Vaginal Microbiome Exposure and Immune Responses in C-section Infants

Exposure to Vaginal Microbiome in C-section Infants at High-risk for Allergies - A Pilot Study

The purpose of this research study is to assess at how differences in the microbiome (naturally occurring bacteria) of a baby may protect, or put a baby at risk, for allergic problems. The microbiome refers to the thousands of bacteria and molds that live in and on our bodies. The microbiome plays an important role in our health. Differences in the microbiome can affect our immune system in ways that might make some people more likely to get allergies and asthma.

Early life events and exposures are very important for establishing the human microbiome. The newborn baby's microbiome changes very quickly during the first weeks and months of life. There is information that suggests C-section birth is associated with higher risk of certain diseases, including allergies and asthma. Some researchers think one reason for this is that passing through the mother's vaginal canal during birth exposes the baby to bacteria that promote healthy immune system development, something that C-section babies don't get. Transferring these potentially beneficial vaginal bacteria to C-section babies may help prevent some diseases later.

Study Overview

• Status: Recruiting
• Conditions: Asthma; Allergic Diseases
• Intervention / Treatment: Biological: C-section -Vaginal seeding; Drug: C-section - Placebo Seeding; Other: standard care

Detailed Description

This is a pilot study of 120 pregnant women and their infants conducted at hospitals in the Mount Sinai Health System in New York, NY. Eighty women will deliver via elective, unlabored C-section, and 40 will undergo spontaneous vaginal delivery. The 80 women undergoing C-section will be randomized in a masked (blinded) 1:1 fashion to have their neonates undergo vaginal seeding or placebo seeding immediately after birth (within 10 minutes) followed by standard care.The infants of the 40 women undergoing spontaneous vaginal delivery will receive usual standard care.

All 120 pregnant women will have biospecimens collected to assess their vaginal, skin, gut, placental, breast milk, and oral microbiome. All infants will have biospecimens collected to assess their gut, skin, nasal, and oral microbiome, as well as blood to assess allergen sensitization and immune markers. Infants will be followed with at-home stool collections and questionnaires weekly for the first 4 weeks and at weeks 8, 26, and 39. An in-person study visit will occur at 13 weeks and 52 weeks, and the primary endpoint will be assessed at 52 weeks. Study enrollment is projected to occur over 24 months.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Contact: Konica Fleming; Phone Number: 212-241-8449; Email: konica.fleming@mssm.edu
      • Principal Investigator: Hugh A. Sampson, MD
    • New York, New York, United States, 10019
      • Recruiting
      • Mount Sinai West
      • Contact: Konica Fleming; Phone Number: 212-241-8449; Email: konica.fleming@mssm.edu
      • Principal Investigator: Hugh A. Sampson, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pregnant woman must be able to understand and provide informed consent;
• Pregnant women with singleton pregnancies with a non-anomalous, appropriately-grown fetus; and
• Atopic disease (asthma, allergic rhinoconjunctivitis, or atopic dermatitis) or food allergy in a first-degree relative of the infant to-be-delivered (for exception, see exclusion criteria*).

Exclusion Criteria:

For C-Section Mothers:

• In labor with evidence of cervical change prior to the scheduled C-section;
• Rupture of the amniotic sac; or
• Vaginal pH > 4.5 on the day of delivery.

For Vaginal Delivery Mothers:

- Use of induction agents for cervical ripening (cervical prostaglandin or Foley catheter).

For All Mothers and Their Infants:

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
• History of moderate to severe atopic dermatitis within the past year in the mother;
• Express no intention to breastfeed;
• History of diabetes mellitus or gestational diabetes mellitus;
• History of inflammatory bowel disease (IBD) (e.g., Crohn's Disease or ulcerative colitis);
• Evidence of an active sexually transmitted infection (STI) (e.g., primary herpes or genital warts, or trichomonas), yeast infection, or vaginosis on the day of delivery;

• Evidence of prior or current hepatitis B or C infection as demonstrated by the presence of the hepatitis B surface antigen, antibody positivity against the hepatitis B core antigen, or antibody positivity against the hepatitis C virus;

  --Assessment for active hepatitis B and hepatitis C infection will be repeated for this study even if prior testing during the current pregnancy was negative;

