Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Gestational diabetes mellitus

Nature Reviews Disease Primers volume 5, Article number: 47 (2019) Cite this article

Subjects

Abstract

Hyperglycaemia that develops during pregnancy and resolves after birth has been recognized for over 50 years, but uniform worldwide consensus is lacking about threshold hyperglycaemic levels that merit a diagnosis of ‘gestational diabetes mellitus’ (GDM) and thus treatment during pregnancy. GDM is currently the most common medical complication of pregnancy, and prevalence of undiagnosed hyperglycaemia and even overt diabetes in young women is increasing. Maternal overweight and obesity, later age at childbearing, previous history of GDM, family history of type 2 diabetes mellitus and ethnicity are major GDM risk factors. Diagnosis is usually performed using an oral glucose tolerance test (OGTT), although a non-fasting, glucose challenge test (GCT) is used in some parts of the world to screen women for those requiring a full OGTT. Dietary modification and increased physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is used when normoglycaemia is not achieved. Oral hypoglycaemic agents, principally metformin and glibenclamide (glyburide), are also used in some countries. Treatment improves immediate pregnancy outcomes, reducing excess fetal growth and adiposity and pregnancy-related hypertensive disorders. GDM increases the risk of long-term complications, including obesity, impaired glucose metabolism and cardiovascular disease, in both the mother and infant. Optimal management of mother and infant during long-term follow-up remains challenging, with very limited implementation of preventive strategies in most parts of the world.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Global prevalence of GDM in 2005–2018.
Fig. 2: Country-specific prevalence of GDM according to different diagnostic criteria.
Fig. 3: Pathophysiology of GDM.
Fig. 4: Pregnancy as a metabolic stress test for future metabolic disorders.
Fig. 5: Changes in insulin sensitivity during pregnancy in normoglycaemic women and women with GDM.
Fig. 6: Insulin sensitivity–secretion relationships in normoglycaemic women and women with GDM.
Fig. 7: Changes in insulin signalling in normoglycaemic and GDM pregnancies.
Fig. 8: Pathophysiology of fetal phenotype in GDM.
Fig. 9: Application of the DOHAD hypothesis to GDM.

Similar content being viewed by others

References

  1. Carrington, E. R., Shuman, C. R. & Reardon, H. S. Evaluation of the prediabetic state during pregnancy. Obstet. Gynecol. 9, 664–669 (1957).

    Article  CAS  PubMed  Google Scholar 

  2. O’Sullivan, J. B. Gestational diabetes. Unsuspected, asymptomatic diabetes in pregnancy. N. Engl. J. Med. 264, 1082–1085 (1961).

    Article  PubMed  Google Scholar 

  3. O’Sullivan, J. B. & Mahan, C. M. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 13, 278–285 (1964).

    PubMed  Google Scholar 

  4. Hadden, D. R. Prediabetes and the big baby. Diabet Med. 25, 1–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Metzger, B. E. & Coustan, D. R. Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 21 (Suppl. 2), B161–B167 (1998).

    PubMed  Google Scholar 

  6. Menke, A., Casagrande, S. & Cowie, C. C. Contributions of A1c, fasting plasma glucose, and 2-hour plasma glucose to prediabetes prevalence: NHANES 2011–2014. Ann. Epidemiol. 28, 681–685 (2018).

    Article  PubMed  Google Scholar 

  7. Metzger, B. E. et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33, 676–682 (2010).

    Article  PubMed  Google Scholar 

  8. World Health Organization. Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy (WHO Press, Geneva, 2013). This paper provides the rationale for, and current basis of, diagnostic recommendations for GDM on a global scale.

  9. Omori, Y. & Jovanovic, L. Proposal for the reconsideration of the definition of gestational diabetes. Diabetes Care 28, 2592–2593 (2005).

    Article  PubMed  Google Scholar 

  10. Clausen, T. D. et al. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Clausen, T. D. et al. 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 (2008).

    Article  PubMed  Google Scholar 

  12. Daly, B. et al. Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: a population-based cohort study. PLOS Med. 15, e1002488 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhu, Y. & Zhang, C. Prevalence of gestational diabetes and risk of progression to type 2 diabetes: a global perspective. Curr. Diab. Rep. 16, 7 (2016). This article provides a global review of the relationship between GDM and the risk of later maternal T2DM.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Harville, E. W., Viikari, J. S. & Raitakari, O. T. Preconception cardiovascular risk factors and pregnancy outcome. Epidemiology 22, 724–730 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hedderson, M. M., Darbinian, J. A., Quesenberry, C. P. & Ferrara, A. Pregravid cardiometabolic risk profile and risk for gestational diabetes mellitus. Am. J. Obstet. Gynecol. 205, 55.e1–55.e7 (2011).

    Article  Google Scholar 

  16. Solomon, C. G. et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 278, 1078–1083 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Retnakaran, R. et al. Fetal sex and maternal risk of gestational diabetes mellitus: the impact of having a boy. Diabetes Care 38, 844–851 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Rauh-Hain, J. A. et al. Risk for developing gestational diabetes in women with twin pregnancies. J. Matern. Fetal Neonatal Med. 22, 293–299 (2009).

    Article  PubMed  Google Scholar 

  19. Morikawa, M. et al. Prevalence of hyperglycaemia in singleton versus twin pregnancy. Diabetes Metab. Res. Rev. 31, 198–203 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Hedderson, M. et al. Racial/ethnic disparities in the prevalence of gestational diabetes mellitus by BMI. Diabetes Care 35, 1492–1498 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Anna, V., van der Ploeg, H. P., Cheung, N. W., Huxley, R. R. & Bauman, A. E. Sociodemographic correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and 2005. Diabetes Care 31, 2288–2293 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhang, C. & Ning, Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am. J. Clin. Nutr. 94, 1975S–1979S (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bao, W. et al. Parental smoking during pregnancy and the risk of gestational diabetes in the daughter. Int. J. Epidemiol. 45, 160–169 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tobias, D. K., Zhang, C., van Dam, R. M., Bowers, K. & Hu, F. B. Physical activity before and during pregnancy and risk of gestational diabetes mellitus: a meta-analysis. Diabetes Care 34, 223–229 (2011).

