Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02556840 |
| Other study ID # |
2015-A00261-48 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 25, 2016 |
| Est. completion date |
December 9, 2020 |
Study information
| Verified date |
April 2021 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Maturity-onset diabetes of youth (MODY) are the most frequent monogenic diabetes with
autosomic dominant inheritance (2% of diabetes). The MODY2 diabetes is related to a defect in
the glucokinase (GCK) enzyme, the first limiting step of insulin secretion. An abnormal GCK
leads to a delayed insulin secretion. Patients with GCK mutations have only mild raised
fasting plasma glucose. Treatment is usually unnecessary since hyperglycemia is stable and
MODY2 patients have no microvascular complications of diabetes. In contrast, pregnancy in
MODY2 women is a challenging situation. A non-mutated fetus will produce excess insulin in
response to raised maternal blood glucose leading to an accelerated growth and a higher risk
of macrosomia. The mother of non-mutated fetus should therefore be treated to normalize her
blood glucose levels. On contrary, a mutated fetus will produce a delayed insulin secretion
(as his MODY2 mother) in response to maternal hyperglycemia. Consequently insulin therapy
during pregnancy would reduce fetal insulin secretion and result in a low birth weight.
Moreover, insulin therapy exposes pregnant women to more labor induction, prematurity and
cesarean deliveries. In these MODY2 women whose glucose set point is physiologically higher,
glycemic goals are difficult to achieve while often requiring extensive insulin therapy. An
optimal situation would consist in initiating insulin therapy only for women with non-mutated
offsprings. Unfortunately no antenatal diagnosis of the GCK mutation on fetal cells is
available yet. In literature, birth weight differences between mutated and non-mutated
neonates may reach up to 700g. In clinical practice, two strategies are used but without
standardized protocol on glycemic targets, delay and doses of insulin : 1) insulin at
diagnosis of pregnancy 2) treatment based on fetal abdominal circumference and fetal weight
measurements by ultrasonography (US) and initiated if fetal biometry is greater than the 75th
percentile.
The purpose of the study is to evaluate for the first time these two management strategies
through a prospective and standardized study. Hypothesis: US assessment would be sufficient
to identify fetuses at risk of macrosomia and to initiate insulin treatment in mothers.
Description:
Study design The investigators propose to conduct a national multicenter prospective study on
the clinical management of pregnancy in women with GCK mutations.
Medical management of the pregnancy After obtaining written informed consent, each
investigator of the Diabetes Departments will include MODY2 women, at the time of gestation
planning or at the first prenatal appointment. Pre-gestational maternal parameters (maternal
age, pre-gestational weight, blood glucose, mean blood glucose levels before and 2 hours post
prandial over one week when available, HbA1c, parity, medical history of macrosomia) will be
collected.
Antenatal care will be provided according to the local routine protocol for MODY2. All women
will receive dietary and physical activity counselling according to current recommendations
for pregnant women with pregestational diabetes. Vitamin B9, 0.4 or 5 mg/day, according to
local habits, will be prescribed as usual care from pregestational appointment until the end
of first trimester.
- Women with a pregestational HbA1c ≥ 6.5 % will be systematically treated with insulin
because of a potential increase in the malformation rate as documented in women with
type 1 diabetes (Bell, Glinianaia et al. 2012).
- In women with pregestational HbA1c < 6.5%, insulin therapy will be initiated either
according to capillary maternal blood glucose target values or according to fetal growth
assessed by ultrasonography, according to each Diabetes Department habits.
In both groups, care will be standardized as follows:
- Ultrasonography (US) examinations will be performed as usually at 12, 22 and 32
gestational weeks. Additional US will be performed at 25, 28, 35 and 38 gestational
weeks, as performed in the several randomized controlled trials that showed that this
strategy allows prevention of an increase in the rate of macrosomia in women with GDM
(Schaefer-Graf, Kjos et al. 2004). A referent sonographer will be identified in each
center to limit the inter-examiner variability. At each US, fetal biometry (with
abdominal circumference and fetal weight estimations) and the percentiles according to
gestational age will be determined.
- Blood glucose self-monitoring, comprising 6 measures (before and 2 hours after the
beginning of each meal), will be registered during a whole week at the end of the three
trimesters of pregnancy.
- Women body weight will be measured before pregnancy, at each Diabetology appointment and
before delivery.
- Fetal monitoring will be performed according to local routine protocols. Modalities of
delivery will be decided as usual care in each obstetrics department. No specific
gestational age and modalities of delivery will be recommended for the study.
Group of women with insulin therapy from the beginning of pregnancy :
Treatment will be conducted according to national guidelines for GDM (2010) and consists in:
- Blood glucose self-monitoring before and 2 hrs after each meal, i.e. 6 tests per day.
Recommended targets are less than 0.95 g/L before meals and less than 1.20 g/L
postprandial.
- Diet counseling with carbohydrate intake divided into three meals and two to three
snacks.
- After 7-10 days of glucose monitoring, insulin therapy will be instituted if capillary
glucose levels exceed the targets in 20% of all measurements or in 40% of a single time
slot. Each caregiver will manage insulin therapy according to local habits (use of
long-acting insulin, regular insulin, insulin analogs, continuous subcutaneous insulin
infusion by an external pump), and will increase the doses in order to obtain
recommended glucose targets. Preliminary data suggest that high insulin doses may be
necessary and that normalizing fasting blood glucose may be difficult. Thus, insulin
doses will not be further increased in case of the occurrence of repeated hypoglycemia
(i.e. 2 mild hypoglycemic episodes in a single slot over one week or one single severe
hypoglycemic episode even when blood glucose targets are not achieved).
Insulin treatment will be stopped only in case of fetal restricted growth defined by an
estimated fetal weight < 10th percentile, on two consecutive US with at least 3 weeks
interval and no other etiology.
Group of women with insulin therapy initiated according to fetal US measurements :
Women will monitor their blood glucose levels before and 2 hours after meals twice a week
during the whole pregnancy.
In this group, MODY2 women will not be treated with insulin until delivery, except when:
- the fetal abdominal circumference exceeds ≥ the 75 percentile on one US. This threshold
is similar to the one chosen to initiate insulin therapy in several RCTs that showed
that this strategy allowed prevention of an increase in the rate of macrosomia in women
with GDM (Schaefer-Graf, Kjos et al. 2004, Kjos and Schaefer-Graf 2007).
- or maternal fasting capillary blood glucose is ≥ 1,20 g/L or maternal post-prandial
capillary blood glucose is ≥ 2,00 g/L. In the mentioned RCTs, women followed with
monthly fetal growth evaluations were not treated with insulin except when fetal
abdominal circumference was ≥ 75th percentile, or when their glucose levels exceeded the
same safety thresholds. No increase in macrosomia and other pregnancy adverse outcomes
was observed using this strategy, as compared to conventional treatment with insulin
(Kjos and Schaefer-Graf 2007).
When initiated, insulin therapy will be conducted as described in 11.2, with the same
capillary blood glucose targets
-Maternal care Systematic visits in the Diabetes department will be scheduled at 2- 4 weeks
intervals. A monthly visit in the Obstetrics department will be scheduled from 22 weeks of
gestation.
Routine care, including measurement of weight, height and arterial pressure, as well an
urinary testing for proteinuria will be performed at the first appointment and at each
following visit.
In case of insulin treatment, the type and dose of insulin will be recorded, as well as the
frequency of mild or severe hypoglycemia.
Women with pre-gestational HbA1c > 6.5% will be treated with insulin from the pregnancy
planning period or from the beginning of the pregnancy as described in part 6.2.1 and all
data concerning these pregnancies will be registered.
- Quality of life Three self-questionnaires, already used in randomized studies of GDM
treatment (Crowther, Hiller et al. 2005), will be proposed to all women at the first
appointment and at three months post partum.
- Maternal health status will be assessed by means of the Medical Outcomes Study 36-Item
Short-Form General Health Survey (SF-36), which assesses eight aspects of health status:
general and mental health, physical and social functioning, physical and emotional role,
pain, and vitality. Scores on each scale can range from 0 (worst) to 100 (best).
- Maternal anxiety will be assessed with the use of the short form of the Spielberger
State-Trait Anxiety Inventory, a self-rating scale consisting of 6 items (scores below
15 are considered normal).
The presence of a maternal depression will be reflected by a score of more than 12 on the
Edinburgh Postnatal Depression Scale at three months post partum.
-Anthropometrics and biological measures in neonates
Anthropometrics parameters will be recorded the first day of life for each neonate:
- Weight to determine "large for gestational age" defined as birth weight above the 90th
percentile and "small for gestational age" defined as birth weight below the 10th
percentile on sex-specific neonatal growth standards published by the AUDIPOG group
(Mamelle et al, 1996)
- Skin fold between 1st and 3rd day of life (bicipital, tricipital, scapular, iliac) for
departments experienced in this type of measurement.
Capillary blood glucose test will be collected 3 hours before the first feeding to look for
hypoglycaemia. After the second feeding, blood glucose tests will be repeated every 6 hours
if > 2.5 mmol/L. If blood glucose is normal during 24 hours and feeding is also normal,
neonate glucose monitoring will be stopped.
Infants will be categorized as having clinical neonatal hypoglycaemia if there are symptoms
and/or treatment with a glucose infusion or a glucose value ≤ 2 mmol/L.
C-peptide will be measured on cord blood. Hyperinsulinemia is defined by a C-peptide level
above the 90th percentile of a neonate reference population. Samples will be centralized in a
single laboratory for determination of the C-peptide level.
Neonatal leptin will be measured on cord blood as a biological marker of infant adiposity.
Leptin is specifically produced by adipose tissue and placenta, and maternal leptin does not
cross the placenta. Fetal leptin reflects the amount of adipose tissue, and its production
could be regulated by insulin (Hauguel-de Mouzon, Lepercq et al. 2006).
-GCK genotyping In order to analyze the effect of the maternal treatment according to the
fetal genotype, a targeted sequencing of the maternal GCK mutation will be performed on DNA
extracted from blood cord sample. The mother (and her partner) will sign an informed written
consent for the genetic testing of their baby.
