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.

Improving pregnancy outcomes in women with diabetes mellitus: modern management

Abstract

Women with pre-existing (type 1 or type 2) diabetes mellitus are at increased risk of pregnancy complications, such as congenital malformations, preeclampsia and preterm delivery, compared with women who do not have diabetes mellitus. Approximately half of pregnancies in women with pre-existing diabetes mellitus are complicated by fetal overgrowth, which results in infants who are overweight at birth and at risk of birth trauma and, later in life, the metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus. Strict glycaemic control with appropriate diet, use of insulin and, if necessary, antihypertensive treatment is the cornerstone of diabetes mellitus management to prevent pregnancy complications. New technology for managing diabetes mellitus is evolving and is changing the management of these conditions in pregnancy. For instance, in Europe, most women with pre-existing diabetes mellitus are treated with insulin analogues before and during pregnancy. Furthermore, many women are on insulin pumps during pregnancy, and the use of continuous glucose monitoring is becoming more frequent. In addition, smartphone application technology is a promising educational tool for pregnant women with diabetes mellitus and their caregivers. This Review covers how modern diabetes mellitus management with appropriate diet, insulin and antihypertensive treatment in patients with pre-existing diabetes mellitus can contribute to reducing the risk of pregnancy complications such as congenital malformations, fetal overgrowth, preeclampsia and preterm delivery.

Key points

  • The cornerstones of modern diabetes mellitus management in pregnancy are appropriate diet and insulin therapy with a focus on prevention of maternal hypoglycaemia and hyperglycaemia to reduce the risk of pregnancy complications.

  • Implementing an appropriate diet with a focus on the quantity and quality of carbohydrates and limiting maternal gestational weight gain are promising treatment areas to reduce the risk of fetal overgrowth.

  • The use of insulin analogues, insulin pumps, continuous glucose monitoring and bolus calculators might help improve glycaemic control and reduce the risk of severe maternal hypoglycaemia in pregnancy.

  • Early and intensive antihypertensive treatment with antihypertensive agents approved for use in pregnancy might reduce the risk of preeclampsia and preterm delivery, especially in women with diabetic kidney disease.

  • Easily accessible patient education (that is, via smartphone application technology) is useful to reach pregnant women and provide information on modern diabetes mellitus management to improve pregnancy outcomes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The prevalence of severe maternal hypoglycaemia in pregnancy can be reduced.
Fig. 2: Treatment algorithm for antihypertensive treatment in pregnancy.

References

  1. 1.

    Colstrup, M., Mathiesen, E. R., Damm, P., Jensen, D. M. & Ringholm, L. Pregnancy in women with type 1 diabetes: have the goals of St. Vincent declaration been met concerning foetal and neonatal complications? J. Matern. Fetal Neonatal Med. 26, 1682–1686 (2013).

    CAS  PubMed  Google Scholar 

  2. 2.

    Bell, R., Glinianaia, S. V., Tennant, P. W., Bilous, R. W. & Rankin, J. Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia 55, 936–947 (2012).

    CAS  Google Scholar 

  3. 3.

    Ekbom, P. et al. Elevated third-trimester haemoglobin A 1c predicts preterm delivery in type 1 diabetes. J. Diabetes Compl. 22, 297–302 (2008).

    Google Scholar 

  4. 4.

    Glinianaia, S. V., Tennant, P. W., Bilous, R. W., Rankin, J. & Bell, R. HbA(1c) and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study. Diabetologia 55, 3193–3203 (2012).

    CAS  PubMed  Google Scholar 

  5. 5.

    Murphy, H. R. et al. Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study. Diabetologia 60, 1668–1677 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Norgaard, S. K. et al. Diastolic blood pressure is a potentially modifiable risk factor for preeclampsia in women with pre-existing diabetes. Diabetes Res. Clin. Pract. 138, 229–237 (2018).

    PubMed  Google Scholar 

  7. 7.

    Mathiesen, E. R. Pregnancy outcomes in women with diabetes-lessons learned from clinical research: the 2015 Norbert Freinkel Award Lecture. Diabetes Care 39, 2111–2117 (2016).

    CAS  PubMed  Google Scholar 

  8. 8.

    Mills, J. L., Baker, L. & Goldman, A. S. Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 28, 292–293 (1979).

    CAS  PubMed  Google Scholar 

  9. 9.

    Jensen, D. M. et al. Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care 32, 1046–1048 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Eriksson, U. J., Borg, L. A. H., Forsberg, H. & Styrud, J. Diabetic embryopathy studies with animal and in vitro models. Diabetes 40 (Suppl. 2), 94–98 (1991).

    CAS  PubMed  Google Scholar 

  11. 11.

    Guerin, A., Nisenbaum, R. & Ray, J. G. Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care 30, 1920–1925 (2007).

    CAS  PubMed  Google Scholar 

  12. 12.

    American Diabetes Association. Standards of medical care in diabetes 2018. Diabetes Care 41, 137–143 (2018).

    Google Scholar 

  13. 13.

    Clausen, P. et al. Signs of maternal vascular dysfunction precede preeclampsia in women with type 1 diabetes. J. Diabetes Compl. 21, 288–293 (2007).

    Google Scholar 

  14. 14.

    Ekbom, P. et al. Urinary albumin excretion and 24-hour blood pressure as predictors of pre-eclampsia in Type I diabetes. Diabetologia 43, 927–931 (2000).

    CAS  PubMed  Google Scholar 

  15. 15.

    Hanson, U. & Persson, B. Epidemiology of pregnancy-induced hypertension and preeclampsia in type 1 (insulin-dependent) diabetic pregnancies in Sweden. Acta Obstet. Gynecol. Scand. 77, 620–624 (1998).

    CAS  PubMed  Google Scholar 

  16. 16.

    Hiilesmaa, V., Suhonen, L. & Teramo, K. Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with type I diabetes mellitus. Diabetologia 43, 1534–1539 (2000).

    CAS  PubMed  Google Scholar 

  17. 17.

    Holmes, V. A. et al. Optimal glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabetes Care 34, 1683–1688 (2011).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Klemetti, M. M. et al. Obstetric and perinatal outcome in type 1 diabetes patients with diabetic nephropathy during 1988–2011. Diabetologia 58, 678–686 (2015).

    CAS  PubMed  Google Scholar 

  19. 19.

    Vestgaard, M., Sommer, M. C., Ringholm, L., Damm, P. & Mathiesen, E. R. Prediction of preeclampsia in type 1 diabetes in early pregnancy by clinical predictors: a systematic review. J. Matern. Fetal Neonatal Med. 31, 1933–1939 (2018).

    PubMed  Google Scholar 

  20. 20.

    Boulot, P. et al. French multicentric survey of outcome of pregnancy in women with pregestational diabetes. Diabetes Care 26, 2990–2993 (2003).

    PubMed  Google Scholar 

  21. 21.

    Law, G. R. et al. Analysis of continuous glucose monitoring in pregnant women with diabetes: distinct temporal patterns of glucose associated with large-for-gestational-age infants. Diabetes Care 38, 1319–1325 (2015).

    CAS  PubMed  Google Scholar 

  22. 22.

    Seaquist, E. R. et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 36, 1384–1395 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Rosenn, B. M., Miodovnik, M., Holcberg, G., Khoury, J. C. & Siddiqi, T. A. Hypoglycemia: the price of intensive insulin therapy for pregnant women with insulin-dependent diabetes mellitus. Obstet. Gynecol. 85, 417–422 (1995).

    CAS  PubMed  Google Scholar 

  24. 24.

    International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 40, 155–157 (2017).

    Google Scholar 

  25. 25.

    Evers, I. M. et al. Risk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy. Diabetes Care 25, 554–559 (2002).

    PubMed  Google Scholar 

  26. 26.

    Nielsen, L. R. et al. Hypoglycemia in pregnant women with type 1 diabetes: predictors and role of metabolic control. Diabetes Care 31, 9–14 (2008).

    PubMed  Google Scholar 

  27. 27.

    Ringholm, L. et al. The incidence of severe hypoglycaemia in pregnant women with type 1 diabetes mellitus can be reduced with unchanged HbA1c levels and pregnancy outcomes in a routine care setting. Diabetes Res. Clin. Pract. 101, 123–130 (2013).

    CAS  PubMed  Google Scholar 

  28. 28.

    Secher, A. L., Mathiesen, E. R., Andersen, H. U., Damm, P. & Ringholm, L. Severe hypoglycemia in pregnant women with type 2 diabetes-A relevant clinical problem. Diabetes Res. Clin. Pract. 102, e17–e18 (2013).

    PubMed  Google Scholar 

  29. 29.

    Maresh, M. J. et al. Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes. Diabetes Care 38, 34–42 (2015).

