, Volume 61, Issue 5, pp 1071–1080 | Cite as

Impact of type 1 diabetes on maternal long-term risk of hospitalisation and mortality: a nationwide combined clinical and register-based cohort study (The EPICOM study)

  • Sine Knorr
  • Svend Juul
  • Birgitte Bytoft
  • Zuzana Lohse
  • Tine D. Clausen
  • Rikke B. Jensen
  • Peter Damm
  • Henning Beck-Nielsen
  • Elisabeth R. Mathiesen
  • Dorte M. Jensen
  • Claus H. Gravholt



The aims of this study were to examine long-term mortality and morbidity rates in mothers with type 1 diabetes, both overall and according to the level of albuminuria prior to pregnancy, the presence of hypertension, pre-eclampsia and periconceptional HbA1c.


This study was a part of the EPICOM (Environmental Versus Genetic and Epigenetic Influences on Growth, Metabolism and Cognitive Function in Offspring of Mothers with Type 1 Diabetes) study, which is a prospective follow-up study focusing on pregnancies complicated by maternal type 1 diabetes. We carried out a nationwide combined clinical and register-based cohort study of mortality rates and hospital admissions in mothers with diabetes (n = 986) who gave birth between 1992 and 2000. Control mothers (n = 91,441) were women from the background population, matched according to age and year of childbirth. Age at follow-up was 32–66 years.


Mortality rate was increased threefold in mothers with diabetes compared with control mothers (HR 3.41 [95% CI 2.42, 4.81]; p < 0.0001), and was also increased with pre-gestational kidney dysfunction (normoalbuminuria, HR 2.17 [95% CI 1.28, 3.68]; microalbuminuria, HR 3.36 [95% CI 0.82, 13.8]; macroalbuminuria, HR 12.9 [95% CI 5.45, 30.7]). Moreover, the presence of hypertension prior to or at any time during pregnancy and of pre-eclampsia also increased mortality rate (hypertension, HR 4.34 [95% CI 2.13, 8.84]; pre-eclampsia, HR 5.55 [95% CI 2.71, 11.4]). Mortality rate also increased with higher levels of HbA1c in early pregnancy (HbA1c ≤75 mmol/mol [≤9%], HR 2.15 [95% CI 1.31, 3.53]; HbA1c >75 mmol/mol [>9%], HR 6.10 [95% CI 2.67, 14.0]). However, in mothers with diabetes and HbA1c <64 mmol/mol (<8%) in the first trimester and normal pre-gestational urinary albumin excretion rate (n = 517), mortality rate was comparable with that of control mothers. Among mothers with diabetes, mortality rate was associated with HbA1c level: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.52 (95% CI 1.19, 1.94; p = 0.001). In mothers with diabetes, the overall incidence of hospital admissions was more than double (incidence rate ratio [IRR] 2.69 [95% CI 2.59, 2.80]; p < 0.0001) that of control mothers, as were admissions with various diagnoses from 14 out of 19 ICD-10 chapters. Among mothers with diabetes, the IRR for hospital admissions increased with the level of HbA1c: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.07 (95% CI 1.04, 1.10; p < 0.0001).


Overall, mothers with type 1 diabetes have a two- to threefold increase in mortality and morbidity rates. HbA1c levels, level of albuminuria around the time of conception, and the presence of hypertension and pre-eclampsia are important risk factors for mortality/morbidity in this cohort. However, it is reassuring that mothers with type 1 diabetes without kidney complications and with HbA1c <64 mmol/mol (<8%) in early pregnancy have a similar survival potential during the period where they are raising their children to that of control mothers from the background population.


Albuminuria HbA1c Hypertension Maternal Morbidity Mortality Pre-eclampsia Type 1 diabetes 



Incidence rate ratio


Urinary albumin excretion rate



The Danish Diabetes Association is acknowledged for originally assisting in the creation of a registry of pregnant women with type 1 diabetes. In addition, data collection in the original registry was performed by P. Ovesen, L. Mølsted-Pedersen, J. Klebe, N. Hahnemann, M. Møller, J. G. Westergaard, H. Gjessing, J. Kragh Mostrup, K. H. Frandsen, E. Stage, A. Thomsen, T. Lousen, K. Rubeck Petersen, B. Øvlisen, J. Kvetny and H. Poulsen (Working Group for Type 1 Diabetes Pregnancy). Apart from H. Beck-Nielsen and P. Damm, the original registry working group included A. Frøland, L. Mølsted-Pedersen, J. Klebe and C. E. Mogensen.

Contribution statement

HB-N and PD contributed to the establishment of the original registry, and PD and DMJ contributed to data collection. SK, ZL, BB, TDC, RBJ, PD, ERM, HB-N, DMJ and CHG all contributed substantially to the conception and design of the study. SK, SJ and CHG analysed and interpreted the data, and SK drafted the manuscript and designed the tables. All authors critically revised the article and approved the final version for publication. SK had full access to the data and takes full responsibility for the contents of the paper.


The study was funded by the European Foundation for the Study of Diabetes/Lilly 2015 Programme and the Lundbeck Foundation.

Data availability

The dataset generated and analysed during this study is not publicly available due both to considerations of the privacy and anonymity of the participants and also due to restrictions from Statistics Denmark. Other researchers may apply for access to the data if they have obtained official approval.

Duality of interest

SK, ZL, BB, TDC, RBJ and SJ declare that there is no duality of interest associated with their contribution to this manuscript. HB-N, PD and CHG have received lecture fees from Novo Nordisk. DMJ has received lecture fees from Eli Lilly. ERM and HB-N receive grant support from Novo Nordisk.

Supplementary material

125_2018_4575_MOESM1_ESM.pdf (199 kb)
ESM Tables (PDF 199 kb)


  1. 1.
    Bojestig M, Arnqvist H, Hermansson G et al (1994) Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 330:15–18CrossRefPubMedGoogle Scholar
  2. 2.
    Andrésdóttir G, Jensen ML, Carstensen B et al (2014) Improved prognosis of diabetic nephropathy in type 1 diabetes. Kidney Int 71:1–10Google Scholar
  3. 3.
    Mathiesen ER, Hommel E, Hansen HP et al (1999) Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 319:24–25CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lewis E, Hunsicker L, Bain R, Rohde R (1993) The effect of angiotensin-converting-enzyme on diabetic nephropathy. N Engl J Med 329:1456–1462CrossRefPubMedGoogle Scholar
  5. 5.
    Lind M, Svensson A-M, Kosiborod M et al (2014) Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 371:1972–1982CrossRefPubMedGoogle Scholar
  6. 6.
    Groop P, Thomas MC, Moran JL et al (2009) The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 58:1651–1658CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Orchard TJ, Secrest AM, Miller RG, Costacou T (2010) In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 53:2312–2319CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Livingstone SJ, Looker HC, Hothersall EJ et al (2012) Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med 9:1–11CrossRefGoogle Scholar
  9. 9.
    Soedamah-Muthu SS, Fuller JH, Mulnier HE et al (2006) All-cause mortality rates in patients with type 1 diabetes mellitus compared with a non-diabetic population from the UK general practice research database, 1992-1999. Diabetologia 49:660–666CrossRefPubMedGoogle Scholar
  10. 10.
    Secrest AM, Becker DJ, Kelsey SF et al (2010) Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 59:3216–3222CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Laing SP, Swerdlow AJ, Carpenter LM et al (2003) Mortality from cerebrovascular disease in a cohort of 23 000 patients with insulin-treated diabetes. Stroke 34:418–421CrossRefPubMedGoogle Scholar
  12. 12.
    Laing SP, Swerdlow AJ, Slater SD et al (2003) Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia 46:760–765CrossRefPubMedGoogle Scholar
  13. 13.
    Skrivarhaug T, Bangstad H-J, Stene LC et al (2006) Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 49:298–305CrossRefPubMedGoogle Scholar
  14. 14.
    Donnelly J, Nair S, Griffin R et al (2016) Diabetes and insulin therapy are associated with increased risk of hospitalization for infection but not mortality: a longitudinal cohort study. Clin Infect Dis 64:435–442Google Scholar
  15. 15.
    Kornum JB, Thomsen RW, Riss A et al (2008) Diabetes, glycemic control, and risk of hospitalization with pneumonia. Diabetes Care 31:1541–1545CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cooper MN, Lin A, Alvares GA et al (2017) Psychiatric disorders during early adulthood in those with childhood onset type 1 diabetes: rates and clinical risk factors from population-based follow-up. Pediatr Diabetes 18:599–606CrossRefPubMedGoogle Scholar
