Metformin Use to Improve Pregnancy Outcome in Women With Type 1 Diabetes.

Study Overview
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Brief Summary
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The study investigates whether additional metformin medication in combination with regular insulin treatment will decrease the need of insulin for women with diabetes mellitus type 1 during pregnancy.

Detailed Description
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Insulin resistance during pregnancy of diabetes mellitus type 1 patients (DM1) increases the need for insulin and makes it more difficult to maintain normoglycemia. Fetal exposure to hyperglycemia induces macrosomia which increases fetal and neonatal morbidity and mortality. Further more obesity and excess weight gain during pregnancy enhances insulin resistance and it's an independent risk factor for fetal macrosomia. Metformin is a medical treatment for type 2 diabetes (DM2) where consequential pathophysiology includes insulin resistance. It reduces hepatic glucose production and enhances the use of glucose in muscles relieving insulin resistance. Metformin has also found to inhibit weight gain effectively. Metformin has approved to be safe and effective in patients with gestational diabetes (GDM). It has found to reduce weight gain and improve postprandial blood glucose levels during pregnancy and reduce neonatal birth trauma in GDM. However, there are no previous studies about the use of metformin in pregnant women with DM1. Two hundred women with DM1 will be randomized to get placebo or metformin in addition to regular insulin treatment. The sample size has been estimated to demonstrate the difference of 15 % in the need to increase insulin dosages during the pregnancy between the study groups.

Official Title
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Metformin Use to Improve Pregnancy Outcome in Women With Type 1 Diabetes. A Randomized Double-blind Placebo-controlled Multicenter Study.

Conditions
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Diabetic Pregnancy, Insulin Resistance, Type1diabetes

Intervention / Treatment
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* Drug: metforminhydrochloride
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a pregnancy of a woman with type 1 diabetes. Exclusion Criteria: multiple pregnancy, significant underlying disease (hearth disease, kidney transplant, IBD (inflammatory bowel disease ), SLE (systemic lupus erythematosus ), diseases with use of high dosage corticosteroids (severe asthma or rheumatic disease), severe complications of diabetes (nephropathy, neuropathy, gastroparesis or severe retinopathy), substance abuse, smoking, BMI <18, strong early pregnancy nausea (=hyperemesis)
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: metforminhydrochloride<br>Metformin medication starts on 12-14 weeks of gestation. The starting dosage is 1 tablet (500 mg) x1 and it is increased gradually 1 tablet a week up to 2+2 tablets (2000mg) daily. Duration of the treatment is approximately until one week before delivery. Otherwise metformin treatment combined with regular insulin and follow-up during pregnancy follows the national guidelines. | Drug: metforminhydrochloride<br>* metformin 500 mg tablets and insulin<br>* Other names: Metformin;|
| Placebo Comparator: Placebo Oral Tablet<br>Placebo tablets starts on 12-14 weeks of gestation. The starting dosage is 1 tablet x1 and it is increased gradually 1 tablet a week up to 2+2 tablets daily. Duration of the treatment is approximately until one week before delivery. Otherwise placebo treatment combined with regular insulin and follow-up during pregnancy follows the national guidelines. | Drug: Placebo Oral Tablet<br>* Placebo tablets mimic metformin 500 mg tablets and insulin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the insulin need during pregnancy | The insulin dosage (IU/ml) in two weeks sets | from 5-10 gestational weeks until the delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood glucose balance during pregnancy HbA1c | HbA1c (mmol/mol) | from gestational weeks 5 until the delivery | 
| Blood glucose balance during pregnancy AVG, SD, CV | mean blood glucose (mmol/l) level, standard deviation (SD) and the coefficient of variation of the blood glucose levels | from gestational weeks 5 until the delivery | 
| Change in the weight | Weight gain (g) during pregnancy | from gestational weeks 5 until the delivery | 
| Change in the blood pressure | Blood pressure (mmHg) | from gestational weeks 5 until the delivery | 
| Incidence of pre-eclampsia | Incidence of pre-eclampsia (%) | from gestational weeks 20 until the delivery | 
| Incidence hepatogestosis | Incidence hepatogestosis (%) | from gestational weeks 20 until the delivery | 
| Pregnancy complications | Incidence proteinuria (mg/mmol or mg/d) | from gestational weeks 5 until the delivery | 
| macrosomia | estimated fetal weight in ultrasound (grams) | from gestational weeks 20 until the delivery | 
| Pregnancy complications | incidence of miscarriage (intrauterine death before 22 weeks of gestation or fetal weigth under 500g) (%) | 12-22 weeks of gestation | 
| Pregnancy complications | incidence of intrauterine death (intrauterine death after 22 weeks of gestation or fetal weigth over 500g) (%) | 22-40 weeks of gestation | 
| Thigh fractional volume ultrasound | Fetal weight estimation (g) is specified by thigh fractional volume ultrasound program | from gestational weeks 20 until delivery | 
| Rate of the caesarean sections | Rate of the caesarean sections (%) | The delivery | 
| Labour | rate of spontaneous delivery (%) | The delivery | 
| Rate of the operative vaginal deliveries | Rate of the operative vaginal deliveries (%) | The delivery | 
| Rate of the shoulder dystocia | Rate of the shoulder dystocia (%) | The delivery | 
| Labor complications | rate of induced delivery (%) | The delivery | 
| Rate of the perineal tears | Rate of the perineal tears (%) | The delivery | 
| Postpartum bleeding | postpartum bleeding (ml) | The delivery | 
| Newborn variables (gestational age) | Rate of the premature deliveries (=deliveries before 37 weeks of gestation) (%) | After the delivery | 
| Newborn variables | weight of the newborn (g) | After the delivery | 
| Newborn outcome | Acidosis of the newborn (pH) | After the delivery | 
| Newborn outcome (intensive care) | The need of NICU (neonatal intensive care unit) treatment (days) | After the delivery | 
| Newborn outcome (hypoglycemia) | The occurrence of hypoglycemia (=plasma glucose under 2.6mmol/l or usage of iv glucose infusion) (%) | After the delivery | 
| Newborn outcome (Erb's) | Incidence of the Erb's paresis (%) | After the delivery | 
| Cost benefit calculations (sick leaves) | The need of sick leaves during pregnancy (days) | from gestational weeks 12 until delivery | 
| Cost benefit calculations (visits to maternity outpatient clinic or internal medicine policlinic) | The need of polyclinical controls during pregnancy (number of visits/pregnancy) | 14-40 weeks of gestation | 
| Cost benefit calculations (hospitalization) | The need of hospitalization during pregnancy (days/pregnancy) | 14-40 weeks of gestation | 
| Cost benefit calculations (all outpatient visits after delivery ) | The need of policlinical controls of the diabetic mother after the delivery (number of visits) | One year after the delivery | 
| Cost benefit calculations (hospitalization after delivery, all departments) | The need of hospitalization of the diabetic mother after the delivery (days) | Up to one year after the delivery | 
| Cost benefit calculations (all hospitalization of the child) | The need of hospitalization of the child (days) | Until the age of one year | 
| Cost benefit calculations (all policlinical controls of the child) | The need of policlinical controls of the child (number of visits) | Until the age of one year | 
| high sensitive-CRP | high sensitive-CRP (mg/l) | 7-10, 26-28 and 34-36 weeks of gestation | 
| lipids | cholesterol, high density lipoprotein, low density lipoprotein, triglyserids (mmol/l) | 7-10, 26-28 and 34-36 weeks of gestation | 
| Inflammatory markers | adiponectin, leptin, resistin, IL-6, TNF-α (pg/ml) | 7-10, 26-28 and 34-36 weeks of gestation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin need, diabetic pregnancy, insulin resistance, metformin