    PubMed  Google Scholar 

  30. 30.

    Secher, A. L., Bytoft, B., Tabor, A., Damm, P. & Mathiesen, E. R. Fetal sonographic characteristics associated with shoulder dystocia in pregnancies of women with type 1 diabetes. Acta Obstet. Gynecol. Scand. 94, 1105–1111 (2015).

    CAS  PubMed  Google Scholar 

  31. 31.

    Institute of Medicine and National Research Council. Weight Gain During Pregnancy: Reexamining the Guidelines (The National Academies Press, 2009).

  32. 32.

    Secher, A. L. et al. Higher gestational weight gain is associated with increasing offspring birth weight independent of maternal glycemic control in women with type 1 diabetes. Diabetes Care 37, 2677–2684 (2014).

    CAS  PubMed  Google Scholar 

  33. 33.

    Morrens, A. et al. Risk factors for large-for-gestational age infants in pregnant women with type 1 diabetes. BMC Pregnancy Childbirth 16, 162 (2016).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Owens, L. A., Egan, A. M., Carmody, L. & Dunne, F. Ten years of optimizing outcomes for women with type 1 and type 2 diabetes in pregnancy — the Atlantic DIP Experience. J. Clin. Endocrinol. Metab. 101, 1598–1605 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (The National Academies Press, 2005).

  36. 36.

    Felig, P. & Lynch, V. Starvation in human pregnancy: hypoglycemia, hypoinsulinemia, and hyperketonemia. Science 170, 990–992 (1970).

    CAS  PubMed  Google Scholar 

  37. 37.

    Knopp, R. H., Magee, M. S., Raisys, V., Benedetti, T. & Bonet, B. Hypocaloric diets and ketogenesis in the management of obese gestational diabetic women. J. Am. Coll. Nutr. 10, 649–667 (1991).

    CAS  PubMed  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  Google Scholar 

  39. 39.

    Stehbens, J. A., Baker, G. L. & Kitchell, M. Outcome at ages 1, 3, and 5 years of children born to diabetic women. Am. J. Obstet. Gynecol. 127, 408–413 (1977).

    CAS  PubMed  Google Scholar 

  40. 40.

    Roskjaer, A. B., Andersen, J. R., Ronneby, H., Damm, P. & Mathiesen, E. R. Dietary advices on carbohydrate intake for pregnant women with type 1 diabetes. J. Matern. Fetal Neonatal Med. 28, 229–233 (2015).

    CAS  PubMed  Google Scholar 

  41. 41.

    Asbjornsdottir, B. et al. The influence of carbohydrate consumption on glycemic control in pregnant women with type 1 diabetes. Diabetes Res. Clin. Pract. 127, 97–104 (2017).

    CAS  PubMed  Google Scholar 

  42. 42.

    Ringholm, L., Ásbjörnsdóttir, B., Andersen, H. U., Damm, P. & Mathiesen, E. R. in Nutrition and Diet in Maternal Diabetes: An Evidence-Based Approach (eds Rajendram, R., Preedy, V. R. & Patel, V. B.) 385–397 (Springer Nature, 2018).

  43. 43.

    Hod, M. et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am. J. Obstet. Gynecol. 198, 186–187 (2008).

    PubMed  Google Scholar 

  44. 44.

    Hod, M. et al. A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes. J. Matern. Fetal Neonatal Med. 27, 7–13 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    Mathiesen, E. R. et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 30, 771–776 (2007).

    CAS  PubMed  Google Scholar 

  46. 46.

    Mathiesen, E. R. et al. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care 35, 2012–2017 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Feig, D. S. et al. Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial. Lancet 390, 2347–2359 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Murphy, H. R. et al. Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ 337, a1680 (2008).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Secher, A. L., Ringholm, L., Andersen, H. U., Damm, P. & Mathiesen, E. R. The effect of real-time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care 36, 1877–1883 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Voormolen, D. N. et al. Continuous glucose monitoring during diabetic pregnancy (GlucoMOMS): A multicentre randomized controlled trial. Diabetes Obes. Metab. 20, 1894–1902 (2018).

    CAS  PubMed  Google Scholar 

  51. 51.

    European Medicines Agency. NovoRapid. Annex I: summary of product characteristics. EMA https://www.ema.europa.eu/documents/product-information/novorapid-epar-product-information_en.pdf (updated 23 May 2018).

  52. 52.

    European Medicines Agency. Apidra. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000557/WC500025250.pdf (updated 14 May 2018).

  53. 53.

    European Medicines Agency. Insulin lispro Sanofi. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004303/WC500235294.pdf (updated 04 Dec 2018).

  54. 54.

    Toledano, Y., Hadar, E. & Hod, M. Pharmacotherapy for hyperglycemia in pregnancy — the new insulins. Diabetes Res. Clin. Pract. 145, 59–66 (2018).

    CAS  PubMed  Google Scholar 

  55. 55.

    Mathiesen, J. M. et al. Changes in basal rates and bolus calculator settings in insulin pumps during pregnancy in women with type 1 diabetes. J. Matern. Fetal Neonatal Med. 27, 724–728 (2014).

    CAS  PubMed  Google Scholar 

  56. 56.

    Murphy, H. R. et al. Pathophysiology of postprandial hyperglycaemia in women with type 1 diabetes during pregnancy. Diabetologia 55, 282–293 (2012).

    CAS  PubMed  Google Scholar 

  57. 57.

    European Medicines Agency. Abasaglar. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002835/WC500175381.pdf (updated 21 Mar 2018).

  58. 58.

    European Medicines Agency. Lantus. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000284/WC500036082.pdf (updated 13 Jul 2018).

  59. 59.

    European Medicines Agency. Toujeo. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000309/WC500047935.pdf (updated 23 Nov 2018).

  60. 60.

    European Medicines Agency. Fiasp. Annex I: summary of product characteristics. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004046/WC500220890.pdf (updated 27 Apr 2018).

  61. 61.

    Heise, T., Pieber, T. R., Danne, T., Erichsen, L. & Haahr, H. A. Pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clin. Pharmacokinet. 56, 551–559 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zijlstra, E. et al. Investigation of pump compatibility of fast-acting insulin aspart in subjects with type 1 diabetes. J. Diabetes Sci. Technol. 12, 145–151 (2018).

    CAS  PubMed  Google Scholar 

  63. 63.

    Haahr, H. & Heise, T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin. Pharmacokinet. 53, 787–800 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Formoso, G., Ginestra, F., Di Dalmazi, G. & Consoli, A. Empagliflozin, metformin and insulin degludec, during pregnancy: a case report. Acta Diabetol. 55, 759–761 (2018).

    CAS  PubMed  Google Scholar 

  65. 65.

    Milluzzo, A. et al. Insulin degludec in the first trimester of pregnancy: report of two cases. J. Diabetes Investig. 9, 629–631 (2017).

    PubMed Central  Google Scholar 

  66. 66.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03377699 (2019).

  67. 67.

    Gabbe, S. G., Carpenter, L. B. & Garrison, E. A. New strategies for glucose control in patients with type 1 and type 2 diabetes mellitus in pregnancy. Clin. Obstet. Gynecol. 50, 1014–1024 (2007).

    PubMed  Google Scholar 

  68. 68.

    Abell, S. K. et al. Pregnancy outcomes and insulin requirements in women with type 1 diabetes treated with continuous subcutaneous insulin infusion and multiple daily injections: cohort study. Diabetes Technol. Ther. 19, 280–287 (2017).

    CAS  PubMed  Google Scholar 

  69. 69.

    Kallas-Koeman, M. M. et al. Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes. Diabetologia 57, 681–689 (2014).

    CAS  PubMed  Google Scholar 

  70. 70.

    Rys, P. M., Ludwig-Slomczynska, A. H., Cyganek, K. & Malecki, M. T. Continuous subcutaneous insulin infusion versus multiple daily injections in pregnant women with type 1 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials and observational studies. Eur. J. Endocrinol. 178, 545–563 (2018).

    CAS  PubMed  Google Scholar 

  71. 71.

    Feig, D. S. et al. Pumps or multiple daily injections in pregnancy involving type 1 diabetes: a prespecified analysis of the CONCEPTT Randomized Trial. Diabetes Care 41, 2471–2479 (2018).

    CAS  PubMed  Google Scholar 

  72. 72.

    Abraham, M. B. et al. Reduction in hypoglycemia with the predictive low-glucose management system: a long-term randomized controlled trial in adolescents with type 1 diabetes. Diabetes Care 41, 303–310 (2018).

    PubMed  Google Scholar 

  73. 73.

