Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes

Caitlin Higgins, Mercer University College of Pharmacy

According to the American Diabetes Association (ADA), insulin is the preferred agent for management of pregestational type 1 diabetes (T1DM) and type 2 diabetes (T2DM) that are not adequately controlled with diet, exercise, and metformin.  All insulins are pregnancy category B except for glargine, glulisine, and degludec, which are labeled category C. [1]

During pregnancy, a glycated hemoglobin (A1C) target of 6–6.5% (42–48 mmol/mol) is recommended, but less than 6% (42 mmol/mol) may be optimal as pregnancy progresses. [1]

The American College of Obstetricians and Gynecologists (ACOG) recommends the following targets for women with pregestational T1DM or T2DM:

  • Fasting: <90 mg/dL (5.0 mmol/L)
  • One-hour postprandial: <130–140 mg/dL (7.2–7.8 mmol/L)
  • Two-hour postprandial: <120 mg/dL (6.7 mmol/L) [2]

The ADA suggests these levels should be achieved without hypoglycemia, which is linked to increasing the risk of low birth weight.  If these targets cannot be achieved without significant hypoglycemia, the ADA suggests less stringent targets based on clinical experience and individualization of care. [1]

A meta-analysis on glycemic control in T1DM suggests that insulin pumps can assist women achieve their glucose target, but similar control can be attained with an intensified multidose insulin regimen. Continuous glucose monitors are sometimes used to fine-tune management. [3]

There is an increased risk of hypoglycemia in early pregnancy, and hyperemesis may complicate glucose management.  Insulin requirements are suggested to increase substantially during the second half of pregnancy, when hyperglycemia accelerates fetal growth.  Hypertension, oedema, proteinuria and signs of evolving pre-eclampsia are recommended to be carefully monitored and treated aggressively, with consideration given to expediting delivery when clinically appropriate. [3]

Severe hypoglycemia, affecting up to 40% of women, is suggested to cause substantial morbidity (seizures, fractures and road-traffic accidents), and is considered the leading cause of death in T1DM pregnancy. [4]

A meta-analysis of the use of real-time continuous glucose monitoring (CGM) compared with self-monitoring of blood glucose (SMBG) in T1DM included six trials consisting of 449 patients randomized to CGM versus 443 to SMBG.  The overall mean difference in A1C was -0.3% better for CGM users (95 % CI -0.43 to -0.17 %). [5]

A review on CGM in T1DM suggested that the most effective way to use CGM data in real time is to fully integrate it with algorithimized insulin delivery, known as a closed-loop system. [6]

In a crossover, randomized, controlled study of long-term home use of a closed-loop control, the MD-Logic automated insulin delivery system proved to be a safe and effective tool for overnight treatment of T1DM when compared to a sensor automated pump.  Glycemic control with MD-Logic was suggested to significantly reduce nocturnal hypoglycemia when used during real-life conditions in patients’ homes. [7]

Title: Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes [8]
Design Open-label, multicenter, randomized, crossover trial; N= 17
Objective To compare overnight closed-loop (automated) therapy with sensor-augmented pump therapy used for glycemic control during pregnancy
Study Groups Sensor-augmented pump therapy verses closed-loop insulin delivery
Methods Patients were initiated on overnight closed-loop therapy or sensor-augmented pump therapy, followed by a continuation phase in which the closed-loop system was used day and night.  Participants underwent the following:

1.     Run-in period of 2 to 4 weeks for device training and optimization of insulin doses

2.     Randomization into permuted blocks of four to either the overnight closed-loop system (intervention) or sensor-augmented pump therapy (control)

3.     Two-week washout period after completing the first assigned intervention and before starting the second intervention; during the washout phase, participants used finger-stick testing, with or without continuous glucose monitoring or pump therapy, but could not use the closed-loop system

4.     After randomization, participants chose to continue sensor-augmented pump therapy or the day-and-night closed-loop system with manually administered boluses before meals until delivery.

5.     Finger-stick glucose testing at least seven times daily, with standard glucose targets in both groups (63 to 99 mg/dl [3.5 to 5.5 mmol per liter] before a meal and <140 mg/dl [7.8 mmol per liter] 1 hour after a meal)

6.     Routine antenatal clinic visits were scheduled every 2 weeks, with fetal ultrasonographic assessments performed at 12, 20, 28, 32, and 36 weeks of gestation

7.     C-peptide levels were measured when the serum glucose level was within the target range at baseline, and glycated hemoglobin levels were measured at baseline, after each intervention phase, and at 28, 32, and 36 weeks of gestation

 

Closed-Loop Insulin Delivery System:

–       To initiate closed-loop therapy, participant’s weight and total daily insulin dose were entered into a computer program

–       During the 4-week randomized phase, participants started closed-loop therapy after their evening meal and stopped before breakfast.

