Inorganic Nitrate Supplementation in Chronic Hypertensive Pregnancies (NIT_CH)

April 15, 2026 updated by: Ricardo de Carvalho Cavalli, University of Sao Paulo

Inorganic Nitrate Supplementation for Blood Pressure Control in Chronic Hypertensive Pregnancies From the 2nd Trimester (NIT_CH): a Triple-Blind Randomized Placebo-Controlled Trial

High blood pressure during pregnancy poses significant risks to both the mother and baby. A combination of factors, including advancing maternal age, rising obesity rates, and metabolic health issues, have amplified the prevalence of this condition. While conventional medicines are available, safety during pregnancy remains a concern. Recent studies suggest that inorganic nitrate might be a safer alternative. The power of nitrate lies in its ability to stimulate the body's production of a compound that aids in dilating and relaxing blood vessels. Preliminary studies conducted on mice and a select group of pregnant women have yielded encouraging results. Early tests indicated that after consuming inorganic nitrate, there was a reduction in blood pressure and an improvement in the health of the mother's uterine artery-a vital vessel responsible for nourishing the fetus. Our study aims to investigate the effects of inorganic nitrate supplementation on pregnant women from the start of their pregnancy and continuing it throughout their term. If our findings are positive, it could revolutionize how we approach blood pressure management during pregnancy, paving the way for healthier futures for both mothers and babies.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Eligible pregnant women with chronic hypertension will be identified and invited to participate through posters displayed in the municipality's health units, as well as by medical professionals within the local health network, based on the inclusion criteria. An appointment will be promptly scheduled to verify eligibility and present the informed consent form, during which all questions and concerns will be addressed.

On the enrollment day, the subsequent visit will be scheduled for the 16th week of their pregnancy, marking the commencement of the study. By then, participants will already have been randomly allocated to respective groups by an external professional who is not directly involved in the study, ensuring blinding. Randomization will occur on a 1:1 ratio, employing blocks of 2-4 pregnant women as determined by specialized software. Regardless of allocation, participants will continue with standard medications for preeclampsia prophylaxis: acetylsalicylic acid, taken at 100 mg nightly up to 36 weeks of gestation, and calcium carbonate, taken at 1000 mg daily until delivery, alongside routine antihypertensive treatment.

From the 16th week of pregnancy onward, participants will receive either a capsule containing 400 mg of inorganic nitrate (540 mg of sodium nitrate, equivalent to 140 mg of sodium chloride and 400 mg of nitrate) or a placebo (140 mg of sodium chloride and 400 mg of flour). Both capsules will be identical in color and appearance. All participants will be instructed to take one capsule each morning, continuing this regimen for 22 weeks (154 days), ending either at the 38th week of pregnancy or at childbirth, whichever occurs first.

Visits will take place at predetermined intervals based on the progression of the pregnancy. Initially set at a frequency of every 4 weeks, but as the end of the pregnancy approaches, the visits will become more frequent. The baseline appointment is set for the 16th week of gestation, with subsequent appointments scheduled for the 20th, 24th, 28th, 32nd, 34th, 36th, 37th, and 38th weeks. It is important to note that scheduled visits may conclude earlier if childbirth occurs sooner, or they might be extended if the pregnancy progresses beyond the anticipated delivery date. During these visits, participants will undergo an obstetric clinical examination, blood pressure measurement, biochemical analysis, and an ultrasound paired with a Doppler study of the uterine arteries.

To ensure consistent and optimal blood pressure levels, the overseeing medical team will closely monitor and adjust participants' antihypertensive medications as necessary. Ensuring adherence to the regimen is paramount; thus, participants will be asked to return any unused capsules during their visits and will then be supplied with their next batch for the ensuing period.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
144

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

  • Name: PRISCILA O BARBOSA, Dr
  • Phone Number: +5531971349289
  • Email: barbosapo@usp.br

Study Locations

  • Brazil
    • São Paulo
      • Ribeirão Preto, São Paulo, Brazil
        • Recruiting
        • Hospital Das Clinicas da Faculdade de Medicina de Ribeirão Preto - USP
        • Contact:
        • Principal Investigator:
          • RICARDO C CAVALLI, Dr
        • Sub-Investigator:
          • PRISCILA O BARBOSA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pregnant women diagnosed with chronic hypertension (systolic blood pressure above 140 mmHg and/or diastolic blood pressure above 90 mmHg before pregnancy or before 20 weeks of gestation) as defined by the Brazilian Network for Studies on Hypertension in Pregnancy (RBEHG, Brazilian acronym) Protocol and Chronic Hypertension/Preeclampsia by the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO, Brazilian acronym) Protocol.
  • Patients on monotherapy with methyldopa as treatment at the time of inclusion.
  • Women with less than 16 weeks of gestation confirmed by first-trimester ultrasonography confirming gestational age.

