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Impact on Birth Weight of Two Therapeutic Strategies (Insulin Therapy From the Beginning of Pregnancy vs. Insulin Therapy Initiated According to Fetal Growth Evaluated by Ultrasonography Measurements) in Pregnant Women With Monogenic Diabetes (MODY2)

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ClinicalTrials.gov Identifier: NCT02556840
Recruitment Status : Recruiting
First Posted : September 22, 2015
Last Update Posted : March 19, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE July 13, 2015
First Posted Date  ICMJE September 22, 2015
Last Update Posted Date March 19, 2018
Actual Study Start Date  ICMJE April 25, 2016
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2015)
Birth weight for gestational age [ Time Frame: at birth ]
this end point will sustain two derived criteria: birth weight for gestational age as a quantitative criterion and birth weight considered as small (below the 10th percentile), normal, or large (above the 90th percentile).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2015)
  • Number of neonatal hypoglycaemia [ Time Frame: at birth ]
    defined as the presence of symptoms and/or the need for treatment with a glucose infusion, and/or a plasma or capillary glucose value ≤ 2 mmol/L within the first 24 hrs
  • Number of hyperinsulinemia [ Time Frame: at birth ]
    defined by a C-peptide level >90th
  • Neonatal leptin level [ Time Frame: at birth ]
  • Number of fetal and neonatal complications [ Time Frame: at birth ]
    Major and minor complications, stillbirth, shoulder dystocia, birth trauma, admission to neonatal intensive care unit, jaundice, respiratory distress syndrome, 5-min Apgar score <7, Cord blood glucose pH<7.2 mmol/L.
  • Composite obstetrical outcome [ Time Frame: at birth ]
    Gestational age at delivery, mode of delivery, elective cesarean delivery, emergency cesarean delivery, labor induction
  • Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, before pregnancy ]
  • Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 14-16 of pregnancy ]
  • Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 25-27 of pregnancy ]
  • Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 36-38 of pregnancy ]
  • Post-prandial hyperglycaemic peak (level and delay) [ Time Frame: at 22 weeks of pregnancy ]
  • Post-prandial hyperglycaemic peak (level and delay) [ Time Frame: at 32 weeks of pregnancy ]
  • HbA1c level [ Time Frame: pre-gestational and monthly during pregnancy ]
    according to the HPLC method
  • Fructosamine level [ Time Frame: monthly during pregnancy ]
  • Number of women requiring insulin treatment [ Time Frame: at 38 weeks of pregnancy ]
  • Term of insulin therapy [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy
  • Type of insulin [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy
  • Number of injections [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy
  • Number of units/kg.day of insulin [ Time Frame: over one week at weeks 14/16, 25/27 and 36/38 ]
    in case of insulin therapy
  • Weight gain during pregnancy [ Time Frame: at 38 weeks of pregnancy ]
  • Number of pregnancy induced hypertension [ Time Frame: at delivery ]
    to evaluate maternal complications
  • Number of preeclampsia [ Time Frame: at delivery ]
    to evaluate maternal complications
  • Number of medical appointments [ Time Frame: at delivery ]
    to evaluate maternal complications
  • Duration of hospital stay [ Time Frame: at delivery ]
    to evaluate maternal complications
  • depression (Edinburgh Postnatal Depression Scale. [ Time Frame: at delivery ]
    to evaluate maternal complications
  • Quality of Life (SF-36 questionary) [ Time Frame: at delivery ]
    to evaluate maternal complications
  • Anxiety score (short form of the Spielberger State - Trait Anxiety Inventory [ Time Frame: at delivery ]
    to evaluate maternal complications
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact on Birth Weight of Two Therapeutic Strategies (Insulin Therapy From the Beginning of Pregnancy vs. Insulin Therapy Initiated According to Fetal Growth Evaluated by Ultrasonography Measurements) in Pregnant Women With Monogenic Diabetes
Official Title  ICMJE Impact of Two Standardized Clinical Care Protocols on Pregnancy Outcomes in Women With Monogenic Diabetes MODY2
Brief 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.

Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Maturity-Onset Diabetes of the Young
Intervention  ICMJE Other: insulin therapy
Study Arms  ICMJE
  • Active Comparator: Insulin therapy from the beginning of pregnancy

    Insulin therapy (Glargine/Lantus®, Détémir/Levemir® , Insulatard® , Umuline NPH® , Lispro/Humalog® , Asparte/Novorapid® or Actrapid ®) administered from the beginning of pregnancy according to maternal blood glucose (if fasting blood glucose > 0.95g/l or post-prandial blood glucose > 1.20g/l) as recommended by the national guidelines for gestational diabetes mellitus.

    Insulin administered to patients either by subcutaneous injections or by pump.

    Intervention: Other: insulin therapy
  • Experimental: Insulin therapy initiated according to fetal growth

    Insulin therapy (Glargine/Lantus®, Détémir/Levemir® , Insulatard® , Umuline NPH® , Lispro/Humalog® , Asparte/Novorapid® or Actrapid ®) initiated according to fetal growth evaluated by ultrasonography measurements. MODY2 women will not be treated with insulin until delivery, except when the fetal abdominal circumference exceeds ≥ the 75 percentile on one US or maternal fasting capillary blood glucose is ≥ 1,20 g/L or maternal post-prandial capillary blood glucose is ≥ 2,00 g/L.

    Insulin administered to patients either by subcutaneous injections or by pump.

    Intervention: Other: insulin therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2015)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2020
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Women diagnosed with a GCK mutation before pregnancy
  • Aged ≥ 18 years old
  • Pre-gestational BMI < 30kg/m²
  • Term of pregnancy < 14 WG , if delay overdue, to be validated by investigators
  • Written informed consent

Exclusion Criteria:

  • Twin pregnancy
  • Not able to understand and sign written informed consent
  • Not affiliated to the French Social Security
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Cécile Ciangura, MD, +33 1 42 17 80 51 cecile.ciangura@aphp.fr
Contact: Adèle Bellino, Master +33 1 58 41 11 95 adele.bellino@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02556840
Other Study ID Numbers  ICMJE 2015-A00261-48
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Christine Bellanné-Chantelot, PharmaD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP