Pregnancy Salt Substitution Trial for Hypertensive Disorders of Pregnancy Prevention (PREG-Salt)

The PREG-Salt study is to evaluate the effect, safety and cost-effectiveness of low-sodium salt in reducing blood pressure and preventing hypertensive disorders in pregnant women at high risk in China. Specifically, the study aims include:

1. to evaluate whether salt substitute significantly reduces mean blood pressure, while observing adherence and safety, in a high-risk population for hypertensive disorders of pregnancy. 2. to further evaluate whether salt substitute significantly reduces the incidence of hypertensive disorders of pregnancy, while assessing its safety and cost-effectiveness.

The study is a two-phase, multicenter, randomized, double-blind, parallel-group controlled study. High-risk pregnant women at ≤16 weeks of gestation will be enrolled and randomly assigned in a 1:1 ratio to either the salt substitute(intervention) group or the usual salt (control) group. The study salt will be provided free of charge until delivery. Follow-up will be conducted through all antenatal visits and delivery to collect blood pressure data and information on the incidence of hypertensive disorders of pregnancy (including gestational hypertension, preeclampsia, eclampsia, death, stillbirth, preterm birth, etc.). The study employs an adaptive design. An interim analysis will be conducted after the completion of the first phase. Based on pre-specified efficacy and safety criteria, a decision will be made regarding the continuation of the study and potential adjustments to the subsequent sample size and randomization ratio.

The study will recruit about 3,200 participants(400 participants in the first phase) from approximately 100 hospitals (with an annual delivery volume of \>1,000) at the county level or above, across multiple provinces in China.

Inclusion Criteria:

1. Singleton pregnancy with a viable fetus at ≤16 weeks of gestation. 2. Meets at least one of the following criteria (enrolled sequentially):

1. Systolic Blood Pressure (SBP) ≥130 mmHg and \<160 mmHg at enrollment, OR current monotherapy with antihypertensive medications such as labetalol or nifedipine (priority enrollment). 2. At least one of the following 4 items: advanced maternal age (≥35 years), pre-pregnancy obesity (BMI ≥28 kg/m²), history of preeclampsia, or pre-existing type 1 or type 2 diabetes. 3. At least two of the following 5 items: history of adverse pregnancy outcome (e.g., fetal death, placental abruption, fetal growth restriction), personal history of gestational hypertension or family history of preeclampsia (mother or sister), history of gestational diabetes, obstructive sleep apnea, or pre-pregnancy overweight (BMI 24-28 kg/m²). 3. Routinely eats at least two meals per day at home (including meals brought from home). 4. Able to attend regular antenatal check-ups and is expected to complete the study follow-up. 5. Provides written informed consent.

Exclusion Criteria:

1. SBP ≥160 mmHg or Diastolic Blood Pressure (DBP) ≥110 mmHg at enrollment. 2. Conditions or history associated with high uterine tension (e.g., polyhydramnios, macrosomia, hydatidiform mole); autoimmune diseases (e.g., systemic lupus erythematosus, antiphospholipid syndrome). 3. History of chronic kidney disease, OR any antenatal check-up with a confirmed estimated Glomerular Filtration Rate (eGFR) \<70 ml/min/1.73m², OR dipstick urine protein ≥2+. 4. A confirmed diagnosis of hyperkalemia. 5. History of hypotension or syncope. 6. A household member who shares meals has a confirmed diagnosis of chronic kidney disease or hyperkalemia.

Outcome Measures:

Primary outcomes:

Phase 1: Mean change in systolic blood pressure. Phase 2: New-onset Hypertensive Disorders of Pregnancy and Related Maternal Adverse Events

• Change in Diastolic Blood Pressure [Срок оценки: from baseline to 36-37 weeks of gestation]
• Incidence of new-onset hypertensive disorders of pregnancy [Срок оценки: from randomization to delivery]
• Incidence of clinically meaningful increase in blood pressure [Срок оценки: from randomization to delivery]
• Incidence of preeclampsia or eclampsia [Срок оценки: from randomization to delivery]
• Incidence of maternal death [Срок оценки: from randomization to delivery]
• Incidence of pregnancy loss [Срок оценки: from randomization to delivery]
• Incidence of Placental abruption [Срок оценки: from randomization to delivery]
• Incidence of adverse events (AEs) and serious adverse events (SAEs) [Срок оценки: from randomization to delivery]
• Incidence of all-cause maternal mortality [Срок оценки: from randomization to delivery]
• Incidence of hyperkalemia [Срок оценки: from randomization to delivery]
• Incidence of sudden cardiac death [Срок оценки: from randomization to delivery]
• Incidence of hyponatremia [Срок оценки: from randomization to delivery]