    Article  PubMed  Google Scholar 

  25. Zhang, C., Solomon, C. G., Manson, J. E. & Hu, F. B. A prospective study of pregravid physical activity and sedentary behaviors in relation to the risk for gestational diabetes mellitus. Arch. Intern. Med. 166, 543–548 (2006).

    Article  PubMed  Google Scholar 

  26. Zhang, C. et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLOS ONE 3, e3753 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Zhang, C. et al. Maternal plasma ascorbic acid (vitamin C) and risk of gestational diabetes mellitus. Epidemiology 15, 597–604 (2004).

    Article  PubMed  Google Scholar 

  28. Zhu, Y. et al. A prospective and longitudinal study of plasma phospholipid saturated fatty acid profile in relation to cardiometabolic biomarkers and the risk of gestational diabetes. Am. J. Clin. Nutr. 107, 1017–1026 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Looman, M. et al. Pre-pregnancy dietary carbohydrate quantity and quality, and risk of developing gestational diabetes: the Australian longitudinal study on women’s health. Br. J. Nutr. 120, 435–444 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Chen, L., Hu, F. B., Yeung, E., Willett, W. & Zhang, C. Prospective study of pre-gravid sugar-sweetened beverage consumption and the risk of gestational diabetes mellitus. Diabetes Care 32, 2236–2241 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bao, W., Tobias, D. K., Hu, F. B., Chavarro, J. E. & Zhang, C. Pre-pregnancy potato consumption and risk of gestational diabetes mellitus: prospective cohort study. BMJ 352, h6898 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Bao, W., Tobias, D. K., Olsen, S. F. & Zhang, C. Pre-pregnancy fried food consumption and the risk of gestational diabetes mellitus: a prospective cohort study. Diabetologia 57, 2485–2491 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bowers, K. et al. A prospective study of prepregnancy dietary iron intake and risk for gestational diabetes mellitus. Diabetes Care 34, 1557–1563 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bowers, K., Tobias, D. K., Yeung, E., Hu, F. B. & Zhang, C. A prospective study of prepregnancy dietary fat intake and risk of gestational diabetes. Am. J. Clin. Nutr. 95, 446–453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bao, W., Bowers, K., Tobias, D. K., Hu, F. B. & Zhang, C. Prepregnancy dietary protein intake, major dietary protein sources, and the risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care 36, 2001–2008 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bao, W. et al. Prepregnancy low-carbohydrate dietary pattern and risk of gestational diabetes mellitus: a prospective cohort study. Am. J. Clin. Nutr. 99, 1378–1384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, C., Liu, S., Solomon, C. G. & Hu, F. B. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus. Diabetes Care 29, 2223–2230 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Tobias, D. K. et al. Prepregnancy adherence to dietary patterns and lower risk of gestational diabetes mellitus. Am. J. Clin. Nutr. 96, 289–295 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, C. et al. Adherence to healthy lifestyle and risk of gestational diabetes mellitus: prospective cohort study. BMJ 349, g5450 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Zalbahar, N., Najman, J., McIntyre, H. D. & Mamun, A. Parental pre-pregnancy obesity and the risk of offspring weight and body mass index change from childhood to adulthood. Clin. Obes. 7, 206–215 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. Smarr, M. M. et al. Persistent organic pollutants and pregnancy complications. Sci. Total Environ. 551–552, 285–291 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Zhang, C. et al. A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes. Fertil. Steril. 103, 184–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Hinkle, S. N. et al. A longitudinal study of depression and gestational diabetes in pregnancy and the postpartum period. Diabetologia 59, 2594–2602 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, C. et al. Genetic variants and the risk of gestational diabetes mellitus: a systematic review. Hum. Reprod. Update 19, 376–390 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Kwak, S. H. et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes 61, 531–541 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ren, J. et al. Genetic variation in MTNR1B is associated with gestational diabetes mellitus and contributes only to the absolute level of beta cell compensation in Mexican Americans. Diabetologia 57, 1391–1399 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ding, M. et al. Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations. Diabetologia 61, 1758–1768 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Catalano, P. M., Tyzbir, E. D. & Sims, E. A. Incidence and significance of islet cell antibodies in women with previous gestational diabetes. Diabetes Care 13, 478–482 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Ellard, S., Bellanne-Chantelot, C. & Hattersley, A. T. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 51, 546–553 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hattersley, A. T. et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat. Genet. 19, 268–270 (1998). This landmark paper outlines the differing phenotypes encountered when maternal and fetal glucokinase genes are matched or mismatched.

    Article  CAS  PubMed  Google Scholar 

  51. Catalano, P. M. et al. Longitudinal changes in basal hepatic glucose production and suppression during insulin infusion in normal pregnant women. Am. J. Obstet. Gynecol. 167, 913–919 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Catalano, P. M., Tyzbir, E. D., Roman, N. M., Amini, S. B. & Sims, E. A. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am. J. Obstet. Gynecol. 165, 1667–1672 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Catalano, P. M., Huston, L., Amini, S. B. & Kalhan, S. C. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am. J. Obstet. Gynecol. 180, 903–916 (1999). This paper provides detailed insight into the pathophysiology of GDM as compared with and contrasted to obesity without diabetes in a longitudinal cohort of women monitored over the course of pregnancy.

    Article  CAS  PubMed  Google Scholar 

  54. Buchanan, T. A. Pancreatic B cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 989–993 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. DeFronzo, R. A. et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Primers 1, 15019 (2015).

    Article  PubMed  Google Scholar 

  56. Friedman, J. E. et al. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes 48, 1807–1814 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. McIntyre, Discovery H. D. knowledge, and action-diabetes in pregnancy across the translational spectrum: the 2016 Norbert Freinkel Award Lecture. Diabetes Care 41, 227–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. Hotamisligil, G. S. et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665–668 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Kirwan, J. P. et al. Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. J. Clin. Endocrinol. Metab. 89, 4678–4684 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Waters, T. P. et al. Does maternal insulin sensitivity improve immediately after delivery or do we need to wait unti six weeks postpartum? Am. J. Obstet. Gynecol. 212, S20 (2015).

    Article  Google Scholar 

  61. Friedman, J. E., Kirwan, J. P., Jing, M., Presley, L. & Catalano, P. M. Increased skeletal muscle tumor necrosis factor-alpha and impaired insulin signaling persist in obese women with gestational diabetes mellitus 1 year postpartum. Diabetes 57, 606–613 (2008).

    Article  PubMed  Google Scholar 

  62. Berggren, E. K., Presley, L., Amini, S. B., Hauguel-de Mouzon, S. & Catalano, P. M. Are the metabolic changes of pregnancy reversible in the first year postpartum? Diabetologia 58, 1561–1568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Peters, R. K., Kjos, S. L., Xiang, A. & Buchanan, T. A. Long-term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet 347, 227–230 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Lewis, R. M. et al. The placental exposome: placental determinants of fetal adiposity and postnatal body composition. Ann. Nutr. Metab. 63, 208–215 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Desoye, G. & Shafrir, E. Placental metabolism and its regulation in health and diabetes. Mol. Aspects Med. 15, 505–682 (1994).

    Article  CAS  PubMed  Google Scholar 

  66. Hauguel, S., Desmaizieres, V. & Challier, J. C. Glucose uptake, utilization, and transfer by the human placenta as functions of maternal glucose concentration. Pediatr. Res. 20, 269–273 (1986).

    Article  CAS  PubMed  Google Scholar 

  67. Osmond, D. T., Nolan, C. J., King, R. G., Brennecke, S. P. & Gude, N. M. Effects of gestational diabetes on human placental glucose uptake, transfer, and utilisation. Diabetologia 43, 576–582 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Desoye, G. & Nolan, C. J. The fetal glucose steal: an underappreciated phenomenon in diabetic pregnancy. Diabetologia 59, 1089–1094 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Haggarty, P., Page, K., Abramovich, D. R., Ashton, J. & Brown, D. Long-chain polyunsaturated fatty acid transport across the perfused human placenta. Placenta 18, 635–642 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Lewis, R. M., Wadsack, C. & Desoye, G. Placental fatty acid transfer. Curr. Opin. Clin. Nutr. Metab. Care 21, 78–82 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Dancis, J., Jansen, V., Kayden, H. J., Schneider, H. & Levitz, M. Transfer across perfused human placenta. II. Free fatty acids. Pediatr. Res. 7, 192–197 (1973).

    CAS  PubMed  Google Scholar 

  72. Pagan, A. et al. Materno-fetal transfer of docosahexaenoic acid is impaired by gestational diabetes mellitus. Am. J. Physiol. Endocrinol. Metab. 305, E826–E833 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Prieto-Sanchez, M. T. et al. Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clin. Nutr. 36, 513–521 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Sen, D. K., Kaufmann, P. & Schweikhart, G. Classification of human placental villi. II. Morphometry. Cell Tissue Res. 200, 425–434 (1979).

    CAS  PubMed  Google Scholar 

  75. Gauster, M., Desoye, G., Totsch, M. & Hiden, U. The placenta and gestational diabetes mellitus. Curr. Diab. Rep. 12, 16–23 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Cvitic, S., Desoye, G. & Hiden, U. Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus. Biomed. Res. Int. 2014, 145846 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Lassance, L. et al. Hyperinsulinemia stimulates angiogenesis of human fetoplacental endothelial cells: a possible role of insulin in placental hypervascularization in diabetes mellitus. J. Clin. Endocrinol. Metab. 98, E1438–E1447 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Loegl, J. et al. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis. Reproduction 152, 447–455 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Loegl, J. et al. Pigment epithelium-derived factor (PEDF): a novel trophoblast-derived factor limiting feto-placental angiogenesis in late pregnancy. Angiogenesis 19, 373–388 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sun, Y. et al. Gestational diabetes mellitus modulates cholesterol homeostasis in human fetoplacental endothelium. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1863, 968–979 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Scholler, M. et al. Phospholipid transfer protein is differentially expressed in human arterial and venous placental endothelial cells and enhances cholesterol efflux to fetal HDL. J. Clin. Endocrinol. Metab. 97, 2466–2474 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Desoye, G. The human placenta in diabetes and obesity: friend or foe? The 2017 Norbert Freinkel Award Lecture. Diabetes Care 41, 1362–1369 (2018). This article provides a comprehensive overview of placental structure and function in diabetic pregnancy.

    Article  PubMed  CAS  Google Scholar 

  83. Gauster, M. et al. Dysregulation of placental endothelial lipase in obese women with gestational diabetes mellitus. Diabetes 60, 2457–2464 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cvitic, S. et al. The human placental sexome differs between trophoblast epithelium and villous vessel endothelium. PLOS ONE 8, e79233 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Knabl, J. et al. GDM alters expression of placental estrogen receptor alpha in a cell type and gender-specific manner. Reprod. Sci. 22, 1488–1495 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Sedlmeier, E. M. et al. Human placental transcriptome shows sexually dimorphic gene expression and responsiveness to maternal dietary n-3 long-chain polyunsaturated fatty acid intervention during pregnancy. BMC Genomics 15, 941 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Strutz, J. et al. Gestational diabetes alters microRNA signatures in human feto-placental endothelial cells depending on fetal sex. Clin. Sci. 132, 2437–2449 (2018).

    Article  CAS  Google Scholar 

  88. Desoye, G. & Hauguel-de Mouzon, S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care 30 (Suppl. 2), S120–S126 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Watson, A. L., Skepper, J. N., Jauniaux, E. & Burton, G. J. Changes in concentration, localization and activity of catalase within the human placenta during early gestation. Placenta 19, 27–34 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Lappas, M. et al. The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid. Redox Signal. 15, 3061–3100 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Hoch, D., Gauster, M., Hauguel-de Mouzon, S. & Desoye, G. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta. Mol. Aspects Med. 66, 21–30 (2018).

    Article  PubMed  CAS  Google Scholar 

  92. Desoye, G. & van Poppel, M. The feto-placental dialogue and diabesity. Best Pract. Res. Clin. Obstet. Gynaecol. 29, 15–23 (2015).

    Article  PubMed  Google Scholar 

  93. Eder, M. et al. Sex differences in the association of cord blood insulin with subcutaneous adipose tissue in neonates. Int. J. Obes. 40, 538–542 (2016).