–       During the day-and-night continuation phase, closed-loop therapy was used continuously, with manually administered boluses before meals.

–       The device had to be within approximately 30 m of the participant in order to maintain connectivity.  There were no programming changes in anticipation of antenatal glucocorticoid use, labor, or delivery.

–       A computer program used continuous glucose measurements to determine an appropriate insulin dose; insulin was delivered by means of an insulin pump every 12 minutes

–       Pre-meal boluses were administered manually (15 to 30 minutes before the meal) as clinically indicated

Duration 16 weeks
Primary Outcome Measure Percentage of time that overnight glucose levels were within the target range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]), as recorded by continuous glucose monitoring (CGM) during the 28 day intervention periods
Baseline Characteristics Baseline Characteristics (n= 16)
Age, year 34.1 +/- 4.6
Body-mass index (BMI), kg/m2 29.7 +/- 5.7
Glycated hemoglobin, % 6.8 +/- 0.6
Duration of diabetes, year 23.6 +/- 7.2
Previous pump use, n (%) 10 (63)
Pervious use of CGM, n (%) 2 (13)
Total daily insulin dose, units 52.8 +/- 18.1
Median euglycemic C-peptide, pmol/liter 20
Status of gestation, weeks 12 +/- 3.3
First pregnancy, n (%) 7 (44)
Results Variable Sensor-Augmented Pump Therapy Closed-Loop Insulin Delivery P-value
Glucose in target range, % of time 59.5 74.7 0.002
Glucose above target at >140 mg/dl, % of time 38.6 24.0 0.005
Glucose above target at >180 mg/dl, % of time 15.7 7.4 0.004
Glucose below target at <63 mg/dl, % of time 1.9 1.3 0.28
Glucose below target at <50 mg/dl, % of time 0.6 0.3 045
Mean glucose, mg/dl 133 119 0.009
Adverse Events Common Adverse Events: device deficiencies (n= 95), skin reactions (n= 14), minor illnesses (n= 12)
Serious Adverse Events: Serious adverse events including persistent vomiting, threatened labor, spontaneous rupture of membranes, preeclampsia, hypertension (n= 8)
Discontinuation: termination of pregnancy for chromosomal anomaly, trisomy 13 (n= 1)
Study Author Conclusions Overnight closed-loop therapy resulted in better glucose control than sensor-augmented pump therapy in pregnant women with T1DM.  Women receiving day-and-night closed-loop therapy maintained glycemic control during a high proportion of the time in a period that encompassed antenatal hospital admission, labor, and delivery.

While only a small population size was analyzed, the study included women with longstanding diabetes.  Overnight closed-loop insulin delivery can be used in T1DM pregnant patients for glycemic control, with an additional advantage of decreasing hypoglycemia, which leads to better patient health outcomes.  These improvements were achieved without an increased incidence of hypoglycemia or an increase in the total insulin dose but with more variable insulin delivery to minimize hyperglycemic excursions. [8]

Those being initiated on insulin pump delivery systems must be taught how to use the devices and should be able to recognize if the device is not working properly by monitoring the signs and symptoms of hypoglycemia and hyperglycemia.  Device deficiencies are linked to sensing errors, which may be 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.  Thus, more studies are needed to evaluate the ability of patients to recognize deficiencies and the clinical effectiveness of closed loop insulin delivery systems versus sensor-augmented pumps.

References

  1. Management of Diabetes in Pregnancy. Diabetes Care. 2016;39 Suppl 1:S94-8.
  2. Practice Bulletin No. 137: Gestational diabetes mellitus. Obstet Gynecol. 2013;122(2 Pt 1):406-416.
  3. Kyi M, Wentworth JM, Nankervis AJ, Fourlanos S, Colman PG. Recent advances in type 1 diabetes. Med J Aust. 2015;203(7):290-3.
  4. Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ. 2011;343:d3805.
  5. Mauras N, Fox L, Englert K, Beck RW. Continuous glucose monitoring in type 1 diabetes. Endocrine. 2013;43(1):41-50.
  6. Nimri R, Muller I, Atlas E, et al. MD-Logic overnight control for 6 weeks of home use in patients with type 1 diabetes: randomized crossover trial. Diabetes Care. 2014;37(11):3025-32.
  7. Stewart ZA, Wilinska ME, Hartnell S, et al. Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes. N Engl J Med. 2016;375(7):644-54.
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