    Battelino, T., Nimri, R., Dovc, K., Phillip, M. & Bratina, N. Prevention of hypoglycemia with predictive low glucose insulin suspension in children with type 1 diabetes: a randomized controlled trial. Diabetes Care 40, 764–770 (2017).

    CAS  PubMed  Google Scholar 

  74. 74.

    Aberer, F. et al. Evaluation of subcutaneous glucose monitoring systems under routine environmental conditions in patients with type 1 diabetes. Diabetes Obes. Metab. 19, 1051–1055 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Buckingham, B. A. et al. Evaluation of a predictive low-glucose management system in-clinic. Diabetes Technol. Ther. 19, 288–292 (2017).

    CAS  PubMed  Google Scholar 

  76. 76.

    Messer, L. H. et al. Optimizing hybrid closed-loop therapy in adolescents and emerging adults using the MiniMed 670G System. Diabetes Care 41, 789–796 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    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).

    PubMed  Google Scholar 

  78. 78.

    Corcoy, R., Balsells, M., Garcia-Patterson, A., Shmueli, A. & Hadar, E. Pharmacotherapy for hyperglycemia in pregnancy — do oral agents have a place? Diabetes Res. Clin. Pract. 145, 51–58 (2018).

    CAS  PubMed  Google Scholar 

  79. 79.

    Damm, J. A. et al. Diabetic nephropathy and microalbuminuria in pregnant women with type 1 and type 2 diabetes: prevalence, antihypertensive strategy, and pregnancy outcome. Diabetes Care 36, 3489–3494 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Barbour, L. A. et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am. J. Obstet. Gynecol. 219, 367.e1–367.e7 (2018).

    Google Scholar 

  81. 81.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    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).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    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).

    PubMed  Google Scholar 

  84. 84.

    Feig, D. S. et al. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial. BMC Pregnancy Childbirth 16, 173 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Danne, T. et al. International consensus on use of continuous glucose monitoring. Diabetes Care 40, 1631–1640 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Secher, A. L. et al. Real-time continuous glucose monitoring as a tool to prevent severe hypoglycaemia in selected pregnant women with Type 1 diabetes - an observational study. Diabet. Med. 31, 352–356 (2014).

    CAS  PubMed  Google Scholar 

  87. 87.

    Cordua, S., Secher, A. L., Ringholm, L., Damm, P. & Mathiesen, E. R. Real-time continuous glucose monitoring during labour and delivery in women with Type 1 diabetes — observations from a randomized controlled trial. Diabet. Med. 30, 1374–1381 (2013).

    CAS  PubMed  Google Scholar 

  88. 88.

    Stenninger, E., Lindqvist, A., Aman, J., Ostlund, I. & Schvarcz, E. Continuous Subcutaneous Glucose Monitoring System in diabetic mothers during labour and postnatal glucose adaptation of their infants. Diabet. Med. 25, 450–454 (2008).

    CAS  PubMed  Google Scholar 

  89. 89.

    Leelarathna, L. & Wilmot, E. G. Flash forward: a review of flash glucose monitoring. Diabet. Med. 35, 472–482 (2018).

    CAS  PubMed  Google Scholar 

  90. 90.

    Kerssen, A., de Valk, H. W. & Visser, G. H. Do HbA1c levels and the self-monitoring of blood glucose levels adequately reflect glycaemic control during pregnancy in women with type 1 diabetes mellitus? Diabetologia 49, 25–28 (2006).

    CAS  PubMed  Google Scholar 

  91. 91.

    Scott, E. M., Bilous, R. W. & Kautzky-Willer Accuracy, A. User acceptability, and safety evaluation for the FreeStyle Libre Flash Glucose Monitoring System when used by pregnant women with diabetes. Diabetes Technol. Ther. 20, 180–188 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Cavan, D. A. et al. Use of an insulin bolus advisor facilitates earlier and more frequent changes in insulin therapy parameters in suboptimally controlled patients with diabetes treated with multiple daily insulin injection therapy: results of the ABACUS trial. Diabetes Technol. Ther. 16, 310–316 (2014).

    CAS  PubMed  Google Scholar 

  93. 93.

    Hommel, E. et al. Effects of advanced carbohydrate counting guided by an automated bolus calculator in Type 1 diabetes mellitus (StenoABC): a 12-month, randomized clinical trial. Diabet. Med. 34, 708–715 (2017).

    CAS  PubMed  Google Scholar 

  94. 94.

