Clinical trial NCT04769167: Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes
Official title: Congenital Heart Anomaly Risk in Maternal Enteroviral Infection and Diabetes
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Congenital Heart Disease
Viremia
Virus Diseases
Enterovirus
Enterovirus Infections
Heart Defects, Congenital
Heart Diseases
Prenatal Infection
Diabetes
Diabetes Mellitus, Type 2
Diabetes Mellitus, Type 1
Diabetes Mellitus
Pregnancy in Diabetic
Pregnancy Complications
Prenatal
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2021-02-24
Enrollment: 1500
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: All participants will provide the same biologic specimens (stool \& blood) during their study arm's designated timeframe. All collected specimens will be analyzed per the study protocol.
Primary purpose: SCREENING

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Prevalence of EVB Viremia
timeFrame: 6 years
measure: Cardiotropic Virus Detection
timeFrame: 6 years
measure: Maternal Immune Response
timeFrame: 6 years
Secondary outcomes:
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: St Louis Childrens Hospital
state: Missouri
Study officials:
affiliation: Faculty
name: Pirooz Eghtesady, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: