shows the trial profile. Of the 762 women enrolled, 379 were randomly allocated to receive vitamins C and E and 383 to placebo. Outcome data were available for 761 women (379 vitamin, 382 placebo), and 749 women were assessed for pre-eclampsia, by original assigned group (375 vitamin, 374 placebo). There were 12 deviations from the inclusion and exclusion criteria—eight women were enrolled outside the 22-week cutoff for gestation (all were within 4 days of this threshold) and four patients were later reclassified as having type 2 diabetes. All 12 women were included in the analysis.
Although most maternal baseline characteristics did not differ between groups, history of pre-eclampsia, hypertension, antihypertensive treatment, and microalbuminuria were more common in the placebo group than in the vitamin group (). On the basis of counts of returned pills after delivery (or at the 34-week visit if no count was available after delivery, n=45) from 618 women, 524 (85%) took at least 50% of their tablets, 434 (70%) took 80% or more, and 237 (38%) took all their tablets; 17 (3%) did not take any. Estimated percentage adherence did not differ between groups (vitamin C, median 95% [IQR 75–100] vs placebo, 96% [74–100]; vitamin E, 93% [78–100] vs placebo, 93% [74–100]).
Baseline maternal characteristics
Overall, 127 (17%) women developed pre-eclampsia. Risk of pre-eclampsia did not differ between vitamin and placebo groups (). There were no significant differences between groups in risk of gestational hypertension or birthweight lower than the tenth centile for gestational age (). PAI-1 to PAI-2 ratios did not differ between groups at baseline (p=0·40), 26 weeks (p=0·32), and 34 weeks (p=0·78) ().
Primary and secondary clinical outcomes
PAI-1 to PAI-2 ratio by weeks' gestation
We noted no significant differences between vitamin and placebo groups for any maternal outcome, including delivery after a hypertension-related admission before 34 or 37 weeks, but fewer babies were born preterm (<37 weeks' gestation) in the vitamin group than in the placebo group (). There were no significant differences between vitamin and placebo groups for any clinical neonatal outcome including fetal malformation, fetal loss, infant death, or miscarriage. Rates of admission to neonatal care, including intensive care, were similar in both groups, as were rates of respiratory diagnoses and other complications (). shows mean birthweights for both vitamin and placebo groups; risk of birthweights of 2500 g or less (RR 0·82, 95% CI 0·56–1·20) and 4000 g or more (1·25, 0·95–1·64) did not differ between groups. No significant differences were found in SD scores for weight, length, or head circumference between infants from each group at birth or follow-up (). We noted no adverse events or side effects attributable to supplementation with vitamin C or E in mothers or infants.
Maternal and neonatal outcomes
Growth measures at birth and at postnatal follow-up (6–12 weeks of age)
Mean plasma ascorbate concentrations (vitamin, 44·4 [SD 26·0] μmol/L vs placebo, 44·2 [26·0] μmol/L) and cholesterol-corrected serum α-tocopherol concentrations (6·15 [1·24] μmol/mmol vs 6·19 [1·20] μmol/mmol) were similar at baseline in both groups (). Blood samples were available for plasma ascorbate analysis in 590 (77%) patients at 26 weeks (299 vitamin, 291 placebo) and 511 (67%) at 34 weeks (263 vitamin, 248 placebo), and for serum α-tocopherol analysis in 614 (81%) patients at 26 weeks (309 vitamin, 305 placebo) and 536 (70%) at 34 weeks (267 vitamin, 269 placebo). Concentrations of both vitamins were significantly higher in the vitamin group than in the placebo group at 26 weeks' and 34 weeks' gestation (p<0·0001) ().
Plasma ascorbate and serum α-tocopherol concentrations, by weeks' gestation
compares rates of pre-eclampsia in predefined subgroup analyses. Rates of pre-eclampsia did not vary with baseline control of diabetes or baseline smoking status. However, fewer women with baseline plasma ascorbate concentrations lower than 10 μmol/L developed pre-eclampsia in the vitamin group than in the placebo group. Furthermore, fewer women with baseline serum α-tocopherol of 3–5 μmol/mmol cholesterol developed pre-eclampsia in the vitamin group compared with placebo.
Rates of pre-eclampsia in 11 predefined subgroups