Calcium supplementation for prevention of pre-eclampsia
| ISRCTN | ISRCTN12033893 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12033893 |
| EudraCT/CTIS number | 2020-004435-25 |
| IRAS number | 262719 |
| Secondary identifying numbers | IRAS 262719 RG 20-128, HTA - NIHR127325 |
- Submission date
- 19/05/2021
- Registration date
- 25/05/2021
- Last edited
- 14/05/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Pregnancy and Childbirth
Plain English Summary
Background and study aims
Pre-eclampsia affects around one in 30 pregnancies in the UK. It usually presents with high blood pressure and protein in the urine but may also affect other organs in the body. While most women have a good outcome, the complications of pre-eclampsia can make women very unwell, and include fits and bleeding. The baby may also be affected by reduced growth and being born too early. In severe cases, the mother or baby may even die. The impact of the disease on women and their families is often considerable, related to the effect on their wellbeing as well as needing additional tests, admission to hospital and early delivery. This is also costly for the NHS.
At present doctors use aspirin to prevent pre-eclampsia in women who are more likely to develop it, but it only reduces the chance of getting pre-eclampsia by 10-20%. Delivery is the only cure.
Previous studies suggest calcium may be beneficial for preventing pre-eclampsia. 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 focused on the impact of calcium on women at high risk of pre-eclampsia.
This study will assess whether calcium supplementation during pregnancy along with usual antenatal care (including aspirin) is more effective than usual antenatal care alone in reducing the risk of pre-eclampsia in women who are at high risk.
Who can participate?
Pregnant women over the age of 16 years who are at high risk of developing pre-eclampsia based on various risk factors.
What does the study involve?
Once the women agree to participate in the trial, they will sign a consent form and be asked to provide information about their dietary calcium intake as well as general health (some information will also be taken from their medical notes). Half of the women will receive calcium tablets and the other half will receive placebo (dummy) tablets. The groups will be decided by chance, and neither the maternity team at the hospital, the research team, nor the participant will know which treatment they have received during the trial. The tablets will be started from between 12 to 22 weeks’ gestation, and taken until delivery, along with usual antenatal care (including aspirin). Participants will be asked to respond to text messages sent over their phone once a month to ask them how many of their tablets they have taken over the past week. Once the study is completed, information about pregnancy outcomes for the woman and her baby will be collected from medical notes.
What are the possible benefits and risks of taking part in the study?
By taking part in the study participants may reduce their risk of developing pre-eclampsia and its complications. It is also possible that participation may not lower their risk. The knowledge gained from their participation in this study will help inform future treatments and possibly lead to improved care for women at risk of pre-eclampsia.
Calcium supplementation given at the prescribed dose in this trial is unlikely to put the woman or her developing baby at risk of any side effects. However, as with taking any medication there is always a risk no matter how small. The rare side-effects reported for calcium are: feeling sick, stomach ache, constipation, diarrhoea, wind, or heartburn. Excessive calcium in the blood or urine can lead to very rare effects (less than 1 in 10,000 women) of skin rashes and itching and kidney stones or other kidney problems.
Where is the study run from?
University of Birmingham (UK)
When is the study starting and how long is it expected to run for?
