Mortality rate in mothers with type 1 diabetes compared with matched control mothers
A total of 986 mothers with diabetes were included in the study along with 91,441 matched control mothers. Of these, 38 mothers with diabetes and 1049 control mothers died during the observation period.
Mortality rate was significantly increased in mothers with diabetes (HR 3.41 [95% CI 2.42, 4.81]; p < 0.0001) (Fig. 1, Table 2). The specific cause of death was known for 963 individuals, and cause-specific mortality rates could be estimated for ten of 19 ICD-10 chapters (Table 2). The most frequent causes of death are listed in electronic supplementary material (ESM) Table 1.
Mortality in relation to albuminuria, hypertension, pre-eclampsia and HbA1c level
In mothers with diabetes, we had information on the pre-gestational level of albuminuria for 74%, on hypertension prior to or during pregnancy for 76%, on pre-eclampsia for 82% and on knowledge of the first trimester level of HbA1c for 84%. Of the deceased mothers with diabetes, nine had HbA1c >75 mmol/mol (>9%), six had macroalbuminuria, two had microalbuminuria, eight had hypertension and nine were diagnosed with pre-eclampsia. Some mothers with diabetes were represented in more than one subgroup.
There was a close relation between the level of albuminuria and mortality rate, but even type 1 diabetic mothers with normoalbuminuria had significantly increased mortality rate compared with the matched control mothers (Table 2). The same applied to the presence of hypertension and pre-eclampsia (Table 2). Similarly, we found increasing mortality rate with increasing HbA1c in index compared with control mothers (Table 2). Compared with matched control mothers, mortality rate was also increased in the group of mothers with type 1 diabetes and no information on the level of albuminuria, hypertension, pre-eclampsia or HbA1c (ESM Table 2). Only in the group of mothers with diabetes who had normoalbuminuria prior to pregnancy and HbA1c below 64 mmol/mol (8%) in the first trimester (n = 517) was mortality rate not significantly increased compared with control mothers (Table 3). Mothers with diabetes, normoalbuminuria and HbA1c <52 mmol/mol (<6.9%) had an HR of 1.11 (95% CI 0.36, 3.47), mothers with normoalbuminuria and HbA1c 52–63 mmol/mol (6.9–7.9%) had an HR of 1.53 (95% CI 0.57, 4.11) and mothers with normoalbuminuria and HbA1c 64–75 mmol/mol (8–9%) had an HR of 4.02 (95% CI 1.64, 9.84), whereas mortality rate in the group of mothers with normoalbuminuria and HbA1c >75 mmol/mol (>9%) was increased with an HR of 3.64 (95% CI 1.15, 11.6) (Table 3).
Using mothers with normoalbuminuria as a reference, the HR in diabetic mothers with microalbuminuria was 1.07 (95% CI 0.24, 4.76) and 4.76 (95% CI 1.73, 13.1) in mothers with macroalbuminuria, and this trend was significant (p = 0.006).
Mortality rate was associated with the level of HbA1c among mothers with diabetes; per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.52 (CI 1.19, 1.94; p = 0.001). For deaths related to circulatory diseases (e.g. heart failure or acute myocardial infarction) and endocrine diseases (e.g. type 1 diabetic complications), we found increased mortality rate with increasing HbA1c, and for endocrine diseases mortality rate also increased with increasing levels of albuminuria.
Incidence of hospital admissions in mothers with type 1 diabetes compared with matched control mothers
The overall incidence of hospital admissions was significantly increased in mothers with diabetes compared with matched control mothers (IRR 2.69 [95% CI 2.59, 2.80]; p < 0.0001) (Fig. 2, ESM Tables 3–6). The incidence of admissions was increased for several ICD-10 chapters, including endocrine diseases, eye diseases, infections, central nervous system diseases, circulatory diseases and genitourinary diseases. We also found an elevated risk of ever being admitted with diseases of the blood and immune system, psychiatric diseases, respiratory diseases, skin and musculoskeletal diseases, as well as pregnancy-associated diseases, unspecified diseases and admissions due to external influences (e.g. car accident, falling, exposure to fire). Altogether, mothers with diabetes had an increased risk of hospital admissions with diagnoses from 14 out of 19 ICD-10 chapters compared with control mothers.
When excluding admissions with diagnoses relating to endocrine and eye diseases, the overall incidence of hospital admissions was still increased in mothers with diabetes compared with control mothers (IRR 1.71 [95% CI 1.64, 1.78]; p < 0.0001) (Fig. 2).
Most of the increased IRRs are explained by an increased proportion of mothers with diabetes ever admitted rather than by a higher number of admissions among those ever admitted (ESM Table 7). When excluding all outpatient and emergency room visits, we still found an increased risk of admissions (HR 2.38 [95% CI 2.20, 2.57]; p < 0.0001), and the risk of admissions with specific diagnoses was increased in 15 out of 19 ICD-10 chapters (ESM Table 8).
Incidence of hospital admissions in relation to albuminuria, hypertension, pre-eclampsia and HbA1c levels
In diabetic mothers we found an increased risk of hospital admissions with increasing levels of albuminuria compared with matched control mothers (ESM Table 3). In particular, the risk of admission with infections, endocrine, eye, circulatory, skin and unspecified diseases, as well as diseases caused by external influences, was consistently associated with the level of albuminuria prior to pregnancy (ESM Table 3).
When analysing the incidence of hospital admissions among mothers with diabetes, using mothers with normoalbuminuria as a reference, we found a trend towards an increased incidence with increasing level of albuminuria: microalbuminuria, IRR 1.09 (95% CI 0.94, 1.28); macroalbuminuria, IRR 1.18 (95% CI 0.98, 1.42); test for trend, p = 0.051 (data not shown).
In diabetic mothers the presence of hypertension and pre-eclampsia was also found to be associated with an increased risk of being admitted both overall and for diagnoses from several ICD-10 chapters, including infections, endocrinology, eye and circulatory diseases (ESM Tables 4 and 5).
With increasing levels of HbA1c in early pregnancy, we found an overall increasing risk of being admitted to hospital in diabetic mothers compared with control mothers (ESM Table 6).
Among mothers with diabetes, we found an IRR for hospital admissions of 1.07 per 11 mmol/mol (1 percentage point) increase in HbA1c (95% CI 1.04, 1.10; p < 0.0001). Admissions with diagnoses from the following ICD-10 chapters increased significantly with HbA1c: infections, endocrine, eye, skin, musculoskeletal, genitourinary, external influences and unspecified diseases (data not shown).
Fewer mothers with type 1 diabetes had a bachelor’s degree (Table 1). However, when adjusting for education, the estimates of mortality and hospital admission rates remained largely unchanged (data not shown).