Maternal-fetal Immune Responses to Fetal Surgery

Performing surgery in utero on fetuses with certain birth defects has led to significant improvements in outcomes after birth; however, many of these infants are born preterm which can decrease the effectiveness of these procedures. The investigators aim to understand the effects of surgery on the maternal and fetal immune system and whether immune activation may be causing some of these infants to be born prematurely.

Study Overview

• Status: Active, not recruiting
• Conditions: Congenital Diaphragmatic Hernia; Myelomeningocele; Spina Bifida; Lower Urinary Tract Obstructive Syndrome
• Intervention / Treatment: Other: Blood and placenta specimen collection.

Detailed Description

Over 300,000 neonates worldwide die in their first month of life due to a congenital birth defect. Thanks to advancements in diagnostic technology and imaging, the field of fetal surgery was developed to treat some of these conditions in utero. Results have demonstrated improved short and long-term outcomes following surgery, especially for those fetuses diagnosed with congenital diaphragmatic hernia, lower urinary tract obstruction and spina bifida. However, over 30% of the surgical cases will have preterm labor, leading to complications related to neonatal prematurity. The cause of this surgery-induced preterm birth is unknown; however, disruption in fetal-maternal tolerance may lead to immune activation and inflammation of the maternal and fetal immune systems. Maintaining immunologic tolerance is essential during pregnancy, as a women shares only half of her genetic material with the fetus. Previous work has demonstrated that fetal surgery leads to an increase in maternal cells identified in cord blood. Animal studies have also shown that in utero intervention leads to the activation of maternal cells against fetal (paternal) antigen. Based on this previous data, it is hypothesized that surgical trauma following in utero intervention results in mixing of maternal and fetal cells leading to activation of systemic (adaptive maternal immunity) and regional (fetal placental macrophages) immune responses that disrupt fetal-maternal tolerance, which can result in preterm birth. Blood will be collected from pregnant women and their partners. Blood and placental tissue will be collected from infants that do and do not undergo in utero surgery to determine whether maternal T cells specific to fetal antigen are activated and expand after in utero intervention; and 2) to determine whether placental macrophages (Hofbauer Cells) and histology in the maternal-fetal interface exhibit increased activation and inflammation in surgical cases born preterm (<37 weeks) compared to term. Should this exploratory study reveal activation of maternal and/or fetal immune responses following in utero surgery, modalities aimed at therapeutically suppressing these acute responses may prolong gestation, significantly benefiting newborns diagnosed with a congenital anomaly.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Maureen A Lemens, BSN; Phone Number: 507-293-1487; Email: lemens.maureen@mayo.edu
• Study Contact Backup: Name: Elizabeth Ann L Enninga, PhD; Phone Number: 507-538-7615; Email: enninga.elizabethann@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester, Minnesota
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will compare two groups of pregnant women. Each group will be comprised of maternal, paternal, fetal trios. The study cohort will be comprised of adult women carrying a fetus with a diagnosed congenital anomaly and scheduled to undergo fetal surgical intervention. The control cohort will enroll pregnant women with normal ultrasound findings that will be matched with the subjects enrolled in the study cohort for parity, maternal age, ethnicity, fetal sex and gestational age at time of surgical intervention.

Description

Inclusion Criteria for study group:

• Maternal age ≥18 years
• Pregnant with a congenital anomaly diagnosis AND undergoing fetal intervention in utero
• Delivery planned at Mayo Clinic, Rochester MN

Inclusion Criteria for control group:

• Maternal age ≥18 years
• Pregnant with normal ultrasound findings
• Delivery planned at Mayo Clinic, Rochester MN

Exclusion Criteria:

• Delivery planned elsewhere
• Abnormal fetal karyotype

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Fetal surgical intervention group; Pregnant adult women carrying a fetus with a diagnosed congenital anomaly and scheduled to undergo fetal surgical intervention at Mayo Clinic.	Other: Blood and placenta specimen collection.; Collection of maternal and paternal blood. Collection of infant cord blood and placenta.
Control group - normal pregnancy; Pregnant adult women with normal ultrasound findings. These women will be matched with the subjects enrolled in the intervention cohort for parity, maternal age, ethnicity, fetal sex and gestational age at time of surgical intervention.	Other: Blood and placenta specimen collection.; Collection of maternal and paternal blood. Collection of infant cord blood and placenta.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal T cell activation following in utero intervention.	T cells from maternal blood will be isolated and CDR3 spectra typing will be completed. These samples will be compared to each other to identify high frequency T cell clones as well as longitudinal changes in the dynamics of clones. Blood collected at the four time points above will be profiled for changes in immune activation using mass cytometry (CyTOF) and plasma collected to measure changes in cytokine responses pre- and post-surgery by multiplex.	Baseline, 1-2 days post intervention, 1 week post intervention, delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Placental histology in the maternal-fetal interface in term and preterm fetal intervention cases	Placental macrophages will be phenotyped for subtypes (M1 classical versus M2 repair), activation (CD25 and CD40), and apoptosis status by CyTOF. Comparisons will be made between those born before 37 weeks and those born after 37 weeks in the surgical group, as well as to those who didn't undergo surgery. From each placenta, 5 sections will be dissected and submitted for histological evaluation of placental villitis. Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus and Herpes (TORCH) infection panels will be completed to distinguish infectious villitis from immune-mediated villitis.	Delivery

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Mauro Schenone, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 20, 2020
• First Submitted That Met QC Criteria: July 20, 2020
• First Posted (Actual): July 23, 2020

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Fetal Surgery; Fetal Intervention; In Utero Surgery; In Utero Intervention
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Pathological Conditions, Anatomical; Internal Hernia; Nervous System Malformations; Hernia; Neural Tube Defects; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic; Meningomyelocele; Spina Bifida Cystica; Spinal Dysraphism
• Other Study ID Numbers: 19-011382

Drug and device information, study documents

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