CaPE - Information for investigators

Pre-eclampsia affects around 3% of pregnant women in the UK. It generally presents with hypertension and proteinuria after 20 weeks' gestation. Complications of pre-eclampsia are a leading cause of adverse outcomes for both the mother and baby, and need substantial input from NHS resources. The underlying cause of pre-eclampsia is unclear, and delivery remains the only cure. Preventative interventions are limited to low dose aspirin which has a modest effect on reducing the risk of pre-eclampsia and its complications.

Evidence from epidemiological studies and randomised trials suggest calcium may reduce the risk of pre-eclampsia and its complications. However, most studies have been conducted in populations with low dietary calcium intake, so findings have not been viewed as applicable to a population with adequate calcium intake, such as in the UK. Moreover, little research has focussed on the impact of calcium supplementation in women at high risk of pre-eclampsia.

The CaPE trial is looking to assess whether calcium supplementation in high risk women reduces their risk of developing pre-eclampsia and its complications, regardless of their baseline dietary calcium intake levels, to guide clinical practice in the UK.

CaPE is parallel-two-arm, randomised, triple-blinded, placebo-controlled multi-centre trial, with a 12-month internal pilot and health economics evaluation.

We plan to recruit 7756 pregnant women at increased risk of pre-eclampsia.

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

We will recruit pregnant women from approximately 40 NHS maternity hospitals across the UK.

Intervention group

Calcium tablets 2 grams per day starting between 12 to 22 weeks' gestation, taken until delivery, plus usual care (including aspirin).

Control group

Placebo tablets starting between 12 to 22 weeks' gestation, taken until delivery, plus usual care (including aspirin)

Primary Objective

To test the hypothesis that in pregnant women at increased risk of pre-eclampsia, calcium supplementation given in a dose of 2 grams per day during pregnancy plus usual care (including aspirin) is more effective than usual care alone in reducing the relative risk for the occurrence of pre-eclampsia by at least 20%.

Secondary Objectives

1.      To assess the impact of calcium supplements on other important outcomes for the mother and baby.

2.      To assess the cost-effectiveness of calcium plus usual care compared to usual care alone.

3.      To assess the degree to which pregnant women are able to adhere to calcium supplementation regimen.

4.      To assess whether calcium has a differential effect in pre-specified subgroups of women.

Primary outcome

Clinician diagnosis of pre-eclampsia, based on the ISSHP definition: a blood pressure ≥140/90mmHg AND either:

1.      Significant proteinuria (protein/creatinine ratio (PCR) of 30 mg/mmol or more) OR

2.      Maternal multiorgan dysfunction:

a.      Acute kidney injury (AKI) (creatinine ≥90 μmol/L)

b.      Liver involvement (elevated transaminases e.g. alanine transaminase (ALT) or aspartate transaminase (AST) >40IU/L) with or without right upper quadrant or epigastric abdominal pain)

c.       Neurological complications (including eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, persistent visual scotomata)

d.      Haematological complications (thrombocytopenia – platelet count below 150,000/μL, DIC, haemolysis) OR

3.      Uteroplacental insufficiency (fetal growth restriction, abnormal Umbilical artery doppler, stillbirth)

 developing at or after 20 weeks gestation.

Secondary outcomes

• For the woman: death, eclampsia, stroke, HELLP syndrome, cortical blindness, pulmonary oedema, acute kidney injury, liver capsule haematoma, abruption, postpartum haemorrhage, ITU admission, intubation, mechanical ventilation, gestational and severe hypertension, early onset pre-eclampsia <34 weeks, need for elective delivery, mode of delivery, composite morbidity, adverse effects.
• For the baby: death before hospital discharge, gestational age at delivery, birthweight, small for gestational age, admission to neonatal unit and level of care, number of admission days, neonatal brain injury syndromes, respiratory support, preterm birth <34 and <37 weeks, chronic lung disease, necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity, and composite neonatal morbidity/mortality.
• Adherence to calcium.
• Health economics analyses.

Funder: National Institute of Health Research (HTA programme ref. NIHR 127325)

Sponsor: University of Birmingham (ref. RG_20-128)

EudraCT number: 2020-004435-25

ISRCTN number: ISRCTN 12033893

Chief Investigator: Dr Shireen Meher

This study is funded by the National Institute for Health Research (NIHR) [HTA programme (NIHR 127325)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.