Scholar
  • 5 Qiu C, Vadachkoria S, Meryman L, Frederick IO, Williams MA. Maternal plasma concentrations of IGF-1, IGFBP-1, and C-peptide in early pregnancy and subsequent risk of gestational diabetes mellitus. Am J Obstet Gynecol 2005; 193 (5) 1691-1697
    CrossrefPubMedGoogle Scholar
  • 6 Ballesteros M, Simón I, Vendrell J , et al. Maternal and cord blood adiponectin multimeric forms in gestational diabetes mellitus: a prospective analysis. Diabetes Care 2011; 34 (11) 2418-2423
    CrossrefPubMedGoogle Scholar
  • 7 Luo ZC, Nuyt AM, Delvin E , et al. Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes. J Clin Endocrinol Metab 2012; 97 (5) 1720-1728
    CrossrefPubMedGoogle Scholar
  • 8 Lindsay RS, Westgate JA, Beattie J , et al. Inverse changes in fetal insulin-like growth factor (IGF)-1 and IGF binding protein-1 in association with higher birth weight in maternal diabetes. Clin Endocrinol (Oxf) 2007; 66 (3) 322-328
    CrossrefPubMedGoogle Scholar
  • 9 Regnault N, Gillman MW, Rifas-Shiman SL, Eggleston E, Oken E. Sex-specific associations of gestational glucose tolerance with childhood body composition. Diabetes Care 2013; 36 (10) 3045-3053
    CrossrefPubMedGoogle Scholar
  • 10 Rosa MJ, Just AC, Tamayo Y Ortiz M , et al. Prenatal and postnatal stress and wheeze in Mexican children: Sex-specific differences. Ann Allergy Asthma Immunol 2016; 116 (4) 306-312.e1
    CrossrefPubMedGoogle Scholar
  • 11 Andres A, Hull HR, Shankar K, Casey PH, Cleves MA, Badger TM. Longitudinal body composition of children born to mothers with normal weight, overweight, and obesity. Obesity (Silver Spring) 2015; 23 (6) 1252-1258
    CrossrefPubMedGoogle Scholar
  • 12 Katkhuda R, Peterson ES, Roghair RD, Norris AW, Scholz TD, Segar JL. Sex-specific programming of hypertension in offspring of late-gestation diabetic rats. Pediatr Res 2012; 72 (4) 352-361
    CrossrefPubMedGoogle Scholar
  • 13 Ricart W, López J, Mozas J , et al; Spanish Group for the study of the impact of Carpenter and Coustan GDM thresholds. Maternal glucose tolerance status influences the risk of macrosomia in male but not in female fetuses. J Epidemiol Community Health 2009; 63 (1) 64-68
    CrossrefPubMedGoogle Scholar
  • 14 Sojo L, Garcia-Patterson A, María MA , et al. Are birth weight predictors in diabetic pregnancy the same in boys and girls?. Eur J Obstet Gynecol Reprod Biol 2010; 153 (1) 32-37
    CrossrefPubMedGoogle Scholar
  • 15 HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics. Diabetes 2009; 58 (2) 453-459
    CrossrefPubMedGoogle Scholar
  • 16 Oken E, Baccarelli AA, Gold DR , et al. Cohort profile: project viva. Int J Epidemiol 2015; 44 (1) 37-48
    CrossrefPubMedGoogle Scholar
  • 17 American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004; 27 (Suppl. 01) S88-S90
    CrossrefPubMedGoogle Scholar
  • 18 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) 215-220
    CrossrefPubMedGoogle Scholar
  • 19 Parker M, Rifas-Shiman SL, Belfort MB , et al. Gestational glucose tolerance and cord blood leptin levels predict slower weight gain in early infancy. J Pediatr 2011; 158 (2) 227-233
    CrossrefPubMedGoogle Scholar
  • 20 Mantzoros CS, Rifas-Shiman SL, Williams CJ, Fargnoli JL, Kelesidis T, Gillman MW. Cord blood leptin and adiponectin as predictors of adiposity in children at 3 years of age: a prospective cohort study. Pediatrics 2009; 123 (2) 682-689
    CrossrefPubMedGoogle Scholar
  • 21 Provenzano AM, Rifas-Shiman SL, Herring SJ, Rich-Edwards JW, Oken E. Associations of maternal material hardships during childhood and adulthood with prepregnancy weight, gestational weight gain, and postpartum weight retention. J Womens Health (Larchmt) 2015; 24 (7) 563-571
