Clinical trial NCT06105775: Inorganic Nitrate Supplementation in Chronic Hypertensive Pregnancies
Official title: Inorganic Nitrate Supplementation for Blood Pressure Control in Chronic Hypertensive Pregnancies From the 2nd Trimester (NIT_CH): a Triple-Blind Randomized Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hypertension in Pregnancy
Hypertension
Pregnancy
Keywords: Endothelial Dysfunction
Hypertension in Pregnancy
Nitric Oxide
inorganic nitrate
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Hospital das Clínicas de Ribeirão Preto
First posted: 2023-10-30
Enrollment: 144
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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 16 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.

Primary outcomes:
measure: Blood Pressure Control in Chronic Hypertensive Pregnant Women with Inorganic Nitrate Supplementation Compared to Placebo.
timeFrame: From baseline (16th week) up to delivery
measure: Increased Antihypertensive Medication Requirements in Patient Groups
timeFrame: From baseline (16th week) up to delivery
Secondary outcomes:
measure: Doppler Analysis of Maternal and Fetal Vessel Behavior Across Pregnancy in Both Groups
timeFrame: From baseline (16th week) up to delivery
measure: Fetal Growth Assessment and Incidence of Fetal Growth Restriction in Both Groups
timeFrame: From baseline (16th week) up to delivery
measure: Incidence of Preeclampsia Overlap and Adverse Maternal Outcomes in Each Group
timeFrame: At the time of delivery
measure: Incidence of Perinatal Outcomes
timeFrame: Immediately after delivery.
measure: Vascular Reactivity of the Umbilical Artery In Vitro in Both Groups After Delivery
timeFrame: Approximately 15 to 30 minutes post-delivery, with some additional time for the in vitro evaluations.
measure: Evaluation of Complete Blood Count, Lipid and Glycemic Profiles, and Fasting Insulin Levels in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Nitric Oxide Metabolite Concentrations in Plasma, Urine, and Saliva in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Serum Markers for Preeclampsia in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Inflammatory Markers in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Oxidative Stress Markers in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Matrix Metalloproteinases and Inhibitors in Each Group
timeFrame: From baseline (16th week) up to delivery
measure: Evaluation of Diet Quality in Each Group Using the SISVAN Protocol
timeFrame: The SISVAN protocol will be employed at the enrollment.
Other outcomes:
Locations:
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
state: São Paulo
Study officials:
affiliation: Medical School of Ribeirao Preto, USP
name: Ricardo C Cavalli, Dr
role: PRINCIPAL_INVESTIGATOR
References: