Abstract: Twenty-one trials, involving 22,129 women were eligible for this review. Four trials did not contribute data. All of the remaining 17 trials assessed vitamin E in combination with vitamin C and/or other agents. Overall the risk of bias ranged from low to unclear to high; 10 trials were judged to be at low risk of bias, six trials to be at unclear risk of bias and five trials to be at high risk of bias. No clear difference was found between women supplemented with vitamin E in combination with other supplements during pregnancy compared with placebo for the risk of stillbirth (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.88 to 1.56, nine studies, 19,023 participants, I² = 0%; moderate quality evidence), neonatal death (RR 0.81, 95% CI 0.58 to 1.13, nine trials, 18,617 participants, I² = 0%), pre-eclampsia (average RR 0.91, 95% CI 0.79 to 1.06; 14 trials, 20,878 participants; I² = 48%; moderate quality evidence), preterm birth (average RR 0.98, 95% CI 0.88 to 1.09, 11 trials, 20,565 participants, I² = 52%; high quality evidence) or intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06, 11 trials, 20,202 participants, I² = 17%; high quality evidence). Women supplemented with vitamin E in combination with other supplements compared with placebo were at decreased risk of having a placental abruption (RR 0.64, 95% CI 0.44 to 0.93, seven trials, 14,922 participants, I² = 0%; high quality evidence). Conversely, supplementation with vitamin E was associated with an increased risk of self-reported abdominal pain (RR 1.66, 95% CI 1.16 to 2.37, one trial, 1877 participants) and term prelabour rupture of membranes (PROM) (average RR 1.77, 95% CI 1.37 to 2.28, two trials, 2504 participants, I² = 0%); however, there was no corresponding increased risk for preterm PROM (average RR 1.27, 95% CI 0.93 to 1.75, five trials, 1999 participants, I² = 66%; low quality evidence). There were no clear differences between the vitamin E and placebo or control groups for any other maternal or infant outcomes. There were no clear differing patterns in subgroups of women based on the timing of commencement of supplementation or baseline risk of adverse pregnancy outcomes. The GRADE quality of the evidence was high for preterm birth, intrauterine growth restriction and placental abruption, moderate for stillbirth and clinical pre-eclampsia, and low for preterm PROM. The data do not support routine vitamin E supplementation in combination with other supplements for the prevention of stillbirth, neonatal death, preterm birth, pre-eclampsia, preterm or term PROM or poor fetal growth. Further research is required to elucidate the possible role of vitamin E in the prevention of placental abruption. There was no convincing evidence that vitamin E supplementation in combination with other supplements results in other important benefits or harms.

Plain-language summary: This review included 21 trials involving over 21,000 women. Four trials did not contribute data to the analyses. The trials were generally of variable quality. There were just three studies on vitamin E supplementation alone, but none of these studies contributed data. All other studies included vitamin C, and additional supplements or drugs. The findings indicate that routine supplementation with vitamin E in combination with other supplements during pregnancy did not improve outcomes for babies or women. There was a reduction in the number of placentas coming away early (placental abruption) in women given vitamin E supplements in combination with other agents, which was rated as high-quality evidence. However, it is unclear whether this finding was due to vitamin E or the other agents used in the supplement. This should be explored in further research examining the mechanisms leading to placental abruption. The review found there may be harms associated with vitamin E supplements in pregnancy, as there was an increased risk of abdominal pain and term prelabour rupture of fetal membranes in women supplemented with vitamin E in combination with other supplements. There was no increase in preterm prelabour rupture of membranes in women supplemented with vitamin E and other agents. The large body of evidence does not support taking vitamin E supplements, alone or in combination, during pregnancy. This is because taking vitamin E in combination with other supplements during pregnancy does not help to prevent problems in pregnancy including stillbirth, baby death, preterm birth, pre-eclampsia or low birthweight babies. In fact, it may increase abdominal pain for women and also increase the number of women having early rupture of membranes at term.