Risk for Congenital Anomaly With Exposure to Insulin Analogues in the First Trimester

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Planned pregnancy was associated with a lower risk for major congenital anomalies and congenital heart defects.
Planned pregnancy was associated with a lower risk for major congenital anomalies and congenital heart defects.

The fetuses of women exposed to insulin analogues during the first trimester of pregnancy may not be at increased risk for a major congenital anomaly compared with fetuses exposed to human insulin, according to a study published in BMJ Open

Researchers performed a retrospective population-based study of 1661 women diagnosed with pre-gestational diabetes who had given birth between 1996 and 2012 to offspring exposed to insulin analogues, human insulin, or both insulin analogues and human insulin during the first trimester of their pregnancy. 

The primary outcome of this study was to determine whether exposure to insulin analogues compared with exposure to human insulin during the first trimester of pregnancy was associated with a higher risk for having offspring with a major congenital anomaly.

Based upon the type of insulin the fetus was exposed to during the first trimester, 3 groups were established: human insulin (n=870, 52.4%), insulin analogues (n=397, 23.9%), and both human insulin and insulin analogues (n=394, 23.7%). 

Results showed no overall increase in the risk for a major congenital anomaly in fetuses exposed to insulin analogues compared with fetuses exposed to human insulin only (odds ratio [OR] 0.54; 95% CI, 0.29-1.01); however, this finding was not statistically significant. The only statistically significant lower risk was found in fetuses exposed to both human insulin and insulin analogues (OR 0.43; 95% CI, 0.21-0.89). The risk for congenital heart defects was the only significantly lower risk related to exposure to insulin analogues (adjusted relative risk 0.14; 95% CI, 0.03-0.62). 

Women with type 1 diabetes who planned their pregnancies and had a longer duration of diabetes more commonly had fetuses exposed to insulin analogues during the first trimester compared with exposure to human insulin only. Exposure to insulin analogues only was associated with a higher rate of spontaneous abortions at 1.5%, while spontaneous abortion rates of 1.3% and 0.1% were associated with fetuses exposed to both insulin analogues and human insulin, and human insulin alone, respectively.  In addition, lower risks of major congenital anomalies and congenital heart defects were associated with planned pregnancies (OR 0.73; 95% CI, 0.37-1.46 and OR 0.28; 95% CI, 0.20-1.58, respectively).

The relative risk adjusted for glycemic control and region was 0.56 (95% CI, 0.29-1.06), with a significantly associated risk for a major congenital anomaly associated with mean glycated hemoglobin (HbA1c) levels in the first trimester higher than 67 mmol/mol (OR 2.87; 95% CI, 1.28-6.42).  An increased risk for adverse outcomes was not found to be associated with exposure to insulin analogues either alone or in combination with human insulin (OR 0.76; 95% CI, 0.44-1.33). 

Researchers concluded that there were no differences in the risk for offspring with congenital abnormalities in fetuses exposed to either insulin analogues or human insulin during the first trimester, although there was a significantly lower risk for congenital heart defects in fetuses exposed to insulin analogues. As seen in previous studies, unplanned pregnancies and elevated HbA1c levels were associated with a higher rate of congenital anomalies. Researchers suggested that “insulin analogues reduced the risk of congenital anomalies by achieving better glucose stability and consequently reduced glucose-level variation.” However, the association between insulin analogues and higher spontaneous abortion rate needs be further investigated as it was not a primary outcome of this study.

Reference

Wang H, Wender-Ozegowska E, Garne E, et al. Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study. BMJ Open. 2018;8(2):e014972.

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