    Schmidt, S. et al. Use of an automated bolus calculator in MDI-treated type 1 diabetes: the BolusCal Study, a randomized controlled pilot study. Diabetes Care 35, 984–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Ziegler, R. et al. Use of an insulin bolus advisor improves glycemic control in multiple daily insulin injection (MDI) therapy patients with suboptimal glycemic control: first results from the ABACUS trial. Diabetes Care 36, 3613–3619 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Schmidt, S., Norgaard, K., Neergaard, K., Almdal, T. & Hommel, E. E. Long-term adherence to automated bolus calculators. J. Diabetes Sci. Technol. 11, 174–175 (2017).

    PubMed  Google Scholar 

  97. 97.

    Cundy, T., Slee, F., Gamble, G. & Neale, L. Hypertensive disorders of pregnancy in women with type 1 and type 2 diabetes. Diabet. Med. 19, 482–489 (2002).

    CAS  PubMed  Google Scholar 

  98. 98.

    Ringholm, L., Damm, J. A., Vestgaard, M., Damm, P. & Mathiesen, E. R. Diabetic nephropathy in women with preexisting diabetes: from pregnancy planning to breastfeeding. Curr. Diab Rep. 16, 12 (2016).

    PubMed  Google Scholar 

  99. 99.

    Napoli, A. et al. Twenty-four-hour blood pressure monitoring in normoalbuminuric normotensive type 1 diabetic women during pregnancy. J. Diabetes Compl. 17, 292–296 (2003).

    Google Scholar 

  100. 100.

    Nielsen, L. R., Damm, P. & Mathiesen, E. R. Improved pregnancy outcome in type 1 diabetic women with microalbuminuria or diabetic nephropathy: effect of intensified antihypertensive therapy? Diabetes Care 32, 38–44 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Khoury, J. C., Miodovnik, M., LeMasters, G. & Sibai, B. Pregnancy outcome and progression of diabetic nephropathy. What’s next? J. Matern. Fetal Neonatal Med. 11, 238–244 (2002).

    CAS  PubMed  Google Scholar 

  102. 102.

    Nielsen, L. R., Muller, C., Damm, P. & Mathiesen, E. R. Reduced prevalence of early preterm delivery in women with type 1 diabetes and microalbuminuria—possible effect of early antihypertensive treatment during pregnancy. Diabet. Med. 23, 426–431 (2006).

    CAS  PubMed  Google Scholar 

  103. 103.

    Bar, J. et al. Pregnancy outcome in patients with insulin dependent diabetes mellitus and diabetic nephropathy treated with ACE inhibitors before pregnancy. J. Pediatr. Endocrinol. Metab. 12, 659–665 (1999).

    CAS  PubMed  Google Scholar 

  104. 104.

    Dunne, F. P. et al. Pregnancy outcome in women with insulin-dependent diabetes mellitus complicated by nephropathy. QJM 92, 451–454 (1999).

    CAS  PubMed  Google Scholar 

  105. 105.

    Ekbom, P. et al. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 24, 1739–1744 (2001).

    CAS  PubMed  Google Scholar 

  106. 106.

    Yu, Y. et al. Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women. Diabetologia 52, 160–168 (2009).

    CAS  PubMed  Google Scholar 

  107. 107.

    Kimmerle, R. et al. Pregnancies in women with diabetic nephropathy: long-term outcome for mother and child. Diabetologia 38, 227–235 (1995).

    CAS  PubMed  Google Scholar 

  108. 108.

    Carr, D. B. et al. Diabetic nephropathy in pregnancy: suboptimal hypertensive control associated with preterm delivery. Am. J. Hypertens. 19, 513–519 (2006).

    PubMed  Google Scholar 

  109. 109.

    Pels, A. et al. Influence of gestational age at initiation of antihypertensive therapy: secondary analysis of CHIPS Trial Data (Control of Hypertension in Pregnancy Study). Hypertension 71, 1170–1177 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Mathiesen, E. R., Ringholm, L., Feldt-Rasmussen, B., Clausen, P. & Damm, P. Obstetric nephrology: pregnancy in women with diabetic nephropathy—the role of antihypertensive treatment. Clin. J. Am. Soc. Nephrol. 7, 2081–2088 (2012).

    CAS  PubMed  Google Scholar 

  111. 111.

    Khandelwal, M., Kumanova, M., Gaughan, J. P. & Reece, E. A. Role of diltiazem in pregnant women with chronic renal disease. J. Matern. Fetal Neonatal Med. 12, 408–412 (2002).