November 2020 to August 2027
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Dr Shireen Meher
smeher@nhs.net
Contact information
Scientific
3rd Floor, Birmingham Women’s Hospital
Edgbaston
Birmingham
B15 2TG
United Kingdom
 ORCID ID |
0000-0002-9866-7932 |
|---|---|
| Phone | +44 (0)121 4721377 |
| smeher@nhs.net |
Public
Birmingham Clinical Trials Unit
School of Health and Population Sciences
Public Health Building
University of Birmingham
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 414 7023 |
|---|---|
| cape@trials.bham.ac.uk |
Study information
| Study design | Randomized triple-masked placebo-controlled multi-centre trial with a 12-month internal pilot and a health economic evaluation |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Study type | Participant information sheet |
| Scientific title | Calcium supplementation for Prevention of Pre-Eclampsia in high-risk women (CaPE) |
| Study acronym | CaPE |
| Study hypothesis | In pregnant women at increased risk of pre-eclampsia, calcium supplementation given in a dose of 2 g/day during pregnancy plus usual care (including aspirin) is more effective than usual care alone at reducing the occurrence of pre-eclampsia. |
| Ethics approval(s) | Approved 29/12/2021, East Midlands - Leicester Central Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, UK; +44 (0)2071048181; leicestercentral.rec@hra.nhs.uk), ref: 21/EM/0281 |
| Condition | Prevention of pre-eclampsia in women at increased risk |
| Intervention | Pregnant women who meet the eligibility criteria of the trial will be randomised using a minimisation algorithm to ensure balance in treatment allocation (central randomisation, 1:1 ratio, with minimisation). Participants will be allocated to receive either calcium carbonate tablets 2 g/day (1g tablet twice daily) commenced from 12 to 22 weeks’ gestation, taken until delivery, plus usual care (including aspirin), or to placebo tablets plus usual care. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Calcium carbonate |
| Primary outcome measure | Pre-eclampsia, as defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP), assessed up to primary hospital discharge after birth |
| Secondary outcome measures | All secondary outcomes will be measured using patient medical records up to hospital discharge or 4 weeks after estimated delivery, whichever is sooner. For the woman: Pre-eclampsia Core Outcome Set (COS) outcomes, namely: 1. Death 2. Eclampsia 3. Stroke 4. Visual impairment: retinal detachment or cortical blindness 5. Pulmonary oedema 6. Acute kidney injury: creatinine ≥90 μmol/l; 1 mg/dl 7. Liver capsule haematoma (confirmed on ultrasound) 8. Raised liver enzymes: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >40 IU/l 9. Low platelets < 150,000/μl 10. Abruption 11. Postpartum haemorrhage: estimated or measured blood loss ≥500 ml and ≥1000 after birth 12. Admission to Intensive Treatment Unit (ITU): 12.1. Any admission 12.2. Days of admission 13. Use of mechanical ventilation or intubation (for other than Caesarean section) In addition to these core outcomes (woman), the researchers will record: 14. Gestational hypertension: new-onset hypertension ≥140/90 mmHg (at least two measurements several hours apart) after 20 weeks gestation in the absence of proteinuria or other features of pre-eclampsia 15. Severe hypertension: blood pressure ≥160 mmHg systolic and/or 110 mmHg diastolic 16. Severe pre-eclampsia, defined as pre-eclampsia with severe features (ACOG definition) including severe hypertension or low platelets <100,000 x 10e9/l, or abnormal liver function tests (LFTs) (liver enzymes at least twice the upper limit of normal) and right upper quadrant pain not accounted for by other diagnosis, or abnormal renal function (creatinine >1.1 mg/dl), or pulmonary edema or visual impairment or severe headache unresponsive to medication and no other cause found. 17. HELLP syndrome based on a clinician diagnosis, supported by low platelets and raised liver enzymes as defined above with or without evidence of haemolysis (raised LDH enzyme or blood film) 18. Preterm pre-eclampsia: 18.1. Diagnosed before 37 weeks 18.2. Diagnosed before 32 weeks 19. Use of magnesium sulphate for pre-eclampsia 20. Onset of birth: spontaneous, induction of labour or elective Caesarean section 21. Mode of birth: vaginal birth, assisted vaginal birth, Caesarean section (emergency or elective) 22. Adverse effects: maternal hypercalcaemia, renal stones, neonatal hypocalcaemia, stopping of medication due to adverse effects For the baby: COS outcomes namely: 1. Any death in the baby up to hospital discharge. The researchers will collect data separately for: 1.1. Fetal loss <22 weeks gestation 1.2. Fetal loss ≥22 weeks’ gestation (stillbirth) 1.3. Neonatal death (from birth up to 28 days) 1.3.1. Early neonatal death (up to 7 days after birth) 1.3.2. Late neonatal death (from 7 days up to 28 days) 1.4. Perinatal death – stillbirth or neonatal death up to 7 days 2. Gestational age at delivery (median, <28 weeks, <32 weeks, <37 weeks) 3. Birthweight (mean, <3rd centile, <10th centile) 4. Admission to NNU 4.1. Any admission 4.2. Days of admission 5. Neonatal brain injury - hypoxic-ischaemic encephalopathy requiring therapeutic hypothermia of