WHO 2006.
| Methods | Double‐blind, randomised trial. Randomisation stratified by centre, with computer‐generated blocks of 6‐8. Allocation by consecutively numbered treatment packs containing calcium tablets or identical placebo. Treatment packs were prepared centrally. | |
| Participants | Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. Enrolment from 2001‐2003 Populations with median daily calcium intake < 600 mg; primiparous women less than 20 weeks' pregnant Exclusion criteria: renal disease or urolithiasis; parathyroid disease; BP > 140 mmHg systolic or > 90 mmHg diastolic; history of hypertension; antihypertensive therapy; diuretic, digoxin, phenytoin or tetracycline treatment |
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| Interventions | Chewable calcium carbonate tablets with 500 mg elemental calcium, 3 daily, or identical placebo, from enrolment till delivery. | |
| Outcomes | Primary outcomes: pre‐eclampsia (BP diastolic 90 mmHg or more, or systolic 140 mmHg or more, plus proteinuria 2+ on dipsticks or 300 mg per day; preterm birth (< 37 weeks). Secondary outcomes: severe pre‐eclampsia (diastolic 110 mmHg or more or systolic 160 mmHg or more); early onset pre‐eclampsia (< 32 weeks), PIH; eclampsia; placental abruption; birthweight < 2500 g; spontaneous preterm delivery; medically indicated preterm delivery; admission to neonatal ICU for > 2 days; fetal, neonatal and perinatal mortality (before discharge from hospital). |
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| Notes | Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. Enrolment from 2001‐2003
14,362 women screened, 8325 randomised. Exclusions: 6 calcium (4 not pregnant, 2 lost before treatment started) and 7 placebo (5 not pregnant, 2 lost before treatment started). Loss to follow‐up: 143 and 155 in calcium and placebo group respectively (some data available on women not followed up to delivery). Treatment compliance 84.5% and 86.2% respectively. Baseline characteristics were well matched. An ancillary study in Argentina assessed 510 of the participants by Doppler ultrasound for RI, PI in uterine and umbilical arteries, and for bilateral uterine artery notching (Carroli 2010). Similarly, a group of 708 participants in South Africa were assessed for serum and urine parameters of endothelial damage (Hofmeyr 2008). Source of funding: the study was supported by UNDP/UNFPA/World Health Organization/World Bank Special Programme of Research, Development and Research Training. CoI: not stated. |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation lists for each site with random blocks of 6 to 8 women |
| Allocation concealment (selection bias) | Low risk | Consecutively numbered identical treatment boxes were allocated for each woman enrolled. Randomisation codes remained at the WHO Clinical Trial Unit until analysis. Boxes and tablet bottles were prepared and numbered by Magistra SA, Geneva and shipped to trial centres. The placebo and calcium tablets were identical. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Double‐blind |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 143/4151 and 155/4161 women in calcium and placebo groups respectively were missing delivery data but were included in other analyses. |
| Selective reporting (reporting bias) | Low risk | Expected outcomes reported |
| Other bias | Low risk | ITT principle. Baseline characteristics, compliance and dropout rates were similar. |
ASA: acetylsalicylic acid BMI: body mass index BP: blood pressure DBP: diastolic blood pressure dl: decilitre g: gram GDM: gestational diabetes mellitus ICU: intensive care unit ITT: intention to treat IU: international units IUGR: intrauterine growth restriction MAP: mean arterial pressure mcg: microgram mg: milligram mmHg: millimetre of mercury NICU: neonatal intensive care unit PE: pulmonary embolism PI: pulsatility index PIH: pregnancy‐induced hypertension RCT: randomised controlled trial RI: resistance index SBP: systolic blood pressure SD: standard deviation SEM: standard error of the mean vs: versus