Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes

Diabetes Mellitus, Type 2 Clinical Trial

— CHARMED  

Official title:

Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04769167
• Other study ID #: 202002043
• Status: Active, not recruiting
• Phase: N/A
• Start date: February 1, 2021
• Est. completion date: December 2027

Study information

• Verified date: April 2024
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Beyond EV-B, there are clinical observations to implicate other viruses in birth defects, including CHD. Since the Rubella epidemic of 1960s', however, viruses have received little attention and certainly no comprehensive study, especially using next generation sequencing (NGS), has been undertaken in this context. The current pandemic as well as those caused by Zika, influenza, Ebola and Lassa Fever (among many) have shown pregnant women and their baby are at high risk. Therefore, an open-minded approach is warranted when considering the role of maternal viral infections in CHD. Even less is known about maternal immune response, such as antibody production, to these viruses.

The investigator's goal is to answer the above gaps in knowledge. The investigators propose to do that using two different approaches; one retrospective (analysis of samples in two existing, large biorepositories) and the other prospective. The investigator's have created a multi-disciplinary team to bring together the needed expertise from individuals who have overlapping and vested interest in this project.

The investigator's specific aim is to examine the diversity of the gut virome in non-pregnant and pregnant women with and without diabetes, with special emphasis on known cardiotropic viruses (those with tropism for cardiac tissues). This study is seen by the investigator's as the first step prior to a larger prospective multi-institutional study to specifically assess the linkage between the maternal virome and CHD pathogenesis.

Description:

To determine prevalence in non-pregnant women (i) the investigators will perform PCR analysis of stool and blood from a prospective cohort of 225 women with diabetes (and 225 without) and sequence the amplicons, and (ii) perform ELISA (IgM and IgG) analysis of sera collected concurrently. They will assay IgM/IgG positive samples for neutralizing antibodies. To determine prevalence in pregnant women (i) the investigators will perform PCR analysis of 1st trimester stool and blood from a prospective cohort of 450 women with diabetes (and 450 without diabetes) and sequence the amplicons, and (ii) perform ELISA (IgM and IgG) analysis of sera collected at 1st and 2nd or 3rd trimester. They will assay IgM/IgG positive samples for neutralizing antibodies.

The investigators will also perform a comprehensive virome analysis using metagenomic shotgun sequencing with ViroCap enrichment, a method developed by co-PI, on 1st trimester stool samples from a subset (~4-500) of women (both EVB positive and negative) enrolled in Aim 1. The investigators will complement this data with VirScan® analysis of blood collected from the same women at 1st and 2nd/3rd trimester. VirScan® is a revolutionary new technique for comprehensive profiling of sera for antibodies against ~400 species and strains of pathogenic viruses.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1500
• Est. completion date: December 2027
• Est. primary completion date: February 20, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Exclusion Criteria - All Cohorts

1. Women under the age of 18 or older than 45.

2. Prediabetes defined as an HbA1C between 5.7% and 6.5% or current diagnosis of pancreatic diabetes or gestational diabetes (GDM).

3. Body Mass Index greater than or equal to 35 or less than or equal to 18.

4. Women unable to give informed consent and/or considered a prisoner.

5. Use of any of the following drugs within the last 6 months:

5a.Systemic antibiotics, antifungals, antivirals or antiparasitics (intravenous, intramuscular, or oral); 5b.Cytokines; 5c. Immunomodulators or immunosuppressive cytotoxic agents; 5d. Large doses of commercial probiotics consumed (greater than or equal to 108 cfu or organisms per day) - includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component. Ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply.

6. A positive test for HIV, HBV or HCV or any confirmed or suspected condition/state of immunosuppression or immunodeficiency.

7. History of autoimmune disorders other than T1D or treated thyroid disease.

8. Major surgery of the GI tract, except for cholecystectomy and appendectomy, in the past five years.

9. Any major bowel resection at any time.

10. History of active uncontrolled gastrointestinal disorders or diseases including: 10a. Inflammatory bowel disease (IBD) including ulcerative colitis (mild-moderate-severe), 10b. Crohn's disease (mild-moderate-severe), or indeterminate colitis; 10c. Irritable bowel syndrome (IBS) (moderate-severe); 10d. Persistent, infectious gastroenteritis, colitis or gastritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated).

11. Acute disease at the time of enrollment (defer sampling until subject recovers). Acute disease is defined as the presence of a moderate or severe illness with or without fever.

12. Use of assisted reproductive technology (ART)including but not limited to In vitro Fertilization (IVF), Gamete intrafallopian transfer (GIFT) and Zygote intrafallopian transfer (ZIFT).

13. Any other condition which, in the opinion of the investigators, renders the patient unfit for study participation and procedures.

Related Conditions & MeSH terms

• Communicable Diseases
• Congenital Abnormalities
• Congenital Heart Disease
• Diabetes
• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Diabetes Mellitus, Type 2
• Enterovirus
• Enterovirus Infections
• Heart Defects, Congenital
• Heart Diseases
• Infections
• Pregnancy Complications
• Pregnancy in Diabetic
• Pregnancy in Diabetics
• Prenatal
• Prenatal Infection
• Viremia
• Virus Diseases

Intervention

Other:
• Stool and Blood Specimen Collection
Stool and Blood specimens will be collected at 3 designated time points
• Follow-up Medical Record Review
Participant medical records as well as the medical records of infants during study enrollment will be reviewed up to 3 years from the date of enrollment.

Locations

Country	Name	City	State
United States	Barnes Jewish Hospital	Saint Louis	Missouri
United States	St Louis Childrens Hospital	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prevalence of EVB Viremia	Determine the prevalence of EVB among women with or without diabetes. For this aim, the investigators will use PCR analysis of stool and blood to detect EVB and ELISA (IgM and IgG) of blood to detect anti-EVB antibodies in samples collected from pregnant and non-pregnant women (with or without diabetes) at multiple time points. The investigators will also sequence the PCR amplicons and carry out antibody neutralization assays of IgM/IgG positive samples to identify the specific EVB. The non-pregnant cohort will consist of 225 women with diabetes (and 225 without) sampled at 3-month intervals over 1 years. The pregnant cohort will consist of 450 women with diabetes (and 450 without) with sampling at 1st, 2nd and 3rd trimesters.	6 years
Primary	Cardiotropic Virus Detection	Determine the burden of other pathogenic human viruses in pregnant women with diabetes. Beyond EVB, other viruses could (and likely do) cause CHD. Further, while PCR is quite sensitive for detection of nucleic acid sequences of interest, its results are primer dependent. Therefore, in this aim, the investigators will perform a comprehensive virome analysis (the viral component of the microbiome) using metagenomic shotgun sequencing with ViroCap enrichment, a method developed by a co-PI of this proposal, on 1st trimester stool samples from a subset (~4-500) of women (both EVB positive and negative) enrolled in Aim 1. The investigators will complement this data with VirScan® (version 3) analysis of blood collected from the same women at 1st and 2nd/3rd trimester. VirScan® is a revolutionary new technique for comprehensive profiling of sera for antibodies against ~400 species and strains of pathogenic human viruses.	6 years
Primary	Maternal Immune Response	Determine the extent of correlation between EVB and other viruses with CHD. Because CHD cannot typically be diagnosed until 20-24 weeks gestation and the investigators are prospectively enrolling participants at 6-14 weeks, they will not know which participants will develop CHD during the enrolled pregnancies. The investigators anticipate ~40-50 CHD-affected pregnancies. If not done in Aim 2, the investigators will carry out virome (blood and stool) and VirScan® (blood) analysis of 1st trimester samples from these women.	6 years