Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06362356 |
| Other study ID # |
24-106 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 5, 2024 |
| Est. completion date |
December 31, 2026 |
Study information
| Verified date |
April 2024 |
| Source |
The Cleveland Clinic |
| Contact |
Cara Dolin, M.D. |
| Phone |
440-312-2229 |
| Email |
dolinc[@]ccf.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Emerging data connect diet, the gut microbiota and its metabolites in cardiometabolic
disease. Hypertensive disorders of pregnancy (HDP) are common and are a leading cause of
maternal and neonatal morbidity. HDP likely share similar pathophysiology as cardiometabolic
disease in non-pregnant people with a yet unrevealed role of diet and the gut microbiota,
including systemic inflammation and endothelial dysfunction.
Despite high biological plausibility that nutrition, the gut microbiota and its metabolites
may play a role in health and disease in pregnancy, there is a paucity of data regarding
these associations, thus limiting advancement of the field. Similar to the proposed
pathogenesis for diet, gut microbiota and the microbial metabolite trimethylamine-N-oxide
(TMAO) in cardiovascular disease, we hypothesize that the interplay between maternal diet,
the gut microbiota and its associated microbial metabolites play a mechanistic role in HDP.
We propose to test this hypothesis in a racially-diverse US cohort to determine association
with adverse pregnancy outcomes, specifically future development of HDP. We propose to
prospectively collect plasma and urine TMAO throughout pregnancy from a cohort of 200
pregnant participants.
Through 1) characterizing plasma and urine TMAO levels across each trimester of pregnancy,
and 2) assessment of this microbial metabolite as a predictor of development of HDP, we have
the potential to identify a biomarker that would allow us to identify people at risk of HDP
early in pregnancy and provide new opportunities for therapeutic interventions to improve
maternal and neonatal outcomes.
Description:
Overall Plan:
To evaluate maternal markers of metabolism including the maternal microbial metabolite,
Trimethylamine N-oxide (TMAO), across pregnancy, and its association with development of
hypertensive disorders of pregnancy.
Research Design and Methods:
This prospective longitudinal cohort will enroll pregnant patients in their first trimester
of pregnancy (10-14 weeks gestation). Plasma, serum, blood ribonucleic acid (RNA) and urine
samples will be collected at the time of enrollment, along with dietary assessment, and
self-reported demographic information. The total volume of blood for research lab purposes
will be 22.5 cc (one 10 ml lavender top tube, one 10 ml serum separator tube, and one 2.5 ml
PAXgene blood RNA tube). If research labs are drawn in coordination with other necessary
prenatal labs, the anticipated maximum volume at blood draw would be 42-50 cc of blood,
depending on combination of commonly ordered prenatal labs. The total amount of blood drawn
from pregnant subjects (including clinical and research draws) will not exceed 50ml in a
two-week period. Plasma, serum, blood RNA and urine samples will again be collected in the
second trimester, at 24-28 weeks. In addition, maternal plasma, serum, blood RNA and urine
will be collected at the time of delivery admission. A 10 cc sample of cord blood will be
obtained after delivery and the placenta will be sent to pathology for evaluation. The
investigators will measure TMAO levels and other markers of metabolism on all three maternal
samples and that of the cord blood. Deoxyribonucleic acid (DNA) from the buffy coat of plasma
collection and RNA from a PAXgene blood tube will be obtained for molecular testing of
metabolic biomarkers. The placenta will be examined pathologically with attention to vascular
pathology. In addition, a dietary history will be obtained at each time point using the
interviewer-guided ASA24 (Automated self-administered 24-hour dietary assessment tool)-a
web-based survey provided at no cost through the National Institutes of Health website under
a researcher-only password protected account (https://epi.grants.cancer.gov/asa24/).
Data and Sample Collection:
Phlebotomy and midstream urine self-collection will be performed at pre-specified time points
(10-14 weeks, 24-28 weeks, and at time of admission for delivery). Placenta and cord blood
samples will be collected following delivery by delivering clinician.
Data and Sample Storage:
Data security will be ensured by limiting access to those team members involved in the
collection and analysis of patient data. Medical record data will be stored securely through
Cleveland Clinic REDCap database. Dietary assessment data will be similarly stored within the
web-based NIH Automated Self-Administered 24-hour (ASA24) Dietary Assessment Tool researcher
password-protected account. Safety monitoring will include ensuring safe and clean clinical
environment for specimen collection, following appropriate safety protocol for venipuncture,
and proper disposal of supplies in designated clinical areas.
Sample Size:
Since the investigators have limited information regarding TMAO in pregnancy, the power
calculation was estimated to detect mean TMAO differences between groups using a two sample
T-test at a significance level of 0.05, 80% power and total sample size of 200 patients with
10% dropout rate. Standard deviations of TMAO estimated from the literature are ranging from
0.61 to 10.15 micromole/L, assuming the ratio of hypertensive disorders of pregnancy group to
normal group is 1:10, the detectable mean TMAO differences were calculated to be 0.451 to
7.497 micromole/L.
Analysis plan:
Patients with hypertensive disorders of pregnancy will be compared to those without.
Approximately normally-distributed continuous measures will be summarized using means and
standard deviations and will be compared using two-sample t-tests. Continuous measures that
show departure from normality and ordinal measures will be summarized using medians and
quartiles and will be compared using Wilcoxon rank sum tests. Categorical factors will be
summarized using frequencies and percentages and will be compared using Pearson's chi-square
tests or Fisher's Exact tests. If groups differ on baseline characteristics, linear
regression adjusting for factors of clinical importance will be performed. Depending on the
distribution of final data, Pearson or Spearman correlation will be calculated between TMAO
level and other continuous variables. For each level of categorical factors, TMAO level will
be summarized using mean and standard deviation or median and quartiles and will be compared
using analysis of variance (ANOVA) or Kruskal-Wallis tests. All analyses will be done using
SAS (version 9.4, The SAS Institute, Cary, NC) and a p < 0.05 will be considered
statistically significant.
