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. The study will recruit about 3,200 participants from approximately 100 hospitals across multiple provinces in China. Eligible pregnant women (≤16 weeks of gestation) will be randomly assigned in a 1:1 ratio to the following 2 groups:
1. Salt subsittute(intervention); 2. Usual salt (control) .
The intervention will last until delivery. The study employs an adaptive two-phase design. An interim analysis after the first phase (n=400) will inform whether the trial continues into the second phase and if any adjustments to the sample size are needed. The primary outcomes are:
Phase 1: The mean systolic blood pressure across antenatal visits (excluding the last week before delivery).
Phase 2: New-onset hypertensive disorders of pregnancy and related adverse events from randomization to delivery.
Singleton pregnancy with a viable fetus at ≤16 weeks of gestation.
Systolic Blood Pressure (SBP) ≥130 mmHg and <160 mmHg at enrollment, OR current monotherapy with antihypertensive medications such as labetalol or nifedipine (priority enrollment).
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.
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).
SBP ≥160 mmHg or Diastolic Blood Pressure (DBP) ≥110 mmHg at enrollment.
Conditions or history associated with high uterine tension (e.g., polyhydramnios, macrosomia, hydatidiform mole); autoimmune diseases (e.g., systemic lupus erythematosus, antiphospholipid syndrome).
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+.
Diagnosed hyperkalemia.
Parallel
Potassium-enriched salt substitute
Other interventionreplace usual salt with potassium-enriched salt containing 25% potassium chloride
Usual salt
Other interventionUsual salt (NaCl \>99%)
Change in Systolic Blood Pressure
Mean change in systolic blood pressure across antenatal visits (excluding the week before delivery) during the follow-up period.
Incidence of new-onset hypertensive disorders of pregnancy and related maternal adverse events
A prespecified hierarchical composite endpoint including the first occurrence of any of the following events from randomization to delivery: 1）Maternal death or pregnancy loss; 2）New-onset preeclampsia, eclampsia, or placental abruption; 3）New-onset gestational hypertension or clinically meaningful elevation in blood pressure meeting diagnostic criteria.
Change in Diastolic Blood Pressure
Mean change in diastolic blood pressure across antenatal visits (excluding the week before delivery) during the follow-up period.
Incidence of new-onset hypertensive disorders of pregnancy
hypertensive disorders of pregnancy is defined as a baseline blood pressure \<140/90 mmHg without antihypertensive medication, followed by any two consecutive measurements of systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg during follow-up, or the initiation of antihypertensive medication under a physician's guidance.
Incidence of clinically meaningful increase in blood pressure
Clinically meaningful increase in blood pressure is defined as an average systolic blood pressure increase of \>10 mmHg from baseline, measured at any two consecutive follow-up visits, in participants with a baseline blood pressure ≥140/90 mmHg or those receiving antihypertensive therapy.
Incidence of preeclampsia or eclampsia
Preeclampsia is defined as the presence of gestational hypertension or chronic hypertension in pregnancy, accompanied by any one of the following: a 24-hour urinary protein excretion ≥0.3 g; a urinary albumin-to-creatinine ratio ≥0.3, a random urine protein ≥1+(for patients with chronic hypertension and pre-existing baseline proteinuria, in the absence of organ dysfunction, the diagnosis of superimposed preeclampsia requires a doubling of the proteinuria level (either 24-hour urinary protein or urinary microalbumin-to-creatinine ratio) from the baseline); no proteinuria but accompanied by any of the following organ or system involvement(cardiac, pulmonary, hepatic, renal, hematologic, digestive, or nervous system, or evidence of placental-fetal involvement). Eclampsia is defined as the occurrence of new-onset, tonic-clonic seizures in a woman with preeclampsia, which cannot be attributed to other explainable causes.
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