    CAS  PubMed  Google Scholar 

  112. 112.

    von Dadelszen, P. et al. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 355, 87–92 (2000).

    Google Scholar 

  113. 113.

    Parving, H. H. et al. Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy. Am. J. Kidney Dis. 22, 188–195 (1993).

    CAS  PubMed  Google Scholar 

  114. 114.

    Pedersen, B. W. et al. Stable fetal hemodynamics measured by Doppler flow after initiation of anti-hypertensive treatment with methyldopa in pregnant women with diabetes. J. Matern. Fetal Neonatal Med. 29, 550–553 (2016).

    CAS  PubMed  Google Scholar 

  115. 115.

    Folic, M. M., Jankovic, S. M., Varjacic, M. R. & Folic, M. D. Effects of methyldopa and nifedipine on uteroplacental and fetal hemodynamics in gestational hypertension. Hypertens. Pregnancy 31, 31–39 (2012).

    CAS  PubMed  Google Scholar 

  116. 116.

    Montan, S., Anandakumar, C., Arulkumaran, S., Ingemarsson, I. & Ratnam, S. S. Effects of methyldopa on uteroplacental and fetal hemodynamics in pregnancy-induced hypertension. Am. J. Obstet. Gynecol. 168, 152–156 (1993).

    CAS  PubMed  Google Scholar 

  117. 117.

    Montan, S., Anandakumar, C., Arulkumaran, S., Ingemarsson, I. & Ratnam, S. S. Randomised controlled trial of methyldopa and isradipine in preeclampsia—effects on uteroplacental and fetal hemodynamics. J. Perinat. Med. 24, 177–184 (1996).

    CAS  PubMed  Google Scholar 

  118. 118.

    Rolnik, D. L. et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N. Engl. J. Med. 377, 613–622 (2017).

    CAS  PubMed  Google Scholar 

  119. 119.

    Bujold, E. et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet. Gynecol. 116, 402–414 (2010).

    PubMed  Google Scholar 

  120. 120.

    Duley, L., Henderson-Smart, D. J., Meher, S. & King, J. F. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst. Rev. 18, CD004659 (2007).

    Google Scholar 

  121. 121.

    Norgaard, S. K. et al. Use of the smartphone application “Pregnant with Diabetes”. Dan. Med. J. 64, A5417 (2017).

    PubMed  Google Scholar 

  122. 122.

    Arnhold, M., Quade, M. & Kirch, W. Mobile applications for diabetics: a systematic review and expert-based usability evaluation considering the special requirements of diabetes patients age 50 years or older. J. Med. Internet Res. 16, e104 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Jensen, D. M. et al. Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes Care 27, 2819–2823 (2004).

    PubMed  Google Scholar 

  124. 124.

    Vlachova, Z. et al. Increased metabolic risk in adolescent offspring of mothers with type 1 diabetes: the EPICOM study. Diabetologia 58, 1454–1463 (2015).

    CAS  PubMed  Google Scholar 

  125. 125.

    Ringholm, L., Pedersen-Bjergaard, U., Thorsteinsson, B., Damm, P. & Mathiesen, E. R. Hypoglycaemia during pregnancy in women with Type 1 diabetes. Diabet. Med. 29, 558–566 (2012).

    CAS  PubMed  Google Scholar 

Download references

Reviewer information

Nature Reviews Endocrinology thanks F. Brown and other anonymous reviewers for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

L.R. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. P.D. and E.R.M. contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Lene Ringholm.

Ethics declarations

Competing interests

L.R., P.D. and E.R.M. are participating in multi-centre and multi-national clinical studies on the use of insulin in pregnant women with pre-existing diabetes mellitus in collaboration with Novo Nordisk; no personal honorarium is involved. E.R.M. is in the speaker’s bureau of Novo Nordisk.

Additional information

Publisher’s note

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

Related links

FreeStyle Libre System: https://provider.myfreestyle.com/freestyle-libre-clinical-evidence.html

Pregnant with Diabetes: https://itunes.apple.com/us/app/pregnant-with-diabetes/id797791382

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ringholm, L., Damm, P. & Mathiesen, E.R. Improving pregnancy outcomes in women with diabetes mellitus: modern management. Nat Rev Endocrinol 15, 406–416 (2019). https://doi.org/10.1038/s41574-019-0197-3

Download citation

Further reading

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