Aim

To investigate the clinical and cost-effectiveness of calcium supplementation plus usual care compared with usual care alone for prevention of pre-eclampsia and its complications in women at high risk of pre-eclampsia.

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Total number participants

7756 women (approximately 3878 in each group). This will allow 90% power (p=0.05) to detect a 20% relative risk reduction in pre-eclampsia from 11.5% down to 9.2%, allowing for a 5% loss to follow up.

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Outcome Measures

Primary outcome:
Clinician diagnosis of pre-eclampsia, as defined by the International Society for Study of Hypertension in Pregnancy (ISSHP): (blood pressure ≥140/90mmHg AND either significant proteinuria (protein/creatinine ratio< (PCR) of 30 mg/mmol or more) OR maternal multiorgan dysfunction: acute kidney injury (AKI) (creatinine ≥90 μmol/L; 1 mg/dL), liver involvement (elevated transaminases e.g. ALT or AST>40IU/L) with or without right upper quadrant or epigastric abdominal pain), neurological complications (examples include eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, persistent visual scotomata), haematological complications (thrombocytopenia – platelet count below 150,000/μL, DIC, haemolysis) OR uteroplacental insufficiency (fetal growth restriction, abnormal doppler, stillbirth) developing at or after 20 weeks gestation, assessed up to primary hospital discharge.

Key secondary outcomes
1. Severe pre-eclampsia index: any one of severe pre-eclampsia, early onset pre-eclampsia <32 weeks, eclampsia, placental abruption, HELLP syndrome or severe gestational hypertension.

2. Preterm birth <37 weeks

Secondary outcomes:
1. For the woman: Core outcome set (COS) outcomes: death, eclampsia, stroke, retinal detachment or cortical blindness, pulmonary edema, acute kidney injury, liver capsule haematoma or rupture, raised liver enzymes, low platelets, abruption, postpartum haemorrhage, ITU admission, and mechanical ventilation. In addition to these COS outcomes, we will record gestational hypertension, severe hypertension, severe pre-eclampsia, HELLP syndrome, early onset pre-eclampsia, preterm delivery at <37 weeks for pre-eclampsia, use of magnesium sulphate for pre-eclampsia, onset of birth, mode of birth, adverse effects: maternal hypercalcaemia, renal stones, and stopping of medication due to adverse effects.

2. For the baby: COS outcomes: death up to hospital discharge, gestational age at delivery, birthweight, small for gestational age, neonatal seizures, admission to neonatal unit, respiratory support, and neonatal brain injury (hypoxic ischaemic encephalopathy, stroke, intraventricular haemorrhage, periventricular leukomalacia). In addition to these COS outcomes, we will record chronic lung disease, necrotising enterocolitis requiring surgery, retinopathy of prematurity requiring treatment, a composite of death or serious morbidity, level of neonatal care and length of stay.

3. Health economics outcomes: We will combine the clinical data collected within the trial with cost data from previous studies and the NHS to calculate the cost per case of pre-eclampsia avoided.