MOdification Of THe Early-Life Respiratory Microbiome Through Vaginal SEEDing

Study Overview
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Brief Summary
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This is a single-center, parallel-arm, blind, sham-controlled, feasibility randomized controlled trial (RCT) to be conducted in healthy cesarean-born infants. Eligible infants will be randomized 1:1 to have their nose swabbed with either maternal vaginal secretions or a sterile swab (intervention vs. control group, respectively) following birth by cesarean section (C-section). The main hypothesis is that conducting an RCT assessing the utility of vaginal seeding in modifying the early-life upper respiratory tract (URT) microbiome of infants born by C-section is feasible and that the intervention is safe.

Detailed Description
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Eligible infants will be randomized 1:1 to have their nose swabbed with either maternal vaginal secretions or a sterile swab (intervention vs. control group, respectively) following birth by C-section. The procedure will be performed immediately after the initial newborn care by the general pediatric team. The mother and infant will then receive usual medical care as determined by their health care providers. Follow-up will occur at multiple time points during the child's first year of life. One planned interim analysis to assess the safety of the procedure will be conducted. The intervention aims to transfer the maternal vaginal microbiome to the nasal cavity of cesarean-born infants at birth (i.e., vaginal seeding of the URT). Hence, the intervention simply attempts to replicate the natural exposure to maternal vaginal secretions during vaginal delivery in infants born by C-section.

Official Title
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MOdification Of THe Early-Life Respiratory Microbiome Through Vaginal SEEDing

Conditions
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Cesarean Section, Vaginal Seeding, Nose, Microbiome

Intervention / Treatment
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* Procedure: Vaginal Seeding
* Procedure: Sterile Swab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For the mother: Female 18-40 years of age who is in good general health, is fully able to provide consent to participate in the study, anticipates being available for the duration of the study, and is willing to comply with all study procedures Singleton pregnancy Completed ≧3 prenatal care visits at Vanderbilt University Medical Center (VUMC) (any facility) Scheduled for a planned C-section due to a repeat C-section at VUMC (main campus only) Planning to have general pediatric care for the infant at VUMC (main campus or One Hundred Oaks campus) Intention to breastfeed partially or exclusively No intent to relocate outside the middle Tennessee region within 18-24 months of recruitment For the infant: Estimated gestational age ≧37 weeks Birth weight ≧2,500 grams Exclusion Criteria: For the mother: Previous child with Group B Streptococcus (GBS) infection at any age Hepatitis B, hepatis C, or human immunodeficiency virus infection at any age Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the 4 weeks prior to delivery or a household contact with a confirmed SARS-CoV-2 infection in the 4 weeks prior to delivery Fever (≧100.4°F [38°C]) in the 72 hours prior to delivery Symptoms (e.g., dysuria, pruritus, or discharge) suggestive of a genitourinary infection (e.g., bacterial vaginosis, vaginal yeast infection, chorioamnionitis, or urinary tract infection) on the day of delivery Physical exam findings (e.g., fever [≧100.4°F (38°C)] or vesicles, warts, or ulcers in the genital, perineal, or anal region) suggestive of a genitourinary infection on the day of delivery (performed as part of the screening procedures for this study if not performed as standard of care) Laboratory evidence of any of the following: GBS bacteriuria in urine samples collected at any time during current pregnancy (performed as standard of care) GBS colonization in rectovaginal swabs collected at ≧35 weeks of current pregnancy (performed as standard of care) Chlamydia, trichomoniasis, or gonorrhea in urine samples collected in the first trimester current pregnancy (performed as standard of care) Chlamydia, trichomoniasis, or gonorrhea in urine samples collected at ≧35 weeks of current pregnancy (performed as part of the screening procedures for this study) Hepatitis B, hepatis C, human immunodeficiency virus, or syphilis infection in blood samples collected in the first trimester current pregnancy (performed as standard of care) Hepatitis B, hepatis C, human immunodeficiency virus, or syphilis in blood samples collected at ≧35 weeks of current pregnancy (performed as part of the screening procedures for this study) SARS-CoV-2 infection in nasal swabs collected in the 72 hours prior to delivery (performed as standard of care) Maternal vaginal pH>4.5 on the day of delivery (performed as part of the screening procedures for this study) For women 21-29 years of age: Abnormal Pap smear in the 3 years prior to delivery (performed as standard of care) For women 21-40 years of age: Abnormal Pap smear with cervical human papilloma virus co-testing in the 5 years prior to delivery, abnormal Pap Smear alone in the 3 years prior to delivery, or abnormal cervical human papilloma virus testing alone in the 5 years prior to delivery (performed as standard of care) Pelvic inflammatory disease at any age Diabetes (including type I, type II, and gestational diabetes) at any age Any serious obstetric disease (e.g., preeclampsia, placenta previa, placental abruption, severe bleeding, or thromboembolic disease) C-section scheduled for a genitourinary infection that would have interfered with vaginal delivery (e.g., genital herpetic lesions) Lack of available prenatal screening tests Expected preterm delivery Need for a switch from a planned C-section to an emergency C-section Onset of labor or rupture of membranes prior to delivery Use of systemic (oral, intramuscular, or intravenous) antibiotics in the 4 weeks prior to delivery (except for those being administered as part of the C-section) Use of systemic (oral, intramuscular, or intravenous) immunosuppressive, biologic, or chemotherapeutic agents in the 3 months prior to delivery (except for systemic immunosuppressive agents not being used for their immunosuppressive effects [e.g., prenatal intramuscular beclomethasone for fetal lung maturation]) Pregnancy as the result of an assisted reproductive technology or surrogacy Participation in another clinical trial that involves an intervention that could impact the quality or interpretation of the study data as deemed by the PI or co-investigators Other past or current medical problems that could compromise the safety of participants, interfere with their ability to comply with study requirements, or impact the quality or interpretation of the study data as deemed by the PI or co-investigator For the infant: Need for neonatal measures outside routine clinical care (i.e., drying, tactile stimulation, bulb syringe or catheter suction of nose and mouth, or temperature maintenance) or transfer to the neonatal intensive care unit immediately after delivery Thick particulate meconium noted during delivery Physical exam findings (e.g., tachypnea, nasal flaring, retractions, cyanosis, or grunting) suggestive of neonatal acute respiratory distress immediately after delivery (performed as part of the screening procedures for this study) Prenatal or immediate postnatal diagnosis of a serious genetic, respiratory, cardiovascular, or neurological disease Prenatal or immediate postnatal diagnosis of intrauterine growth restriction Prenatal or immediate postnatal diagnosis of a major congenital anomaly (e.g., cleft lip or palate, cystic hygroma, or giant omphalocele) Participation in another clinical trial that involves an intervention that could impact the quality or interpretation of the study data as deemed by the PI or co-investigators Other past or current medical problems that could compromise the safety of participants, interfere with their ability to comply with study requirements, or impact the quality or interpretation of the study data as deemed by the PI or co-investigators

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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No

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
Interventional Model Description: This is a single-center, parallel-arm, blind, sham-controlled, feasibility RCT to be conducted in healthy cesarean-born infants.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention Group<br>Vaginal Seeding | Procedure: Vaginal Seeding<br>* Following delivery by C-section, participating infants randomized to the intervention group will have their nasal cavity swabbed with maternal vaginal secretions.<br>|
| Sham Comparator: Control Group<br>Sterile Swab | Procedure: Sterile Swab<br>* Following delivery by C-section, participating infants randomized to the control group will have their nasal cavity swabbed with a sterile swab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of the RCT | The study will be considered definitively feasible as proposed, possibly feasible as proposed, or not feasible as proposed based on eligibility, consent, enrollment, and loss to follow-up rates, which could be used as preliminary data to inform the design of a future phase II RCT. For this study, the eligibility, consent, enrollment, and loss to follow-up rates will be calculated using the following formulas: 1) eligibility rate = number of participants who are eligible * 100 / number of participants pre-screened, 2) consent rate = number of participants who provide consent * 100 / number of participants who are eligible, 3) enrollment rate = number of participants who are enrolled * 100 / number of participants consented and who complete screening procedures, and 4) loss to follow-up rate = number of participants who did not complete the end-of-study visit * 100 / number of participants randomized. Enrolled will be defined as consented and screened, with eligibility verified. | One year following randomization | 
| Safety of the intervention | To be determined by the number of adverse events, serious adverse events, and unanticipated problems throughout the study, as defined using the standards set forth in the National Cancer Institute's - Common Terminology Criteria (NCI-CTCAE) for AEs version 4.0 and the United States Department of Health and Human Services - Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events: Office for Human Research Protections Guidance 2007. | One year following randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Timing of the intervention | The number of minutes after birth when the intervention is performed. | Immediately following administration of the intervention | 
| Proportion of in-person study visits completed | The total number of in-person study visits completed by all participants / total number of in-person visits expected for all participants for each study time point . | One year following randomization | 
| The alpha-diversity, beta-diversity, and specific taxa abundance of the maternal vaginal microbiome and early-life URT microbiome as characterized by 16S ribosomal ribonucleic acid gene sequencing | The comparisons of the maternal vaginal microbiome on the day of delivery between study groups will be conducted using alpha-diversity (e.g., observed taxa, Shannon index, and Simpson indices), beta-diversity (e.g., Bray-Curtis, Jaccard, weighted UniFrac, and unweighted UniFrac indices), and differential abundance (at the amplicon sequence variant, genus, and/or family level) analyses. The early-life URT microbiome at each time point and over time will be compared between study groups using similar microbial ecology metrics. In pre-specified analyses, we will also compare the presence and abundance of the genus Lactobacillus and the predominant Lactobacillus amplicon sequence variants in the URT of infants at each time point and over time between study groups, as this is the predominant taxa of the maternal vaginal microbiome during pregnancy. | At each study time point (birth and  2 days,  5 days, 4 weeks, and 6 months of age) and over time (longitudinally from birth to age 6 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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C-section, Vaginal seeding, Respiratory, Microbiome