    Article  CAS  Google Scholar 

  94. Houshmand-Oeregaard, A. et al. DNA methylation and gene expression of TXNIP in adult offspring of women with diabetes in pregnancy. PLOS ONE 12, e0187038 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Houshmand-Oeregaard, A. et al. Differential adipokine DNA methylation and gene expression in subcutaneous adipose tissue from adult offspring of women with diabetes in pregnancy. Clin. Epigenetics 9, 37 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Hjort, L. et al. Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children. JCI Insight 3, e122572 (2018).

    Article  PubMed Central  Google Scholar 

  97. Pettitt, D. J., Knowler, W. C., Baird, H. R. & Bennett, P. H. Gestational diabetes: infant and maternal complications of pregnancy in relation to third-trimester glucose tolerance in the Pima Indians. Diabetes Care 3, 458–464 (1980).

    Article  CAS  PubMed  Google Scholar 

  98. Beischer, N. A., Wein, P., Sheedy, M. T. & Steffen, B. Identification and treatment of women with hyperglycaemia diagnosed during pregnancy can significantly reduce perinatal mortality rates. Aust. N. Z. J. Obstet. Gynaecol. 36, 239–247 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Casey, B. M., Lucas, M. J., McIntire, D. D. & Leveno, K. J. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet. Gynecol. 90, 869–873 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Aberg, A., Rydhstrom, H., Kallen, B. & Kallen, K. Impaired glucose tolerance during pregnancy is associated with increased fetal mortality in preceding sibs. Acta Obstet. Gynecol. Scand. 76, 212–217 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Persson, B. & Hanson, U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care 21(Suppl. 2), B79–B84 (1998).

    PubMed  Google Scholar 

  102. Jensen, D. M. et al. Proposed diagnostic thresholds for gestational diabetes mellitus according to a 75-g oral glucose tolerance test. Maternal and perinatal outcomes in 3260 Danish women. Diabet Med. 20, 51–57 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Sermer, M. et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project. Am. J. Obstet. Gynecol. 173, 146–156 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Sacks, D. A. et al. Toward universal criteria for gestational diabetes: the 75-gram glucose tolerance test in pregnancy. Am. J. Obstet. Gynecol. 172, 607–614 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. Moses, R. G. & Calvert, D. Pregnancy outcomes in women without gestational diabetes mellitus related to the maternal glucose level. Is there a continuum of risk? Diabetes Care 18, 1527–1533 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Jensen, D. M. et al. Clinical impact of mild carbohydrate intolerance in pregnancy: a study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus. Am. J. Obstet. Gynecol. 185, 413–419 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Jarrett, R. J. Gestational diabetes: a non-entity? BMJ 306, 37–38 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Metzger, B. E. et al. Hyperglycemia and adverse pregnancy outcomes. N. Engl. J. Med. 358, 1991–2002 (2008). This landmark epidemiological study defines, on a worldwide basis, the relationship between impaired glucose metabolism that is less severe than overt diabetes and pregnancy complications.

    Article  PubMed  Google Scholar 

  109. Crowther, C. A. et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N. Engl. J. Med. 352, 2477–2486 (2005). This landmark randomized controlled trial demonstrates that treatment of GDM is effective in reducing immediate pregnancy complications, including excess fetal growth and pregnancy-related hypertension.

    Article  CAS  PubMed  Google Scholar 

  110. Landon, M. B. et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N. Engl. J. Med. 361, 1339–1348 (2009). This USA-based randomized controlled trial confirms that treatment of GDM reduces excess fetal growth, excess fetal adiposity and pregnancy-related hypertension.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bellamy, L., Casas, J. P., Hingorani, A. D. & Williams, D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 373, 1773–1779 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Cheung, N. W. & Byth, K. Population health significance of gestational diabetes. Diabetes Care 26, 2005–2009 (2003).

    Article  PubMed  Google Scholar 

  113. Lauenborg, J. et al. Increasing incidence of diabetes after gestational diabetes: a long-term follow-up in a Danish population. Diabetes Care 27, 1194–1199 (2004).

    Article  PubMed  Google Scholar 

  114. Damm, P. Future risk of diabetes in mother and child after gestational diabetes mellitus. Int. J. Gynaecol. Obstet. 104 (Suppl. 1), S25–S26 (2009).

    Article  PubMed  Google Scholar 

  115. Damm, P., Kuhl, C., Bertelsen, A. & Molsted-Pedersen, L. Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus. Am. J. Obstet. Gynecol. 167, 607–616 (1992).

    Article  CAS  PubMed  Google Scholar 

  116. Lowe, W. L. Jr. et al. Association of gestational diabetes with maternal disorders of glucose metabolism and childhood adiposity. JAMA 320, 1005–1016 (2018). This follow-up study from the landmark HAPO study demonstrates that GDM diagnosed using the IADPSG criteria is associated with long-term risk of T2DM in the mother and with risk of obesity in offspring (WHO 2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lauenborg, J. et al. The prevalence of the metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population. J. Clin. Endocrinol. Metab. 90, 4004–4010 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Retnakaran, R. Hyperglycemia in pregnancy and its implications for a woman’s future risk of cardiovascular disease. Diabetes Res. Clin. Pract. 145, 193–199 (2018).

    Article  PubMed  Google Scholar 

  119. Retnakaran, R. & Shah, B. R. Role of type 2 diabetes in determining retinal, renal, and cardiovascular outcomes in women with previous gestational diabetes mellitus. Diabetes Care 40, 101–108 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Kramer, C. K., Campbell, S. & Retnakaran, R. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia 62, 905–914 (2019).

    Article  PubMed  Google Scholar 

  121. Harder, T. et al. Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring. Neurosci. Lett. 299, 85–88 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Aerts, L. & Van Assche, F. A. Animal evidence for the transgenerational development of diabetes mellitus. Int. J. Biochem. Cell Biol. 38, 894–903 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Silverman, B. L. et al. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 40 (Suppl. 2), 121–125 (1991).

    Article  PubMed  Google Scholar 

  124. Dabelea, D. et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49, 2208–2211 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Fraser, A. & Lawlor, D. A. Long-term health outcomes in offspring born to women with diabetes in pregnancy. Curr. Diab. Rep. 14, 489 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Kelstrup, L. et al. Insulin resistance and impaired pancreatic beta-cell function in adult offspring of women with diabetes in pregnancy. J. Clin. Endocrinol. Metab. 98, 3793–3801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Grunnet, L. G. 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 40, 1746–1755 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lowe, W. L. Jr. et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes and childhood glucose metabolism. Diabetes Care 42, 372–380 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Lowe, W. L. Jr. et al. Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study. Diabetologia 62, 598–610 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Clausen, T. D. et al. Cognitive function in adult offspring of women with gestational diabetes—the role of glucose and other factors. PLOS ONE 8, e67107 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Xiang, A. H. et al. Association of maternal diabetes with autism in offspring. Jama 313, 1425–1434 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Xiang, A. H. et al. Maternal gestational diabetes mellitus, type 1 diabetes, and type 2 diabetes during pregnancy and risk of ADHD in offspring. Diabetes Care 41, 2502–2508 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Gillman, M. W. et al. Effect of treatment of gestational diabetes mellitus on obesity in the next generation. Diabetes Care 33, 964–968 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Landon, M. B. et al. Mild gestational diabetes mellitus and long-term child health. Diabetes Care 38, 445–452 (2015).

    Article  PubMed  Google Scholar 

  135. Luoto, R. et al. Primary prevention of gestational diabetes mellitus and large-for-gestational-age newborns by lifestyle counseling: a cluster-randomized controlled trial. PLOS Med. 8, e1001036 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Dodd, J. M. et al. Antenatal lifestyle advice for women who are overweight or obese: LIMIT randomised trial. BMJ 348, g1285 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Zhang, C., Rawal, S. & Chong, Y. S. Risk factors for gestational diabetes: is prevention possible? Diabetologia 59, 1385–1390 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Song, C. et al. Long-term risk of diabetes in women at varying durations after gestational diabetes: a systematic review and meta-analysis with more than 2 million women. Obes. Rev. 19, 421–429 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Russo, L. M., Nobles, C., Ertel, K. A., Chasan-Taber, L. & Whitcomb, B. W. Physical activity interventions in pregnancy and risk of gestational diabetes mellitus: a systematic review and meta-analysis. Obstet. Gynecol. 125, 576–582 (2015).

    Article  PubMed  Google Scholar 

  140. Sanabria-Martinez, G. et al. Effectiveness of physical activity interventions on preventing gestational diabetes mellitus and excessive maternal weight gain: a meta-analysis. BJOG 122, 1167–1174 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Song, C., Li, J., Leng, J., Ma, R. C. & Yang, X. Lifestyle intervention can reduce the risk of gestational diabetes: a meta-analysis of randomized controlled trials. Obes. Rev. 17, 960–969 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Han, S., Crowther, C. A., Middleton, P. & Heatley, E. Different types of dietary advice for women with gestational diabetes mellitus. Cochrane Database Syst. Rev. 3, CD009275 (2013).

    Google Scholar 

  143. Bain, E. et al. Diet and exercise interventions for preventing gestational diabetes mellitus. Cochrane Database Syst. Rev. 4, CD010443 (2015).

    Google Scholar 

  144. Celentano, C. et al. Myo-Inositol supplementation to prevent gestational diabetes mellitus. Curr. Diab Rep. 16, 30 (2016).

    Article  PubMed  CAS  Google Scholar 

  145. Santamaria, A. et al. Myo-inositol may prevent gestational diabetes onset in overweight women: a randomized, controlled trial. J. Matern. Fetal Neonatal Med. 29, 3234–3237 (2016).

    Article  PubMed  Google Scholar 

  146. Farren, M. et al. The prevention of gestational diabetes mellitus with antenatal oral inositol supplementation: a randomized controlled trial. Diabetes Care 40, 759–763 (2017).

    Article  CAS  PubMed  Google Scholar 

  147. Crawford, T. J., Crowther, C. A., Alsweiler, J. & Brown, J. Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes. Cochrane Database Syst. Rev. 12, CD011507 (2015).

    Google Scholar 

  148. Luoto, R., Laitinen, K., Nermes, M. & Isolauri, E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br. J. Nutr. 103, 1792–1799 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Callaway, L. K. et al. Probiotics for the prevention of gestational diabetes mellitus in overweight and obese women: findings from the SPRING double-blind randomized controlled trial. Diabetes Care 42, 364–371 (2019).

    PubMed  Google Scholar 

  150. Lindsay, K. L. et al. Probiotics in obese pregnancy do not reduce maternal fasting glucose: a double-blind, placebo-controlled, randomized trial (probiotics in pregnancy study). Am. J. Clin. Nutr. 99, 1432–1439 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Lindsay, K. L., Walsh, C. A., Brennan, L. & McAuliffe, F. M. Probiotics in pregnancy and maternal outcomes: a systematic review. J. Matern. Fetal Neonatal Med. 26, 772–778 (2013).

    Article  PubMed  Google Scholar 

  152. Pellonpera, O. et al. Efficacy of fish oil and/or probiotic intervention on the incidence of gestational diabetes mellitus in an at-risk group of overweight and obese women: a randomized, placebo-controlled, double-blind clinical trial. Diabetes Care 42, 1009–1017 (2019).

    Article  PubMed  Google Scholar 

  153. Jarde, A. et al. Pregnancy outcomes in women taking probiotics or prebiotics: a systematic review and meta-analysis. BMC Pregnancy Childbirth 18, 14 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Zheng, J., Feng, Q., Zheng, S. & Xiao, X. The effects of probiotics supplementation on metabolic health in pregnant women: an evidence based meta-analysis. PLOS ONE 13, e0197771 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Barrett, H. L., Dekker Nitert, M., Conwell, L. S. & Callaway, L. K. Probiotics for preventing gestational diabetes. Cochrane Database Syst. Rev. 2, CD009951 (2014).

    Google Scholar 

  156. Chiswick, C. et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 3, 778–786 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Dodd, J. M. et al. Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 7, 15–24 (2019).

    Article  CAS  PubMed  Google Scholar 

  158. Glueck, C. J., Pranikoff, J., Aregawi, D. & Wang, P. Prevention of gestational diabetes by metformin plus diet in patients with polycystic ovary syndrome. Fertil. Steril. 89, 625–634 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Tang, T., Lord, J. M., Norman, R. J., Yasmin, E. & Balen, A. H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 5, CD003053 (2012).

