Here we demonstrate clinically and statistically acceptable accuracy of the FreeStyle Navigator CGM and MPC algorithm in women with type 1 diabetes during pregnancy. Closed-loop insulin delivery was associated with nearly normoglycemia overnight, both in early and in late pregnancy, suggesting that the MPC algorithm safely adapts insulin delivery for advancing gestational age.
Sensing errors have been considered a major obstacle to effective closed-loop systems. This represents a particular challenge given the narrow glucose reference range and risk of hypoglycemia during pregnancy. Despite tighter glycemic targets, sensor accuracy in this study was comparable to previously published data (19
). As in nonpregnant individuals, accuracy was greatest for glucose levels within and above the target range and least for glucose levels ≤70 mg/dL. The MPC algorithm compensated for discrepancies between the sensor and reference glucose level during hypoglycemia by suspending insulin delivery when sensor glucose values fell <80 mg/dL.
Despite this safety barrier, there was one episode of unexplained asymptomatic hypoglycemia at 0500 h, which could not be attributed to sensor discrepancy or to the MPC advice, because only 0.4 units of insulin was infused over the preceding 6 h. Considered in the context of conventional treatment, whereby women with type 1 diabetes spend on average 16.2% overnight (1.3 h) hypoglycemic during pregnancy (2
) and assuming this group of women were representative, it suggests potential safety benefits of closed-loop insulin delivery. Note that in this proof of concept study, we did not modify the algorithm to distinguish between pre- and postprandial glucose targets and that even tighter glycemic thresholds (60–99 fasting and <130 after meals) may be required for optimal fetal growth.
Nocturnal hyperglycemia was minimized in women requiring established continuous subcutaneous insulin infusion as well as in those using multiple daily injections. This also compares favorably with previous CGM studies describing 36.4% time hyperglycemic (2.9 h >140, 1.0 h >200 mg/dL) (2
The level of overnight glucose control obtained during early and late gestation was similar to that recently obtained in children and adults with type 1 diabetes (18
). Our group has shown that using off-the-shelf sensors and earlier versions of this MPC algorithm, children achieved 53% (48–57%) overnight time in target after eating a large, rapidly absorbed evening meal and 55% (37–64%) after a large, slowly absorbed meal (18
). Adults using closed-loop did even better, spending 72 ± 15% overnight time in target after a large evening meal (100 g carbohydrate) and generous alcohol consumption (0.75 g/kg ethanol) (22
). These studies suggest potential superiority of overnight closed-loop insulin delivery over conventional pump therapy outside pregnancy.
The difference between conventional and close-loop insulin delivery is the ability of the latter to rapidly respond to glucose excursions, with more variability of the insulin infusion rates despite comparable overall insulin doses. In our current study, the MPC algorithm was able to safely increase the insulin infusion rates for advancing gestational age, based on the women’s weight and total daily insulin dose.
This study also illustrates the challenges of postprandial hyperglycemia, particularly after a high-carbohydrate breakfast. After nearly optimal overnight control, women had more glucose variability and spent more time hyperglycemic after breakfast compared with after dinner. Despite apparently more prolonged hyperglycemia after breakfast in late pregnancy (), differences in the time spent hyperglycemic between early and late pregnancy (28% in early and 44% in late gestation) did not reach statistical significance, most likely due to the small sample size and intraindividual variability.
There were also no significant differences in the insulin infusion rates (when corrected for maternal weight) in early and late gestation. However, there is a trend to higher glucose levels at various points in later pregnancy, after starting at a lower glucose, and a trend to an increased average insulin infusion rate. The latter would be expected given the increasing insulin resistance of pregnancy and with larger numbers may have reached statistical significance.
We now plan to perform randomized controlled studies of closed-loop insulin delivery with tighter glycemic targets, first in the hospital and then over multiple nights in the home setting. To evaluate clinical effectiveness of closed-loop insulin delivery, a large, multicenter randomized study comparing closed-loop with sensor-augmented pump therapy will be needed. Meanwhile, the MPC safety and sensor accuracy data from this study pave the way for future research to refine closed-loop insulin delivery in pregnancy.