    CrossrefPubMedGoogle Scholar
  • 22 Walter JR, Perng W, Kleinman KP, Rifas-Shiman SL, Rich-Edwards JW, Oken E. Associations of trimester-specific gestational weight gain with maternal adiposity and systolic blood pressure at 3 and 7 years postpartum. Am J Obstet Gynecol 2015; 212 (4) 499.e1-499.e12
    CrossrefPubMedGoogle Scholar
  • 23 Kleinman KP, Oken E, Radesky JS, Rich-Edwards JW, Peterson KE, Gillman MW. How should gestational weight gain be assessed? A comparison of existing methods and a novel method, area under the weight gain curve. Int J Epidemiol 2007; 36 (6) 1275-1282
    CrossrefPubMedGoogle Scholar
  • 24 Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 2003; 3 (1) 6
    CrossrefPubMedGoogle Scholar
  • 25 VanderWeele TJ, Mumford SL, Schisterman EF. Conditioning on intermediates in perinatal epidemiology. Epidemiology 2012; 23 (1) 1-9
    PubMedGoogle Scholar
  • 26 Tu YK, West R, Ellison GT, Gilthorpe MS. Why evidence for the fetal origins of adult disease might be a statistical artifact: the “reversal paradox” for the relation between birth weight and blood pressure in later life. Am J Epidemiol 2005; 161 (1) 27-32
    CrossrefPubMedGoogle Scholar
  • 27 Tam WH, Ma RC, Yang X , et al. Glucose intolerance and cardiometabolic risk in children exposed to maternal gestational diabetes mellitus in utero. Pediatrics 2008; 122 (6) 1229-1234
    CrossrefPubMedGoogle Scholar
  • 28 Tam WH, Ma RC, Yang X , 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) 1382-1384
    CrossrefPubMedGoogle Scholar
  • 29 Silverman BL, Rizzo TA, Cho NH, Metzger BE ; The Northwestern University Diabetes in Pregnancy Center. Long-term effects of the intrauterine environment. Diabetes Care 1998; 21 (Suppl. 02) B142-B149
    PubMedGoogle Scholar
  • 30 Chao W, D'Amore PA. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev 2008; 19 (2) 111-120
    CrossrefPubMedGoogle Scholar
  • 31 Denley A, Bonython ER, Booker GW , et al. Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol 2004; 18 (10) 2502-2512
    CrossrefPubMedGoogle Scholar
  • 32 Denley A, Wallace JC, Cosgrove LJ, Forbes BE. The insulin receptor isoform exon 11- (IR-A) in cancer and other diseases: a review. Horm Metab Res 2003; 35 (11–12) 778-785
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Yan-Jun L, Tsushima T, Minei S , et al. Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBP-1, -2 and -3) in diabetic pregnancy: relationship to macrosomia. Endocr J 1996; 43 (2) 221-231
    CrossrefPubMedGoogle Scholar
  • 34 Ostlund E, Bang P, Hagenäs L, Fried G. Insulin-like growth factor I in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation. Hum Reprod 1997; 12 (4) 840-844
    CrossrefPubMedGoogle Scholar
  • 35 Lepercq J, Challier JC, Guerre-Millo M, Cauzac M, Vidal H, Hauguel-de Mouzon S. Prenatal leptin production: evidence that fetal adipose tissue produces leptin. J Clin Endocrinol Metab 2001; 86 (6) 2409-2413
    CrossrefPubMedGoogle Scholar
  • 36 Sivan E, Mazaki-Tovi S, Pariente C , et al. Adiponectin in human cord blood: relation to fetal birth weight and gender. J Clin Endocrinol Metab 2003; 88 (12) 5656-5660
    CrossrefPubMedGoogle Scholar
  • 37 Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304 (5667) 108-110
    CrossrefPubMedGoogle Scholar
  • 38 Vickers MH. Developmental programming and adult obesity: the role of leptin. Curr Opin Endocrinol Diabetes Obes 2007; 14 (1) 17-22
    CrossrefPubMedGoogle Scholar