Exclusion Criteria:

  • Multiple pregnancies, age below 18 years old, inability to provide informed consent, or history of low adherence to medication therapy.
  • Patients with uncontrolled chronic hypertension, with blood pressure values above 160x110mmHg.
  • History of food allergies, especially hypersensitivity to beetroot.
  • Users of illicit drugs, smokers, or alcohol abusers.
  • Diagnosis of coronary artery disease, congestive heart failure (moderate to severe), moderate to severe liver failure, chronic renal insufficiency (with plasma creatinine clearance less than 30 ml/min/1.73 m² of body surface), pre-existing type 1 diabetes, and type 2 diabetes.
  • Pregnant women who frequently used non-steroidal anti-inflammatory drugs, nasal decongestants, and anorectics before getting pregnant; users of proton pump inhibitors and H2 receptor antagonists or any other medication that interferes with stomach pH, starting 2 weeks before the beginning and continuing throughout the remainder of the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Inorganic Nitrate Capsule
Once daily capsule containing sodium nitrate (400 mg of nitrate and 140 mg of sodium), for 154 consecutive days.
Dietary supplement: Inorganic Nitrate Capsule
Starting from the 16th week of gestation and continuing for 22 weeks (154 days) or until delivery, whichever comes first, participants will consume a daily capsule containing 400 mg of inorganic nitrate. Participants will maintain standard preeclampsia prophylaxis (acetylsalicylic acid 100mg nightly until 36 weeks of gestation and calcium carbonate 1000mg daily until delivery) and regular antihypertensive treatment.
Placebo Comparator: Placebo Capsule.
Once daily capsule containing sodium chloride (140 mg of sodium chloride and 400 mg of flour), for 154 consecutive days.
Dietary supplement: Placebo Capsule
From the 16th week of gestation and lasting 22 weeks (154 days) or until delivery, participants will consume a daily capsule containing sodium chloride with the nitrate replaced by plant-based flour, design to mimic the appearance of the active capsule. Participants will maintain standard preeclampsia prophylaxis (acetylsalicylic acid 100mg nightly until 36 weeks of gestation and calcium carbonate 1000mg daily until delivery) and regular antihypertensive treatment.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Blood Pressure Control in Chronic Hypertensive Pregnant Women with Inorganic Nitrate Supplementation Compared to Placebo.
Time Frame: From baseline (16th week) up to delivery
Blood pressure will be assessed using semiautomatic equipment, measuring systolic and diastolic pressures in millimeters of mercury (mmHg). Ambulatory Blood Pressure Monitoring (ABMP) will be employed at the beginning of the clinical trial. Lower readings indicate better blood pressure control, while higher readings suggest poorer control.
From baseline (16th week) up to delivery
Increased Antihypertensive Medication Requirements in Patient Groups
Time Frame: From baseline (16th week) up to delivery
The investigators will monitor both the inorganic nitrate group and the placebo group for any need to increase the dosage of antihypertensive medications, frequency or introduce a new agent.
From baseline (16th week) up to delivery

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Fetal Growth Assessment and Incidence of Fetal Growth Restriction in Both Groups
Time Frame: From baseline (16th week) up to delivery
Fetal growth will be assessed using biometric measurements and evaluations like the fetal biophysical profile, placental maturity grade, and amniotic fluid evaluations. Key biometric parameters include biparietal diameter, cranial circumference, abdominal circumference, femur length, and estimated fetal weight (EFW). The "Hadlock" formula will help determine EFW, classifying the fetus as small for gestational age, average or large for gestational age. The biophysical profile will give insights into fetal movements and conditions over a 30-minute period. Placental maturity and amniotic fluid status will further provide context to the overall fetal health and growth.
From baseline (16th week) up to delivery
Incidence of Preeclampsia Overlap and Adverse Maternal Outcomes in Each Group
Time Frame: At the time of delivery
Clinical data will be collected to evaluate the presence of preeclampsia overlap and any associated adverse maternal outcomes. The collected data will include the gestational age at the time of delivery (in weeks + days), type of delivery (vaginal or cesarean), and specific clinical outcomes related to the mother's health
At the time of delivery
Incidence of Perinatal Outcomes
Time Frame: Immediately after delivery.
Post childbirth, perinatal outcomes will be assessed by recording essential metrics of the newborn. The collected data will include the newborn's gender, weight (measured in grams), length (measured in cm), and the Apgar scores documented at both the first- and fifth minutes post-birth.
Immediately after delivery.
Vascular Reactivity of the Umbilical Artery In Vitro in Both Groups After Delivery
Time Frame: Approximately 15 to 30 minutes post-delivery, with some additional time for the in vitro evaluations.
Umbilical cord fragments will b collected for evaluation. The fragments will be used to assess vascular tone changes in the umbilical artery using isometric force transducers. The viability and reactivity of the vessel rings will be determined using specific stimuli such as potassium chloride (KCl) and serotonin.
Approximately 15 to 30 minutes post-delivery, with some additional time for the in vitro evaluations.
Evaluation of Complete Blood Count, Lipid and Glycemic Profiles, and Fasting Insulin Levels in Each Group
Time Frame: From baseline (16th week) up to delivery
Participants' overall health will be evaluated through a series of blood tests, including complete blood count, glucose and insulin levels, creatinine, urea, liver enzymes, serum bilirubins and lipid profile.
From baseline (16th week) up to delivery
Evaluation of Nitric Oxide Metabolite Concentrations in Plasma, Urine, and Saliva in Each Group
Time Frame: From baseline (16th week) up to delivery
The concentrations of nitrate and nitrite, as key metabolites of nitric oxide, will be assessed in participants' plasma, urine, and saliva samples. The determination will be done using the Sievers Nitric Oxide Analyzer
From baseline (16th week) up to delivery
Evaluation of Serum Markers for Preeclampsia in Each Group
Time Frame: From baseline (16th week) up to delivery
The risk of developing preeclampsia will be assessed by calculating the soluble fms-like tyrosine kinase (sFLT-1) and placenta growth factor (PlGF) ratio using serum values of the angiogenic factors PlGF and sFLT-1. This ratio provides an indication of the likelihood of preeclampsia onset within specified time frames or the presence of placental insufficiency.
From baseline (16th week) up to delivery
Evaluation of Inflammatory Markers in Each Group
Time Frame: From baseline (16th week) up to delivery
Serum concentrations of various inflammatory markers, including adiponectin, intercellular adhesion molecule 1 (ICAM-1), interleukin-6 (IL6), interleukin-8 (IL8), interleukin-10 (IL10), leptin, resistin, tumor necrosis factor-alpha (TNFa), vascular cell adhesion molecule 1 (VCAM-1), vascular endothelial growth factor (VEGF), and visfatin, will be determined to evaluate inflammatory status in the participants.
From baseline (16th week) up to delivery
Evaluation of Oxidative Stress Markers in Each Group
Time Frame: From baseline (16th week) up to delivery
The extent of lipid peroxidation will be represented by plasma levels of malondialdehyde (MDA). Lower MDA levels suggest decreased oxidative damage. Simultaneously, the overall antioxidant activity in the plasma will be gauged through the ferric-reducing ability of plasma (FRAP). Elevated FRAP values indicate a heightened ability to resist oxidative stress.
From baseline (16th week) up to delivery
Evaluation of Matrix Metalloproteinases and Inhibitors in Each Group
Time Frame: From baseline (16th week) up to delivery
Serum concentrations of matrix metalloproteinases (MMPs) 2 and 9, as well as their inhibitors tissue inhibitor of metalloproteinases (TIMPs) 1 through 4, will be determined.
From baseline (16th week) up to delivery
Doppler Analysis of Maternal and Fetal Vessel Behavior Across Pregnancy in Both Groups
Time Frame: From baseline (16th week) up to delivery
Using Doppler velocimetry, the investigators will evaluate fetal vessels, focusing on the middle cerebral artery and umbilical artery. These tests will be conducted with mothers resting in left lateral decubitus during fetal rest periods, excluding respiratory movements. Key parameters, including the systole/diastole (A/B) ratios, resistance index, and pulsatility index, will be captured. Concurrently, maternal Doppler velocimetry of the uterine artery and pulse wave velocity will be measured to assess arterial stiffness.
From baseline (16th week) up to delivery
Evaluation of Diet Quality in Each Group Using the SISVAN Protocol
Time Frame: The SISVAN protocol will be employed at the enrollment.
The quality of participants' diets will be assessed using a standardized SISVAN protocol. Concurrently, dietary recalls will be employed to provide a detailed account of participants' food consumption and nutritional patterns.
The SISVAN protocol will be employed at the enrollment.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Sao Paulo

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Hospital das Clínicas de Ribeirão Preto

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ricardo C Cavalli, Dr, Medical School of Ribeirao Preto, USP

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 6, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 23, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 23, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 30, 2023

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 20, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 15, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 21/12010-7-SP2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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