neonatal stroke, severe intraventricular haemorrhage (IVH) grade III/IV and/or cystic periventricular leukomalacia In addition to these core outcomes (baby), the researchers will record: 6. Level of neonatal care (admission to neonatal intensive care unit (NICU)/special care baby unit (SCBU)) 7. Respiratory support morbidity 7.1. Surfactant use 7.2. Use of mechanical ventilation 7.3. Duration of respiratory support 8. Chronic lung disease (CLD) requiring oxygen therapy at 36 weeks post-menstrual age. 9. Necrotising enterocolitis (NEC) requiring surgery 10. Retinopathy of prematurity (ROP) requiring treatment with laser or anti-VEGF injection 11. Composite of death or serious morbidity: death or chronic liver disease (CLD), intraventricular hemorrhage (IVH) grade III/IV, necrotizing enterocolitis (NEC) requiring surgery or retinopathy of prematurity (ROP) requiring treatment |
| Overall study start date | 01/11/2020 |
| Overall study end date | 31/08/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Female |
| Target number of participants | 7756 |
| Participant inclusion criteria | 1. Over 16 years of age 2. Able to provide informed consent to participate 3. After a dating scan has confirmed viability (usually between 10 and 14 weeks gestation) 4. 22 weeks’ 0 days gestation or less 5. Women deemed eligible for aspirin therapy based on NICE guideline criteria below where a woman has either: 5.1. One high-risk factor: 5.1.1. Hypertensive disease during a previous pregnancy 5.1.2. Chronic renal disease 5.1.3. Autoimmune disease such as SLE or antiphospholipid syndrome 5.1.4. Type 1 or 2 diabetes 5.1.5. Chronic hypertension 5.2. Or two or more moderate risk factors: 5.2.1. First pregnancy 5.2.2. Age more than 40 years 5.2.3. BMI ≥35 at first visit 5.2.4. Family history of pre-eclampsia 5.2.5. Multiple pregnancy 5.2.6. Pregnancy interval of 10 years or more 5.3. Or the Fetal Medicine Foundation (FMF) algorithm for pre-eclampsia risk assessment, as used locally 5.4. Or any other national pre-eclampsia screening criteria guidelines that may be used in the future The study will also include women identified to be at high risk of pre-eclampsia based on any other national screening criteria guidelines that may be used in the future. |
| Participant exclusion criteria | 1. Any known contraindications to regular calcium intake (history of renal stones, known renal impairment with pre-pregnancy eGFR <30 ml/min/1.73m² or serum creatinine >150 (μmol/l), known history of hypercalcaemia or hypercalcaemia-causing diseases (e.g. parathyroid disease, sarcoidosis, malignancy), current severe persistent vomiting leading to dehydration or requiring hospitalisation (if persisting vomiting resolves, the patient may be re-assessed for inclusion in the trial, providing all other inclusion and exclusion criteria are met) 2. Use of drugs with potential for severe interactions with calcium: digoxin or other cardiac glycosides; antiretroviral drugs for HIV treatment, anti-neoplastic drugs, and diuretics (thiazide, thiazide-like or xipamide). 3. Use of any additional calcium supplement either on its own or as part of other multivitamin or Vitamin D preparations, and unwilling to stop them or change to other multivitamins, as this could lead to higher doses of calcium supplementation in the calcium group and contamination in the placebo group 4. Women who are taking vitamin D regularly in high doses >1000 IU/day, as supplements or for conditions such as malabsorption syndromes. Note: a short course of high dose Vitamin D (e.g., 20,000 IU weekly for 6 weeks) to treat Vitamin D deficiency during pregnancy is NOT an exclusion criteria 5. Known contraindications to excipient Isomalt (e.g. hereditary fructose intolerance) |
| Recruitment start date | 11/08/2022 |
| Recruitment end date | 30/11/2026 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Mindelsohn Way
Birmingham
B15 2TG
United Kingdom
Sponsor information
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 415 8011 |
|---|---|
| Reserachgovernance@contacts.bham.ac.uk | |
| Website | http://www.birmingham.ac.uk/index.aspx |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 29/02/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The results of this trial will be submitted for publication in a peer-reviewed journal. The manuscript will be prepared by the chief investigator and authorship will be determined by the trial publication policy. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the CaPE trial management group (cape@trials.bham.ac.uk). |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | 24/03/2023 | No | Yes | ||
| Protocol (other) | 24/03/2023 | No | No | ||
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
14/05/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 01/05/2024 to 30/11/2026.
2. The overall study end date was changed from 30/04/2025 to 31/08/2027.
3. The intention to publish date was changed from 01/06/2025 to 29/02/2028.
24/03/2023: The following changes were made to the trial record:
1. Ethics approval details and protocol and participant information sheet link added.
2. Contact details updated.
3. The recruitment start date was changed from 01/07/2021 to 11/08/2022.
25/05/2021: Trial's existence confirmed by the NIHR.