• Evidence of Human Immunodeficiency Virus (HIV) infection (e.g., positive HIV serology or detectable viral load);
• Positive Group B Streptococcus (GBS) test results by rectovaginal swab performed within 5 weeks of delivery, a prior infant with invasive GBS disease, or GBS bacteriuria at any point during pregnancy;
• Evidence of N. gonorrhoeae or C. trachomatis infection by testing performed within 5 weeks of delivery;
• History of antibiotic administration during the third trimester of the current pregnancy;
• Mothers with serious chronic conditions during pregnancy;
• Mothers with complicated pregnancies including pre-eclampsia, chorioamnionitis, placenta previa, vasa previa, placental abruption, or active vaginal bleeding;
• Maternal fever on the day of delivery (visit 0);
• Infants with complications during delivery, such that the infant requires more than the standard neonatal resuscitation after delivery;
• Infants delivered prior to 37 weeks of gestation;
• Thick particulate meconium noted upon delivery of the infant;
• Presence of a congenital abnormality in the infant for which study participation is not recommended;
• Current, diagnosed mental illness or current, diagnosed or self-reported drug or alcohol abuse in the mother that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements;
• Use of investigational drugs during the third trimester of pregnancy; or

• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator may:

  • Pose additional risks from participation in the study,
  • Interfere with the participant's ability to comply with study requirements, or
  • May impact the quality or interpretation of the data obtained from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: C-section -Vaginal seeding; Pregnant women who undergo C-section and (neonate) vaginal seeding. Infants that are scheduled to be born in a hospital by standard C-section procedure (e.g., elective, unlabored C-section) will be wiped with gauze containing their mother's vaginal microbiota just after delivery.	Biological: C-section -Vaginal seeding; Mother-infant pair randomized to vaginal microbiota intervention. As soon as the infant is delivered, the infant will be brought to the neonate lamp, and unless the obstetrician or pediatric staff believes it is not in the best interest of the infant, s/he will be swabbed with the vaginal microbiota soaked gauze. Swabbing will take place ideally within 1 minute after delivery (but no longer than 5 minutes). The swabbing should take approximately 15 seconds. Infants will only undergo the seeding.; Other Names: vaginal microbiota; maternal vaginal microbiota
Experimental: C-section - Placebo Seeding; Pregnant women who undergo C-section and (neonate) placebo seeding. Infants that are scheduled to be born in a hospital by standard C-section procedure (e.g., elective, unlabored C-section) will be wiped with sterile gauze (placebo).	Drug: C-section - Placebo Seeding; Mother-infant pair randomized to placebo microbiota intervention. As soon as the infant is delivered, the infant will be brought to the neonate lamp, and unless the obstetrician or pediatric staff believes it is not in the best interest of the infant, s/he will be swabbed with the placebo gauze. Swabbing will take place ideally within 1 minute after delivery (but no longer than 5 minutes). The swabbing should take approximately 15 seconds.; Other Names: vaginal microbiota; placebo vaginal microbiota
Active Comparator: standard care; Pregnant women who undergo spontaneous vaginal delivery (of neonate) . Pregnant women who undergo spontaneous vaginal delivery and (neonate) receives standard care.	Other: standard care; Mother-infant pair where mother undergoes spontaneous vaginal delivery, with both receiving standard of care.; Other Names: standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Sensitization to at Least One Food Allergen at 12 months of age - by Treatment Group	Evaluation for the presence of food allergens (egg, milk, and peanut) in infants at 12 months of age. Sensitization is defined by a serum IgE ≥ 0.1 kUA/mL for each allergen.	Infants at 12 months of age (=Month 12 visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Adverse Events (AEs) -by Treatment Group	Adverse events reported as possibly related, probably related, or definitely related to study participation.	From birth to 12 months of age (=Month 12 visit)
Presence of Sensitization to at Least One Aeroallergen at 12 months of age - by Treatment Group	Evaluation for the presence of aeroallergens (house dust mite (Dermatophagoides pteronyssinus), cat (Felis domesticus), and/or cockroach (Blattella germanica)), in infants at 12 months of age as determined by serum IgE assessment. Sensitization is defined by a serum IgE ≥ 0.1 kUA/mL for each allergen.	Infants at 12 months of age (=Month 12 visit)
