Vitamins in Preeclampsia (VIP): a multicentre randomised clinical trial of vitamin C and E supplementation in pregnancy for the prevention of pre-eclampsia (India, Peru, Vietnam)

INTERVENTION: Randomised to Vitamin C (1000 mg) and Vitamin E (400 IU), or placebo to be taken daily until delivery. CONDITION: Pre‐eclampsia ; Pregnancy and Childbirth ; Pre‐eclampsia PRIMARY OUTCOME: Occurrence of pre‐eclampsia: defined as gestational, severe gestational hypertension and proteinuria:; 1. Gestational hypertension will be defined as two or more readings of diastolic blood pressure greater than or equal to 90 mmHg (using Korotkoff V) taken more than or equal to 4 hours, but less than 168 hours apart, and occurring after 20 weeks of pregnancy or in the early postnatal period, and excluding labour; 2. Severe gestational hypertension will be defined as two recordings of diastolic blood pressure of 110 mmHg or higher at least 4 hours apart, (but less than 168 hours apart) or one recording of diastolic blood pressure greater than 120 mmHg; 3. Proteinuria will be defined as excretion of greater than 300 mg protein in 24 hours or 2 readings of greater than or equal to 1+ on dipstick of Mid‐Stream Urine (MSU)/Catheter Specimen Urine (CSU) where 24 hour collection is not available SECONDARY OUTCOME: 1. Pre‐eclampsia as defined in the context of the WHO calcium supplementation trial:; Pre‐eclampsia is defined as hypertension associated with proteinuria. Hypertension is defined as blood pressure greater than or equal to 140 mmHg systolic and/or 90 mmHg diastolic occurring in two occasions at least four hours to a week apart after the 20th week of pregnancy. Diastolic blood pressure will be measured at the 5th Korotkoff sound, which is the disappearance of the sounds. Proteiunuria is defined if protein in urine is greater than or equal to 300 mg in 24 hours urine specimen or corresponding level of 1+ or more on dipstick. ; 2. Principal neonatal outcomes:; 2.1. Death, intrauterine or neonatal before discharge from the hospital; 2.2. Low birthweight, defined as below 2.5kg; 2.3. Small for gestational age as defined by WHO guidelines: infants below the 10th percentile of the birth‐weight‐for‐gestational age, sex specific, single/twins curve; 3. Other secondary outcome measures (also adequately powered to detect important effects):; 3.1. Preterm birth (before 37+0 weeks); 3.2. Use of health care resources: antenatal inpatient days; 3.3. Gestational age at delivery INCLUSION CRITERIA: 14^+0 ‐ 21^+6 weeks pregnant women with one or more of the following risk factors: 1. Chronic hypertension ‐ diastolic Blood Pressure (BP) greater than 90 mmHg 2. Pre‐gestational diabetes 3. Arterial, venous or small vessel thrombosis in any organ tissue 4. Unexplained death of morphologically normal foetus at or beyond ten weeks gestation 5. Premature births before 34 weeks due to pre‐eclampsia, eclampsia or severe placental insufficiency 6. Unexplained consecutive spontaneous abortions before ten weeks 7. Chronic renal disease 8. Multiple pregnancy 9. Past history of pre‐eclampsia, eclampsia, HELLP syndrome (Haemolysis, Elevated Liver enzyme Levels and low Platelet count)