    Google Scholar 

  160. Carpenter, M. W. & Coustan, D. R. Criteria for screening tests for gestational diabetes. Am. J. Obstet. Gynecol. 144, 768–773 (1982).

    Article  CAS  PubMed  Google Scholar 

  161. Berggren, E. K., Boggess, K. A., Stuebe, A. M. & Jonsson Funk, M. National Diabetes Data Group versus Carpenter-Coustan criteria to diagnose gestational diabetes. Am. J. Obstet. Gynecol. 205, 253.e1–253.e7 (2011).

    Article  Google Scholar 

  162. ACOG Committee on Practice Bulletins. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet. Gynecol. 122, 406–416 (2013).

    Article  Google Scholar 

  163. Metzger, B. E. et al. The hyperglycemia and adverse pregnancy outcome (HAPO) Study. Int. J. Gynaecol. Obstet. 78, 69–77 (2002).

    Article  Google Scholar 

  164. Metzger, B. E. et al. Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia. Pediatrics 126, e1545–e1552 (2010).

    Article  PubMed  Google Scholar 

  165. Sacks, D. A. et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the hyperglycemia and adverse pregnancy outcome (HAPO) study. Diabetes Care. 35, 526–528 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Diabetes, I. Ao. et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33, 676–682 (2010).

    Article  CAS  Google Scholar 

  167. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care 42, S13–S28 (2019).

    Article  Google Scholar 

  168. Blumer, I. et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 98, 4227–4249 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Nankervis, A., McIntyre, H. D., Moses, R. G., Ross, G. P. & Callaway, L. K. Testing for gestational diabetes mellitus in Australia. Diabetes Care 36, e64 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Ikenoue, S. et al. Clinical impact of women with gestational diabetes mellitus by the new consensus criteria: two year experience in a single institution in Japan. Endocr. J. 61, 353–358 (2014).

    Article  PubMed  Google Scholar 

  171. Kautzky-Willer, A. et al. Gestational diabetes mellitus [German]. Wien. Klin. Wochenschr. 124 (Suppl. 2), 58–65 (2012).

    Article  PubMed  Google Scholar 

  172. Hod, M. et al. The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int. J. Gynaecol. Obstet. 131, S173–S211 (2015).

    Article  PubMed  Google Scholar 

  173. Diehl, K. et al. German gynecologists’ experience with a universal screening for gestational diabetes mellitus in daily practice: a qualitative study. J. Turk. Ger. Gynecol. Assoc. 17, 10–15 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Rowan, J. et al. New Zealand National GDM Guidelines: an alternative view of some good practice points. Aust. N. Z. J. Obstet. Gynaecol. 55, 17–20 (2015).

    Article  PubMed  Google Scholar 

  175. Benhalima, K. et al. A proposal for the use of uniform diagnostic criteria for gestational diabetes in Europe: an opinion paper by the European Board & College of Obstetrics and Gynaecology (EBCOG). Diabetologia 58, 1422–1429 (2015).

    Article  PubMed  Google Scholar 

  176. Sadikot, S., Purandare, C. N., Cho, N. H. & Hod, M. FIGO-IDF joint statement and declaration on hyperglycemia in pregnancy. Diabetes Res. Clin. Pract. 145, 1–4 (2018).

    Article  PubMed  Google Scholar 

  177. Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: gestational diabetes mellitus. Obstet. Gynecol. 131, e49–e64 (2018).

    Article  Google Scholar 

  178. Feig, D. S. et al. Diabetes and pregnancy. Can. J. Diabetes 42 (Suppl. 1), 255–282 (2018).

    Article  PubMed  Google Scholar 

  179. National Institute for Health and Care Excellence. Diabetes in Pregnancy: Management from Preconception to the Postnatal Period (NICE, 2015).

  180. van Leeuwen, M. et al. Glucose challenge test for detecting gestational diabetes mellitus: a systematic review. BJOG 119, 393–401 (2012).

    Article  PubMed  CAS  Google Scholar 

  181. Saccone, G., Khalifeh, A., Al-Kouatly, H. B., Sendek, K. & Berghella, V. Screening for gestational diabetes mellitus: one step versus two step approach. A meta-analysis of randomized trials. J. Matern. Fetal Neonatal Med. https://doi.org/10.1080/14767058.2018.1519543 (2018).

  182. Sievenpiper, J. L., McDonald, S. D., Grey, V. & Don-Wauchope, A. C. Missed follow-up opportunities using a two-step screening approach for gestational diabetes. Diabetes Res. Clin. Pract. 96, e43–e46 (2012).

    Article  PubMed  Google Scholar 

  183. Donovan, L. E., Savu, A., Edwards, A. L., Johnson, J. A. & Kaul, P. Prevalence and timing of screening and diagnostic testing for gestational diabetes mellitus: a population-based study in Alberta, Canada. Diabetes Care 39, 55–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. McIntyre, H. D. Diagnosing gestational diabetes mellitus: rationed or rationally related to risk? Diabetes Care 36, 2879–2880 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  185. McIntyre, H. D. et al. Gestational diabetes mellitus: does one size fit all? A challenge to uniform worldwide diagnostic thresholds. Diabetes Care 41, 1339–1342 (2018).

    Article  PubMed  Google Scholar 

  186. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetes — 2019. Diabetes Care 42, S165–S172 (2019).

    Article  Google Scholar 

  187. Gunderson, E. P. Gestational diabetes and nutritional recommendations. Curr. Diab. Rep. 4, 377–386 (2004).

    Article  PubMed  Google Scholar 

  188. Viana, L. V., Gross, J. L. & Azevedo, M. J. Dietary intervention in patients with gestational diabetes mellitus: a systematic review and meta-analysis of randomized clinical trials on maternal and newborn outcomes. Diabetes Care 37, 3345–3355 (2014).

    Article  PubMed  Google Scholar 

  189. Rasmussen, K. M., Catalano, P. M. & Yaktine, A. L. New guidelines for weight gain during pregnancy: what obstetrician/gynecologists should know. Curr. Opin. Obstet. Gynecol. 21, 521–526 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Rizzo, T., Metzger, B. E., Burns, W. J. & Burns, K. Correlations between antepartum maternal metabolism and intelligence of offspring. N. Engl. J. Med. 325, 911–916 (1991).