  17. 17.
    Shu X, Ji J, Li X et al (2010) Cancer risk among patients hospitalized for type 1 diabetes mellitus: a population-based cohort study in Sweden. Diabet Med 27:791–797CrossRefPubMedGoogle Scholar
  18. 18.
    Hsiao Y-T, Cheng W-C, Liao W-C et al (2015) Type 1 diabetes and increased risk of subsequent asthma: a nationwide population-based cohort study. Medicine 94:1–6Google Scholar
  19. 19.
    Jensen DM, Damm P, Mølsted-Pedersen L et al (2004) Outcomes in type 1 diabetic pregnancies: a nationwide, population-based study. Diabetes Care 27:2819–2823CrossRefPubMedGoogle Scholar
  20. 20.
    Parsons LS (2001) Reducing bias in a propensity score matched-pair sample using greedy matching techniques. Available from Accessed 14 Jan 2014
  21. 21.
    Knorr S, Stochholm K, Vlachovâ Z et al (2015) Multisystem morbidity and mortality in offspring of women with type 1 diabetes (The EPICOM Study): a register-based prospective cohort study. Diabetes Care 38:821–826CrossRefPubMedGoogle Scholar
  22. 22.
    Jensen DM, Korsholm L, Ovesen P et al (2009) Peri-conceptional A1c and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care 32:1046–1048CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Helweg-Larsen K (2011) The Danish Register of Causes of Death. Scand J Public Health 39:26–29CrossRefPubMedGoogle Scholar
  24. 24.
    Schmidt M, Schmidt SAJ, Sandegaard JL et al (2015) The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol 7:449–490CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Mors O, Perto GP, Mortensen PB (2011) The Danish Psychiatric Central Research Register. Scand J Public Health 39:54–57CrossRefPubMedGoogle Scholar
  26. 26.
    Livingstone SJ, Levin D, Looker HC et al (2015) Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA 313:37–44CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shankar A, Klein R, Klein BEK, Moss SE (2007) Association between glycosylated hemoglobin level and cardiovascular and all-cause mortality in type 1 diabetes. Am J Epidemiol 166:393–402CrossRefPubMedGoogle Scholar
  28. 28.
    Lachin JM, Bebu I, Nathan DM et al (2016) Mortality in type 1 diabetes in the DCCT/EDIC versus the general population. Diabetes Care 39:1378–1383Google Scholar
  29. 29.
    Schjoedt KJ, Hansen HP, Tarnow L et al (2008) Long-term prevention of diabetic nephropathy: an audit. Diabetologia 51:956–961CrossRefPubMedGoogle Scholar
  30. 30.
    Jonasson J, Brismar K, Sparén P (2007) Fertility in women with type 1 diabetes: a population-based cohort study in Sweden. Diabetes Care 30:2271–2276CrossRefPubMedGoogle Scholar
  31. 31.
    Secher AL, Ringholm L, Andersen HU et al (2013) The effect of real-time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care 36:1877–1883CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sine Knorr
    • 1
    • 2
  • Svend Juul
    • 3
  • Birgitte Bytoft
    • 4
    • 5
  • Zuzana Lohse
    • 6
  • Tine D. Clausen
    • 7
  • Rikke B. Jensen
    • 5
    • 8
  • Peter Damm
    • 4
    • 5
  • Henning Beck-Nielsen
    • 6
  • Elisabeth R. Mathiesen
    • 5
    • 9
  • Dorte M. Jensen
    • 6
  • Claus H. Gravholt
    • 1
    • 2
  1. 1.Department of Endocrinology and Internal MedicineAarhus University HospitalAarhus CDenmark
  2. 2.Department of Molecular MedicineAarhus University HospitalAarhusDenmark
  3. 3.Section for Epidemiology, Department of Public HealthAarhus UniversityAarhusDenmark
  4. 4.Center for Pregnant Women with Diabetes, Department of ObstetricsRigshospitaletCopenhagenDenmark
  5. 5.Institute of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Department of EndocrinologyOdense University HospitalOdenseDenmark
  7. 7.Department of Gynaecology and ObstetricsNordsjællands HospitalHillerødDenmark
  8. 8.Department of Growth and ReproductionRigshospitaletCopenhagenDenmark
  9. 9.Center for Pregnant Women with Diabetes, Department of EndocrinologyRigshospitaletCopenhagenDenmark

Personalised recommendations