Improving preconceptional glycaemic regulation using RealTime Continuous Glucose Monitoring in women with type 1 diabetes who have *acceptable but not optimal* HbA1c values: an observational study

Despite major advances in diabetes care the incidence of adverse pregnancy
outcomes in women with type 1 diabetes mellitus is still significantly higher
than in non-diabetic pregnancies. It is has been established that suboptimal
glucose regulation is associated with adverse pregnancy outcomes. Therefore
there is general consensus that prepregnancy care and optimal glycaemic
control as well as during pregnancy is mandatory to achieve the best possible
pregnancy outcome in these women with HbA1c as the parameter available
reflecting the quality of glycaemic control. The latest guidelines state that
we should aim for a preconceptional HbA1c-level as near the normal range (below
43 mmol/mol, 6.1%) as possible to achieve the best outcomes. However, lowering
the HbA1c-level towards the normal range can cause an increases risk of
(severe) hypoglycaemia increases, often posing a barrier to reach optimal
control. As a compromise, an HbA1c level less than 53 mmol/mol (7.0%) is
accepted as good enough to become pregnant. It was thought that glycaemic
control with an HbA1c <53 mmol/mol was associated with rates of malformations
no greater than those in pregnancies in non-diabetic women. Recent studies have
indicated that there is probably still a residual extra risk in this situation.
This is this basis for the quest for possibilities to achieve the lowest
possible Hba1c-level without excess hypoglycaemia.
Glucose monitoring by self-measurement of glucose levels in capillary blood is
an important part of the day-to-day management of diabetes and a cornerstone of
treatment. But self -measurement of blood glucose levels does on provide
snapshot images, limiting the possibilities to improve glycaemic control.
Real-Time Continuous Glucose Monitoring System (RT-CGMS) allows instantaneous
display of actual glucose values combined with an alert-function when glucose
levels or changes in levels fall outside preset individualised limits. Studies
have shown that RT-CGMS can improve glycaemic control or sustain adequate
control in patients with type 1 diabetes without increasing hypoglycaemic
episodes, also in well-regulated patients. However studied populations were
heterogenic and no studies have been done with RT-CGMS during the
preconceptional period; the population of this study.
In November 2011 College Voor Zorgverzekeringen (CVZ) decided to approve
reimbursement RT-CGMS for specific groups of diabetic patients including
pregnant women but not in preconceptional women because of a lack of studies in
this particular group

This study is designed to investigate whether it is possible to achieve
substantial improvement in HbA1c values using RT-CGMS in women with type 1
diabetes with acceptable but not optimal glycaemic control in preconceptional
period (which is HbA1c between 47-53 mmol/mol).

Primary outcome
- Absolute reduction in HbA1c
Secondary outcomes
- Incidence of severe hypoglycaemia
- Percentage of women with a fall in HbA1c of >= 5 mmol/mol
- number of consultations (by telephone, internet and in out-patient clinic)
- Change in glycaemic variability
- Composite end point: reduction of HbA1 >= 5 mmol/mol without an episode of
severe hypoglycaemia
- Frequency of use RT-CGMS
- Fear of hypoglycaemia
- Quality-of-life
- Satisfaction with the device

This is a 16-week non-randomised intervention, single centre, single-arm,
exploratory study analyzing the effect of RT-CGMS use in preconceptional women
with diabetes type 1 women who have acceptable but not uptimal regulated blood
sugars.

Setting:
The study will be carried out in the setting of the already longstanding
collaborative group of the UMC Utrecht Departments of Internal Medicine and
*Vrouw en Baby*. This group has founded in the nineties a joint
Obstetrics-Internal Medicine clinic for pregnant patients with any kind of
diabetes which has served as a role model for other institutions.

Approach of patients:
every women with suboptimal regulated type 1 diabetes mellitus who is treated
at the out-patient clinic for Diabetology of the UMC Utrecht and who has a
child wish will be approached for this study

Interventie:
Medical consultation by:
- Diabetes nurse educator (scheduled every two weeks, plus possibility of 24h a
day by telephone or email)
- Diabetes specialist (scheduled week 0, week 1, week 4, week 8, week 12, week
16)
Every therapy change will be made under supervision (from nurse to research
physician to supervising physician) and noted
Intervention:
- Questionnaires every 4 weeks
- RT-CGMS during 7 consecutive days every other week (in total: 8 of 16 weeks)
Results will be used for counseling / treatment adjustments
3 times blinded RT-CGMS for 48 hours in week 0 and 16 and 20

Standard therapy:
- Insulin pump therapy (replaced by RT_CGMS: insulin pump and glucose sensor in
one)
- SMBG at least 5 times a day for at least 5 days a week
- Standard blood controls:
HbA1c and fructosamine every 4 weeks
TSH and FT4, cholesterol, Hb, Kreatinine and urinesediment at baseline

Post study:
=> Patients will be offered to use RT-CGMS after end of study until eventually
pregnancy. At that moment they can obtain RTCGMS as regular, reimbursed
treatment

RT-CGMS during 7 consecutive days every other week (in total: 8 of 16 weeks)
Results will be used for counseling / treatment adjustments

Participation with this trial can be a burden on some fronts:
- Some patients have to change physician (namely the research-physician with
supervision of the specialist who is concerned with the diabetic care of
pregnant women). However, when they get pregnant (although not participating
this study) they then also become under the supervision of the named specialist
because this is common care in pregnant diabetes patients in the UMC Utrecht.
- The use of RT-CGMS can be a burden because the alert-function, besides the
advantage of the warning possibilities, causes unpredictable disturbances of
daily (meetings, visits, shopping etc) or nocturnal (sleeping) activities.
- Patients will have to connect the RT-CGMS themselves (every other week) and
will have to replace the needle after 3 days of use
- Patients always have to confirm glucose values given from the RT-CGMS with
SMBG before making therapy adjustments
- Former studies showed some possible skin irritative adverse affects from
(RT-)CMGS use
- We will ask patients to fill in some questionnaires every 4 weeks
- Risk of hypoglycaemic events. It is possible that there will be hypoglycaemic
events during this trial. However, we expect that the incidence during this
study is as high or even less high as in common care. In common care one should
also aim for the lowest glucose levels. In this study, by using RT-CGMS, the
alert-function has the potential to early warning for, and therefor preventing,
a hypoglycaemic episode. A systematic review of 7 RCT studies using devices
(Hoeks et Greven, 1 april 2011 Diabetic Medicine) describes that 6 of 7 studies
did not show an increase in hypoglycaemic events. One study did show an
increase in severe hypoglycaemia (however the authors reported that this was
because of non-use and/or incorrect use of the device. Two studies showed a
decrease in HbA1c in absence of severe or non-severe hypoglycemia in the
RT-CGMS group. No study was powered enough to demonstrate a decrease in
hypoglycaemic events.