Level of Allergen-Specific Atopy at 12 months of age - by Treatment Group	Defined by serum IgE levels. Sensitization is defined by a serum IgE ≥ 0.1 kUA/mL for each allergen. The following allergen-specific IgE levels will be included: egg, milk, peanut, house dust mite (Dermatophagoides pteronyssinus), cat (Felis domesticus) and cockroach (Blattella germanica).	Infants at 12 months of age (=Month 12 visit)
Level of Combined Allergen-Specific Atopy at 12 Months of Age - by Treatment Group	Defined as the sum of the serum IgE levels to: egg, milk, peanut, house dust mite (Dermatophagoides pteronyssinus), cat (Felis domesticus), and cockroach (Blattella germanica). Necessary for inclusion in this outcome measure: Available results for all six allergen-specific IgE levels.	Infants at 12 months of age (=Month 12 visit)
Number of Food Allergens and Aeroallergens Each Infant is Sensitized to at 12 Months of Age-by Treatment Group	Defined by serum IgE levels. Sensitization is defined by a serum IgE ≥ 0.1 kUA/mL.	Infants at 12 months of age (=Month 12 visit)
Severity of Atopic Dermatitis - by Treatment Group	Severity will be measured using the Eczema Area and Severity Index (EASI), a standardized investigator-assessed instrument.	Infants at 3 months and 12 months of age (=Month 3 and -12 visits)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EXPLORATORY: Comparison by Treatment Group in Bacterial Composition of the Infant Microbiome	Microbiome composition will be examined initially by 16S rRNA sequencing in order to determine the bacterial communities present in samples, their relative abundance, and overall diversity. Samples: gastrointestinal, oral, skin and nasal samples.	Infants at 12 months of age (=Month 12 visit)
EXPLORATORY: Comparison by Treatment Group in Fungal Composition of the Infant Microbiome	Microbiome composition will be examined initially by 16S rRNA sequencing in order to determine the fungal communities present in samples, their relative abundance, and overall diversity. Samples: gastrointestinal, oral, skin and nasal samples.	Infants at 12 months of age (=Month 12 visit)
EXPLORATORY: Comparison by Treatment Group in T Cell Profiles	Evaluation of differences by treatment group in Th2 cell and Treg populations.	Infants at 12 months of age (=Month 12 visit)
EXPLORATORY: Comparison by Treatment Group in Innate Immune System Profiles	Evaluation of differences by treatment group in pro-inflammatory cytokine production.	Infants at 12 months of age (=Month 12 visit)
EXPLORATORY: Comparison by Treatment Group in the Composition of Metabolites of the Fecal Metabolome	Qualitative assessment: Fecal samples will be assessed to evaluate differences in profile of pro-inflammatory metabolites.	Infants at day of delivery and months 3, -6, -9 and -12
EXPLORATORY: Comparison by Treatment Group in the Concentration of Metabolites of the Fecal Metabolome	Quantitative assessment: Fecal samples will be assessed to evaluate differences in the amount of profiled pro-inflammatory metabolites.	Infants at day of delivery and months 3, -6, -9 and -12
EXPLORATORY: Comparison by Treatment Group in Immunomodulatory Influences of the Fecal Metabolome	An exploration of how vaginal seeding influences subsequent development of the infant microbiome for the first 12 months of life.	Infants at day of delivery through month 12
EXPLORATORY: Evaluation of the Maternal Vaginal Microbiome Transfer	Skin and oral samples from mothers and infants will be profiled to determine the extent of transfer from the mother to the infant gut microbiota.	Infants at 12 months of age (=Month 12 visit)
EXPLORATORY: Comparison by Treatment Group in Transepidermal Water Loss (TEWL)	TEWL skin barrier assessment is a noninvasive in vivo measurement of water loss across the stratum corneum that is used to characterize skin water barrier function.	Month 3 and month 12 Follow-up Visits

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: PPD; Rho Federal Systems Division, Inc.; Immune Tolerance Network (ITN)
• Investigators: Study Chair: Jose C. Clemente, PhD, Icahn Institute for Genomics & Multiscale Biology; Study Chair: Hugh A. Sampson, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN)
• ITN website for trial

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2018
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: June 13, 2018
• First Submitted That Met QC Criteria: June 13, 2018
• First Posted (Actual): June 26, 2018

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Immune responses; Vaginal seeding; Allergen sensitization
• Other Study ID Numbers: DAIT ITN079AD; ACTIVATE (Immune Tolerance Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: The aim is to share data available to the public within 24 months upon completion of the study.
• IPD Sharing Access Criteria: ImmPort public data access.

Drug and device information, study documents

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