Synbiotics in Patients at RIsk fOr Preterm Birth (PRIORI)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Preterm Birth; Microbial Colonization; Vaginal Microbiome; Preterm Spontaneous Labor With Preterm Delivery; Synbiotics; Microbiome Dysbiosis
• Intervention / Treatment: Other: Placebo; Other: Synbiotics

• Study Type: Interventional
• Enrollment (Estimated): 402
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Caroline Van Holsbeke, PhD; Phone Number: 003289804057; Email: Caroline.van.holsbeke@zol.be
• Study Contact Backup: Name: Katrien Nulens, MD; Phone Number: 003289804125; Email: Katrien_Nulens@hotmail.com

Study Locations

• Belgium
  • Kortrijk, Belgium, 8500
    • Recruiting
    • Az Groeninge
    • Contact: Kim Demets; Phone Number: 0032 56 63 32 40
    • Principal Investigator: Eva Simoens
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Recruiting
      • Universitaire Ziekenhuis Antwerpen
      • Contact: Laury Knollenburg; Phone Number: 0032 3 436 85 32; Email: Laury.Knollenburg@uza.be
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Recruiting
      • Ziekenhuis Oost-Limburg
      • Principal Investigator: Caroline Van Holsbeke, PhD
      • Contact: Els Papy, MSc; Phone Number: 0032 89 80 40 57; Email: studies.gynaecologie@zol.be
      • Contact: Myrthe Hoeven, MSc; Phone Number: 0032 89 80 40 58; Email: studies.gynaecologie@zol.be
      • Sub-Investigator: Katrien Nulens, MD
    • Leuven, Limburg, Belgium, 3000
      • Recruiting
      • Universitaire Ziekenhuizen Leuven
      • Principal Investigator: Roland Devlieger, PhD
      • Contact: Ellen Reynders; Phone Number: 0032 16 34 29 96; Email: ellen.reynders@uzleuven.be
  • Liège
    • Liège, Liège, Belgium, 4000
      • Recruiting
      • CHR Citadelle
      • Contact: Marie Timmermans; Phone Number: 0032 4 321 75 57; Email: marie.timmermans@chuliege.be
      • Principal Investigator: Véronique Masson
  • Oost-Vlaanderen
    • Ghent, Oost-Vlaanderen, Belgium, 9000
      • Recruiting
      • UZ Gent
      • Contact: Astrid Luypaert, PhD; Phone Number: 0032 9 332 07 58; Email: gynobs.studies@uzgent.be
      • Principal Investigator: Isabelle Dehaene, PhD
  • West-Vlaanderen
    • Bruges, West-Vlaanderen, Belgium, 8300
      • Recruiting
      • AZ Sint-Jan
      • Principal Investigator: Joachim Van Keirsbilck
      • Contact: Hanna Van Horen; Phone Number: 0032 50 45 32 46; Email: hanne.vanhoren@azsintjan.be
    • Bruges, West-Vlaanderen, Belgium, 8310
      • Recruiting
      • AZ Sint-Lucas
      • Principal Investigator: Caroline Van Holsbeke, PhD
      • Contact: Veerle De Prest; Phone Number: 0032 50 36 51 04; Email: studies.gynaeco@stlucas.be
    • Ghent, West-Vlaanderen, Belgium, 9000
      • Recruiting
      • AZ Maria Middelares
      • Contact: Jolien Lansens; Phone Number: 0032 9 246 18 54; Email: Jolien.Lansens@mijnziekenhuis.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Signed written informed consent must be obtained before any study assessment is performed;
2. 18 years of age or older;
3. Singleton pregnancy;
4. Pregnancy consultation between 8 and 10 weeks gestation.

5. At least one of the following risk factors for spontaneous preterm birth:

   • Prior spontaneous preterm birth, defined as delivery between 24 and 36 weeks following PPROM, preterm labor or cervical insufficiency
   • PPROM ≤36 weeks in previous pregnancy
   • Prior spontaneous second-trimester pregnancy loss, defined as PPROM, preterm labor or cervical insufficiency with birth between 14 and 24 weeks.

Exclusion Criteria:

1. Patients who are already using pro-, pre- or synbiotics and not willing to stop
2. Multiple pregnancy
3. Need for primary (type 1) cerclage
4. Inflammatory bowel disease
5. Known congenital uterine anomaly
6. History of LLETZ conization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
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
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 average 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of antibiotics on the vaginal microbiome	When the patient is admitted in case the pregnancy was complicated with PPROM	During pregnancy until 28 days after PPROM
Effect on the gastrointestinal microbiome of the neonate in case of PPROM	When the neonate is born after a pregnancy complicated with PPROM	Between 13 to 36 weeks from the date of randomization
Placental microbiome in case of preterm birth	In case the pregnancy was complicated with preterm birth (delivery before 37 weeks of gestation)	Between 13 to 36 weeks from the date of randomization

Collaborators and Investigators

• Sponsor: Ziekenhuis Oost-Limburg
• Collaborators: Federaal Kenniscentrum voor Gezondheidszorg, Belgium

Publications and helpful links

General Publications

• Nulens K, Papy E, Tartaglia K, Dehaene I, Logghe H, Van Keirsbilck J, Chantraine F, Masson V, Simoens E, Gysemans W, Bruckers L, Lebeer S, Allonsius CN, Oerlemans E, Steensels D, Reynders M, Timmerman D, Devlieger R, Van Holsbeke C. Synbiotics in patients at risk for spontaneous preterm birth: protocol for a multi-centre, double-blind, randomised placebo-controlled trial (PRIORI). Trials. 2024 Sep 17;25(1):615. doi: 10.1186/s13063-024-08444-8.

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2023
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: March 2, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Probiotics; Preterm birth; Vaginal microbiome; Synbiotics
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Infections; Pathological Conditions, Signs and Symptoms; Premature Birth; Communicable Diseases; Dietary Supplements; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Prebiotics; Probiotics; Synbiotics
• Other Study ID Numbers: Z-2022080

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No