Measuring Immune Tolerance to Predict Miscarriage or Failed Embryo Transfer

Measuring Markers of Immune Tolerance to Predict Women at Risk of Miscarriage or Failed Embryo Transfer Prior to Symptoms

Pregnancy is a unique period which requires alterations in the immune system to allow for tolerance of a haploidentical fetus. The goal of this study is to measure maternal blood levels of proteins known to promote immune tolerance in early implantation and pregnancy to look for associations between tolerance, miscarriage and failed embryo transfer. Establishing predictive factors of miscarriage and failed in vitro fertilization could have implications for a large portion of couples and serve to guide current and future family planning efforts.

Study Overview

• Status: Active, not recruiting
• Conditions: Infertility; Pregnancy Loss; Spontaneous Abortion
• Intervention / Treatment: Other: Blood Collection

Detailed Description

There is increasing evidence of the importance of T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in suppressing allograft rejection, and thus it is hypothesized to play a role in pregnancy. Galectin-9 (Gal-9) is a ligand for Tim-3 activation which promotes Th1 apoptosis signaling. Activation of Tim-3 by Gal-9 has also been shown to suppress NK cell cytotoxicity at the maternal-fetal interface. Previous studies have evaluated Tim-3 expression on NK cells in the first trimester and found in comparison to normal pregnancies, patients with recurrent miscarriage had decreased Tim-3 expression and less anti-inflammatory cytokine production. In a mouse model, transfer of Tim-3 expressing NK cells reduced miscarriage rates. During the first trimester, Gal-9 levels increase and remain elevated throughout pregnancy. Preliminary data in a small population of patients who had miscarriages were found to have significantly lower Gal-9 levels detected at 8 weeks gestation compared to those who continued on to have a term pregnancy. Additionally there is evidence that Gal-9 increases production of interleukin (IL-4), and in patients with recurrent miscarriage IL-4 levels are decreased [5]. These identifications have prompted further investigation into predictive value of Gal-9 and IL-4 levels in early pregnancy on the outcome of a pregnancy.

Angiogenic factors, such as vascular endothelial growth factors (VEGF), have been shown to have a critical role in pregnancy at both the local and systemic level. Locally, CD56+ uterine natural killer cells within the endometrium express higher levels of VEGF in women with recurrent miscarriage versus women with proven fertility. Histological differences in VEGF expression and placental vascular bed patterns have been observed in tissue from patients with a miscarriage compared to women with a viable pregnancy. Serum VEGF levels are significantly different in patients with recurrent pregnancy loss than in women with proven fertility [8]. Serum VEGF levels, including VEGF-A, -C, and -D, are significantly higher at 8 weeks gestation in pregnancies that result in a spontaneous loss compared to pregnancies that go on to result in a live birth. Therefore, additional studies are needed to establish if early first trimester serum levels of VEGFs, Gal-9, and IL-4 are significantly different in pregnancies that result in miscarriage or live birth. Miscarriage affects approximately 15-20% of pregnancies. Therefore, establishing predictive factors of miscarriage could have implications for a large portion of couples and could serve to guide current and future family planning efforts. It is, essential to gain an understanding of mechanisms underlying infertility and miscarriage, so that more effective treatments and protocols can be developed.

The study hypothesis states low levels of Gal-9 and IL-4, and high levels of VEGF at the time of embryo transfer will be predictive of failed embryo transfer and spontaneous miscarriage. The primary endpoint is the maternal blood levels of galectin-9, IL-4 and VEGF-A,-C,-D on the day of embryo transfer in cycles that result in live birth versus no live birth, or that result in miscarriage compared to live birth.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Females age 18 or older who are undergoing a frozen embryo transfer or have a confirmed intrauterine pregnancy between 5 0/7 weeks and 9 6/7 week gestation.

Description

Inclusion Criteria:

• Females, 18 years old or older
• Patients undergoing a frozen embryo transfer OR confirmed intrauterine pregnancy between 5 0/7 weeks and 9 6/7 weeks gestation
• Patients planning to have all bloodwork done at Mayo Clinic Rochester
• Patients planning to deliver at Mayo Clinic or within the Mayo Clinic Health Systems

Exclusion Criteria:

• Non English speaking
• Pregnancy with multiple fetuses
• Patient has non-viable pregnancy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Infertility - Frozen Embryo Transfer; Adult females undergoing a frozen embryo transfer	Other: Blood Collection; Blood Collection
Spontaneous Conception; Adult females presenting with positive pregnancy test to the Obstetrics Department	Other: Blood Collection; Blood Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spontaneous Conception Cohort: change in immune tolerance, as measured by Enzyme Linked Immunosorbent Assay (ELISA)	Tolerance markers galectin-9, IL-4 and VEGF (-A,-B,-C,-D) will be measured for their concentration in maternal blood in women who conceived naturally, as determined by experimental standard curves.	Baseline (6-12 weeks gestation)
Infertility Cohort: change in immune tolerance, as measured by Enzyme Linked Immunosorbent Assay (ELISA)	Tolerance markers galectin-9, IL-4 and VEGF (-A,-B,-C,-D) will be measured for their concentration in maternal blood in women who undergo embryo transfer, as determined by experimental standard curves.	Change from baseline (day of transfer) at Day 11

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Chandra C Shenoy, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2019
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 12, 2019
• First Submitted That Met QC Criteria: November 6, 2019
• First Posted (Actual): November 7, 2019

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

• Additional Relevant MeSH Terms: Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility; Abortion, Spontaneous
• Other Study ID Numbers: 18-011413

Drug and device information, study documents

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