Synbiotics in Patients at RIsk fOr Preterm Birth

Study Overview
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Brief Summary
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Prematurity remains the main cause of death and serious health problems in new-borns. Besides the need for hospitalization and medical interventions in the first weeks or months of the new-borns' life, prematurity can cause long-lasting health problems (e.g. multiple hospital admissions, developmental delay, learning difficulties, motor delay, hearing or eye problems, ...). Moreover, prematurity places an enormous economic burden on the society. Aside from the medical problems and the financial cost, the emotional stress and psychological impact on the parents, siblings and other family members should not be underestimated. Previous preterm delivery (before 37 weeks of pregnancy) increases the risk for recurrent preterm delivery in a subsequent pregnancy. Therefore, these women should be considered as 'high risk' for preterm birth. Infections ascending from the vagina may be an important cause of preterm delivery in certain cases. Some women have an abnormal vaginal microbiome and are therefore at risk for infections and preterm birth. On the other hand, the vaginal flora is more stable and resistant to infections in healthy pregnant women who deliver at term (after 37 weeks of gestation). Synbiotics are a mixture containing probiotics and prebiotics. Probiotics are living bacteria with potential beneficial effects that can be used safely in pregnancy, while prebiotics are consumed by the bacteria. It is known that probiotics, when used for a long period of time, can maintain a healthy and stable vaginal flora that may protect against infections. In this study, pregnant patients with a history of preterm birth will be included in the first trimester of pregnancy to start with synbiotics or placebo. The investigators will examine the effect of synbiotics on the vaginal flora and on the pregnancy duration. The hypothesis is that synbiotics, when started early in the pregnancy, can change the disturbed vaginal flora into a stable micro-environment.

Official Title
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Synbiotics in Patients at RIsk fOr Preterm Birth: a Multi-center Double-blind Randomized Placebo-controlled trIal

Conditions
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Preterm Birth, Preterm Spontaneous Labor With Preterm Delivery, Microbial Colonization

Intervention / Treatment
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* Other: Synbiotics
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent must be obtained before any study assessment is performed; 18 years of age or older; Singleton pregnancy; Pregnancy consultation between 8 and 10 weeks gestation. At least one of the following risk factors for spontaneous preterm birth: Prior spontaneous preterm birth, defined as delivery between 24 and 37 weeks following PPROM, preterm labor or cervical insufficiency PPROM ≤37 weeks in previous pregnancy but delivery ≥37 weeks Prior spontaneous second-trimester pregnancy loss, defined as PPROM, preterm labor or cervical insufficiency with birth between 14 and 24 weeks. Exclusion Criteria: Patients who are already using pro-, pre- or synbiotics Multiple pregnancy Need for primary (type 1) cerclage Inflammatory bowel disease Known congenital uterine anomaly History of LLETZ conization

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Synbiotics<br>Oral synbiotic (food supplement) containing 8 probiotic Lactobacillus strains, the prebiotics inulin, fructooligosaccharides (FOS) and D-mannose. | Other: Synbiotics<br>* Oral synbiotic (food supplement) containing 8 probiotic Lactobacillus strains, the prebiotics inulin, fructooligosaccharides (FOS) and D-mannose.<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Other: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at delivery |  | Through study completion - at delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of PTB, defined as GA at delivery < 37 weeks |  | Through study completion - at delivery | 
| Proportion of PTB in different categories | of patients that deliver < 28 weeks: extreme PTB of patients that deliver from 28 until 37 weeks: very PTB of patients that deliver from 32 until 37 weeks: moderate to late PTB | Through study completion - at delivery | 
| PPROM | Incidence | Up to 34 weeks from the date of randomization | 
| PPROM | Gestational age at PPROM | Up to 34 weeks from the date of randomization | 
| PPROM | Time to delivery | Up to 34 weeks from the date of randomization | 
| Composition of the vaginal microbiome | The vaginal microbiome will be assessed throughout pregnancy at 4 well-defined stages of pregnancy (9, 20, 30 weeks and at delivery) and at admission at the MIC unit for preterm labor, PPROM or cervical insufficiency. | Assessed 3 times during the study period: at randomization, 11-13 weeks after randomization (at gestational age 19-21 weeks), and 21-23 weeks after randomization (29-31 weeks of gestation) | 
| Incidence of neonatal admissions |  | Neonatal admission at a neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Duration of neonatal admissions |  | Neonatal admission at a neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Incidence of maternal admissions |  | Up to 34 weeks from the date of randomization | 
| Duration of maternal admissions |  | Up to 34 weeks from the date of randomization | 
| Quality Of Life during pregnancy and during neonatal admission at a neonatal intensive care unit | Using EQ5D questionnaire (5 questions and scale from 1 to 100) | Trough study completion, on avarage 1 year | 
| Neonatal outcome: infectious parameters | Sepsis (early, late and culture negative), number of episodes (min 72 hours) of antibiotic treatment, duration of antibiotic treatment in days | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: bronchopulmonary dysplasia (BPD) | Proportion of each category (no, mild, moderate and severe) | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: intraventricular haemorrhage | Incidence | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: periventricular leukomalacia | Incidence | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: respiratory support | Need for respiratory support (CPAP: continuous positive airways pressure, non-invasive positive pressure ventilation or mechanical endotracheal ventilation) and the duration of respiratory support in days. Use and administration of surfactant | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: retinopathy | Incidence | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: neonatal morbidity | Incidence | During the admission at the neonatal intensive care unit (when the neonate is admitted at a neonatal intensive care unit within 7 days of delivery) | 
| Neonatal outcome: birth weight |  | After the neonate is born | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm birth, Vaginal microbiome, Probiotics, Synbiotics