Modulation of the Intestinal Flora With the Probiotic VIVOMIXX™ in Pregnant Women at Risk of Metabolic Complications

Study Overview
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Brief Summary
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The investigators aimed at evaluating the effectiveness of probiotics ingestion in changing maternal microbiota and preventing gestational diabetes in overweight and obese women. To achieve these goals, obese (BMI> 30 kg/m^2) or overweight (BMI> 25 kg/m^2) pregnant women with risk factors were enrolled in the study and randomized to the supplementation with the probiotic VIVOMIXX® or with placebo. The endpoints of this study are to evaluate if the dietary supplementation with the probiotic VIVOMIXX® modifies the maternal fecal microbiota (bifidobacteria and lactobacilli) and related enzymatic activity (alkaline sphingomyelinase and alkaline phosphatase), and if this if this is linked to an improvement of the intermediate metabolism (positive Oral Glucose Tolerance Test at 24-26 weeks).

Detailed Description
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This is a prospective, multicenter, randomized, double-blind, placebo-controlled trial. 208 pregnant women from the recruiting centers will be enrolled as follow: Women eligible to participate, prior informed consent, will be randomized to 2 capsules twice daily before breakfast and before dinner from randomization until delivery. The boxes will be given to the patients coded and blinded to investigators and participants, and will contain either the active ingredient (VIVOMIXX®, a mixture of 112 billion of eight strains for each capsule, namely Streptococcus thermophilus, bifidobacteria (B. breve, B. longum, B. infantis) and lactobacilli (L. paracasei, L. acidophilus, L. delbrueckii subsp bulgaricus, L. plantarum) or placebo. The protocol includes a screening visit (Visit 1) at 10-12 weeks, two visits during pregnancy (at 26-28 weeks= Visit 2, and at 36-38 weeks=Visit 3) and a postnatal visit (2-3 days after delivery=Visit 4). Eligible women should take two capsules twice daily (2 in the morning and 2 in the evening). Patients will be randomly assigned to the control or the VIVOMIXX® group. The study agent VIVOMIXX® as well as the placebo will be supplied by Mendes SA for the whole study period. During Visit 1 (at 10-12 weeks) written consent will be obtained, after information on expected benefits and possible inconveniences related to participation in the trial. Furthermore, eligible women will be asked to complete two questionnaires, one on dietary habits and one on gastrointestinal symptoms. The questionnaire on gastrointestinal symptoms will be submitted to the patients at each visit. Height will be assessed at Visit 1, while the following parameters will be measured at each visit: weight, waits/hip circumference ratio, arterial blood pressure, plasma hemoglobin (Hb), hematocrit (Ht), fasting glycemia, fasting insulin and fasting glycated hemoglobin (HbA1c1). A blood sample for the evaluation of homocysteine will be taken as well as urine and a faeces sample will be collected for nuclear-magnetic-resonance (NMR)-based metabolomics and intestinal microbiota analysis. Furthermore, an Arm-band will be positioned for monitoring sleep and physical activities for one week at each visit. At Visit 2 and 3 data regarding ultrasound examinations (Amniotic fluid index, abdominal circumference, cephalic circumference ratio) will be also collected. Two-three days after delivery (Visit 4) data regarding the delivery (mode of delivery, gestational age at delivery) as well as the newborn (Apgar score, glycemia and serum bilirubin) were collected. Moreover, a sample of colostrum (for NMR-based metabolomics, microbiota and high performance liquid chromatography-mass spectrometry -HPLC/MS- of vitamins analysis) and newborn faeces (for NMR-based metabolomics and microbiota analysis) sample will be collected.

Official Title
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Modulation of the Intestinal Flora With the Probiotic VIVOMIXX™ in Pregnant Women at Risk of Metabolic Complications

Conditions
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Gestational Diabetes Mellitus in Pregnancy, Diet- Controlled, Exercise Addiction, High-Risk Pregnancy, Dietary Modification

Intervention / Treatment
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* Dietary Supplement: Probiotic VIVOMIXX™
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged between 20 and 40 with singleton pregnancies and BMI at recruitment > 30 kg/m^2 or a BMI> 25 kg/m^2 and the simultaneous presence of at least 1 of the following risk factors: age> 35 years, previous fetal macrosomia (> 4500gr), family history of diabetes (first-degree relative with type 2 diabetes mellitus), previous gestational diabetes mellitus. Adherence to lifestyle prescription including dietary counselling and physical activity stimulation Exclusion Criteria: Subjects who require intervention in addition to the lifestyle changes women with diet and habits much different from the Mediterranean area (Central Africa, Asian, etc..). In such subgroup it will be difficult to obtain adherence to diet prescription since their cultural attitudes and dietary habits. Pre-pregnancy BMI> 40 kg/m^2 Chronic hypertension Fasting glycemia in the first trimester of> 126 mg / dl or random glycemia > 200 mg/dl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Probiotic VIVOMIXX™ | Dietary Supplement: Probiotic VIVOMIXX™<br>* The patients will be randomly assigned to the VIVOMIXX™ (intervention) or the control (placebo) group through a randomization list elaborated by a specific software.<br>|
| Placebo Comparator: Control<br>Placebo | Dietary Supplement: Placebo<br>* The patients will be randomly assigned to the VIVOMIXX™ (intervention) or the control (placebo) group through a randomization list elaborated by a specific software.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal and newborn fecal microbiota changes (bifidobacteria and lactobacilli) and related enzymatic activity (alkaline sphingomyelinase and alkaline phosphatase) modifications | NMR-based metabolomics, microbiota and high performance liquid chromatography-mass spectrometry -HPLC/MS- of vitamins analysis | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Glucose metabolism changes | Positive Oral Glucose Tolerance Test | At 24-26 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight changes | Measured in kg | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Maternal BMI | Measured in kg/m^2 | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Waist/hip circumference ratio |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Gestational weight gain | Measured in kg | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| HOMA Index |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| HbA1c1 |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| glycemia |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| insulinemia |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| homocysteine plasmatic levels |  | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Requirement for insulin therapy | Week of onset | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Requirement for insulin therapy | Dose of insulin | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Quality of sleep | Hours of deep sleep measured through the armband | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Duration of sleep | Measured in hours through the armband | At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery | 
| Onset of hypertension / preeclampsia |  | At delivery | 
| Time of delivery |  | At delivery | 
| Mode of delivery |  | At delivery | 
| Complications during delivery | Surgery and/or hemorrhage >500ml and/or shoulder dystocia | At delivery | 
| Apgar score |  | Within 1 hour after delivery | 
| Newborn's weight |  | Within 1 hour after delivery | 
| Newborn's sex |  | Within 1 hour after delivery | 
| Newborn's abdomen / head ratio |  | 2-3 days after delivery | 
| Newborn's skinfold thickness at birth |  | 2-3 days after delivery | 
| Neonatal hypoglycemia | Neonatal hypoglycemia (measured in mg/dl) that requires therapy | Within 24 hours from delivery | 
| Neonatal bilirubinemia | Measured in mg/dl | At delivery, 2-3 days after delivery | 
| Neonatal complications | Respiratory Distress Syndrome, Necrotizing Enterocolitis, Retinopathy of prematurity, Bronchopulmonary Dysplasia, Neonatal Death | 2-3 days after delivery | 
| Admission to Neonatal Intensive Care Unit (NICU) | Admission to NICU | Within 24 hours after delivery | 
| Admission to Neonatal Intensive Care Unit (NICU) | Duration of stay at the NICU | Within 24 hours after delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maternal Obesity Complicating Pregnancy