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)
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.
KeywordsAlbuminuria 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.
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.
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.
- 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
- 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
- 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
- 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
- 20.Parsons LS (2001) Reducing bias in a propensity score matched-pair sample using greedy matching techniques. Available from www2.sas.com/proceedings/sugi26/p214-26.pdf. Accessed 14 Jan 2014
- 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