  • 39 Plagemann A, Heidrich I, Götz F, Rohde W, Dörner G. Lifelong enhanced diabetes susceptibility and obesity after temporary intrahypothalamic hyperinsulinism during brain organization. Exp Clin Endocrinol 1992; 99 (2) 91-95
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nat Clin Pract Endocrinol Metab 2007; 3 (6) 479-488
    CrossrefPubMedGoogle Scholar
  • 41 Landon MB, Rice MM, Varner MW , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Mild gestational diabetes mellitus and long-term child health. Diabetes Care 2015; 38 (3) 445-452
    CrossrefPubMedGoogle Scholar
  • 42 Geary MP, Pringle PJ, Rodeck CH, Kingdom JC, Hindmarsh PC. Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. J Clin Endocrinol Metab 2003; 88 (8) 3708-3714
    CrossrefPubMedGoogle Scholar
  • 43 Wiley AS, Lubree HG, Joshi SM , et al. Cord IGF-I concentrations in Indian newborns: associations with neonatal body composition and maternal determinants. Pediatr Obes 2016; 11 (2) 151-157
    CrossrefPubMedGoogle Scholar
  • 44 Friedrich N, Wolthers OD, Arafat AM , et al. Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio measured by new automated chemiluminescence assays. J Clin Endocrinol Metab 2014; 99 (5) 1675-1686
    CrossrefPubMedGoogle Scholar
  • 45 Xiao L, Zhao JP, Nuyt AM, Fraser WD, Luo ZC. Female fetus is associated with greater maternal insulin resistance in pregnancy. Diabet Med 2014; 31 (12) 1696-1701
    CrossrefPubMedGoogle Scholar
  • 46 Persson M, Fadl H. Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational and gestational diabetes—a population-based study. Diabet Med 2014; 31 (9) 1047-1054
    CrossrefPubMedGoogle Scholar
  • 47 Kruse MS, Vega MC, Rey M, Coirini H. Sex differences in LXR expression in normal offspring and in rats born to diabetic dams. J Endocrinol 2014; 222 (1) 53-60
    CrossrefPubMedGoogle Scholar
  • 48 Dearden L, Balthasar N. Sexual dimorphism in offspring glucose-sensitive hypothalamic gene expression and physiological responses to maternal high-fat diet feeding. Endocrinology 2014; 155 (6) 2144-2154
    CrossrefPubMedGoogle Scholar
  • 49 O'Tierney-Ginn P, Presley L, Minium J, Hauguel deMouzon S, Catalano PM. Sex-specific effects of maternal anthropometrics on body composition at birth. Am J Obstet Gynecol 2014; 211 (3) 292.e1-292.e9
    CrossrefPubMedGoogle Scholar
  • 50 Bahado-Singh RO, Mele L, Landon MB , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-fetal Medicine Units Network. Fetal male gender and the benefits of treatment of mild gestational diabetes mellitus. Am J Obstet Gynecol 2012; 206 (5) 422.e1-422.e5
    CrossrefPubMedGoogle Scholar
  • 51 Bloomfield FH, Spiroski AM, Harding JE. Fetal growth factors and fetal nutrition. Semin Fetal Neonatal Med 2013;
    PubMedGoogle Scholar
  • 52 Rutanen EM. Insulin-like growth factors in obstetrics. Curr Opin Obstet Gynecol 2000; 12 (3) 163-168
    CrossrefPubMedGoogle Scholar
  • 53 Ong K, Kratzsch J, Kiess W, Costello M, Scott C, Dunger D ; The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. J Clin Endocrinol Metab 2000; 85 (11) 4266-4269
    PubMedGoogle Scholar
  • 54 Kadakia R, Josefson J. The relationship of insulin-like growth factor 2 to fetal growth and adiposity. Horm Res Paediatr 2016; 85 (2) 75-82
    CrossrefPubMedGoogle Scholar
  • 55 St-Pierre J, Hivert MF, Perron P , et al. IGF2 DNA methylation is a modulator of newborn's fetal growth and development. Epigenetics 2012; 7 (10) 1125-1132
    CrossrefPubMedGoogle Scholar
  • 56 Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously in the womb. Am J Hum Biol 2010; 22 (3) 330-335
    CrossrefPubMedGoogle Scholar