Vaginal Microbiome Seeding and Health Outcomes in Cesarean-delivered Neonates.

• ClinicalTrials.gov Identifier: NCT03298334
• Recruitment Status: Recruiting
• First Posted: October 2, 2017
• Last Update Posted: January 20, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Johns Hopkins University; Rutgers University; Inova Health Care Services
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

Neonates delivered by scheduled Cesarean Section will be randomized to receive vaginal seeding (exposing the infant to Mother's vaginal flora) or sham. Infants will be followed for three years to examine health outcomes including microbiome development, immune development, metabolic outcomes, and any adverse events.

Condition or disease	Intervention/treatment	Phase
Cesarean Delivery Affecting Newborn; Obesity, Childhood; Intestinal Microbiome; Microbiota; Host Microbial Interactions; Gastrointestinal Microbiome	Biological: Vaginal Seeding; Other: No Vaginal Seeding	Phase 1; Phase 2

Detailed Description:

Cesarean section (CS) delivery is a common surgical procedure intended to increase the chances of successful delivery and to protect the health of the mother and baby. Yet this intervention is overused and has been associated with higher risk of immune and metabolic disorders in the offspring. It is hypothesized that these associations are due to CS-delivered newborns not receiving the full inoculum of maternal microbes at birth.

While restoring labor is not possible, restoring the microbes that colonize infants during birth through exposure to vaginal flora, is feasible, and has been shown in a small pilot study, to normalize the microbiota of the intestine, skin and mouth during the first month of life.

The investigators hypothesize that the restoration of the vaginal microbiota to the infant at birth will restore the infant microbiome and decrease the risk of obesity and other immune-mediated diseases linked with CS. The investigators aim to test this hypothesis in a randomized controlled trial by first examining the effect of vaginal seeding, in CS-delivered newborns, on the gut microbiota composition, structure and function (Phase I of study; first 50 infants) and then on the BMI z score and other immune-mediated outcomes (Phase II of study; 600 infants).

Methods: CS-delivered neonates will be randomized to either an experimental arm with exposure to the maternal vaginal microbiota at birth, or a control arm with no exposure. Feces, skin, saliva, breast milk, and vaginal swabs will be collected for microbiome analysis. The investigators will obtain clinical information from in-person visits, surveys and the electronic health record.

Implications: this randomized controlled clinical study will provide evidence of whether the "vaginal seeding" procedure can safely transfer microbes from mom-to-baby, and whether these microbes are beneficial for the metabolic and immune health of the child.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 600 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Vaginal Microbiome Seeding and Health Outcomes in Cesarean-delivered Neonates: a Randomized Controlled Trial
• Actual Study Start Date: July 1, 2018
• Estimated Primary Completion Date: April 2027
• Estimated Study Completion Date: April 2029

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Receives Vaginal Seeding	Biological: Vaginal Seeding; A gauze containing the Mother's vaginal flora will be swabbed over the face and body of the neonate shortly after cesarean delivery.
Sham Comparator: No Vaginal Seeding	Other: No Vaginal Seeding; A gauze carrying sterile saline will be swabbed over the face and body of the neonate shortly after cesarean delivery.

Outcome Measures

Primary Outcome Measures :

1. Adiposity [ Time Frame: 2 years ]
   E.g. Body mass index z-score

Secondary Outcome Measures :

1. Adverse events [ Time Frame: 3 years ]
   Monitoring for adverse events
2. Intestinal microbiota [ Time Frame: 3 years ]
   Intestinal microbiota development over the first three years of life
3. Immune and inflammatory regulation [ Time Frame: 3 years ]
   E.g. Monitoring for immune and inflammatory mediated conditions

Eligibility Criteria

• Ages Eligible for Study: 0 Days to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria for Mother:

• Scheduled for cesarean delivery at ≥ 37 weeks
• Pregnant with single fetus, in good general health, age 18 years or older
• Negative maternal testing for infections transmitted through vaginal and/or other body fluids performed as standard of care tests in early pregnancy
• Negative testing for Group B strep at 35-37 weeks gestation
• Vaginal pH ≤ 4.5 indicative of Lactobacillus-dominated vaginal microbiota
• No maternal or fetal complications that may inhibit the ability to perform microbiome restoration per protocol
• English or Spanish speaking
• Negative maternal testing for Gonorrhea, Chlamydia, Hepatitis B, Hepatitis C, Syphilis, and HIV at 35 weeks gestation or later
• Women aged 18-29 years must have a normal Pap test within 3 years
• Women aged 30-65 years must have a normal Pap test and an HPV test (co-testing) within 5 years or FDA-approved primary hrHPV testing alone within 5 years or a normal Pap test alone within 3 years
• Negative maternal testing for SARS-CoV-2 for the delivery admission performed as standard of care test at the Inova Health System.