    Article  CAS  PubMed  Google Scholar 

  191. American Diabetes Association. 13. Management of diabetes in pregnancy: standards of medical care in diabetes — 2018. Diabetes Care 41, S137–S143 (2018).

    Article  Google Scholar 

  192. Ruchat, S. M. et al. Effectiveness of exercise interventions in the prevention of excessive gestational weight gain and postpartum weight retention: a systematic review and meta-analysis. Br. J. Sports Med. 52, 1347–1356 (2018).

    Article  PubMed  Google Scholar 

  193. Vaarasmaki, M. Is it worth treating gestational diabetes: if so, when and how? Diabetologia 59, 1391–1395 (2016).

    Article  CAS  PubMed  Google Scholar 

  194. Kurtzhals, L. L. et al. The impact of restricted gestational weight gain by dietary intervention on fetal growth in women with gestational diabetes mellitus. Diabetologia 61, 2528–2538 (2018).

    Article  CAS  PubMed  Google Scholar 

  195. Kjos, S. L. & Schaefer-Graf, U. M. Modified therapy for gestational diabetes using high-risk and low-risk fetal abdominal circumference growth to select strict versus relaxed maternal glycemic targets. Diabetes Care 30 (Suppl. 2), 200–205 (2007).

    Article  PubMed  Google Scholar 

  196. Charlton, R. A. et al. Prescribing of antidiabetic medicines before, during and after pregnancy: a study in seven European regions. PLOS ONE 11, e0155737 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Lepercq, J. et al. Meta-analysis of maternal and neonatal outcomes associated with the use of insulin glargine versus NPH insulin during pregnancy. Obstet. Gynecol. Int. 2012, 649070 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Mikkelsen, M. R., Nielsen, S. B., Stage, E., Mathiesen, E. R. & Damm, P. High maternal HbA1c is associated with overweight in neonates. Dan. Med. Bull. 58, A4309 (2011).

    CAS  PubMed  Google Scholar 

  199. Herrera, K. M. et al. Randomized controlled trial of insulin detemir versus NPH for the treatment of pregnant women with diabetes. Am. J. Obstet. Gynecol. 213, 426.e1–426.e7 (2015).

    Article  CAS  Google Scholar 

  200. Jia, Y., Lao, Y., Zhu, H., Li, N. & Leung, S. W. Is metformin still the most efficacious first-line oral hypoglycaemic drug in treating type 2 diabetes? A network meta-analysis of randomized controlled trials. Obes. Rev. 20, 1–12 (2019).

    Article  CAS  PubMed  Google Scholar 

  201. Rowan, J. A., Hague, W. M., Gao, W., Battin, M. R. & Moore, M. P. Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med. 358, 2003–2015 (2008).

    Article  CAS  PubMed  Google Scholar 

  202. Ijas, H. et al. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 118, 880–885 (2011).

    Article  CAS  PubMed  Google Scholar 

  203. Balsells, M. et al. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 350, h102 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Barbour, L. A. & Feig, D. S. Metformin for gestational diabetes mellitus: progeny, perspective, and a personalized approach. Diabetes Care 42, 396–399 (2019).

    Article  PubMed  Google Scholar 

  205. Rowan, J. A. et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34, 2279–2284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Battin, M. R. et al. Blood pressure measurement at two years in offspring of women randomized to a trial of metformin for GDM: follow up data from the MiG trial. BMC Pediatr. 15, 54 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Rowan, J. A. 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 6, e000456 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  208. 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 122, 994–1000 (2015).

    Article  CAS  PubMed  Google Scholar 

  209. Langer, O., Conway, D. L., Berkus, M. D., Xenakis, E. M. & Gonzales, O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N. Engl. J. Med. 343, 1134–1138 (2000).

    Article  CAS  PubMed  Google Scholar 

  210. Schwartz, R. A., Rosenn, B., Aleksa, K. & Koren, G. Glyburide transport across the human placenta. Obstet. Gynecol. 125, 583–588 (2015).

    Article  CAS  PubMed  Google Scholar 

  211. Hebert, M. F. et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin. Pharmacol. Ther. 85, 607–614 (2009).

    Article  CAS  PubMed  Google Scholar 

  212. Camelo Castillo, W. et al. Association of adverse pregnancy outcomes with glyburide versus insulin in women with gestational diabetes. JAMA Pediatr. 169, 452–458 (2015).

    Article  PubMed  Google Scholar 

  213. Tobias, D. K. et al. Healthful dietary patterns and type 2 diabetes mellitus risk among women with a history of gestational diabetes mellitus. Arch. Intern. Med. 172, 1566–1572 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Bao, W. et al. Physical activity and sedentary behaviors associated with risk of progression from gestational diabetes mellitus to type 2 diabetes mellitus: a prospective cohort study. JAMA Intern. Med. 174, 1047–1055 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Bao, W. et al. Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study. Diabetologia 58, 1212–1219 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Gunderson, E. P. et al. Lactation and progression to type 2 diabetes mellitus after gestational diabetes mellitus: a prospective cohort study. Ann. Intern. Med. 163, 889–898 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Buchanan, T. A. et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51, 2796–2803 (2002).

    Article  CAS  PubMed  Google Scholar 

  218. Aroda, V. R. et al. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program outcomes study 10-year follow-up. J. Clin. Endocrinol. Metab. 100, 1646–1653 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Diabetes Prevention Program Research Group. Long-term effects of metformin on diabetes prevention: identification of subgroups that benefited most in the Diabetes Prevention Program and Diabetes Prevention Program outcomes study. Diabetes Care 42, 601–608 (2019).

    Article  PubMed Central  Google Scholar 

  220. Wilkinson, S. A., McCray, S., Beckmann, M., Parry, A. & McIntyre, H. D. Barriers and enablers to translating gestational diabetes guidelines into practice. Pract. Diabetes 31, 67–72a (2014).

    Article  Google Scholar 

  221. Dalfra, M. G., Nicolucci, A., Bisson, T., Bonsembiante, B. & Lapolla, A. Quality of life in pregnancy and post-partum: a study in diabetic patients. Qual. Life Res. 21, 291–298 (2012).

    Article  CAS  PubMed  Google Scholar 

  222. Danyliv, A. et al. Health related quality of life two to five years after gestational diabetes mellitus: cross-sectional comparative study in the ATLANTIC DIP cohort. BMC Pregnancy Childbirth 15, 274 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Marchetti, D., Carrozzino, D., Fraticelli, F., Fulcheri, M. & Vitacolonna, E. Quality of life in women with gestational diabetes mellitus: a systematic review. J. Diabetes Res. 2017, 7058082 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Pace, R., Rahme, E., Da Costa, D. & Dasgupta, K. Association between gestational diabetes mellitus and depression in parents: a retrospective cohort study. Clin. Epidemiol. 10, 1827–1838 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Clark, C. E., Rasgon, N. L., Reed, D. E. 2nd & Robakis, T. K. Depression precedes, but does not follow, gestational diabetes. Acta Psychiatr. Scand. 139, 311–321 (2019).

    Article  CAS  PubMed  Google Scholar 

  226. Egan, A. M. et al. Epidemiology of gestational diabetes mellitus according to IADPSG/WHO 2013 criteria among obese pregnant women in Europe. Diabetologia 60, (1913–1921 (2017).

    Google Scholar 

  227. Goveia, P. et al. Lifestyle intervention for the prevention of diabetes in women with previous gestational diabetes mellitus: a systematic review and meta-analysis. Front. Endocrinol. 9, 583 (2018).

    Article  Google Scholar 

  228. Kim, C. Maternal outcomes and follow-up after gestational diabetes mellitus. Diabet. Med. 31, 292–301 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Wexler, D. J. et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Obstet. Gynecol. 132, 496–505 (2018). This paper provides a summary of the areas requiring further research in GDM, which provides an outline of current evidence gaps and a blueprint for future research priorities.

    Article  PubMed  PubMed Central  Google Scholar 

  230. Poon, L. C., McIntyre, H. D., Hyett, J. A., da Fonseca, E. B. & Hod, M. The first-trimester of pregnancy – a window of opportunity for prediction and prevention of pregnancy complications and future life. Diabetes Res. Clin. Pract. 145, 20–30 (2018).

    Article  PubMed  Google Scholar 

  231. Ghosh, P. et al. Plasma glycated CD59, a novel biomarker for detection of pregnancy-induced glucose intolerance. Diabetes Care 40, 981–984 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Bahado-Singh, R. O. et al. Fetal male gender and the benefits of treatment of mild gestational diabetes mellitus. Am. J. Obstet. Gynecol. 206, 422.e1–422.e5 (2012).

    Article  Google Scholar 

  233. van Poppel, M. N., Eder, M., Lang, U. & Desoye, G. Sex-specific associations of insulin-like peptides in cord blood with size at birth. Clin. Endocrinol. 89, 187–193 (2018).

    Article  CAS  Google Scholar 

  234. Guzman-Gutierrez, E. et al. Role of insulin and adenosine in the human placenta microvascular and macrovascular endothelial cell dysfunction in gestational diabetes mellitus. Microcirculation 21, 26–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  235. Li, J. et al. The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy. Kidney Blood Press. Res. 39, 369–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  236. Catalano, P. & deMouzon, S. H. Maternal obesity and metabolic risk to the offspring: why lifestyle interventions may have not achieved the desired outcomes. Int. J. Obes. 39, 642–649 (2015).

    Article  CAS  Google Scholar 

  237. Finneran, M. M. & Landon, M. B. Oral agents for the treatment of gestational diabetes. Curr. Diab. Rep. 18, 119 (2018).

    Article  PubMed  Google Scholar 

  238. Hanem, L. G. E. et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc. Health 3, 166–174 (2019).

    Article  PubMed  Google Scholar 

  239. Hanem, L. G. E. et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: follow-up of two RCTs. J. Clin. Endocrinol. Metab. 103, 1612–1621 (2018).

    Article  PubMed  Google Scholar 

  240. Hod, M., Kapur, A. & McIntyre, H. D. Evidence in support of the international association of diabetes in pregnancy study groups’ criteria for diagnosing gestational diabetes worldwide in 2019. Am. J. Obstet. Gynecol. https://doi.org/10.1016/j.ajog.2019.01.206 (2019).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

C.Z. is supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

Author information

Authors and Affiliations

  1. Mater Research and University of Queensland, Brisbane, Queensland, Australia

    H. David McIntyre

  2. Mother Infant Research Institute, Department of Obstetrics and Gynecology, Tufts University School of Medicine, Friedman School of Nutrition Science and Policy, Boston, MA, USA

    Patrick Catalano

  3. Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    Cuilin Zhang

  4. Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

    Gernot Desoye

  5. Department of Endocrinology, Center for Pregnant Women with Diabetes, Rigshospitalet and The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Elisabeth R. Mathiesen

  6. Department of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet and The Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Peter Damm

Authors
  1. H. David McIntyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Catalano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cuilin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gernot Desoye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elisabeth R. Mathiesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Damm
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (H.D.M.); Epidemiology (C.Z.); Mechanisms/pathophysiology (P.C. and G.D.); Diagnosis, screening and prevention (H.D.M., C.Z. and E.R.M.); Management (P.C. and E.R.M.); Quality of life (P.D.); Outlook (H.D.M., P.C., C.Z., G.D. and P.D.); Overview of the Primer (H.D.M.).

Corresponding author

Correspondence to H. David McIntyre.

Ethics declarations

Competing interests

P.D. is participating in multi-centre and multinational clinical studies on the use of insulin in pregnant women with pre-existing diabetes in collaboration with Novo Nordisk; no personal honorarium is involved. E.R.M. is participating in multinational clinical studies on the use of insulin in pregnant women with pre-existing diabetes in collaboration with Novo Nordisk. E.R.M. has given talks for Novo Nordisk, AstraZeneca, Lilly and Sanofi Aventis and has received a salary for these tasks. H.D.M., C.Z., P.C. and G.D. declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks D. Coustan, T. Buchanan and L. Sobrevia for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related Links

WHO: http://www.who.int/about/regions/en

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McIntyre, H.D., Catalano, P., Zhang, C. et al. Gestational diabetes mellitus. Nat Rev Dis Primers 5, 47 (2019). https://doi.org/10.1038/s41572-019-0098-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-019-0098-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing