Clinical Trial: 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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: 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 measure

Detailed Summary:

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 a
    Sponsor: Assistance Publique - Hôpitaux de Paris

    Current Primary Outcome: 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: Same as current

    Current Secondary Outcome:

    • 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: Same as current

    Information By: Assistance Publique - Hôpitaux de Paris

    Dates:
    Date Received: July 13, 2015
    Date Started: May 2016
    Date Completion: October 2020
    Last Updated: June 23, 2016
    Last Verified: June 2016