Inclusion Criteria for Infant:

• Infant condition after delivery requires no more than standard neonatal resuscitation* or is otherwise medically unable to receive the full VMT procedure

[*] Standard neonatal resuscitation may include: tactile stimulation, bulb suction, oxygen without positive pressure, or drying

Exclusion Criteria for Mother:

• Delivery at a hospital other than Inova Health System
• Cesarean delivery scheduled for active infection that would have interfered with vaginal delivery such as genital herpetic lesions
• Rupture of membranes prior to scheduled cesarean delivery
• Bacterial vaginosis within 30 days of cesarean delivery
• Symptomatic urinary tract infection within 30 days of cesarean delivery
• Antibiotic therapy within 30 days of cesarean delivery (exclusive of medication use for prophylaxis at the time of surgery)
• Symptoms on admission suggesting Chorioamnionitis, e.g. maternal fever, fundal tenderness
• Symptoms on delivery admission of possible vaginal infection such as genital herpetic lesions
• History of genital HSV
• History positive testing for Group B strep infection
• History of a child with a diagnosis of Group B strep sepsis
• Pregnancy a result of donor egg or surrogacy
• Preexisting history of Type I or Type II Diabetes
• Maternal history of documented genital HPV infection, positive HPV testing or genital warts on physician examination
• Positive maternal testing for SARS-CoV-2 within 30 days of delivery or symptoms on admission suggesting potential Covid-19 infection

Contacts and Locations

Contacts

Contact: Suchitra Hourigan, MD; 703-776-8489; suchitra.hourigan@inova.org, suchitra.hourigan@nih.gov

Contact: Shira Levy; 703-776-8489; shira.levy@inova.org

Locations

United States, Virginia

Inova Health System; Recruiting

Falls Church, Virginia, United States, 22042

Contact: Suchitra Hourigan, MD 703-776-8489 suchitra.hourigan@inova.org, suchitra.hourigan@nih.gov

Contact: General Information microbiome@inova.org

Sub-Investigator: Ankit Shah, MD

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Johns Hopkins University

Rutgers University

Inova Health Care Services

Investigators

• Principal Investigator: Suchitra Hourigan, MD, Chief, Clinical Microbiome Unit, NIAID, Pediatric Gastroenterologist; National Institute of Allergy and Infectious Diseases (NIAID), Inova Children's Hospital
• Principal Investigator: Noel Mueller, PhD; Johns Hopkins University
• Principal Investigator: Maria Gloria Dominguez Bello, PhD; Rutgers University
• Principal Investigator: Lawrence Appel, MD, MPH; Johns Hopkins University

More Information

Publications:

Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R, Clemente JC. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016 Mar;22(3):250-3. doi: 10.1038/nm.4039. Epub 2016 Feb 1.

Song SJ, Wang J, Martino C, Jiang L, Thompson WK, Shenhav L, McDonald D, Marotz C, Harris PR, Hernandez CD, Henderson N, Ackley E, Nardella D, Gillihan C, Montacuti V, Schweizer W, Jay M, Combellick J, Sun H, Garcia-Mantrana I, Gil Raga F, Collado MC, Rivera-Vinas JI, Campos-Rivera M, Ruiz-Calderon JF, Knight R, Dominguez-Bello MG. Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding. Med. 2021 Aug 13;2(8):951-964.e5. doi: 10.1016/j.medj.2021.05.003. Epub 2021 Jun 17.

Hourigan SK, Dominguez-Bello MG, Mueller NT. Can maternal-child microbial seeding interventions improve the health of infants delivered by Cesarean section? Cell Host Microbe. 2022 May 11;30(5):607-611. doi: 10.1016/j.chom.2022.02.014.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03298334
• Other Study ID Numbers: 17-2694
• First Posted: October 2, 2017
• Last Update Posted: January 20, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data will be shared with co-principal investigators (Maria Gloria Dominguez-Bello at Rutgers University and Noel Mueller at Johns Hopkins School of Medicine).
• Supporting Materials: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pediatric Obesity; Obesity; Overweight; Overnutrition; Nutrition Disorders; Body Weight