Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden

Abstract

Objective: To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception.

Design: Population based historical cohort study using nationwide health registers.

Setting: Sweden, 2003-15.

Participants: 2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes.

Main outcome measures: Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels.

Results: 122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33).

Conclusion: Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.

Fig 1

Flow of participant inclusion in study cohort

Fig 2

Predicted unadjusted risk of major birth defects associated with type 1 diabetes according to maternal levels of glycated haemoglobin within three months before or after estimated conception

Fig 3

Association between maternal type 1 diabetes and risk of major birth defects, using alternative measures of poor glycaemic control and diabetes severity. *Adjusted for calendar year, maternal age, country of birth, living with partner, education, parity, body mass index, smoking status, and other autoimmune diseases. The reference category in all analyses was infants born to mothers without diabetes (see table 2 for number of infants, number of events, and number of events per 1000 infants). Long term glycaemic control was defined as the mean of the last three measurements for glycated haemoglobin. The risk ratio plot uses a log scale